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P R E S C R I P T I O N M E D I C I N E SC O D E O F P R A C T I C E AU T H O R I T Y

The Prescription Medicines Code of PracticeAuthority was established by TheAssociation of the British PharmaceuticalIndustry (ABPI) in 1993 to operate the Codeof Practice for the Pharmaceutical Industryat arm’s length from the ABPI itself.

Compliance with the Code is obligatory forABPI member companies and, in addition,about sixty non member companies havevoluntarily agreed to comply with the Codeand to accept the jurisdiction of theAuthority.

The Code covers the advertising ofmedicines to health professionals andadministrative staff and also coversinformation about such medicines madeavailable to the general public.

It covers:

● journal and direct mail advertising

● the activities of representatives,including detail aids and other printedmaterial used by representatives

● the supply of samples

● the provision of inducements toprescribe, supply, administer,recommend or buy medicines by thegift, offer or promise of any benefit orbonus, whether in money or in kind

● the provision of hospitality

● the organisation of promotionalmeetings

● the sponsorship of scientific and othermeetings, including payment oftravelling and accommodation expenses

● the provision of information to thegeneral public either directly or indirectly,including by means of the Internet

● all other sales promotion in whateverform, such as participation inexhibitions, the use of audio-cassettes,films, records, tapes, video recordings,electronic media, interactive datasystems, the Internet and the like.

Complaints submitted under the Code areconsidered by the Code of Practice Panelwhich consists of the three members of theCode of Practice Authority acting with theassistance of independent expert adviserswhere appropriate. Both complainants andrespondents may appeal to the Code ofPractice Appeal Board against rulings madeby the Panel. The Code of Practice AppealBoard is chaired by an independent legallyqualified Chairman, Mr Nicholas BrowneQC, and includes independent membersfrom outside the industry.

In each case where a breach of the Code isruled, the company concerned must give anundertaking that the practice in questionhas ceased forthwith and that all possiblesteps have been taken to avoid a similarbreach in the future. An undertaking mustbe accompanied by details of the actiontaken to implement the ruling. Additionalsanctions are imposed in serious cases.

Complaints about the promotion ofmedicines should be sent to the Director ofthe Prescription Medicines Code of PracticeAuthority, 12 Whitehall, London SW1A 2DY(telephone 020 7930 9677facsimile 020 7930 4554).

C O D E O F P R A C T I C E R E V I E WNUMBER 46 NOVEMBER 2004

The Prescription Medicines Code of Practice Authority was established by The Association of the British Pharmaceutical Industry (ABPI) in1993 to operate the ABPI Code of Practice for the Pharmaceutical Industry independently of the Association itself.


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New publication for healthprofessionals, NHS managers, etcThe Authority and the ABPI haveissued a new publication, Guidancenotes for health professionals on theCode. The guidance is a brief summaryof key points to help health professionalsand managers understand the Codeand its operation. Copies are availableon the website (pmcpa.org.uk) and

from the ABPI (020 7930 3477 ext 1446or [email protected]). Thepublication has been sent to NHSexecutives and managers as well asorganizations such as the RoyalColleges and others. Many healthprofessionals have also been suppliedwith copies.

Health SelectCommitteeThe Health Select Committee inquiryinto the influence of the pharmaceuticalindustry on health policies, healthoutcomes and future health prioritiesand needs continues.

The inquiry covers six main areas: druginnovation; conduct of medicalresearch; provision of drug informationand promotion; professional andpatient education; regulatory review ofdrug safety and efficacy and productevaluation.

Many organizations, including thePrescription Medicines Code of PracticeAuthority, have submitted evidence tothe inquiry.

CodechangesThe European Federation ofPharmaceutical Industries andAssociations (EFPIA) has recentlyreviewed the European Code ofPractice for the Promotion ofMedicines. Member Associations arerequired to include the EFPIA Coderequirements in their national codessubject to applicable national law. TheEFPIA Code was established in 1992and revised in 1993 to comply withCouncil Directive 92/28/EEC on theadvertising of medicinal products forhuman use.

The revision of the EFPIA Code isnearly complete. The ABPI and theAuthority, as well as many companies,have been involved in the process. Therevised EFPIA Code is expected to beagreed shortly.

As part of the review of the EFPIACode, codes of conduct within theindustry across Europe are also beingreviewed. The ABPI is in the process ofa review of the Code and its operation.Part of that review will includebringing the ABPI Code into line withthe new EFPIA Code. Manyamendments to the EFPIA Code reflectthe current requirements of the ABPICode. Some will require changes to theABPI Code.

Price reductionsAs companies are aware, the revisedPharmaceutical Price RegulationScheme requires prices of medicines tobe reduced with effect from 1 January2005 so as to achieve an overallreduction for a company of 7%.

It is in the interest of advertisers toindicate the new lower prices onpromotional material as soon aspossible. In the period 1 January to 31March 2005, however, promotionalmaterial will not be considered to be inbreach of the Code if it still carries theprevious higher price.

Care should be taken, however, toensure that there is no discrepancybetween what representatives say andwhat is said on written material leftwith the doctor etc by therepresentative as this could give rise tocomplaints.

It will not be acceptable at any time togive comparative prices in promotionalmaterial where these involve the newlower price of the advertiser’s productand the superseded higher prices ofcompetitor products.

Every effort should be made to ensurethat journal advertisements are correctat the time of publication.

Goodbye LisaLisa Matthews who has been with theAuthority for six years as secretary toEtta Logan and Jane Landles will beleaving this month. Lisa has a new jobat a firm of architects, interior designersand surveyors in her home town inKent. The Authority thanks Lisa forher help and wishes her all the best forthe future.

CODE OF PRACTICE TRAININGTraining seminars on the Code of Practice, run by thePrescription Medicines Code of Practice Authority and open toall comers, are held on a regular basis in central London.

These seminars comprise a full day course offering lectures onthe Code and the procedures under which complaints areconsidered, discussion of case studies in syndicate groups andthe opportunity to put questions to the Code of PracticeAuthority.

Forthcoming Code of Practice seminar dates on which placesremain available are:

Monday, 17 January

Friday, 18 March

Short training sessions on the Code or full all day seminars canbe arranged for individual companies, including advertisingand public relations agencies and member and non membercompanies of the ABPI. Training sessions can be tailored to therequirements of the individual company.

For further information regarding any of the above, pleasecontact Jean Rollingson for details (020 7930 9677 extn 1443).

How to contact theAuthorityOur address is:

Prescription MedicinesCode of Practice Authority12 WhitehallLondon SW1A 2DY

www.pmcpa.org.uk

Telephone: 020 7930 9677Facsimile: 020 7930 4554

Copies of the Code of Practice for thePharmaceutical Industry and of thisReview can be obtained from JeanRollingson (020 7930 9677 extn 1443).

Direct lines can be used to contactmembers of the Authority.

Heather Simmonds: 020 7747 1438Etta Logan: 020 7747 1405Jane Landles: 020 7747 1415

The above are available to giveinformal advice on the application ofthe Code of Practice.

The Authority rather than the ABPI isthe contact point for information on theapplication of the Code.

Pfizer complained that in the course of promoting Lumigan(bimatoprost eye drops), Allergan was offering an ophthalmicslit lamp or equivalent educational grant to any clinician whostarted twenty patients on the product. The scheme wasknown as the Lumigan Case Study Reports initiative. Pfizeralleged that this was an inducement to prescribe. Thisactivity had been brought to Pfizer’s attention by severalclinicians, therefore bringing discredit to the industry.

The Panel noted that materials for the Lumigan Case StudyReports initiative were provided to ophthalmologists byAllergan representatives. No data collected by theophthalmologists was provided to Allergan and the companysubmitted that a payment was made only if requested by theophthalmologist. The payment, in the form of either a slitlamp costing approximately £175 or an educational grant of£250, was a recompense for the administrative time spent.

The Panel did not consider that the Lumigan Case StudyReports initiative was a bona fide clinical study. Inintercompany correspondence Allegan had stated that theinitiative was not a clinical trial. Allergan stated that theLumigan Case Study Reports initiative was forophthalmologists to undertake their own evaluation ofLumigan after it was prescribed in the usual way. The resultscould be used by the ophthalmologists to support formularyapplications, present a summary of data back to thedepartment or for presentations or journal submissions. Therepresentatives’ briefing material issued when the initiativewas piloted stated that the pilot study would ascertain if theinitiative would aid formulary application and be a usefultool for doctors. The Panel considered that whilstophthalmologists might find the case study report formshelpful, the payment of a fee in the form of either a slit lampor an educational grant in association with the use ofLumigan amounted to an unacceptable inducement toprescribe the product. In effect the arrangements amountedto paying doctors to prescribe Lumigan. It was irrelevant thatthe payment was only made upon request from theophthalmologist.

The Panel ruled a breach of the Code. The Panel consideredthat the arrangements brought discredit upon and reducedconfidence in the pharmaceutical industry and a breach ofClause 2 of the Code was ruled. The Panel was veryconcerned about the arrangements and reported Allergan tothe Code of Practice Appeal Board in accordance withParagraph 8.2 of the Constitution and Procedure.

At the consideration of the report Allergan stated that itaccepted the Panel’s rulings and gave details of the stepstaken to avoid similar breaches of the Code in the future.Allergan also volunteered for an audit of its procedures.

The Appeal Board was very concerned about the activities;just over 100 ophthalmologists had been supplied with slitlamps or an educational grant. The Appeal Board consideredthat although the activity had ceased Allergan would havegained a considerable advantage.

The Appeal Board noted Allergan’s offer to undergo avoluntary audit, but decided to require the company to

3 Code of Practice Review November 2004

CASE AUTH/1516/9/03

PFIZER v ALLERGANPromotion of Lumigan

undergo a compulsory audit of its proceduresrelating to the Code as set out in Paragraph 10.4 ofthe Constitution and Procedure. Upon receipt of theaudit report the Appeal Board would considerwhether further action was necessary.

The Appeal Board was very concerned that a largenumber of clinicians might be left with theimpression that the arrangements were acceptableand so it required Allergan to take steps to recoverthe slit lamps and educational grants as set out inParagraph 10.3 of the Constitution and Procedure.The outcome of the steps to recover the lamps andeducational grants would be discussed at the audit.

Upon receipt of the audit report the Appeal Boardconsidered that there were a number of problems inthe company. It was of concern that Allergan hadnot initially known the actual numbers of slit lampsand educational grants distributed. The AppealBoard noted that Allergan accepted the findings ofthe audit report and acknowledged that there were anumber of areas to which it had paid insufficientattention. Allergan would ensure that the reportrecommendations were acted upon. Neverthelessthis was a serious matter. The Appeal Boarddecided that Allergan should be re-audited within 3months. It also decided that the case warranted areport to the ABPI Board of Management inaccordance with Paragraph 12.1 of the Constitutionand Procedure. The report to the ABPI Board wouldbe made after the Appeal Board had considered thereport on the follow-up audit.

Upon receipt of the report of the follow-up audit theAppeal Board noted that substantial progress hadbeen made on implementing the recommendationsof the first audit. Given that it had already decidedto report the matter to the ABPI Board, the AppealBoard decided to take no additional action.

The ABPI Board of Management noted Allerganacknowledged that a serious error had been made;the company had undergone two audits and hadbeen required by the Appeal Board to recover theitems. The ABPI Board considered that Allerganhad demonstrated through the actions taken with itsstandard operating procedures, communication andtraining that it was doing everything it could tocorrect the acknowledged deficiencies. The ABPIBoard decided that no further action should betaken.

Pfizer Limited complained about the promotion ofLumigan (bimatoprost eye drops) by AllerganLimited.

COMPLAINT

Pfizer stated that Allergan was currently offering anophthalmic slit lamp or equivalent educational grant,

to any clinician who started twenty patients onLumigan. The activity, termed the Lumigan CaseStudy Reports initiative was acknowledged byAllergan in its letter of 4 September 2003 to Pfizer. Acopy of the letter was provided. Allergan hadconfirmed that representatives were distributing slitlamps following participation in this programme.

Pfizer alleged that this was an inducement toprescribe in breach of Clause 18.1 of the Code. Thisactivity had been brought to Pfizer’s attention byseveral clinicians, therefore bringing discredit to theindustry and a breach of Clause 2 of the Code wasalleged.

RESPONSE

Allergan stated that Lumigan was launched in the UKin April 2002. Initial feedback from customersshowed that the availability of Lumigan wasgoverned by the local hospital formulary which inturn was usually guided by evidence basedassessment and by the consultant ophthalmologist’spersonal view and experience with the product.

Allergan worked with four ophthalmologists todesign a tool that would assist other ophthalmologiststo gain experience with Lumigan and develop theirview of the product.

The case study reports were intended to helpophthalmologists to objectively assess Lumigan in theclinical setting. Summaries of the data collected couldbe presented back to the department, used asadditional and supportive information for a drugsand therapeutics committee application to have theproduct listed on the formulary, or, in the event of amore refractory case, written up for presentation orjournal consideration. The patient evaluation formwas designed to collect the most pertinent data butalso allowed the ophthalmologist to collect any otheradditional information considered appropriate. Thecase studies produced were solely for the use of thehospital and therefore the data collected was forhospital use only.

The data collection form was designed to captureappropriate medical and drug history anddemographic information. It allowed for three visitsincluding baseline and offered the option to collectpatient feedback. A copy of the pack given toophthalmologists involved in the initiative wasprovided.

The Lumigan Case Study Reports initiative started inSeptember 2002. Initially three representatives pilotedthe scheme. The initiative was rolled out to the rest ofthe ophthalmology sales team at the end of January2003 and ran until 30 April 2003. After this date nofurther packs were supplied to ophthalmologists. Therepresentatives were asked to follow up with thoseophthalmologists involved in the initiative until theend of July 2002. In practice, a number ofophthalmologists were still using the Case StudyReports.

The three representatives who piloted the schemewere briefed on this initiative at the sales meeting inSeptember 2002. Subsequently, at the sales meeting inJanuary 2003 a workshop was run for the entire sales

team to discuss the wider implementation of thisinitiative. Copies of the relevant sections of thematerial presented at both meetings were provided.

The representatives were asked to contact 500 targetophthalmologists regarding this initiative. Overall,305 ophthalmologists agreed to evaluate Lumiganusing the Case Study Reports initiative (102 in thepilot phase and a further 203 between February andApril 2003).

In some instances, an ophthalmologist might havespent a significant amount of administrative timepreparing a report (or similar) on their observations;as recompense Allergan provided the departmentwith a slit lamp. On a small number of occasionswhen recompense was requested but theophthalmologist did not wish to receive a slit lamp aneducational grant of £250 was paid to the department.The provision of a slit lamp or an educational grantwas only considered when there was a clear requestfor recompense for time involved in the preparationof a report (or similar) and after such was seen (butnot taken away) by the representative. Allergan hadsupplied 91 ophthalmologists with hand-heldophthalmic slit lamps and 14 with an educationalgrant. The cost per unit to Allergan for each lampwas approximately £175.

Allergan did not consider that the initiativeconstituted an inducement to prescribe and did notagree that there was a breach of Clause 18.1 or Clause2 of the Code.

PANEL RULING

The Panel noted that the Lumigan Case Study Reportsinitiative had been developed by ophthalmologistsworking with Allergan. The materials were providedto ophthalmologists by Allergan representatives. Nodata collected by the ophthalmologists was providedto Allergan and the company submitted that apayment was made only if requested by theophthalmologist. The payment took the form ofeither a slit lamp costing approximately £175 or aneducational grant of £250. Allergan submitted thatthe provision of a lamp or the educational grant was arecompense for the administrative time spent.

The Panel noted that Allergan had been asked tosupply comprehensive details of the Lumigan CaseStudy Reports initiative. In the Panel’s view thedocumentation provided by Allergan was limited.With regard to its representatives, no briefing materialhad been provided, although copies of slides used attwo meetings had been supplied. With regard to theophthalmologists, Allergan had provided a folderwhich was given to those involved in the initiative; itconsisted solely of case report forms and informationfor patients. There was no written explanation as tothe use or purpose of the materials. The case studyreport form referred to completion of an adverseevent form but this had not been provided. Thefolder included prescribing information. Despite thelack of available detail as to how the Lumigan CaseStudy Reports initiative was run, the Panelnonetheless considered that sufficient information hadbeen supplied for it to make a ruling.


The Panel did not consider that the Lumigan CaseStudy Reports initiative was a bona fide clinical study. Inintercompany correspondence Allegan had stated thatthe initiative was not a clinical trial. Allergan statedthat the Lumigan Case Study Reports initiative was forophthalmologists to undertake their own evaluation ofLumigan after it was prescribed in the usual way. Theresults could be used by the ophthalmologists tosupport formulary applications, present a summary ofdata back to the department or for presentations orjournal submissions. The representatives’ briefingmaterial from the September 2002 sales meeting statedthat the pilot study would ascertain if the initiativewould aid formulary application and be a useful toolfor doctors. The Panel considered that whilstophthalmologists might find the case study reportforms helpful, the payment of a fee in the form of eithera slit lamp or an educational grant in association withthe use of Lumigan amounted to an unacceptableinducement to prescribe the product. In effect thearrangements amounted to paying doctors to prescribeLumigan. It was irrelevant that the payment was onlymade upon request from the ophthalmologist.

The Panel ruled a breach of Clause 18.1 of the Code.The Panel considered that the arrangements broughtdiscredit upon and reduced confidence in thepharmaceutical industry and a breach of Clause 2 ofthe Code was ruled. The Panel was very concernedabout the arrangements and decided to reportAllergan to the Code of Practice Appeal Board inaccordance with Paragraph 8.2 of the Constitutionand Procedure.

APPEAL BOARD CONSIDERATION

At the consideration of the report Allergan stated thatit accepted the Panel’s rulings and had taken anumber of steps to avoid similar breaches of the Codein the future. These included updating and revisingthe standard operating procedure (SOP) forpromotional copy and training staff on the revisedSOP and the importance of the process. The trainingemphasised previous areas of weakness; these being abrief as to how items were to be used, documentationfor the representatives and documentation forcustomers (eg clinicians). Allergan volunteered for anaudit of its procedures.

As background information Allergan explained thatits structure and product portfolio had changed inJuly 2002. There had been no internal copy approvalexpertise from April 2002 until mid October 2002.There had been many new recruits and a failure totrain new personnel. Outdated processes were inplace which were not well designed leading to theapproval of the Lumigan Case Study Reportsinitiative pack without the full context of how itwould be used. The arrangements would be inaccordance with the Code without the provision ofthe slit lamps/educational grants. There was a lack ofsupporting documentation and no full understandingof the context for use of the pack. The fullarrangements, including the provision of slitlamps/educational grants, were not approved.

The Appeal Board noted from Allergan that its salesrepresentatives had been informed by voicemail and

email that the Lumigan Case Study Reports initiativehad ceased and further training would be provided.

The Appeal Board was very concerned about theactivities. It noted that 91 ophthalmologists had beensupplied with hand-held ophthalmic slit lamps and 14with an educational grant for £250. The Appeal Boardconsidered that although the activity had ceasedAllergan would have gained a considerableadvantage.

The Appeal Board noted Allergan’s offer to undergo avoluntary audit, but decided that the company shouldbe required to undergo a compulsory audit of itsprocedures relating to the Code as set out inParagraph 10.4 of the Constitution and Procedure.Following receipt of the audit report the AppealBoard would then consider whether further actionwas necessary.

The Appeal Board was very concerned that a largenumber of clinicians might be left with the impressionthat the arrangements were acceptable. The AppealBoard decided to require Allergan to take steps torecover the slit lamps and educational grants as setout in Paragraph 10.3 of the Constitution andProcedure. The Appeal Board decided that Allerganshould write to each clinician to whom a lamp oreducational grant had been supplied to request,where practicable, its return. The outcome of thesteps to recover the lamps and educational grantswould be discussed at the audit.

FURTHER CONSIDERATION BY THE APPEALBOARD

Upon receipt of the audit report the Appeal Boardconsidered that there were a number of problems inthe company. It was concerned that Allergan had notinitially known the actual numbers of slit lamps andeducational grants distributed. The Appeal Boardnoted that Allergan accepted the findings of the auditreport and acknowledged that there were a number ofareas to which it had paid insufficient attention.Allergan had established a cross functional team torespond to the audit report and ensure that itsrecommendations were acted upon. Nevertheless thiswas a serious matter. The Appeal Board decided thatAllergan should be re-audited within 3 months. Italso decided that the case warranted a report to theABPI Board of Management in accordance withParagraph 12.1 of the Constitution and Procedure.The report to the ABPI Board would be made after theAppeal Board had considered the report on thefollow-up audit.

Upon receipt of the report of the follow-up audit, theAppeal Board noted that substantial progress hadbeen made on implementing the recommendations ofthe first audit. Given that it had already decided toreport the matter to the ABPI Board, the AppealBoard decided to take no additional action.

REPORT TO ABPI BOARD OF MANAGEMENT

Upon receipt of the report from the Appeal Board, theABPI Board of Management noted Allerganacknowledged that a serious error had been made.


The ABPI Board also noted that Allergan hadundergone two audits and had been required by theAppeal Board to recover the items. The ABPI Boardconsidered that Allergan had demonstrated throughthe actions taken with its standard operatingprocedures, communication and training that it wasdoing everything it could to correct the acknowledgeddeficiencies. The ABPI Board decided no furtheraction should be taken.

Complaint received 15 September 2003

Undertaking received 11 November 2003

PMCPA proceedingscompleted 17 June 2004

ABPI Board ofManagement proceedingscompleted 14 September 2004


CASE AUTH/1519/9/03

PRIMARY CARE TRUST CLINICAL GOVERNANCELEAD v TRINITYPractice switch programme

The clinical governance lead at a primary care trust (PCT)complained about a Pulvinal salbutamol switch programmeundertaken by Trinity.

The complainant stated that concerns were raised when thePCT head of medicines management was contacted by apractice which had had a problem printing a prescription fora patient who had been changed to Pulvinal salbutamol aspart of the Pulvinal switch programme. Furtherinvestigations revealed that a ‘freelance’ pharmacist, paid forby Trinity, carried out the switch on 23 July 2003. The PCTunderstood that the pharmacist carried out the patientsearches and made the changes to prescribing on the practicecomputer system. The company had been asked to supply acopy of the protocol followed in the programme. It hadsupplied some paperwork and informed the PCT that thespreadsheet [which was headed ‘Changing to Pulvinal’ anddetailed prices of various asthma medicines including, interalia, their unit price, cost per puff and saving with Pulvinal]was the protocol. The PCT did not consider this was anappropriate protocol – it expected to see details of how thechange was to be implemented, eg patient recall, patientletters, etc. Trinity had been unable to supply a copy of theconfidentiality agreement used. The practice contract wasapproved and signed on 25 July, although the work wasactually carried out at the practice on 23 July.

The Panel noted that Trinity had provided four documentswhich described four stages of the switch service, known asConcept; search to identify areas of rationalisation; analysis,to allow the health professional to make an informeddecision; implementation and review. Each stage was signedoff and managed by the project co-ordinator. Reference wasalso made to a switch co-ordinator whose role was describedas non-promotional. The documents referred to the Conceptmodified release product range and one featured a bar chartcomparing Trinity brands with other modified release brands.

The Panel noted the arrangements at the practice in question.A document, provided by the complainant, headed ‘TrinityPharmaceuticals Practice Switch Contract’ in which thepractice agreed to the switch process did not indicate whichproducts were to be switched, in fact no mention was madeof any changes in medication. The document was signed bya GP and dated 25 July. The date booked for the switch wasgiven as 23 July. The complainant had also provided two

undated letters signed by Trinity’s representative.The letters described the representative as projectmanager. One was addressed to two GPs of thepractice and it was unclear to whom the other wasaddressed as only the first name had been used.Both letters included details of Pulvinal salbutamoland Pulvinal beclometasone dipropionate (BDP) andneither included prescribing information. Bothletters also referred to a Pulvinal inhaler containingformoterol and BDP ‘which would be available inthe not too distant future’. The complainant alsosent a chart headed ‘Changing to Pulvinal’, whichpresented a table of data showing the savings thatcould be made by changing patients from otherinhalers/devices to Pulvinal BDP and Pulvinalsalbutamol. Beneath the table of data was referenceto prescribing information printed overleaf. Itappeared that this document might have been sentwith the letter to two GPs of the practice.

The Panel noted that the switch at the practice inquestion had taken place before the relevant formhad been signed. The form lacked detail and thePanel thus queried whether the form was sufficientin any event. The representative had used his ownletters and not those provided by the company. ThePanel noted a letter dated 30 September from thefreelance pharmacist who had carried out the switchto Trinity’s head office which stated that she was toidentify repeat prescriptions for target drugs anddevices and ‘where appropriate initiate a new repeatmaster for the equivalent Pulvinal product(s)….’.The Panel considered that potentially changes couldhave been made to patients’ therapy on the practicedatabase by the pharmacist without such changesbeing authorized by a GP. Trinity submitted thatthe medication review in question was undertakenexactly in line with the wishes of the GP requestingthe review. It accepted that the representative whoset up the switch programme had breached companypolicy and procedures by not having the switchagreement signed and by not using companyapproved materials. The Panel noted that Trinityhad not provided any documentation from thepractice in question to show unequivocally what

switches had been agreed. Medication changes hadbeen made without the written agreement of the GP.

The Panel considered that, as implemented in thepractice in question, the patient review was in effectlinked to the prescription of Trinity’s products. Abreach of the Code was ruled in this regard.

The Panel considered that the audit arrangements,documentation and training were inadequate. Therewere no clear, comprehensive instructions about theswitch process from the time it was raised by therepresentatives with practices through to theactivities of the pharmacist/nurse. Nor was theredocumentation setting out all the arrangements for apractice to see before agreeing to the process. ThePanel thus considered that the switch process didnot meet the supplementary information of the Codein relation to the provision of medical andeducational goods and services. The Panelconsidered that the overall arrangements anddocumentation were such that the service wasinextricably linked to the promotion of Trinity’smedicines and amounted to an unacceptableinducement to prescribe. In that regard the Panelnoted the freelance pharmacist’s letter whereby itappeared that if any change to a patient’s repeatprescription was to be made at all it was a change toPulvinal products. The Panel ruled a breach of theCode in relation to the arrangements for the switchprocess in general. High standards had not beenmaintained as acknowledged by Trinity. A breach ofthe Code was ruled.

The Panel noted that a pharmacist, sponsored byTrinity, had changed patients’ prescriptions withoutprior written agreement from the GP. The Panelconsidered that such action brought discredit uponand reduced confidence in the pharmaceuticalindustry. A breach of Clause 2 was ruled.

The Panel was very concerned about Trinity’sarrangements in general and what had happened atthe practice in question and decided to report Trinityto the Code of Practice Appeal Board in accordancewith Paragraph 8.2 of the Constitution and Procedure.

The Appeal Board was extremely concerned aboutthe overall arrangements for the audit and switchservice and decided that Trinity should undergo anaudit of its procedures relating to the Code.

Upon receipt of the audit report the Appeal Boardwas very concerned that patients with stable asthmawere being switched to Trinity’s products withouttheir knowledge or consent. It was noted that somepatients were being switched due to thediscontinuation of their current device/medicine.The Appeal Board was also concerned that Trinityhad not completely understood that its activitieswere unacceptable. The amended service was stillof serious concern particularly with regard to thefailure to separate the service from the promotion ofspecific medicines.

The Appeal Board was extremely concernedregarding the ethical issues raised by thearrangements. Trinity was, in effect, using salesrepresentatives to advocate switching stable patientsto Trinity’s medicines. The switch would be carried

out by a Trinity employee. In the Appeal Board’sview any change in medication might destabilisesome patients. The patients who were not switchedwere those that were too young for Pulvinal, elderlypatients, those with complicated or uncontrolledasthma and those who had visited the practice onlyrecently for a prescription. Doctors were not givendetails of patients who were not switched.

The Appeal Board decided that the matter should bereported to the ABPI Board of Management inaccordance with Paragraph 12.1 of the Constitutionand Procedure. The Appeal Board considered that itwould have required Trinity to issue a correctivestatement if it had the power to do so. The AppealBoard therefore recommended that the ABPI Boardconsider such an option. The Appeal Board alsodecided that Trinity should be re-audited within 3months and that it must take immediate action toseparate the roles of the project co-ordinator and theclinical support specialist.

The Appeal Board was deeply concerned about thefindings of the follow-up audit and the lack ofprogress made since the first audit. However giventhat the matter had been reported to the ABPIBoard, the Appeal Board decided to take no furtheraction.

The ABPI Board of Management noted the actionstaken by Trinity to implement the recommendationsof both audits. The ABPI Board had some concernsabout the arrangements but decided that as somecorrective steps had been taken no further actionwas necessary at this stage. It should be emphasisedto Trinity that rigorous procedures must beemployed and adhered to. The ABPI Board reservedthe right to require a further audit.

The clinical governance lead at a primary care trust(PCT) complained about a Pulvinal switchprogramme undertaken by Trinity PharmaceuticalsLimited.

COMPLAINT

The complainant stated that concerns were raisedwhen the PCT head of medicines management wascontacted by a practice which had had a problemprinting a prescription for a patient who had beenchanged to Pulvinal salbutamol as part of thePulvinal switch programme. Further investigationsand discussions with the company and practicerevealed that a ‘freelance’ pharmacist, paid for byTrinity, carried out the switch on the practicecomputer on 23 July 2003. The PCT understood thatthe pharmacist carried out the patient searches andmade the changes to prescribing on the practicecomputer system. The company had been asked tosupply a copy of the protocol followed in theprogramme. It had supplied some paperwork (copieswere supplied) and informed the PCT that thespreadsheet [which was headed ‘Changing toPulvinal’ and detailed prices of various asthmamedicines including, inter alia, their unit price, costper puff and saving with Pulvinal] was the protocol.The PCT did not consider this to be an appropriateprotocol – it expected to see details of how the


change was to be implemented, eg patient recall,patient letters, etc. The company had been unable tosupply a copy of the confidentiality agreement used.The practice contract was approved and signed on 25July 2003, although the work was actually carried outat the practice on 23 July 2003.

When writing to Trinity the Authority asked it torespond in relation to Clauses 2, 9.1 and 18.1 of the2003 edition of the Code.

RESPONSE

Trinity stated that it manufactured and distributedoff-patent medicines, using novel delivery systemsand presentations which cost substantially less thanthe originator products and provided value formoney. Customers saw this as an important benefit inthe current environment and continued heavydownward pressure on drugs budgets. Trinity offereda medication review and switch service to GPs inwhich a Trinity-sponsored pharmacist reviewed aparticular area of prescribing where rationalisationcould provide a cost saving. One of the areas ofinterest, and an area of concern to many cost-conscious prescribers, was the use of dry-powderinhalers for asthma.

Trinity confirmed that this type of medication reviewwas conducted at the surgery in question on 23 July.This review was undertaken by an experiencedindependent pharmacist, whom Trinity understood tobe familiar to the PCT in question. [The complainantstated that the independent pharmacist was notfamiliar to the PCT.] The work was done in line withthe wishes of the GP who had requested the review;Trinity was unaware of any concerns about this workfrom any member of staff at this practice.

The company’s standard practice, and the one onwhich its representatives were trained, was that therequesting GP should sign a practice switch contractbefore the work was undertaken. The parameters onwhich the pharmacist carried out the search andidentified patients was a matter for the pharmacistand doctor to agree. The completed list of identifiedpatients was then reviewed by the doctor to agree,prior to the changes being made. The precise detailsof how patients would be told of the changes variedaccording to practice requirements. The pharmacistwas able to facilitate this process if required, but thecommunication between the practice and the patientsmust remain correspondence between those twoparties. Representatives were not involved at anystage in the switch process.

Whilst there was no obligation to enter into writtenagreements with clinicians, Trinity believed it goodpractice to sign a confidentiality agreement before anywork started. Unfortunately it appeared that therepresentative who set up the switch programme inthis practice breached two aspects of company policyand procedure. Firstly, that a switch agreement formshould be signed before any work was undertakenand secondly that all materials provided to customersmust first be internally approved. Trinity regardedthese breaches as extremely serious and hadinstigated disciplinary procedures against therepresentative in question.

Trinity regretted that its provision of the service to thispractice had created concern for the complainant andit submitted that its services and procedures, whencarried out as defined, were consistent with the Code.

Trinity did not accept that any aspect of its serviceconstituted a breach of Clause 18.1. The service wasoffered to GPs as a non-promotional medication review.The pharmacist and doctor agreed which medicationsshould be reviewed and changed. The doctor agreedany medication changes that were to be made: therewas no requirement for any switches, or indeed anyparticular product to be used. Representatives were notinvolved in the switch process at any point. Trinitystrongly resisted any suggestion that this serviceconstituted inducement to prescribe.

In this case though, Trinity acknowledged that itsrepresentative did not maintain the company’srequired standards and therefore admitted a breach ofClause 9.1. However, the practice staff had nocomplaints about the representative or the servicereceived. Whilst Trinity regarded the representative’sbreach of company procedures and failure to maintainhigh standards to be extremely serious, it did notconsider that the representative’s activities broughtdiscredit on the industry or merited particularcensure. It therefore denied any breach of Clause 2.

In response to a request for additional informationTrinity stated that the switch programme was aservice provided at the request of a practice in whichpatients’ medication was reviewed with the aim ofreducing prescribing costs while maintaining clinicaloutcomes. The switch service was entirely non-promotional and was not linked to the use of anyparticular product – in fact, it was the Practice (notPulvinal) Switch Programme. The representative hadno involvement with the switch process or patientdata. The representative only conducted the initialaudit using anonymous patient identificationnumbers, such that the practice was provided with acost-savings report indicating the savings that ‘could’be made. Representatives did not access patientrecords that could identify individual patients.Practices were then provided with the services ofeither a qualified nurse or pharmacist to review thepractice-prescribing database and suggest appropriatechanges. Switches and subsequent communicationwith patients were agreed between the practice andthe nurse/pharmacist. A letter from the pharmacist,who conducted the review at the practice in question,which outlined the process, was provided togetherwith an example of a patient letter.

As noted above the sales representative, acting as theproject co-ordinator for this practice switchprogramme, did not follow company procedures andwas now subject to a disciplinary process. Allmembers of the sales force had been reminded aboutthe need to adhere to company procedures relating toapproval of items to be used with customers andconduct of practice switch programmes.

In response to a further request for more informationTrinity stated that the instruction issued torepresentatives in the audit process comprisedtraining on the initial training course andsubsequently ‘hands on’ training in the field.


A similar system existed for training the in-houseswitch co-ordinators, the difference being that switchco-ordinators required more in-depth understandingof the systems themselves to allow the individualidentification of patients and subsequent changes totheir medication. The correspondence from thefreelance pharmacist employed to carry out thepractice switch had been provided.

Trinity reiterated that the letters written by therepresentative were not approved. The representativeshould have submitted draft correspondence to headoffice for approval. Each initial training courseincluded a presentation on the Code and outlined theneed for compliance and the procedures required forsubmitting materials for approval.

The ‘Dear Patient’ letter headed ‘Asthma InhalerReview’ on surgery headed notepaper was not based ona template provided by the company. Part of the role ofthe freelance pharmacist was to encourage the practiceto develop its own materials for communicating withpatients whose treatment had changed.

Trinity provided four documents. These being adocument ‘Putting you in a winning position’ (TR491-April 2002) which referred to Trinity MR brands andincluded a cost comparison of the most expensivemodified release brands and Trinity MR brands. Thisdocument appeared to be for the prescriber. Anotherdocument ‘Concept’ ‘Putting you in a winningposition’ (TR502-April 2002) described Trinity’s‘innovative prescribing support service’ Concept.Another document (TR490-April 2002) referred toConcept as a ‘simple solution to rational prescribing’.The fourth document (TR704-June 2003) described theConcept service and the Trinity PharmaceuticalsSwitch Co-ordinator (Pharmacist) and appeared to bedesigned to give to practices once they had decided toimplement Concept.

PANEL RULING

The Panel noted that Trinity had provided fourdocuments which described four stages of the switchservice, known as Concept; search to identify areas ofrationalisation; analysis, to allow the healthprofessional to make an informed decision;implementation and review. Each stage of the processwas signed off and managed by the project co-ordinator. Reference was also made to a switch co-ordinator whose role was described as non-promotional. The documents referred to the Conceptmodified release product range and one featured a barchart comparing Trinity brands with other modifiedrelease brands.

The Panel noted the arrangements at the practice inquestion. A document, provided by the complainant,headed ‘Trinity Pharmaceuticals Practice SwitchContract’ (TR369) in which the practice agreed to theswitch process did not indicate which products wereto be switched, in fact no mention was made of anychanges in medication. The document was signed bya doctor in the practice and dated 25 July 2003. Thedate booked for the switch was given as 23 July 2003.The complainant had also provided two undatedletters signed by the Trinity representative who wasdescribed as Project Manager. One was addressed to

two doctors in the practice and it was not clear towhom the other was addressed as only the first namehad been used. Both letters included details ofPulvinal salbutamol and Pulvinal beclometasonedipropionate (BDP) and neither referred to orincluded prescribing information. Both letters alsoreferred to a Pulvinal inhaler containing formoteroland BDP ‘which would be available in the not toodistant future’. The complainant also sent a chartheaded ‘Changing to Pulvinal’ (ref TR447), whichpresented a table of data showing the savings thatcould be made by changing patients from otherinhalers/devices to Pulvinal BDP and Pulvinalsalbutamol. Beneath the table of data was reference toprescribing information printed overleaf. It appearedthat this document might have been sent with theletter to the two doctors in the practice.

The Panel considered that Trinity’s response wasconfusing and lacked detail, particularly with regardto the training of staff and the existence of documentsin relation to the switch process. The Panelconsidered nonetheless that sufficient information hadbeen supplied for it to make a ruling.

The Panel noted that the switch at the practice inquestion had taken place before the relevant form hadbeen signed. The form lacked detail and the Panelthus queried whether the form was sufficient in anyevent. The representative had used his own lettersand not those provided by the company. The Panelnoted a letter from the freelance pharmacist dated 30September to Trinity’s head office which stated thatshe was to identify repeat prescriptions for targetdrugs and devices and ‘where appropriate initiate anew repeat master for the equivalent Pulvinalproduct(s)….’. The Panel considered that potentiallychanges could have been made to patients’ therapy onthe practice database by the pharmacist without suchchanges being authorized by a GP. Trinity submittedthat the medication review in question wasundertaken exactly in line with the wishes of the GPrequesting the review. It accepted that therepresentative who set up the switch programme hadbreached company policy and procedures in twoaspects. Firstly by not having the switch agreementsigned and secondly by not using company approvedmaterials. The Panel noted that Trinity had notprovided any documentation from the practice inquestion to show unequivocally what switches hadbeen agreed. Medication changes had been madewithout the written agreement of the GP.

The Panel considered that, as implemented in thepractice in question, the patient review was in effectlinked to the prescription of Trinity’s products. Abreach of Clause 18.1 was ruled in this regard.

The Panel considered that the audit arrangements,documentation and training were inadequate. Therewere no clear, comprehensive instructions about theswitch process from the time it was raised by therepresentatives with practices through to the activitiesof the pharmacist/nurse or documentation setting outall the arrangements for a practice to see beforeagreeing to the process. It thus considered that theswitch process did not meet the supplementaryinformation to Clause 18.1 of the Code in relation tothe provision of medical and educational goods and


services. The Panel considered that the overallarrangements and documentation were such that theservice was inextricably linked to the promotion ofTrinity’s medicines and amounted to an unacceptableinducement to prescribe. In that regard the Panelnoted the freelance pharmacist’s letter whereby itappeared that if any change to a patient’s repeatprescription was to be made at all it was a change toPulvinal products. The Panel ruled a breach of Clause18.1 in relation to the arrangements for the switchprocess in general. The Panel considered that highstandards had not been maintained as acknowledgedby Trinity. A breach of Clause 9.1 was ruled.

With regard to Clause 2, the Panel noted that a rulingof a breach of that clause was a sign of particularcensure and reserved for such use. The matter inhand involved an audit pharmacist, sponsored byTrinity, who had changed patients’ prescriptionswithout prior written agreement from the doctor. ThePanel considered that such action brought discreditupon and reduced confidence in the pharmaceuticalindustry. A breach of Clause 2 was ruled.

During its consideration of this case the Panelconsidered that the letter to the practice from therepresentative was promotional and should haveincluded prescribing information and been certified.It also appeared to promote an unlicensed medicine,the combination inhaler, formoterol and BDP. Therepresentative had signed the letter as projectmanager; it was thus not clear that he was arepresentative. The Panel was also concerned thatpart of the role of the freelance pharmacist was toencourage the practice to develop its own materialsfor communicating with patients whose treatment hadchanged. The Panel did not know the precise processfor generating such material but was concerned thatthe system could be used to circumvent the need tohave documents approved for use under the Code.The patient letter provided by the freelancepharmacist contained a number of claims for thePulvinal inhaler. The document (TR491-April 2002)provided by Trinity which set out the Concept processreferred to specific Trinity modified release (MR)brands and should have included prescribinginformation for each one as required by Clause 4.1 ofthe Code. The Panel requested that its concerns bedrawn to Trinity’s attention.

The Panel was very concerned about Trinity’sarrangements in general and what had happened atthe practice in question and decided to report Trinityto the Code of Practice Appeal Board in accordancewith Paragraph 8.2 of the Constitution and Procedure.


The Appeal Board was extremely concerned about theoverall arrangements for the audit and switch service.The Appeal Board decided that, as set out inParagraph 10.4 of the Constitution and Procedure,Trinity should be required to undergo an audit of itsprocedures relating to the Code. Following receipt ofthe audit report the Appeal Board would thenconsider whether further action was necessary.

FURTHER CONSIDERATION BY THE APPEALBOARD

Upon receipt of the audit report, the Appeal Boardwas very concerned that patients with stable asthmawere being switched to Trinity’s products withouttheir knowledge or consent. It was noted that somepatients were being switched due to thediscontinuation of their current device/medicine. TheAppeal Board was also concerned that Trinity had notcompletely understood that its activities wereunacceptable. The amended service was still ofserious concern, particularly the failure to separate theservice from the promotion of specific medicines.

The Appeal Board was extremely concerned regardingthe ethical issues raised by the arrangements. Trinitywas, in effect, using sales representatives to advocateswitching patients to Trinity’s medicines. The switchwould be carried out by a Trinity employee whowould switch stable patients to Trinity’s medication.In the Appeal Board’s view any change in medicationmight destabilise some patients. The patients whowere not switched were those that were too young forPulvinal, elderly patients, those with complicated oruncontrolled asthma and those who had visited thepractice only recently for a prescription. Doctors werenot given details of patients who were not switched.

The Appeal Board decided that the matter should bereported to the ABPI Board of Management inaccordance with Paragraph 12.1 of the Constitutionand Procedure. The Appeal Board considered that itwould have required Trinity to issue a correctivestatement if it had the power to do so. The AppealBoard therefore recommended that the ABPI Boardconsider such an option.

The Appeal Board also decided that Trinity should bere-audited within 3 months and that it must takeimmediate action to separate the roles of the projectco-ordinator and the clinical support specialist.

The Appeal Board was deeply concerned about thefindings of the follow up audit and the lack ofprogress made since the first audit. However giventhat the matter had been reported to the ABPI Board,the Appeal Board decided to take no further action.

REPORT TO ABPI BOARD OF MANAGEMENT

The ABPI Board of Management noted the actionstaken by Trinity to implement the recommendationsof both audits. The ABPI Board had some concernsabout the arrangements but decided that as somecorrective steps had been taken no further action wasnecessary at this stage. It should be emphasised toTrinity that rigorous procedures must be employedand adhered to. The ABPI Board reserved the right torequire a further audit.

Complaint received 23 September 2003

Undertaking received 23 December 2003

PMCPA proceedingscompleted 17 June 2004

ABPI Boardconsideration 14 September 2004


Lilly complained that Bristol-Myers Squibb and Otsuka werepromoting Abilify (aripiprazole) prior to the grant of amarketing authorization.

The leavepiece ‘Achieving a Balance’ described the receptorbinding of full agonists, antagonists, and partial agonists.The cited reference, Tamminga (2002), dealt with partialdopamine antagonists in the treatment of psychosis andmentioned aripiprazole and stated that it would be marketedby Bristol-Myers Squibb and Otsuka. Lilly stated that sincethe joint marketing arrangement between the two companieswas mainly to commercialise aripiprazole and the jointventure had no other currently marketed products relevant tothe messages in the leavepiece, it was difficult to see how theleavepiece, describing known properties of aripiprazole(which was the first antipsychotic recognised to be a partialagonist at the time of its launch anywhere in the world) couldbe used other than to prompt or solicit a request forinformation about aripiprazole. Lilly also alleged that theleavepiece was disguised promotion.

The Panel noted that Abilify was not licensed in the UK. Itappeared that Bristol-Myers Squibb and Otsuka were usingmedical representatives to provide information to healthprofessionals ahead of launch.

In considering the allegations regarding the two leavepieces‘Achieving a Balance’ and ‘Achieving Stability’ (below) thePanel also bore in mind the allegation and response inrelation to representatives’ training (below), as the use of theleavepieces as well as content were relevant factors. Theleavepieces were used by medical representatives as part ofintroductory discussions about ligand-receptor interactions.

The Panel noted that the leavepiece, ‘Achieving a Balance’did not mention a product by either brand name or genericname. It featured the receptor binding of agonists,antagonists, and partial agonists and was referenced toTamminga (2002) which discussed partial dopamine agonistsin the treatment of psychosis and referred to aripiprazole.The back page gave details of useful contacts; three of thefour contacts stated were mental health charities, two ofwhich were linked particularly with schizophrenia. In thePanel’s view the cited reference and the list of contact detailsgave an implied reference to an antipsychotic medicine.

The Panel considered that overall the features therepresentatives were to discuss with health professionalswere closely associated with Abilify. The Panel consideredthat such activity did not constitute the legitimate exchangeof medical or scientific information during the developmentof a product and went beyond the provision of corporateinformation about an area of research. The leavepieceformed an integral part of the information provided byrepresentatives, which when considered in its totality was, inthe Panel’s view, associated with Abilify which did not havea marketing authorization. The leavepiece and its provisionby the representatives in this context amounted to a breach ofthe Code and the Panel ruled accordingly. The Panel did notconsider that the leavepiece was disguised; it would not beseen as anything other than a promotional item. The Panelthus ruled no breach of the Code.

The leavepiece ‘Achieving Stability’ consisted offour pages and discussed the activities of agonists,antagonists and partial agonists in relation to thehypoactive and hyperactive system.

Lilly stated the inside double-page spread showedgraphs indicating how full agonists, antagonists andpartial agonists might act in the setting of ahypoactive system and a hyperactive system. Theback page stated, beneath a heading ‘StabilisingActivity’, that agonists were effective in ahypoactive system, antagonists were effective in ahyperactive system and that partial agonists had theoverall ability to reduce activity in a hyperactivesystem and to increase activity in a hypoactivesystem. The statements were referenced to Stahl(2001) which described the mode of action ofaripiprazole. Lilly made similar allegations to thosemade about the ‘Achieving a Balance’ leavepiece.

The Panel noted its general comments above. The‘Achieving Stability’ leavepiece was to be used byrepresentatives for three months following the useof the leavepiece ‘Achieving a Balance’ at issueabove. The Panel noted that the leavepiece‘Achieving Stability’ did not mention a product byeither brand name or generic name. The leavepiececompared the action of agonists, antagonists andpartial agonists and was referenced to Stahl whichwas entitled ‘Dopamine System Stabilizers,Aripiprazole and the Next Generation ofAntipsychotics’. No details of useful contacts weregiven. The Panel considered that the leavepiece‘Achieving Stability’ and its provision byrepresentatives within the context above amountedto the promotion of Abilify prior to the grant of themarketing authorization. A breach of the Code wasruled. The Panel did not consider that theleavepiece was disguised and thus ruled no breachof the Code in that regard.

Lilly believed the two leavepieces were being usedas detailing materials. Lilly considered that itwould be difficult for representatives to maintaincredibility when talking to psychiatrists about thematters described in the two leavepieces if they hadnot been trained or otherwise informed about thepharmacological properties of aripiprazole. Clearlytraining representatives about aripiprazole wouldnot be necessary prior to the grant of a marketingauthorization if those representatives were notbeing encouraged to promote the medicine. Lillyalleged that Bristol-Myers Squibb and/or Otsukahad also breached the Code by encouraging anaction which would be in breach of the Code.

The Panel noted that the representatives hadreceived four training modules as part of the‘Arpiprazole Learning System’. The modules didnot feature on aripiprazole in detail but referenceswere made to the product including benefits


CASES AUTH/1559/3/04 and AUTH/1560/3/04

LILLY v BRISTOL-MYERS SQUIBB and OTSUKAPromotion of Abilify

compared to atypical antipsychotics currently on theUK market. Other training material consisted offour slide presentations, ‘Partial Agonism’, ‘TheCompetition’, ‘CNS Business Unit Meeting Cycle 2’dated May 2003 and ‘CNS National ConferenceBahamas’ dated September 2003.

The two CNS business unit presentations weremade up of a number of slides each bearing whatappeared to be the Abilify product logo. Eachpresentation referred to the ROAR programme(Receptor Occupancy and Activity Revision). Thepresentation dated May 2003 included a slideheaded ‘Critical Success Factors’ which instructedrepresentatives to ‘Consistently differentiate Abilifyas “next generation atypical” emphasising efficacy atevery opportunity’, ‘Drive awareness andenthusiasm across the customer base to ensure rapiduptake at launch’ and ‘Build relationships withcustomers of influence to ensure productendorsement’. The subsequent presentation datedSeptember reviewed the ROAR programme andlisted the messages psychiatrists had heardassociated with Abilify as ‘Next generation atypical,superior tolerability and safety, unique mode ofaction, robust efficacy, partial agonism’. One slidereferred to psychiatrists’ sources of information onAbilify/aripiprazole followed by a bar chart whichlisted sales representatives as 49% andconvention/conference as 26% (July 2003 data).Another slide stated that the ROAR II Rationaleobjectives included ‘partial agonism MUST beperceived as a basis for unrivalled efficacy’.

The slide presentation ‘The Competition’ gavedetails about the strengths and weaknesses ofdifferent treatments including Lilly’s productZyprexa. A section headed ‘unmet needs’ referred tothe high risk of weight gain, sedation,dyslipidaemia and diabetes. One slide stated thatphysicians needed medicines which did not raiseconcerns about obesity, diabetes and elevated lipidsor cardiovascular problems among other things.Another slide stated that patients needed medicinesthat did not interfere inter alia with body weight,alertness and energy.

The slide set ‘Partial Agonism’ did not mentionAbilify. It explained how partial agonism worked inrelation to neurotransmitters and referred to partialagonism as a potential solution to complex diseaseswhere neurotransmitter levels might simultaneouslybe too high in one area of the brain and too low inanother area.

The Panel considered that the four slidepresentations would encourage the representativesto promote Abilify to health professionals.Psychiatrists’ sources of information on Abilifylisted representatives as 49% (July 2003), an increaseof 13% from March 2003. The role of a medicalrepresentative would be seen by the healthprofessionals as promotional. The representativeswere encouraged to discuss what, on the launch ofAbilify, would be competitor products. Criticisingcompetitor products was a promotional activity.

The Panel did not accept Bristol-Myers Squibb andOtsuka’s submission that the representatives had

not been trained on Abilify. Further the Panelqueried whether any medical representative wouldreceive a genuine unsolicited question aboutaripiprazole given their role, their training and thematerials to be used by them.

None of the materials placed the activities in context.The Panel considered that the representatives’training material would lead to the promotion of anunlicensed medicine. The Panel therefore ruled thebriefing material in breach of the Code.

Lilly stated that a medical information request form(that specified aripiprazole) had included the name,territory number, and contact details of arepresentative of Bristol-Myers Squibb. Lilly wasunclear as to why some of these details needed to beincluded on the form. Lilly again alleged thatBristol-Myers Squibb and/or Otsuka had alsobreached the Code by encouraging an action whichwould be in breach of the Code.

With regard to the medical information request formthe Panel did not consider that including therepresentative’s details on the form was itself abreach of the Code as alleged and ruled accordingly.

Lilly noted that a Receptor Occupancy andActivation Review (ROAR) lecture was held inLeeds in October 2003 for which arrangementsappeared to have been made by a public relations(PR) agency. A similar meeting was held in Wales inOctober 2003, also organised by a PR agency. Theinvitation for the Leeds meeting included a replypaid card that would be mailed back to the agencyinvolved. Notably the invitation also contained thename of a representative who was to be contactedfor more information.

According to the invitations the talks focused on thereceptor pharmacology of atypical antipsychotics; itseemed likely that aripiprazole would be mentionedthus, given the novelty of the concept, promotingdiscussion about it. The companies thereforeappeared to have used their PR agency (with the aidof a company representative) to invite doctors to alecture touching on an unlicensed product for thepurposes of soliciting a discussion about it.

The Panel noted that the invitation stated that thelecture would focus on the important role thatreceptor pharmacology played in the battle toeffectively treat serious mental illness. The lecturerwould examine what made an atypical antipsychoticatypical and would review the clinical implications.

The Panel noted that one of the objectives for thepeer-to-peer regional meetings in therepresentatives’ briefing material was to ‘Continuethe positive cascade of anticipation for Abilify’. ThePanel also noted that the stand and materialavailable were similar to those at issue above.

The Panel considered that the meetings organisedby Bristol-Myers Squibb and Otsuka amounted to amarketing exercise designed to raise awareness ofaripiprazole and to raise expectations that the newproduct might meet some of what were seen asproblems with currently licensed medicines. ThePanel considered that the ROAR lectures constitutedpromotion of Abilify prior to the grant of its


marketing authorization and thus ruled a breach ofthe Code.

Lilly stated that Bristol-Myers Squibb and Otsukahad a stand at a meeting in June – July withexhibition panels carrying the clear statement ‘TheRoad to the Future of Atypicals’. The stand wasmanned by medical representatives and at least twoleavepieces were given out with the same colourscheme/background as the stand livery or branding.The contents of the leavepieces made it clear that themedicine, which would be the future atypical, wasaripiprazole.

The Panel noted its comments and rulings upon theprovision of the leavepieces, the ROAR programme,the role of representatives and their training above.The Panel noted that the exhibition panels clearlyrelated to a future atypical antipsychotic whichwould be available from Bristol-Myers Squibb andOtsuka. The Panel considered that the companies’activities went beyond the exchange of medical andscientific information during the development of amedicine. The Panel considered that the exhibitionpanels amounted to the promotion of Abilify priorto the grant of its marketing authorization; a breachof the Code was ruled. The Panel did not considerthat the exhibition panels were disguised; theywould not be seen as anything other thanpromotional. The Panel thus ruled no breach of theCode in that regard.

Lilly also referred to a meeting which had takenplace in Manchester. The company further statedthat it had received anecdotal reports that a claimwas being made that the risk of diabetes withZyprexa was significantly different from that witharipiprazole despite the fact that data showed thisnot to be so. Lilly stated that these further instancesof disguised promotional meetings and detailing ofaripiprazole supported its view that aripiprazolewas being promoted prior to the grant of amarketing authorization.

The Panel noted that although the specific meetingin Manchester referred to by Lilly had not,according to Bristol-Myers Squibb and Otsuka,taken place, a meeting which was part of the ROARprogramme had. The Panel considered that thismeeting was covered by its rulings above. ThePanel also considered that the general allegationabout the promotion of aripiprazole prior to thegrant of a marketing authorization was covered byits previous rulings. With regard to the allegationsof what was said in relation to Zyprexa and diabetesthe Panel was unable to make a ruling as no clauseshad been cited. However it noted its previouscomments made in relation to a similar allegationwhere no prima facie case to answer had been ruled.These being that it was concerned that therepresentatives briefing material did not complywith the Code as it did not reflect the information inthe Zyprexa summary of product characteristics(SPC) and the Panel had requested that Bristol-Myers Squibb and Otsuka be advised of its views.

Lilly stated that it had been told by a nurse inManchester that he had been invited to a localadvisory board meeting that took place in the

autumn of 2003. Around 50 people were present forthe purpose of giving advice and comment onproposed aripiprazole marketing materials.Materials were handed out and then collected at theend of the meeting. The nurse recalled that thismeeting was one of a series of maybe four similarsuch meetings. Payment was made to the attendees.Lilly alleged that this was another example ofrepresentatives promoting Abilify prior to the grantof its marketing authorization.

The Panel noted that there was a difference betweenLilly’s description of the advisory board meetingand that of Bristol-Myers Squibb and Otsuka.

Bristol-Myers Squibb and Otsuka stated that 10advisory boards had been run with a maximum of 12persons per advisory board. The invitation to themeeting in July 2003 stated that the companies wereconvening the advisory board to seek counsel on thecurrent issues surrounding the UK antipsychoticmarket and to evaluate the aripiprazole data from aUK perspective. Input on the launch of the productto both primary and secondary care would besought. The invitation also stated that as a followup the companies anticipated working with someindividual members beyond the advisory boardmeetings. The meetings started at 3.30pm andclosed at 7pm followed by dinner. There were threepresentations; ‘mental health environment’,‘mechanism of action and efficacy’ and ‘tolerability’.There were also workshop breakouts and coffee for45 minutes and discussion of patient types for 45minutes. It appeared from the agenda that somesessions would be run by medical personnel andothers by marketing.

Bristol-Myers Squibb and Otsuka provided theslides for two presentations, ‘Aripiprazole NextGeneration Atypical Antipsychotics’ and‘Aripiprazole Advisory Panel Meeting’. The slideswere branded with what appeared to be the Abilifylogo. The ‘Aripiprazole Next Generation…’presentation focussed on its ‘unique partial agonistmode of action’, ‘excellent long-term efficacy’, statedthat it was ‘very well tolerated,’ and gave resultsfrom a study in the US and its use in the US. Thefinal slide listed three topics for discussion; whetherthe data linked the mode of action of aripiprazolewith its efficacy and tolerability profile, what gapsshould be addressed, and based on the product’sprofile asked what the main opportunities were.

The objectives for the ‘Aripiprazole Advisory PanelMeeting’ presentation were to: ‘Validate marketresearch findings, particularly in the area ofcustomer insight and motivation to prescribe; usereal-life experiences to understand degree andcomfort of using a new anti-psychotic; understandwhether aripiprazole is perceived as the latestatypical or the first in a new class and test thesufficiency of the aripiprazole data set’.

The Panel considered that the slides were promotionalas they included very strong claims for the product. Itdid not appear that the companies were asking forviews on how the product should be promoted.

The Panel noted the companies’ submission that thepurpose of the meeting was to understand the


regional mental health environment and to getfeedback from key national and regional psychiatristson the current treatment and management ofschizophrenia. The invitation also referred to theevaluation of aripiprazole data from a UK perspective.

The Panel considered that although the invitationmentioned the interactive nature of the meeting, itwas not sufficiently clear about the precise role ofthe invitees in that no mention was made of the £500payment per attendee. The agenda did not allowmuch time for feedback from the participants. Nopre-reading/work was required. Paying eachattendee £500 seemed high for the amount of workdone. The Panel queried whether there wassufficient justification for the number of meetingsheld. The Panel questioned whether all thedelegates would have truly acted as consultants,each giving such advice as to justify a £500honorarium. The Panel considered that it wasuntenable to argue that the delegates were beingemployed for their views when the delegates wereonly informed about payment after the meeting.

The Panel was concerned about the wording of theinvitation, the number of meetings held, thematerials presented at the meeting and that it wasnot clear what was expected from the participants.The Panel considered that the arrangements for theadvisory board meetings were unacceptable, theyconstituted a series of promotional meetings forAbilify which was not licensed in the UK. ThePanel ruled a breach of the Code.

The Panel noted Bristol-Myers Squibb and Otsuka’ssubmission that representatives had not attendedthe advisory board meetings. The Panel consideredthat on the evidence before it the representativeshad not promoted Abilify at the advisory boardmeetings and thus ruled no breach of the Code.

Lilly alleged that Bristol-Myers Squibb and/orOtsuka had failed to maintain high standards.Further the companies had brought the industry intodisrepute in breach of Clause 2.

The Panel noted its rulings and considered thatneither Bristol-Myers Squibb nor Otsuka hadmaintained high standards and thus each was ruledin breach of the Code. It also considered thatBristol-Myers Squibb and Otsuka’s activitiesbrought discredit upon and reduced confidence inthe pharmaceutical industry. Each company wasruled in breach of Clause 2 of the Code.

The Panel was concerned about the nature and scaleof the activities and thus reported Bristol-MyersSquibb and Otsuka to the Appeal Board inaccordance with the Constitution and Procedure.

During the consideration of the report the AppealBoard noted that the applications for Abilifylicenses in the US and in Europe were submitted atabout the same time. The US licence was granted inNovember 2002 following FDA accelerated approval.European approval was anticipated in December2002 but the Committee for Proprietary MedicinalProducts (CPMP) asked for additional informationon a number of occasions. The marketingauthorization was not issued until June 2004.

The Appeal Board noted that the delayed marketingauthorization for Abilify meant that representativeshad had to sell other products which were licensed;they had also worked as ‘information gatherers’using the two leavepieces ‘Achieving a Balance’ and‘Achieving Stability’. The companies had acceptedthat their actions had amounted to the promotion ofAbilify prior to the grant of its marketingauthorization. The Appeal Board decided that inaccordance with Paragraph 10.4 of the Constitutionand Procedure, Bristol-Myers Squibb and Otsukashould each be required to undergo audits of theirprocedures relating to the Code of Practice.

Upon consideration of the audit reports the AppealBoard noted that progress had been made whichmust continue. These cases concerned a seriousmatter. Taking all the circumstances into account itdecided that the companies should be re-audited insix months’ time (March 2005).

Eli Lilly and Company Limited complained aboutactivities of Bristol-Myers Squibb PharmaceuticalsLimited and Otsuka Pharmaceuticals (UK) Ltd withregard to Abilify (aripiprazole).

Abilify was not yet licensed in the UK. It wasanticipated that the product would be used to treatschizophrenia. The product was available in the US.

Lilly was concerned that a number of activitiesconstituted promotion prior to the grant of amarketing authorization.

Bristol-Myers Squibb and Otsuka submitted a jointresponse to the complaint. The companies submittedthat their activities in this area to date revolvedaround building relationships founded on Bristol-Myers Squibb’s heritage in psychiatry. Scientificinformation on the disease area was provided by themedical department upon request.

The companies submitted that the complaints wereunfounded and that they had acted at all times inaccordance with the Code and in particular thoseparts of the Code that related to activities permittedprior to the grant of a marketing authorization.

A Detail materials and representative training

1 Leavepiece ‘Achieving a Balance’

The leavepiece (ref ABI/04-03/0127/03-05), consistedof four pages. The inside double-page spread whichwas entitled ‘Receptor Binding’, and referenced toTamminga (2002), described the receptor binding offull agonists, antagonists, and partial agonists.

COMPLAINT

Lilly noted that the pages entitled ‘Receptor Binding’described the mode of action of full agonists,antagonists and partial agonists. The cited reference,Tamminga, dealt with partial dopamine antagonists inthe treatment of psychosis and contained twoparagraphs which mentioned aripiprazole and statedthat it would be marketed by Bristol-Myers Squibband Otsuka. Since a major activity of the jointmarketing arrangement between the two companieswas to commercialise aripiprazole, and since the joint


venture had no other currently marketed productsrelevant to the messages in the leavepiece, it wasdifficult to see how the leavepiece, issued in thenames of both companies and describing knownproperties of aripiprazole (which was the firstantipsychotic recognised to be a partial agonist at thetime of its launch anywhere in the world) could beused other than to prompt or solicit a request forinformation about aripiprazole. Lilly alleged that theleavepiece was disguised promotion of aripiprazole inbreach of Clause 10.1 of the Code and was designedto promote a medicine prior to the grant of amarketing authorization in breach of Clause 3.1.

RESPONSE

Bristol-Myers Squibb and Otsuka stated that theleavepiece was withdrawn from use several monthsago. The leavepiece mentioned ligand-receptorinteractions and partial agonism and carried the logosof Bristol-Myers Squibb and Otsuka. The purposewas to educate the reader as to the various activationstates of receptors. There was no mention ofaripiprazole. It therefore could not be seen aspromotional so did not breach Clause 10.1 of theCode. As this piece was non-promotional there couldbe no ruling of a breach of Clause 3.1 of the Code forpromoting before the grant of a marketingauthorization.

Bristol-Myers Squibb and Otsuka stated that thisexchange of background scientific information did notconstitute promotion of an individual medicine, nordisguised promotion. The companies disputed thathealth professionals would necessarily infer theidentity of a product from the fact that the twocompanies were collaborating on this educationalprogramme. Reference to a scientific paper which areader would have to go to a library or database tolook up, and read thoroughly in order to identify onespecific medicine amongst a number of othermedicines discussed, did not amount to promotion.

In light of the above the companies submitted thatthere was no breach of either Clause 10.1 or 3.1 of theCode.

In response to a request for further informationBristol-Myers Squibb and Otsuka stated that the twoleavepieces ‘Achieving a Balance’ and ‘AchievingStability’ (point A2) were used during introductorydiscussions with health professionals. The role of therepresentatives was to introduce themselves, thecompanies and their heritage in this therapeutic area;to gain information on the local mental healthcareenvironment; to establish relationships and finally tohave introductory discussions focusing on ligand-receptor interactions. The leavepieces depictedgeneral interactions only and were not compound orproduct specific.

The leavepiece ‘Achieving a Balance’ was used fromMay 2003 to September 2003. The leavepiece‘Achieving Stability’ was used from September 2003to November 2003. The only other leavepiece usedduring this period entitled ‘On Track for the Future’(ref ABI/11-02/0076/1004) was provided. Theactivities of Bristol-Myers Squibb and Otsuka

revolved around building relationships founded ontheir heritage in the area of mental health; the ‘OnTrack for the Future’ corporate leavepiece served as atool for this. Where appropriate the ‘AchievingStability’ or ‘Achieving a Balance’ leavepieces mighthave been used in addition to the general introductionof the Bristol-Myers Squibb/Otsuka partnership.

With regard to exchanges of background scientificinformation the companies confirmed that thesediscussions were limited to general ligand-receptorinteractions only. No representative had beeninvolved in exchanging information on aripiprazole inadvance of the marketing authorization. Indeed theyhad had no training on aripiprazole.

A briefing slide headed ‘Partial Agonism’ was usedby the companies’ medical advisor to brief medicalrepresentatives on partial agonism. The informationwas very general information on ligand-receptorinteractions. The slides pertained to the leavepiece‘Achieving a Balance’. There was no specific brief for‘Achieving Stability’, as the principles conveyed bythe two leavepieces were very similar.

PANEL RULING

General comments: The Panel noted that the Codepermitted certain activities prior to the grant of themarketing authorization. The supplementaryinformation to Clause 3 stated that the legitimateexchange of medical and scientific information duringthe development of a medicine was not prohibitedprovided that any such information or activity did notconstitute promotion prohibited by Clause 3 or anyother clause.

In the Panel’s view the closer to the grant of themarketing authorization for a product the moredifficult it was to argue that activities were thelegitimate exchange of medical and scientificinformation during the development of a medicineand not promotion.

The definition of promotion in Clause 1.2 did notinclude replies made in response to individualenquiries from members of the health professions orin response to specific communications whether ofenquiry or comment, including letters published inprofessional journals, but only if they related solely tothe subject matter of the letter or enquiry, wereaccurate and did not mislead and were notpromotional in nature. Genuine unsolicited requestscould be answered in a number of ways. In someinstances it could be by simply sending the papers; inthis regard Clause 1.2 of the Code described a reactiverather than a proactive role. Statements relating tohuman health or diseases were also exempt from thedefinition of promotion provided there was noreference either direct or indirect to specificmedicines.

In the Panel’s view it was not necessarilyunacceptable for companies to have employeesfocussing on the provision of information prior to thegrant of the marketing authorization. Thearrangements and activities of such employees had tocomply with the Code. Such employees should becomprehensively briefed about the Code. The area


was difficult and companies needed to ensure that thearrangements and activities were very carefullycontrolled and managed. The importance ofdocumentation and instruction could not beoverestimated.

The Panel noted that Abilify was not licensed in theUK. It appeared that Bristol-Myers Squibb andOtsuka were using medical representatives to provideinformation to health professionals ahead of launch.

* * * * *

In considering the allegations regarding the twoleavepieces ‘Achieving a Balance’ and ‘AchievingStability’ (points A1 and A2) the Panel also bore inmind the allegation and response in relation torepresentatives’ training (point A3) as the Panelconsidered that the use of the leavepieces as well astheir content were relevant factors. The leavepieceswere used by medical representatives as part ofintroductory discussions focussing on ligand-receptorinteractions.

The Panel noted that the leavepiece, ‘Achieving aBalance’ did not mention a product by either brandname or generic name. It featured a large illustrationwhich was an artist’s impression of the receptorbinding of agonists, antagonists, and partial agonists.The leavepiece was referenced to Tamminga whichdiscussed partial dopamine agonists in the treatmentof psychosis and referred to aripiprazole. The backpage of the leavepiece gave details of useful contacts;three of the four contacts stated were mental healthcharities, two of which were linked particularly withschizophrenia. In the Panel’s view the cited referenceand the list of contact details gave an impliedreference to an antipsychotic medicine.

The Panel noted the role of representatives. Itconsidered that overall the features therepresentatives were to discuss with healthprofessionals were closely associated with Bristol-Myers Squibb and Otsuka’s forthcoming product,Abilify. Overall the Panel considered that suchactivity did not constitute the legitimate exchange ofmedical or scientific information during thedevelopment of a product and went beyond theprovision of corporate information about an area ofresearch. The leavepiece formed an integral part ofthe information provided by representatives, whichwhen considered in its totality was, in the Panel’sview, associated with Abilify which did not have amarketing authorization. The leavepiece and itsprovision by the representatives in this contextamounted to a breach of Clause 3.1 of the Code andthe Panel ruled accordingly. The Panel did notconsider that the leavepiece was disguised; it wouldnot be seen as anything other than a promotionalitem. The Panel thus ruled no breach of Clause 10.1.

2 Leavepiece ‘Achieving Stability’

The leavepiece (ref ABI/08-03/0178/07-05 asprovided by Bristol-Myers Squibb and Otsuka)consisted of four pages and discussed the activities ofagonists, antagonists and partial agonists in relationto the hypoactive and hyperactive system.

COMPLAINT

Lilly stated the inside double-page spread showedgraphs indicating how full agonists, antagonists andpartial agonists might act in the setting of ahypoactive system and a hyperactive system. Theback page stated, beneath a heading ‘StabilisingActivity’, that agonists were effective in a hypoactivesystem, antagonists were effective in a hyperactivesystem and that partial agonists had the overall abilityto reduce activity in a hyperactive system and toincrease activity in a hypoactive system. Thestatements were referenced to Stahl (2001) whichdescribed the mode of action of aripiprazole. Since amajor activity of the joint marketing arrangementbetween Bristol-Myers Squibb and Otsuka was tocommercialise aripiprazole, and since the jointventure had no other marketed products relevant tothe messages in the leavepiece, it was difficult to seehow the leavepiece, issued in the names of bothcompanies and describing known properties ofaripiprazole (which was the first antipsychoticrecognised to be a partial agonist at the time of itslaunch anywhere in the world) could be used otherthan to prompt or solicit a request for informationabout aripiprazole. Lilly alleged that the leavepiecewas disguised promotion of aripiprazole in breach ofClause 10.1 of the Code and was designed to promotea medicine prior to the grant of a marketingauthorization in breach of Clause 3.1.

RESPONSE

Bristol-Myers Squibb and Otsuka stated that theleavepiece as quoted by Lilly ABI/08-03/0128/07-05did not exist. The companies considered that Lillymust be referring to the leavepiece ref ABI/08-03/0178/07-05 which was withdrawn several monthsago. It also contained only scientific informationabout ligand-receptor interactions. Aripiprazole wasnot mentioned in the document. Given this theleavepiece could not be seen as promotional therecould be no breach of Clauses 3.1 or 10.1 of the Code.

PANEL RULING

The Panel noted its general comments in point A1above. The ‘Achieving Stability’ leavepiece was to beused by representatives for three months followingthe use of the leavepiece ‘Achieving a Balance’ atissue in point A1. The Panel noted that the leavepiece‘Achieving Stability’ did not mention a product byeither brand name or generic name. The leavepiececompared the action of agonists, antagonists andpartial agonists. More detail regarding the activity ofthese products was provided than in the leavepiececonsidered at point A1. The leavepiece now inquestion was referenced to Stahl which was entitled‘Dopamine System Stabilizers, Aripiprazole and theNext Generation of Antipsychotics’. No details ofuseful contacts were given. The Panel considered thatthe leavepiece ‘Achieving Stability’ and its provisionby representatives within the context described atpoint A1 amounted to the promotion of Abilify priorto the grant of the marketing authorization. A breachof Clause 3.1 was ruled. The Panel did not considerthat the leavepiece was disguised; it would not be


seen as anything other than a promotional item. ThePanel thus ruled no breach of Clause 10.1 of the Code.

3 Representative training

COMPLAINT

Lilly recognised that although partial agonists thatwere not antipsychotics might be used to treat anxiety,Parkinson’s disease and cardiovascular diseases, thereferences used in support of the two leavepieces(points A1 and A2) clearly related only to psychosisand emphasised to a great extent that partialdopamine agonists might represent the next new classof antipsychotics. Furthermore the leavepieces wereobtained from a Bristol-Myers Squibb stand at ameeting in Edinburgh 30 June – 3 July which clearlystated ‘The Road to the Future of Atypicals’. Medicalrepresentatives manned the stand and at least twoleavepieces were given out with the same colourscheme/background as the stand livery or branding.Lilly could not accept it credible that the theme of theleavepieces could relate to any other partial agonistother than an atypical antipsychotic. Bristol-MyersSquibb and Otsuka were also highly unlikely to beengaging in any activity that related to amisulpride,the only current atypical antipsychotic that wasrecognised to have possible partial agonist properties.

Lilly believed the two leavepieces were being used asdetailing materials by Bristol-Myers Squibb and/orOtsuka representatives. Lilly considered that it wouldbe difficult for representatives to maintain credibilitywhen talking to psychiatrists about the mattersdescribed in the two leavepieces if they had not beentrained or otherwise informed about thepharmacological properties of aripiprazole. Clearlytraining representatives about aripiprazole would notbe necessary prior to the grant of a marketingauthorization if those representatives were not beingencouraged to promote the medicine prior to thegrant of a marketing authorization. For this reasonLilly alleged that Bristol-Myers Squibb and/or Otsukahad also breached Clause 15.9 of the Code byencouraging an action which would be in breach ofthe Code.

In discussions with Bristol-Myers Squibb/Otsuka,Lilly had been told that their representatives had notbeen trained on aripiprazole. On a medicalinformation request form (that specified the productaripiprazole) there was a name given as arepresentative of Bristol-Myers Squibb with a Bristol-Myers Squibb email address and the territory numberand mobile telephone number. It was unclear as towhy the name and contact details (that included onlya mobile telephone number and not the head office ormedical information number) needed to be includedon this form. Lilly again believed that it would bedifficult for representatives to maintain credibilitywhen receiving such requests for information frompsychiatrists if they had not been trained or otherwiseinformed about the pharmacological properties ofaripiprazole. Clearly training representatives aboutaripiprazole would not be necessary prior to the grantof a marketing authorization if those representativeswere not being encouraged to promote the medicine

prior to the grant of a marketing authorization. Forthis reason Lilly alleged that Bristol-Myers Squibband/or Otsuka had also breached Clause 15.9 of theCode by encouraging an action which would be inbreach of the Code.

RESPONSE

Bristol-Myers Squibb/Otsuka stated that the role ofthe representatives was to introduce themselves andthe companies’ heritage in this therapeutic area; togain information on the local mental healthcareenvironment; to establish relationships and finally tohave introductory discussions focusing on ligand-receptor interactions. The representatives wereverbally briefed in relation to the objectivesmentioned above. For the scientific section they werebriefed using slides entitled ‘Partial Agonism’. Nostandard set of questions was given to therepresentatives to ask.

The Bristol-Myers Squibb/Otsuka partnershipcurrently existed solely for the development ofaripiprazole. Fifty two representatives were initiallyemployed by Bristol-Myers Squibb/Otsuka inanticipation of the launch of aripiprazole in April2003. However the final positive opinion from theCommittee for Proprietary Medicinal Products wasreceived later than the companies had originallyexpected (February 2004).

The companies now had a dedicated CNS team inanticipation of launch in May. However during 2003this team was re-deployed to spend the majority of itstime selling Lipostat (pravastatin), Aprovel(irbesartan), Pletal (cilostazol) and Plavix (clopidogrel)to cardiologists and vascular surgeons.

Representatives did not promote licensed medicinesin their meetings with mental health professionals.

The detail aid (ref ABI/04-03/0125/03-05) was usedto discuss general ligand-receptor interactions in aneducational context. The briefing for the detail aidwas the same briefing as for the ‘Achieving a Balance’leavepiece.

The leavepieces (points A1 and A2) had been used toprovide background information on ligand-receptorinteractions as mentioned in the briefing of May 2003.During that specific briefing the educational aspect ofthe medical representatives’ role was highlighted.Clause 3.1 of the Code was quoted to make clear andto ensure medical representatives behavedprofessionally and in compliance with the Code.

Given that no training of representatives had takenplace on aripiprazole and that all representatives weremade fully aware of the Code the companies submittedthat there was no breach of Clause 15.9 of the Code.

The stand at the meeting of the in Edinburgh madegeneral reference to developments in the area ofneuroscience. Although the word atypical wasmentioned, the stand did not make any claim aboutany individual medicine. None of the peoplemanning the stand was permitted to mention thecompound or answer questions about it. Only tworepresentatives were present at the meeting andneither was permitted to mention aripiprazole or


answer questions about it. In addition to the twoleavepieces, request forms for further medicalinformation were available to health professionals.This, therefore, could not constitute a breach of theCode. The two leavepieces (points A1 and A2) wereavailable on the stand.

With regard to the allegation that the two leavepieceswere being used as detailing materials by Bristol-Myers Squibb and Otsuka representatives, Lilly,however, was unable to produce any prima facieevidence. Bristol-Myers Squibb and Otsukarepresentatives were trained only in the disease areaand were not trained specifically on aripiprazole.Given that there had been no training of Bristol-MyersSquibb or Otsuka representatives on aripiprazole andthat Lilly had failed to produce any evidence to thecontrary, Bristol-Myers Squibb and Otsuka submittedthat there could be no ruling of a breach of Clause15.9 of the Code.

With regard to the medical information request form,Bristol-Myers Squibb and Otsuka reiterated thatmedical representatives had not received any trainingon aripiprazole. When a medical representativereceived an unsolicited question about aripiprazolethey had been instructed to refer the healthprofessional to Bristol-Myers Squibb’s medicaldepartment using the medical information requestform. For solely administrative purposes (eg medicalinformation might not be able to read handwriting),medical representative contact details appeared on theform. Doctors were not encouraged to contact therepresentative directly. The fact that therepresentative’s name appeared on the form (foradministrative reasons) was not prima facie evidencethat training to promote aripiprazole had taken place.No breach of Clause 15.9 had occurred.

PANEL RULING

The Panel noted that the representatives had receivedfour training modules as part of the ‘ArpiprazoleLearning System’. These were entitled ‘Introductionto Mental Illness and Mental Health Care’,‘Neuroanatomy and Neurophysiology’, ‘DiseaseStates, Diagnosis and Treatment’, and ‘TheCompetition’. The modules did not feature onaripiprazole in detail but references were made to theproduct including benefits compared to atypicalantipsychotics currently on the UK market.

Other training material consisted of four slidepresentations, ‘Partial Agonism’, ‘The Competition’,‘CNS Business Unit Meeting Cycle 2’ dated 15 May2003 and ‘CNS National Conference Bahamas’ dated10 September 2003.

The two CNS business unit presentations were madeup of a number of slides each bearing what appearedto be the Abilify product logo. Each presentationreferred to the ROAR programme (ReceptorOccupancy and Activity Revision). The presentationdated 15 May 2003 included a slide headed ‘CriticalSuccess Factors’ which instructed representatives to‘Consistently differentiate Abilify as “next generationatypical” emphasising efficacy at every opportunity’,‘Drive awareness and enthusiasm across the customerbase to ensure rapid uptake at launch’ and ‘Build

relationships with customers of influence to ensureproduct endorsement’. The subsequent presentationdated 10 September reviewed the ROAR programmeand listed the messages psychiatrists had heardassociated with Abilify as ‘Next generation atypical,superior tolerability and safety, unique mode ofaction, robust efficacy, partial agonism’. One slidereferred to psychiatrists’ sources of information onAbilify/aripiprazole followed by a bar chart whichlisted sales representatives as 49% and convention/conference as 26% (July 2003 data). Another slidestated that the ROAR II Rationale objectives included‘partial agonism MUST be perceived as a basis forunrivalled efficacy’.

The Panel noted that only the presentation on 15 Mayincluded any reference to the Code and that was inone slide which referred to the supplementaryinformation to Clause 3.1 ‘Advance Notification ofNew Products or Product Changes’.

The slide presentation ‘The Competition’ (undated)identified current opportunities and the marketsituation. Details were given about the strengths andweaknesses of different treatments including Lilly’sproduct Zyprexa. The weaknesses listed for Zyprexaincluded ‘weight gain’, ‘risk of diabetes’ and ‘risk ofdyslipidaemia’. A section headed ‘unmet needs’referred to the high risk of weight gain, sedation,dyslipidaemia and diabetes. One slide stated thatphysicians needed medicines which did not raiseconcerns about obesity, diabetes and elevated lipids orcardiovascular problems among other things.Another slide stated that patients needed medicinesthat did not interfere inter alia with body weight,alertness and energy.

The slide set ‘Partial Agonism’ did not mentionAbilify. It explained how partial agonism worked inrelation to neurotransmitters and referred to partialagonism as a potential solution to complex diseaseswhere neurotransmitter levels might simultaneouslybe too high in one area of the brain and too low inanother area.

The Panel considered that the four slide presentationswould encourage the representatives to promoteAbilify to health professionals. Psychiatrists’ sourcesof information on Abilify listed representatives as 49%(July 2003), an increase of 13% from March 2003. Therole of a medical representative would be seen by thehealth professionals as promotional. Therepresentatives were encouraged to discuss what, onthe launch of Abilify, would be competitor products.Criticising competitor products was a promotionalactivity.

The Panel did not accept Bristol-Myers Squibb andOtsuka’s submission that the representatives had notbeen trained on Abilify. Further the Panel queriedwhether any medical representative would receive agenuine unsolicited question about aripiprazole giventheir role, their training and the materials to be usedby them.

None of the materials placed the activities in context.The Panel considered that the representatives’ trainingmaterial would lead to the promotion of anunlicensed medicine. The Panel therefore ruled thebriefing material in breach of Clause 15.9 of the Code.


With regard to the medical information request formthe Panel did not consider that including therepresentative’s details on the form was itself a breachof the Code as alleged and on this narrow point nobreach of Clause 15.9 of the Code was ruled.

B Meetings

During its consideration of the following allegationsthe Panel bore in mind its comments and rulings inpoints A1, A2 and A3 above.

1 Programme of ROAR lectures

Two meetings entitled ‘Receptor Occupancy andActivation Review (ROAR)’ were referred to by Lilly.

COMPLAINT

Lilly had obtained invitations to two ROAR lectures.One meeting was held in Leeds on 1 October 2003 forwhich arrangements appeared to have been made bya public relations (PR) agency. A similar meeting washeld in Wales on 13 October 2003, also organised by aPR agency. The invitation for the Leeds meetingincluded a reply paid card that would be mailed backto the agency involved. The invitation also containedthe name of a representative who was to be contactedfor more information. This was the same personnamed on the medical information request formreferred to in point A3 above.

The topic of the meetings was ‘Receptor Occupancyand Activation Review’. According to the invitationsthe talks focused on the receptor pharmacology ofatypical antipsychotics. It seemed likely that the talkswould include mention of aripiprazole, and that,given the novelty of the concept, they would promotediscussion about aripiprazole. The two companies,acting jointly, appeared to have used their PR agency(with the aid of a company representative) to invitedoctors to hear a lecture touching on aripiprazole, aproduct that did not have a marketing authorization,for the purposes of soliciting a discussion with thosedoctors about aripiprazole. Lilly alleged that thisconstituted the marketing or promotion of a medicineprior to the grant of its marketing authorization inbreach of Clause 3.1 of the Code.

RESPONSE

Bristol-Myers Squibb and Otsuka stated that the twoROAR lectures referred to were part of a medicaleducation programme for the exchange of medicaland scientific information on the dopaminehypothesis of schizophrenia, and the management ofschizophrenia. These lectures were peer-to-peermeetings organised through a PR agency supportedby Bristol-Myers Squibb and Otsuka. The lecturesreferred to agonists, antagonists and partial agonistsas well as other management approaches. A total ofeighteen ROAR lectures had taken place.

In order to ensure that balanced information wasprovided, distinguished academics were chosen aslecturers. The audiences were restricted to smallnumber of attendees, generally academics and/ormembers of teaching and/or university hospitals.

There were thirty-six attendees at the Leeds meetingand nineteen attendees at the Wales meeting. Bristol-Myers Squibb/Otsuka medical representatives wereinvolved in the logistics but did not attend thelectures. A representative’s name was included onthe invitation in case the health professional requiredmore information on the logistics of the meeting. Asthe representatives were not trained to promotearipiprazole the health professional would not havebeen able to obtain product specific information fromthe person named. The representatives had no furtherrole other than logistical and therefore no briefing wasundertaken. Members of the medical departmentattended the ROAR lectures.

The invitations, speaker brief and slides wereprovided. The leavepieces referred to in points A1and A2 above were also used at the meeting.

The companies submitted that the format of thismeeting was clearly educational, not promotional.The speakers mentioned aripiprazole but in thecontext of a range of other treatments ofschizophrenia. It was necessary for the compound tobe mentioned briefly simply as an example of partialagonism. Other compounds were also mentioned toillustrate scientific points in a similar manner.

Given the purely educational nature of the meetingand that aripiprazole was not specifically the subjectunder discussion no breach of Clause 3.1 could haveoccurred.

In response to a request for further information, Bristol-Myers Squibb and Otsuka stated delegates to the ROARlectures were selected on the basis of their perceivedinterest in neurotransmitters in schizophrenia.

PANEL RULING

The Panel noted that the invitation stated that thelecture would focus on the important role thatreceptor pharmacology played in the battle toeffectively treat serious mental illness. The lecturerwould examine what made an atypical antipsychoticatypical and would review the clinical implications.The lecturer for the Leeds meeting and the twolecturers for the Wales meeting were from theInstitute of Psychiatry.

One set of slides provided gave an overview of therole of dopamine in schizophrenia including therelationship between receptor occupancy, extra-pyramidal side effects (EPS) and response.

Mechanisms of atypicality were discussed andaripiprazole was referred to as a potent partial agonistat certain dopamine receptors. The impression wasgiven that a dopamine partial agonist caused less EPSthan haloperidol. One of the conclusions was that adopamine partial agonist might offer a way oftargeting both dopaminergic deficits and stabilize thesystem.

The Welsh slides included details aboutneurotransmission and the dopamine hypothesis ofschizophrenia as well as information about 5-HTreceptors. Copies were provided.

The Panel noted that one of the objectives for thepeer-to-peer regional meetings in the representatives’


briefing material was to ‘Continue the positivecascade of anticipation for Abilify’.

The Panel noted that the stand and material availableat the meeting were similar to those at issue in pointsA1, A2 and A3 above.

The Panel considered that the meetings organised byBristol-Myers Squibb and Otsuka amounted to amarketing exercise designed to raise awareness ofaripiprazole and to raise expectations that the newproduct might meet some of what were seen asproblems with currently licensed medicines.

The Panel considered that the ROAR lecturesconstituted promotion of Abilify prior to the grant ofits marketing authorization and thus ruled a breach ofClause 3.1 of the Code.

2 Meeting at the Royal College of Psychiatry30 June – 3 July

COMPLAINT

Lilly stated that Bristol-Myers Squibb and Otsuka hada stand at this meeting with exhibition panelscarrying the clear statement ‘The Road to the Futureof Atypicals’. The stand was manned by medicalrepresentatives and at least two leavepieces weregiven out with the same colour scheme/backgroundas the stand livery or branding. The contents of theleavepieces made it clear that the medicine, whichwould be the future atypical, was aripiprazole. It wasdifficult to see how the messages disseminated in thenames of both companies and describing knownproperties of aripiprazole (which was the first partialagonist antipsychotic licensed anywhere in the world)could be intended other than to prompt or solicit arequest for information about aripiprazole. Lillyalleged that the exhibition panels were disguisedpromotion of aripiprazole in breach of Clause 10.1 ofthe Code and were designed to promote a medicineprior to the grant of a marketing authorization inbreach of Clause 3.1.

RESPONSE

Bristol-Myers Squibb and Otsuka stated that many ofthe issues raised here by Lilly had been addressedabove. To reiterate, however, no medicine wasmentioned on the stand. Lilly claimed that theleavepieces (points A1 and A2) made it clear that themedicine was aripiprazole. Neither the stand nor theleavepieces mentioned the medicine. A healthprofessional would have had to have searchedextensively to determine that the medicine wasaripiprazole. Indeed, the obtaining of a full textversion of an article followed by detailed reading of itwould suggest that the disputed link was far fromclear. Given that there was therefore no disguisedpromotion of aripiprazole at this meeting andtherefore no marketing before the granting of amarketing authorization there could be no breach ofClauses 10.1 and 3.1 of the Code.

PANEL RULING

The Panel noted its comments and rulings upon the

provision of the leavepieces, the ROAR programme,the role of representatives and their training at pointsA1, A2, and A3 above. The Panel noted that theexhibition panels clearly related to a future atypicalantipsychotic which would be available from Bristol-Myers Squibb and Otsuka. The Panel considered thatthe companies’ activities went beyond the exchange ofmedical and scientific information during thedevelopment of a medicine. The Panel consideredthat the exhibition panels amounted to the promotionof Abilify prior to the grant of its marketingauthorization; a breach of Clause 3.1 of the Code wasruled. The Panel did not consider that the exhibitionpanels were disguised; they would not be seen asanything other than promotional. The Panel thusruled no breach of Clause 10.1 of the Code.

3 Other meetings

COMPLAINT

Lilly stated that other locations of meetings organisedor sponsored by Bristol-Myers Squibb/Otsuka atwhich promotional stands and other marketingparaphernalia were prominently displayed included alarge advisory meeting for 200 customers fromaround the UK and Ireland who were flown toManchester in the spring of 2003. Lilly had receivedadditional anecdotal reports that a claim was beingmade that Zyprexa was associated with an increasedrisk of diabetes that differed significantly from eitherexisting compounds or from aripiprazole. Thismessage was being disseminated despite the recentcomparative data produced by Bristol-Myers Squibband published by the Food and Drug Administration(FDA) on its website which showed that this was notso. A specific example was the question ‘Does a linkbetween olanzapine and diabetes concern you andadversely affect your prescribing?’ asked of anaudience of around 80 consultants invited to ameeting in Newcastle in 2003. These doctors wereinvited to vote either yes or no.

These further instances of disguised promotionalmeetings and detailing by Bristol-Myers Squibband/or Otsuka representatives supported Lilly’s viewthat at least some Bristol-Myers Squibb or Otsukarepresentatives were actively promoting aripiprazoleto doctors (other than service planners or budgetholders) prior to the grant of a marketingauthorization in breach of Clauses 3.1 and 15.1 andsuggested that that they had been trained to do so inbreach of Clauses 3.1 and 15.9.

Lilly stated that Bristol-Myers Squibb/Otsuka had todate been unable to show that it had received specificrequests for suitably qualified members of its medicaldepartment to attend and give written or orallypresented scientific information at the hospitalsreferred to above.

RESPONSE

Bristol-Myers Squibb and Otsuka stated that ameeting took place Manchester on 8 July 2003, as partof the ROAR programme, and was attended by 18.The invitation was provided. The briefing materials


and slides were the same as the two ROAR meetingsconsidered in point B1 above.

The question regarding the link between olanzapineand diabetes had not been asked at any meeting.Lilly appeared to have based this allegation on beliefand not evidence.

Bristol-Myers Squibb and Otsuka’s standardprocedure was to review and approve allpresentations shown at meetings in advance. Carewas taken to ensure that accurate, balanced and fairinformation was presented. The companies did notseek to disparage competitors’ products.

Given the lack of prima facie evidence and theanecdotal and unsubstantiated nature of theallegations made by Lilly there could be no breach ofClauses 3.1, 15.1 or 15.9.

In relation to the allegation that Lilly had receivedreports that claims were being made that Zyprexa wasassociated with an increase in risk of diabetes thecompanies submitted that on January 26, a joint panelfrom the American Diabetes Association, theAmerican Psychiatric Association, and the NorthAmerica Association for the Study of Obesitypublished a recommendation from a consensusconference held in November 2003 on antipsychotics,obesity, and diabetes. This independent bodyreviewed the effect of second generationantipsychotics on, inter alia, the onset of diabetes. Itconcluded that the data demonstrated that there wasa consistent increased risk for diabetes in patientstreated with olanzapine which had not been shownwith aripiprazole. As the recommendation was in thepublic domain and had triggered an internationaldebate within psychiatry, the companies thought itwas important to specifically tell its medicalrepresentatives not to engage psychiatrists indiscussion around this publication or these sideeffects. If they received an unsolicited question aboutthis recommendation they were instructed to statethat as aripiprazole was an unlicensed product, theywere not in a position to answer the question. Thephysicians were then referred to the medicalinformation department.

Bristol-Myers Squibb and Otsuka believed that thisinternal briefing document confirmed theirwillingness to adhere to the Code. It also confirmedthat they ensured balanced information was providedto medical representatives and that the competitionwas not disparaged in contravention of the Code.

PANEL RULING

The Panel noted that a meeting for 18 delegates hadtaken place on 8 July 2003 in Manchester. This waspart of the ROAR programme. The Panel consideredthat this meeting was covered by its general rulingsabout the ROAR programme set out in point B1above.

The Panel considered that the general allegation thatthe companies’ representatives were activelypromoting aripiprazole prior to the grant of itsmarketing authorization, or had been trained to do so,was already covered by the Panel’s comments andrulings at point A3 above.

The Panel noted that with regard to the allegationabout what was said in relation to Zyprexa anddiabetes, no clauses of the Code had been cited. Itwas thus not able to make a ruling in this regard.However it noted its comments made in relation to asimilar allegation where no prima facie case to answerhad been ruled. These being that references tolicensed products appeared in the training andbriefing material. With regard to Zyprexa, diabeteswas given as an adverse effect, its associated risk ofcausing diabetes was described as a disadvantage andthe risk of diabetes was described as a weakness.Training module 4 ‘The Competition’ included a tableindicating that the relative occurrence of diabetes wasbetween ‘infrequently seen’ and ‘commonly seen’.The Panel noted that the Zyprexa summary ofproduct characteristics (SPC) stated in Section 4.4Special warnings and precautions for use thathyperglycaemia and/or development or exacerbationof diabetes, occasionally associated with ketoacidosisor coma had been reported very rarely includingsome fatal cases. Further that in some cases a priorincrease in body weight had been reported whichmight be a predisposing factor. The Panel consideredthat Bristol-Myers Squibb and Otsuka’s briefingmaterial did not reflect the information in the ZyprexaSPC. The briefing material overall implied thatZyprexa caused diabetes. The Panel was concernedwhether the briefing material complied with Clause15.9 of the Code as it would be likely to lead to abreach of the Code. The Panel requested that Bristol-Myers Squibb and Otsuka be advised of its views.

4 Advisory Board meetings

COMPLAINT

Lilly stated that it had recently been told by a nurse inManchester that he was invited to an advisory boardmeeting that took place in Manchester in the autumnof 2003. He recalled there being around 50 peoplepresent and could name at least one other nursepresent. The purpose of the meeting appeared tohave been for the advisory board to give advice andcomment on some proposed marketing materials thatrelated to aripiprazole. He recalled that thesematerials were handed out and then collected at theend of the meeting. He further recalled that thismeeting was one of a series of maybe four similarsuch meetings. Payment was made to the attendees.

These further instances of disguised promotionalmeetings and detailing by Bristol-Myers Squibband/or Otsuka representatives supported Lilly’s viewthat at least some Bristol-Myers Squibb or Otsukarepresentatives were actively promoting aripiprazoleto nurses (other than service planners or budgetholders) prior to the grant of a marketingauthorization in breach of Clauses 3.1 and 15.1 andsuggested that that they had been trained to do so inbreach of Clauses 3.1 and 15.9.

RESPONSE

Bristol-Myers Squibb and Otsuka stated that betweenAugust and December 2003 its medical departmentshad run 10 regional advisory panels. Representatives


did not attend these meetings. There were 6-12attendees at each meeting the objectives of whichwere to get an understanding of the regional mentalhealth environment and to get feedback from keynational and regional psychiatrists on the currenttreatment and management of schizophrenia. Themeetings were held in the late afternoon andattendees were paid a £500 honorarium. All attendeessigned confidentiality agreements.

Advisory boards were an essential part ofunderstanding a disease area, were non promotionaland an accepted method of gauging the externalenvironment and opportunities in the future.

The companies stated that Lilly had no evidence tosupport its view that the meetings were disguisedpromotion by trained representatives and thus nobreach of Clauses 3.1 and 15.9 could be ruled.

The invitation, agenda, and slides were provided.

Neither Bristol-Myers Squibb nor Otsuka had madethe claims alleged by Lilly. In addition to this Lillyhad failed to provide any evidence that the contrarywas true.

In response to a request for further information,Bristol-Myers Squibb and Otsuka stated that healthprofessionals were informed about payment foradvisory board meetings via a letter, sent out after theadvisory board.

Selection of attendees for the advisory boards wasbased on the understanding that they were recognizedlocal opinion leaders who would help the companiesto understand regional variations in the mental healthenvironment. All attendees participated in workshopsto facilitate an understanding of the currentmanagement of schizophrenia.

PANEL RULING

The Panel noted that there was a difference betweenLilly’s description of the advisory board meeting andthat of Bristol-Myers Squibb and Otsuka.

Bristol-Myers Squibb and Otsuka stated that 10advisory boards had been run with a maximum of 12persons per advisory board. The invitation to themeeting on 31 July 2003 stated that the companieswere convening the advisory board to seek counsel onthe current issues surrounding the UK antipsychoticmarket and to evaluate the aripiprazole data from aUK perspective. Input on the launch of the product toboth primary and secondary care would be sought.The invitation also stated that as a follow up thecompanies anticipated working with some individualmembers beyond the advisory board meetings. Themeetings commenced at 3.30pm (registration from3pm) and closed at 7pm followed by dinner. Theagenda consisted of three presentations; ‘mentalhealth environment’, ‘mechanism of action andefficacy’ and ‘tolerability’. In addition there wereworkshop breakouts and coffee for 45 minutes anddiscussion of patient types for 45 minutes. Itappeared from the agenda that some sessions wouldbe run by medical personnel and others by marketing.

The slides provided by Bristol-Myers Squibb andOtsuka consisted of two presentations, ‘Aripiprazole

Next Generation Atypical Antipsychotics’ and‘Aripiprazole Advisory Panel Meeting’. Each of theslides was branded with what appeared to be theAbilify logo. The ‘Aripiprazole Next Generation…’presentation focussed on its ‘unique partial agonistmode of action’, ‘excellent long-term efficacy’, statedthat it was ‘very well tolerated,’ and gave results froma study in the US and its use in the US. The final slidelisted three topics for discussion; whether the datalinked the mode of action of aripiprazole with itsefficacy and tolerability profile, what gaps should beaddressed, and based on the product’s profile askedwhat the main opportunities were.

The ‘Aripiprazole Advisory Panel Meeting’presentation included the following list of objectives:‘Validate market research findings, particularly in thearea of customer insight and motivation to prescribe;use real-life experiences to understand degree andcomfort of using a new anti-psychotic; understandwhether aripiprazole is perceived as the latest atypicalor the first in a new class and test the sufficiency ofthe aripiprazole data set’.

The Panel considered that the slides were promotionalas they included very strong claims for the product. Itdid not appear that the companies were asking forviews on how the product should be promoted.

The Panel accepted that there was a difference betweenholding a meeting for health professionals andemploying health professionals to act as consultants toa company. In principle it was acceptable forcompanies to pay health professionals and others foradvice as to how their products should be promoted.The arrangements had to comply with the Code.

The Panel noted the companies’ submission that thepurpose of the meeting was to understand the regionalmental health environment and to get feedback fromkey national and regional psychiatrists on the currenttreatment and management of schizophrenia. Theinvitation also referred to the evaluation ofaripiprazole data from a UK perspective.

The Panel considered that although the invitationmentioned the interactive nature of the meeting, itwas not sufficiently clear about the precise role of theinvitees in that no mention was made of the £500payment per attendee. The invitation referred to aform which was not provided. The agenda did notallow much time for feedback from the participants.No pre-reading/work was required. The £500payment per attendee seemed high for the amount ofwork done. Ten regional meetings were to be heldand the Panel queried whether there was sufficientjustification for the number of meetings held. It wasnot clear how the potential delegates had beenselected. The delegates were being ‘employed’ asconsultants and as such their selection should standup to independent scrutiny.

In the Panel’s view it was questionable whether allthe delegates would have truly acted as consultants tothe companies each giving such advice as to justify a£500 honorarium. The Panel considered that it wasuntenable to argue that the delegates were beingemployed for their views when the delegates wereonly informed about payment after the meeting.


The Panel was concerned about the wording of theinvitation, the number of meetings held, the materialspresented at the meeting and that it was not clearwhat was expected from the participants. The Panelconsidered that the arrangements for the advisoryboard meetings were unacceptable, they constituted aseries of promotional meetings for Abilify which wasnot licensed in the UK. The Panel ruled a breach ofClause 3.1 of the Code.

The Panel considered that as the meetings weredeemed promotional it was unacceptable to payattendees. Such an allegation would usually beconsidered in relation to Clause 18.1 of the Code butthis had not been cited by Lilly. The Panel thus couldnot make such a ruling but requested that Bristol-Myers Squibb and Otsuka be advised of its views.

The Panel noted Bristol-Myers Squibb and Otsuka’ssubmission that representatives had not attended theadvisory board meetings. The Panel considered thaton the evidence before it the representatives had notpromoted Abilify at the advisory board meetings andthus ruled no breach of Clauses 15.1 and 15.9 of theCode.

C Alleged breach of Clauses 9.1 and 2

COMPLAINT

Lilly alleged that Bristol-Myers Squibb and/or Otsukahad failed to maintain high standards in breach ofClause 9.1. Further the companies had brought theindustry into disrepute in breach of Clause 2 by theextensive promotion of an unlicensed medicine priorto the grant of the marketing authorization.

RESPONSE

Bristol-Myers Squibb and Otsuka stated that thecomplaints raised by Lilly had largely been made as aresult of unsubstantiated reports that were unfoundedand the companies were concerned that a complaintof this kind should have been made with such a lackof prima facie evidence after a delay of more than fourmonths.

Bristol-Myers Squibb and Otsuka submitted that theyhad acted at all times in accordance with the Codeand particular care was taken to ensure that at anymeeting accurate, balanced and fair information waspresented. The companies did not seek to disparagecompetitors’ products.

Moreover, neither Bristol-Myers Squibb nor Otsukawould encourage any action which would be inbreach of the Code and had at all times sought tomaintain both the highest standards of conduct, andalso the reputation of the industry as a whole. Thecompanies refuted all the allegations made by Lilly.

PANEL RULING

The Panel noted its rulings of breaches of the Code. Itconsidered that neither Bristol-Myers Squibb nor

Otsuka had maintained high standards and thus eachwas ruled in breach of Clause 9.1.

The Panel noted that Clause 2 was used as a sign ofparticular censure and was reserved for such use. ThePanel considered that Bristol-Myers Squibb andOtsuka’s activities brought discredit upon and reducedconfidence in the pharmaceutical industry. Eachcompany was ruled in breach of Clause 2 of the Code.

The Panel was concerned about the nature and scaleof the activities. It thus decided to report Bristol-Myers Squibb and Otsuka to the Appeal Board inaccordance with Paragraph 8.2 of the Constitutionand Procedure.

COMMENTS FROM BRISTOL-MYERS SQUIBBAND OTSUKA

The companies returned the requisite undertakingsand assurances. At the consideration of the report therepresentatives acknowledged that there had been aseries of misjudgements and that they had littleexperience with pre-launch activities. Both companieshad reviewed procedures relating to the Code.Amendments had been made to standard operatingprocedures (SOPs).


During the consideration of the report the AppealBoard noted that the applications for Abilify licencesin the US and in Europe were submitted at about thesame time. The US licence was granted in November2002 following FDA accelerated approval. Europeanapproval was anticipated in December 2002 but theCommittee for Proprietary Medicinal Products(CPMP) asked for additional information on a numberof occasions.

The delayed marketing authorization for Abilify hadmeant that representatives had had to sell otherproducts which were licensed; they had also workedas ‘information gatherers’ using the two leavepieces‘Achieving a Balance’ and ‘Achieving Stability’ forabout 8 months. The companies had accepted thattheir actions had amounted to the promotion ofAbilify prior to the grant of its marketingauthorization. The Appeal Board decided that inaccordance with Paragraph 10.4 of the Constitutionand Procedure, Bristol-Myers Squibb and Otsukashould each be required to undergo audits of theirprocedures relating to the Code of Practice.

Upon consideration of the audit reports the AppealBoard noted that progress had been made which mustcontinue. These cases concerned a serious matter.Taking all the circumstances into account it decidedthat the companies should be re-audited in sixmonths’ time (March 2005).

Complaint received 8 March 2004

Undertaking received 13 May 2004

Proceedings completed 8 September 2004


In Case AUTH/1516/9/03 Pfizer alleged that the provision byAllergan of ophthalmic slit lamps or educational grants toophthalmologists in association with a Lumigan initiativewas an inducement to prescribe and brought discredit uponthe industry. The Panel ruled Allergan in breach of the Codeand was so concerned about the arrangements that it reportedthe company to the Appeal Board. Upon receiving the reportfrom the Panel, the Appeal Board required Allergan to writeto each clinician to whom a slit lamp or educational grant hadbeen supplied to request, where practicable, its return.

Pfizer stated that it had received several reports from centresacross the UK that it was being disparaged by Allergan’srepresentatives as they delivered the letters referred to above.Pfizer did not consider it acceptable that when, upon request,Allergan representatives discussed the ruling in CaseAUTH/1516/9/03, they cast blame upon Pfizer.

The Panel noted that the Authority had not provided Pfizerwith any information about the actions the Appeal Boardrequired Allergan to undertake.

The Panel noted that Pfizer had not provided any substantiveevidence to support its allegations. Allergan had providedcopies of the letter requesting return of the slit lamps oreducational grants, a briefing document about delivery of theletter and a short email which was sent to the representativeson the day after Allergan had accepted the Panel’s rulings.The email began ‘As you are all aware Pfizer havecomplained about [the Lumigan] initiative claiming it was abreach of the ABPI, an inducement to Rx’. Thereafter Pfizerwas not mentioned either implicitly or explicitly. Neither thebriefing document, nor the letter sent to clinicians made anyreference to Pfizer. In answer to the question ‘How could thishappen?’ the answer in the briefing document began ‘Thiswas an error on Allergan’s part …’. The Panel did notconsider that either the briefing document or the emailadvocated disparagement of Pfizer. No breach of the Codewas ruled. There was no evidence before the Panel thatdisparagement of Pfizer had occurred and so the Panel ruledno breach of the Code.

Allergan was required to write to each clinician towhom a slit lamp or educational grant had beensupplied to request, where practicable, its return.These letters were seen by the Authority and handdelivered by Allergan’s representatives.

COMPLAINT

Pfizer stated that it had received several reports fromcentres across the UK that it was being disparaged byAllergan’s representatives as they delivered the lettersreferred to above. Pfizer had asked Allergan forclarification of the representatives’ briefing regardingthese letters as it considered that it might be in breachof Clause 15.9 of the Code. Pfizer did not consider itacceptable that when, upon request, Allerganrepresentatives discussed the ruling in CaseAUTH/1516/9/03, they cast blame upon Pfizer.Pfizer alleged that such activity was in breach ofClause 8.1 of the Code.

RESPONSE

Allergan noted that the letter at issue made nomention of Pfizer. Allergan submitted that itsrepresentatives were briefed beforehand, in writingand by telephone, about the appropriate delivery ofthe letters. Copies of the briefing document and ofthe final letter were provided to the Authority. Noreference was made to Pfizer and there was noinstruction to mention Pfizer in any way. Allergansubmitted that its representatives were careful to stickto the text of the brief and acted in a professionalmanner at all times. Copies of the representatives’briefing document, an email to the representativesand the letter to clinicians were provided.

Allergan did not consider that the briefing given to itsrepresentatives was in breach of Clause 15.9 of theCode. The company strongly refuted the suggestionthat its representatives had ‘cast blame upon Pfizer’and was confident that they had acted appropriately,and had not disparaged Pfizer.

Allergan noted that clinicians occasionally asked itsrepresentatives who had complained and theyresponded as truthfully and factually as they could.This information was only given out in response tounsolicited enquiries, and was never volunteered.

Allergan took the suggestion that any of itsrepresentatives might have disparaged Pfizer veryseriously and had asked Pfizer to provide details ofany rogue representatives that might have acted inthis way, so that the matter could be investigated andappropriate action taken. No such details had beenprovided.

Allergan was confident that its representatives hadacted appropriately, and had not disparaged Pfizer.The company therefore denied a breach of Clause 8.1.


CASE AUTH/1564/3/04 NO BREACH OF THE CODE

PFIZER v ALLERGANAlleged disparagement of Pfizer

In Case AUTH/1516/9/03 Pfizer Limited alleged thatthe provision by Allergan UK Limited of ophthalmicslit lamps or educational grants to ophthalmologistsin association with a Lumigan initiative was aninducement to prescribe and brought discredit uponthe industry. The Panel ruled Allergan in breach ofthe Code and was so concerned about thearrangements that it reported the company to theAppeal Board in accordance with Paragraph 8.2 of theConstitution and Procedure. Allergan provided therequisite undertaking and assurance.

Upon receiving the report from the Panel, the AppealBoard, inter alia, was very concerned that a largenumber of clinicians might be left with the impressionthat the arrangements were acceptable. The AppealBoard required Allergan to take steps to recover theslit lamps and educational grants as set out inParagraph 10.3 of the Constitution and Procedure.

PANEL RULING

The Panel noted that the Authority had not providedPfizer with any information about the actions theAppeal Board required Allergan to undertake. ThePanel further noted that the letter at issue had notbeen pre-approved by the Authority as submitted byAllergan. The Authority had seen the letter andsuggested amendments which had been accepted byAllergan.

The Panel noted that Pfizer had not provided anysubstantive evidence to support its allegations.Allergan had provided copies of the letter requestingreturn of the slit lamps or educational grants togetherwith a briefing document about delivery of the letterand a short email which was sent to therepresentatives on the day after Allergan hadaccepted the Panel’s rulings of breaches of the Code.The email began ‘As you are all aware Pfizer havecomplained about [the Lumigan] initiative claiming itwas a breach of the ABPI, an inducement to Rx’.

Thereafter Pfizer was not mentioned either implicitlyor explicitly. Neither the briefing document, which,inter alia, explained the background to the case andprovided some questions and answers, nor the lettersent to clinicians made any reference to Pfizer. ThePanel noted that the briefing document did not evenrefer to the complaint. In answer to the question‘How could this happen?’ the answer in the briefingdocument began ‘This was an error on Allergan’s part…’. The Panel did not consider that either thebriefing document or the email advocateddisparagement of Pfizer. No breach of Clause 15.9was ruled. There was no evidence before the Panelthat disparagement of Pfizer had occurred and so thePanel ruled no breach of Clause 8.1.


Case completed 23 April 2004



JANSSEN-CILAG/DIRECTOR v LILLYAlleged breach of undertaking

Janssen-Cilag complained about Lilly’s use of a poster(Roychowdhury et al 2004) which compared Zyprexa(olanzapine) with, inter alia, Janssen-Cilag’s productRisperdal (risperidone). The data for the comparison ofZyprexa with risperidone was referenced to Tran et al (1997).The poster concluded that, using multiple definitions ofresponse and relapse olanzapine was better at reducingrelapse in patients with schizophrenia than the comparators.

As the complaint involved an alleged breach of undertakingit was taken up by the Director as it was the responsibility ofthe Authority itself to ensure compliance with undertakings.This accorded with guidance previously given by the AppealBoard.

Janssen-Cilag noted that a Lilly press release relating to theposter prompted an article in Chemist & Druggist whichincluded claims that patients on Zyprexa apparently relapsedless frequently than those receiving Risperdal. The articleended with the statement: ‘For more information LillyMedical Information Tel [number given]. In response toJanssen-Cilag’s request for more information, but notspecifically for the poster, a copy of the poster wasvolunteered and sent.

Janssen-Cilag noted that in Case AUTH/1325/5/02 Lilly hadaccepted the Panel’s ruling of a breach of the Code withregard to claims for Zyprexa of superior efficacy comparedwith Risperdal in preventing relapse based on Tran et al. Inthat case the Panel had noted that Tran et al had not beendesigned to measure relapse rates. Janssen-Cilag thusassumed that claims of superior relapse prevention forZyprexa compared to Risperdal based on the results of Tranet al were unacceptable and so it was surprised to havereceived the poster from Lilly as further information

supporting the article in Chemist & Druggist, whichcontained such claims, when it had not beenspecifically requested.

Janssen-Cilag submitted that the conclusions of theposter were clearly misleading and used datapreviously ruled to be inappropriate to demonstratecomparative rates of relapse between Zyprexa andRisperdal. Medical information departments weresubject to the Code and thus required to supplyinformation that was not misleading, was balancedand represented an up-to-date evaluation of all theevidence. Hence, even if a medical informationdepartment was asked to supply a specific reference,it should not do so if it was misleading unless itpointed out the misleading element to the requesterand attempted to provide a balanced view.

Janssen-Cilag alleged that supply and/or use of thisposter by Lilly (regardless of whether it was from itsmedical information department) was failing tocomply with a previous undertaking and so byconsequence Lilly had not maintained the highstandards expected of the pharmaceutical industry.

The Panel noted that Case AUTH/1325/5/02concerned, inter alia, the claim ‘Significant reductionin relapse rates compared to risperidone’ referencedto Tran et al. The Panel had noted that the Tranpaper had not referred to relapse rates. The primaryobjective of the study was to evaluate theeffectiveness and safety of olanzapine versusrisperidone during double-blind therapy. Themaintenance of response as measured by Tran et alhad only taken into account Positive and Negative

Syndrome Scale (PANSS) total score and ClinicalGlobal Impression (CGI) score. In this regard, thePanel noted that in a study which had specificallyexamined relapse rates in patients withschizophrenia, relapse was defined by any one of 5parameters (Csernansky et al). In the Panel’s viewTran et al had not been designed to measure relapserates; maintenance of response as defined by twoparameters, was not the same as prevention ofrelapse. The Panel had considered that the claimdid not accurately represent the findings of Tran etal and was misleading in that regard. A breach ofthe Code was ruled and accepted by Lilly.

Turning to the case now before it, CaseAUTH/1570/3/04, the Panel noted that olanzapineand risperidone data from Tran et al had been usedin the poster produced by Lilly USA. The posterconcluded that, inter alia, olanzapine was better atreducing relapse in patients with schizophrenia thanrisperidone using different definitions of responseand relapse. The Panel considered that the posterper se was not subject to the Code. It had beendisplayed in an academic forum organised by a thirdparty. Lilly’s use of the poster in the UK, however,must comply with the Code.

Lilly UK had issued a press release to medicaljournals entitled ‘Zyprexa superior head-to-head toother atypicals in schizophrenia relapse-prevention’followed by ‘Additional quality of life data showsZyprexa benefits vs other atypicals may lead to betterpatient outcomes over time’. The press releasereferred to the new data (the poster) whichdemonstrated that Zyprexa-treated patientsexperienced significantly longer delays toschizophrenia-relapse in comparison to patients whoreceived other leading atypical antipsychotics. ThePanel noted its comments and rulings about the Trandata as detailed above. The press release also statedthat Zyprexa-treated patients relapsed significantlyless than Risperdal treated patients (p≤ 0.001).

The Panel noted that the Code stated that the termpromotion did not include replies made in responseto individual enquiries from members of the healthprofessions or appropriate administrative staff or inresponse to specific communications from themwhether of enquiry or comment, including letterspublished in professional journals, but only if theyrelated solely to the subject matter of the letter orenquiry, were accurate and did not mislead and werenot promotional in nature.

The Panel noted that the data in the poster relatingto the comparison of relapse rates with Zyprexa andRisperdal had been taken from Tran et al. Lilly hadaccepted in Case AUTH/1325/5/02 that Tran et al wasnot designed to measure relapse rates.

The Panel considered that the press release and theposter were misleading with regard to thecomparative efficacy of Zyprexa and Risperdal toprevent relapse in schizophrenia. The Panelconsidered that the press release and Lilly’s use ofthe poster meant that the company had not compliedwith its undertaking; high standards had not beenmaintained. Breaches of the Code were ruled. ThePanel also considered that by not complying with an

undertaking Lilly had brought discredit upon andreduced confidence in the pharmaceutical industry.A breach of Clause 2 of the Code was ruled. Theserulings were appealed by Lilly.

The Appeal Board noted the parties’ submissionsthat there was no generally accepted definition ofrelapse in schizophrenia. The Appeal Board furthernoted that the source data which had formed thebasis of Tran et al had been reanalysed andpresented by Roychowdhury et al. It was not areanalysis of the data produced by Tran et al but areanalysis of the data used by that group in itscomparison of olanzapine and risperidone. In theAppeal Board’s view reanalysis of source data was avalid scientific methodology. The Appeal Boardconsidered that Roychowdhury et al had appliedsufficiently different definitions to those used byTran et al such that use of the poster at issue did notrepresent a breach of the undertaking given in CaseAUTH/1325/5/02. No breach of the Code was ruled.Consequently the Appeal Board also ruled nobreach of Clause 2 of the Code.

Janssen-Cilag Ltd complained about Eli Lilly andCompany Limited in relation to use of a poster(Roychowdhury et al 2004). The poster comparedZyprexa (olanzapine) with, inter alia, Janssen-Cilag’sproduct Risperdal (risperidone).

As the complaint involved an alleged breach ofundertaking it was taken up by the Director as it wasthe responsibility of the Authority itself to ensurecompliance with undertakings. This accorded withguidance previously given by the Appeal Board.

The poster was presented at a workshop onschizophrenia held in Switzerland. It was a post-hocanalysis comparing olanzapine with risperidone,ziprasidone and quetiapine in three separate studiesand reported on prevention of relapse. The data forthe comparison with risperidone was referenced toTran et al (1997). The poster concluded that, usingmultiple definitions of response and relapse,olanzapine was better at reducing relapse in patientswith schizophrenia than the comparators.

COMPLAINT

Janssen-Cilag noted that as a result of the release ofthe poster and a subsequent Lilly press releaserelating to it, an article appeared in Chemist &Druggist, February 2004. The article included claimsthat patients on Zyprexa apparently relapsed lessfrequently than those receiving Risperdal. At the endof the article was a statement: ‘For more information:Lilly Medical Information Tel [number given]’.Janssen-Cilag telephoned and requested furtherinformation but did not specifically request a copy ofthe poster. In response, a copy of the poster wasvolunteered by Lilly’s medical informationdepartment and sent without delay. Janssen-Cilagalleged that, by issuing the poster, Lilly had breachedClauses 2, 9.1 and 22 of the Code.

Janssen-Cilag noted that Lilly had previously beenruled in breach of the Code for making claims ofsuperior efficacy in preventing relapse based on Tranet al (Case AUTH/1325/5/02). In that case the Panel


had noted that Tran et al had not been designed tomeasure relapse rates; maintenance of response asdefined by two parameters was not the same asprevention of relapse. The Panel concluded that toclaim superior relapse prevention for Zyprexa overRisperdal did not accurately reflect the findings ofTran et al and was therefore misleading. Lilly hadaccepted this ruling. Janssen-Cilag took this to meanthat Lilly was not permitted to make claims ofsuperior relapse prevention for Zyprexa compared toRisperdal based on the results of Tran et al. Janssen-Cilag was therefore surprised to have received theposter from Lilly’s medical information department asfurther information supporting the article in theChemist & Druggist which claimed superiority forZyprexa over Risperdal when it had not beenspecifically requested.

In intercompany correspondence Lilly had stated that‘…a request to Lilly Medical Information Departmentwas made for a copy of a poster that was presented atDavos in February 2004. Our medical informationdepartment was able to supply the requester with theposter. I am unaware of any situation that might arisethat should lead to the refusal to supply suchpublications of scientific data. Under Clause 1.2, thisis not deemed to be promotional, and there has notbeen a breach of the above ruling’.

Janssen-Cilag noted that it had not specificallyrequested a copy of the poster; it had requestedfurther information (as stated at the end of theChemist & Druggist article) and, in response, a copyof the poster was volunteered.

With regard to Clause 1.2 of the Code, replies made inresponse to a specific request for information wereonly exempt if they were accurate and not misleading.The conclusions of the poster were clearly misleadingand used data previously ruled to be inappropriate todemonstrate comparative rates of relapse betweenZyprexa and Risperdal. Additionally, medicalinformation departments were subject to the Codeand the requirements to supply information that wasnot misleading, was balanced and represented an up-to-date evaluation of all the evidence. Hence, even ifa medical information department was asked tosupply a specific reference, it should not do so if itwas misleading unless it pointed out the misleadingelement to the requester and attempted to provide abalanced view.

Janssen-Cilag alleged that supply and/or use of thisposter by Lilly (regardless of whether it was fromtheir medical information department) was failing tocomply with a previous undertaking and therefore inbreach of Clause 22 of the Code.

By failing to comply with a previous ruling, it wasclear that Lilly had not maintained the high standardsexpected of the pharmaceutical industry. Janssen-Cilag did not know which part of Lilly wasresponsible for issuing the press release relating to theposter. The fact that Chemist & Druggist reportedthis event showed that the press release reached theUK, meaning that Lilly in the UK had responsibilityfor it, even if its international arm actually producedit. Janssen-Cilag stated that the inability of the UKdivision of Lilly to control the activities of its UK

medical information department to prevent suchmisleading information being actively supplied inbreach of previous undertakings meant that it was notmaintaining the expected high standards. IndeedLilly had an obligation to communicate themisleading nature (and the Panel’s rulings) of thisdata to European and global colleagues so that itcould not be misleadingly presented in press releasesthat would be reported in the UK press. If indeedLilly was responsible directly for the release of thispress release in the UK, then manifestly, it was notadhering to its earlier undertaking and would nothave been maintaining high standards.

Given the failure of Lilly’s medical informationdepartment to comply with a previous undertaking,Janssen-Cilag welcomed the Panel’s views on whetherClause 2 of the Code had been breached.

RESPONSE

Lilly denied any breach of the Code and submittedthat it had fully complied with the undertaking givenin Case AUTH/1325/5/02 and would continue to doso. The poster was submitted and written wholly bythe parent USA company and contained no authorsaffiliated with the UK subsidiary. The poster includedcomparisons between Zyprexa and each of quetiapine,ziprasidone and Risperdal. As was standard practicea press release was issued to medical journalists in theUK regarding this and other posters being presentedby the UK affiliate. From a process view it should benoted that following the standard operatingprocedure (SOP) for approval of press releases in theUK all were deemed to be non-promotional in thatthey represented information to the media relating tothe release of new pertinent information. Followingthis press release the Chemist & Druggist contactedLilly advising that the journal was planning an articleand to ask permission to include the telephonenumber of Lilly’s medical information department.Permission was granted. On 24 February 2004 aperson identifying herself as a hospital pharmacistcontacted medical information and stated that she hadseen the article. A routine entry was made in themedical information enquiry log that stated therequester ‘wants data behind article’. At this stage itwas not possible to confirm or deny that what wasasked for was a precise statement of ‘moreinformation’ or if the poster itself had been requested.The person taking the call was unaware of the posterand had no knowledge of its contents. It was agreedthat the poster would be sent by fax.

The only information held by Lilly relating to thisposter was the poster itself; there were no othermaterials that could have been sent in place. Themedical information department behaved in a routinemanner, which was non-promotional and respondedto a request for more information regarding the posterby ascertaining the status of the enquirer and mailingthem an appropriate item, ie the poster. Clearly thecaller did not identify his or herself as a Janssen-Cilagemployee and Lilly noted that the poster containeddata on three comparative antipsychotics to Zyprexaand not only Risperdal. There was nothing to suggestthat the requester specifically asked for ‘data behindthe article’ relating solely to risperidone.


Lilly regarded the sending out of materials from amedical information department in response to anappropriate request as standard practice. It did notseem a credible claim that in response to a request forfurther information that the sending out of a poster(an action that was most likely agreed with the senderduring the call as the item was faxed and thus a faxnumber would have been given) was an unreasonableor promotional type of activity. Indeed in this case itwas the only apparent option in that no othermaterials were available nor had been generated thatwould reasonably meet a level of response consideredappropriate.

Lilly submitted that the whole argument assumed asemantic nature in that Janssen-Cilag had contendedthat ‘the poster was not specifically requested’without clearly stating what forms of informationwere clearly asked for and not commenting on whatmaterials were agreed that could indeed be faxedover. Other than the poster Lilly had no other itemthat would provide any ‘information’ as requested.

With regard to Clause 1.2 of the Code the responsewas both accurate and not misleading. An accuratepiece of information was delivered (ie the posteritself) in the absence of any other specific data.Should the enquirer have asked for furtherinformation relating specifically to relapse ratescomparing Zyprexa and Risperdal they would havebeen advised or sent the appropriate materials. Lillyrepeated that the poster contained data on twocomparators to Zyprexa other than Risperdal.Specifically the enquirer, according to Lilly’s records,did not specifically ask about the Risperdalcomponent to the poster nor of course identifythemselves as a Janssen-Cilag employee but only as ahospital pharmacist. In which case it might not bedeemed necessary in the absence of any specificquestions relating to the Risperdal component of thedata to provide additional supporting materials. Lillytherefore submitted that no breach of Clause 22 of theCode had occurred.

Lilly fully complied with the undertaking givenregarding Tran et al (Case AUTH/1325/5/02) asdetailed above. The press release containing newrelevant information relating to a number of clinicalstudies was considered by Lilly to be a non-promotional item in terms of the SOP that covered itsapproval. It therefore contended that no breach ofClause 9.1 had occurred.

Lilly did not believe that any of its actions had led toa breach of Clause 2 of the Code.

Lilly confirmed that the poster had not been used inany way for promotional materials. The companynoted that the poster contained new data comparingZyprexa to two other antipsychotics in addition toRisperdal. The press release was made on behalf ofLilly by a public relations agency and sent to anumber of appropriate medical journals. The articlethat appeared in the Chemist & Druggist had not beenused in any way. This article would presumably havebeen written by the medical writers from that journaland thus was neither written by nor on behalf of Lilly.Lilly had made every effort to fully comply with theundertaking given in relation to Case

AUTH/1325/5/02. Since that undertaking was givenall promotional materials had made no reference tothe matters referred to in the undertaking.

PANEL RULING

The Panel considered that an undertaking was animportant document. It included an assurance that allpossible steps would be taken to avoid similarbreaches of the Code in future. It was very importantfor the reputation of the industry that companiescomplied with undertakings.

The Panel noted that Case AUTH/1325/5/02concerned a number of items including a leavepiececontaining the claim ‘Significant reduction in relapserates compared to risperidone’ referenced to Tran et al.The Panel had noted that the Tran paper had notreferred to relapse rates. The primary objective of thestudy was to evaluate the effectiveness and safety ofolanzapine versus risperidone during double-blindtherapy. The maintenance of response as measured byTran et al had only taken into account Positive andNegative Syndrome Scale (PANSS) total score andClinical Global Impression (CGI) score. In this regard,the Panel noted that in a study which had specificallyexamined relapse rates in patients with schizophrenia,relapse was defined by any one of 5 parameters(Csernansky et al). In the Panel’s view Tran et al hadnot been designed to measure relapse rates;maintenance of response as defined by twoparameters, was not the same as prevention of relapse.The Panel had considered that the claim did notaccurately represent the findings of Tran et al and wasmisleading in that regard. A breach of Clause 7.2 wasruled. This ruling had been accepted by Lilly whichhad provided the requisite undertaking and assurance.

Turning to the case now before it, CaseAUTH/1570/3/04, the Panel noted that olanzapineand risperidone data from Tran et al had been used inthe poster produced by Lilly USA. The posterconcluded that, inter alia, olanzapine was better atreducing relapse in patients with schizophrenia thanrisperidone, ziprasidone or quetiapine using differentdefinitions of response and relapse. The Panelconsidered that the poster per se was not subject to theCode. It had been displayed in an academic forumorganised by a third party in Switzerland. Lilly’s useof the poster in the UK, however, must comply withthe Code.

Lilly UK had issued a press release to medicaljournals. The press release was entitled ‘Zyprexasuperior head-to-head to other atypicals inschizophrenia relapse-prevention’ followed by‘Additional quality of life data shows Zyprexabenefits vs other atypicals may lead to better patientoutcomes over time’. The press release referred to thenew data (the poster) which demonstrated thatZyprexa-treated patients experienced significantlylonger delays to schizophrenia-relapse in comparisonto patients who received other leading atypicalantipsychotics. The Panel noted its comments andrulings about the Tran data as detailed above. Thepress release also stated that Zyprexa-treated patientsrelapsed significantly less than Risperdal treatedpatients (p≤ 0.001).


With regard to the provision of the poster to Janssen-Cilag in response to the request to Lilly’s medicalinformation department, the Panel wondered whatelse Janssen-Cilag was expecting if not the poster.

The Panel noted that Clause 1.2 of the Code statedthat the term promotion did not include replies madein response to individual enquiries from members ofthe health professions or appropriate administrativestaff or in response to specific communications fromthem whether of enquiry or comment, includingletters published in professional journals, but only ifthey related solely to the subject matter of the letter orenquiry, were accurate and did not mislead and werenot promotional in nature.

The Panel noted that the data in the poster relating tothe comparison of relapse rates with Zyprexa andRisperdal had been taken from Tran et al. Lilly hadpreviously accepted (Case AUTH/1325/5/02) thatTran et al was not designed to measure relapse rates.Lilly had issued a press release about the poster.

The Panel considered that the press release and theposter were misleading with regard to thecomparative efficacy of Zyprexa and Risperdal toprevent relapse in schizophrenia. The Panelconsidered that the press release and Lilly’s use of theposter meant that the company had not compliedwith its undertaking. The Panel thus ruled a breachof Clause 22 of the Code. High standards had notbeen maintained and a breach of Clause 9.1 of theCode was ruled. The Panel also considered that bynot complying with an undertaking Lilly had broughtdiscredit upon and reduced confidence in thepharmaceutical industry. The Panel thus ruled abreach of Clause 2 of the Code.

During its consideration of this case the Panel wasconcerned that the press release referred to the data asnew; Tran et al was published in 1997. Although theposter reported the results of a new post-hoc analysis,the data used was not new. The Panel requested thatLilly be advised of its concerns.

APPEAL BY LILLY

Lilly noted that Case AUTH/1325/5/02 hadconcerned a number of items including a leavepiececontaining the claim ‘Significant reduction in relapserates compared to risperidone’, referenced to Tran etal, and immediately followed by a graph to illustratethe point. The graph was from Tran et al and depictedthe cumulative percentage of patients maintaining aresponse for up to 200 days of treatment. The Panelhad noted that Tran et al had not referred to relapserates and that maintenance of response had onlytaken into account PANSS total score and CGI score.This was considered misleading in that it did notaccurately represent the findings of Tran et al. ThePanel’s ruling further stated ‘maintenance of responseas defined by two parameters was not the same asprevention of relapse’. This ruling was based on areview of Csernansky et al.

With regard to PANSS and CGI, Lilly explained thatPANSS was a 30 item inventory of generalpsychopathology used to evaluate the effects ofmedicinal treatment in schizophrenia. There were 7

items on the positive subscale, 7 on the negativesubscale and 16 items on the general psychopathologyscale. All items were rated with a score from 1(absent) to 7 (extreme), giving a range of scores from30 to 210. CGI assessment reflected the impression ofa skilled observer, fully familiar with themanifestations of schizophrenia, about the overallclinical state of the patient. The CGI scale was a valid,reliable instrument to evaluate severity and treatmentresponse in schizophrenia. Given its simplicity,brevity and clinical face validity, the scale wasappropriate for use in observational studies androutine clinical practice. The scale had a single item,scored from 1 (normal, not ill) to 7 (extremely ill).

Lilly had accepted the Panel’s ruling in CaseAUTH/1325/5/02 and provided the requisiteundertaking and assurance on 15 August 2002.

Lilly noted that during 7-14 February 2004, theRoychowdhury et al poster was presented at a majorschizophrenia conference in Davos, Switzerland.Roychowdhury et al demonstrated that patients withschizophrenia who received Zyprexa experiencedsignificantly longer delays to relapse in comparison topatients who received other atypical antipsychotics.

On 11 February 2004 Lilly issued a press release inrespect of the Roychowdhury et al poster to medicaltrade journalists.

On 21 February 2004 an article appeared in Chemist &Druggist regarding the poster. At the end of thisarticle there was a statement – ‘For more information:Lilly Medical Information …’. A person, identifyingthemselves as a hospital pharmacist (who latertranspired to be a representative of Janssen-Cilag)contacted Lilly medical information requesting furtherinformation regarding the article in Chemist &Druggist and was sent a copy of the poster.

Lilly noted that on 9 March 2004 it had received aletter from Janssen-Cilag alleging that it had failed tocomply with its 2002 undertaking and thus breachedClauses 22, 9.1 and 2 for claiming superior relapseprevention based on Tran et al.

Lilly submitted that the purpose of the aboveinformation was to give the contextual background tothe complaint.

Lilly noted that Janssen-Cilag had alleged:-

● That a copy of the Roychowdhury et al poster wasvolunteered by Lilly’s medical informationdepartment and that, with the supply and/or useof this poster, Lilly had failed to comply with aprevious undertaking in breach of Clause 22 of theCode.

● That the inability of Lilly to control the activities ofits medical information department to preventmisleading information being actively supplied inbreach of previous undertakings meant that it hadnot maintained high standards in breach of Clause9.1 of the Code.

Lilly noted that the Panel had ruled a breach ofClause 22 of the Code. It, however, submitted thatRoychowdhury et al was different to Tran et al. InTran et al, ‘Double-blind comparison of olanzapineversus risperidone in the treatment of schizophrenia


and other psychotic disorders’, the primary intent wasto evaluate the efficacy and safety of olanzapineversus risperidone in 339 patients over 28 weeks.Although a formal definition of relapse was notincluded in the publication, a survival analysis wasperformed to assess ‘time maintaining response’. Forthis analysis, patients were considered to haverelapsed if they showed significant symptomexacerbation defined a priori as a 20% or greaterworsening in the PANSS total score along with a CGI-S score ≥ to 3 after 8 weeks of therapy.

Roychowdhury et al was a post-hoc analyses of threestudies which compared Zyprexa with quetiapine,Risperdal and ziprasidone respectively in preventingrelapse in patients with schizophrenia and relateddisorders. All the studies were multicentre, double-blind, controlled clinical trials, with patientsrandomised 1:1 to two active treatments. They allincluded PANSS total scores as a measure of efficacyand used flexible dosing. This poster was different inmany respects to Tran et al. It was not a re-presentationof Tran et al, it was a new analysis of the patient dataset that was used as the basis for Tran et al plus thedata sets from two other studies. This new analysiswas performed by different authors and reachedseparate conclusions using different statistical methods.

Lilly submitted that the new analysis allowed, unlikeTran et al, a clear definition of a responder as either20% or 30% improvement in PANSS total at 8 weeks.Relapse was defined as 20% or 30% worsening ofPANSS total and a CGI-S severity of 3 or more after 8weeks in the previously clearly defined respondergroups. There was no one universally accepteddefinition of relapse for use in clinical studies hencethese definitions of relapse could be regarded asreasonable and clinically meaningful.

Lilly noted the poster contained additional definitionsof relapse and response. These had been analysedboth by calculating odds ratios and generating newKaplan-Meier survival curves. These were notperformed by the authors of the Tran et al paper.These two statistical comparisons reflected majordifferences as to what was taken into account in theanalysis of the data. Odds ratios did not account fortime, they compared the proportion of patients whorelapsed at any point in the study. Kaplan-Meiersurvival curves took into account the time the eventshappened during the study.

Lilly submitted that there was accordingly bothadditional data and additional analyses inRoychowdhury et al that was not present in Tran et al.The more comprehensive analyses had been presentedin the form of both odds ratios and more detailedsurvival curves. The conclusions were thus based onthese new analyses and allowed clear differentiationof Roychowdhury et al from Tran et al.

Lilly submitted that in the light of this newinformation a press release was reasonably made.The title of the press release paraphrased theconclusions stated a number of times byRoychowdhury et al. It accurately reported the dataand conclusions of their analysis.

Lilly submitted that the complaint was based onLilly’s medical information department supplying a

copy of the Roychowdhury et al to a Janssen-Cilagemployee posing as a hospital pharmacist. TheJanssen-Cilag employee had contacted the medicalinformation department to request furtherinformation after reading an article in Chemist &Druggist. This article described the poster andconcluded ‘The findings of the studies, which weresponsored by Eli Lilly, were presented at the 11thBiennial Winter Workshop in Davos, Switzerland’.Although the Janssen-Cilag employee contended thathe did not specifically request a copy of the posterand was surprised to be offered it, the fact that thearticle was specifically about the poster meant that itwas reasonable to provide it in response to a requestfor further information. This was in keeping with thespirit of Clause 1.2 of the Code. The informationprovided was solely related to the subject matter ofthe enquiry and the statistical analysis was accurateand the conclusions of the Roychowdhury posterwere not misleading because they accuratelyrepresented the authors’ analysis. This poster was notused promotionally and was only provided uponrequest.

Lilly submitted that the presentation of theinformation in the Roychowdhury et al poster wasscientifically valid, and not misleading. There werestill no universally accepted criteria to define relapsein schizophrenia (Lader 1995, Leucht et al, 2003).Since the publication of Tran et al several papers hadbeen published on the subject of relapse inschizophrenia and there was no consistent definitionof what constituted a relapse (Robinson et al 1999;Herz et al 2000; Csernansky et al; Leucht et al andAlmond et al 2004).

Lilly noted that Tran et al had used limited criteria todefine significant symptom exacerbation as ≥ 20%worsening in PANSS total score and CGI-S ≥ 3. Otherrecent studies had used different cut-off points todefine relapse, as discussed above, makingcomparisons between studies difficult.Roychowdhury et al sought to compare a number ofwidely used atypical antipsychotic medicines usingvarious commonly accepted definitions of responseand relapse. The information included in the posterwas not previously available in the public domain.Publication of the poster allowed the reader to make amore direct comparison with subsequent research byLilly and other pharmaceutical companies.

Lilly submitted that in summary, the Panel’s opinionthat the Roychowdhury et al poster and press releasewere misleading with regard to the comparativeefficacy of Zyprexa and Risperdal to prevent relapsein schizophrenia was based on the previous ruling(AUTH/1325/5/02) that Tran et al was not designedto measure relapse rates. As discussed above theposter was a separate piece of work from Tran et al.Roychowdhury et al did not re-present the Tran data;the authors had reanalysed the patient data set usingnew methods as described above using many of thevarious available criteria to describe relapse inschizophrenia. Tran et al was cited in Roychowdhuryet al as this was a prior publication from one of thedata sets used for the analysis and the paperdescribed the methodology of the clinical trial. Theother prior publications were also referenced. This


was done to make it clear that it was not simply a re-publication of Tran et al but a distinct piece of work.Re-analysis in this way was an accepted method ofextracting clinically relevant information from theoriginal patient data set. Every clinical trial generateda source of valuable but expensive information. Tofully exploit the knowledge hidden in thisinformation, the results should be analysed using abroad range of tools. Lilly stated that it was awidespread practice to perform post hoc analyses ofstudies and cited examples of publications generatedin this way (Wyatt et al 1997, Judd et al 2003 andDonaldson et al 2000).

Lilly noted that the Panel had previously ruled thatTran et al described maintenance of response, notrelapse prevention. Roychowdhury et al describedrelapse prevention in patients with schizophrenia andthe press release quoted this. Schizophrenia was alifelong disease characterised by periods of relapseand remission and there were no standard criteria todescribe these events. Lilly therefore maintained thatthe criteria used by Roychowdhury et al to definerelapse were appropriate, measurable, clinicallymeaningful and robust.

With regard to the Panel’s ruling of a breach of Clause9.1, failure to maintain high standards, Lillysubmitted that it not intended to promote thecomparative efficacy of Zyprexa and Risperdal toprevent the relapse of schizophrenia based on Tran etal. Roychowdhury et al was not a re-presentation ofTran et al, it was a new analysis of the patient data setthat was used as the basis for Tran et al plus the datasets from two other studies. As described above, thisnew analysis was performed by different authors andreached separate conclusions using different statisticalmethods.

Lilly also noted that the Panel had ruled a breach ofClause 2 of the Code, based on the fact that by notcomplying with an undertaking, it had broughtdiscredit upon and reduced confidence in thepharmaceutical industry. Lilly did not consider it wasin breach of Clauses 22 and 9.1 of the Code and didnot, therefore, consider it was in breach of Clause 2.

Lilly noted that a ruling of a breach of Clause 2 was asign of ‘particular censure’ which should be reservedfor such circumstances. Lilly submitted that thecriteria used by Roychowdhury et al to define relapsewere appropriate, measurable, clinically meaningfuland robust, and even if the Appeal Board disagreedwith it on this particular point, it believed that itcould well have been a reasonable belief in thecircumstances. Lilly also considered that the pressrelease and the provision of the poster on request wasdone in good faith, based on its interpretation of thedifferences between Roychowdhury et al and Tran et aland not done in deliberate contravention of theundertaking given in Case AUTH/1325/5/02.

COMMENTS FROM JANSSEN-CILAG

Janssen-Cilag alleged that supply and/or use ofRoychowdhury et al by Lilly (regardless of whether itwas by its medical information department) wasfailing to comply with a previous undertaking andconsequently was in breach of Clause 22 of the Code.

Janssen-Cilag alleged that the inability of Lilly tocontrol the activities of its medical informationdepartment to prevent misleading information beingactively supplied in breach of previous undertakingsmeant it was not maintaining the expected highstandards and therefore in breach of Clause 9.1 of theCode. Janssen-Cilag stated that when it submitted itscomplaint it did not know which part of Lilly wasresponsible for issuing the press release. It was nowclear that the UK division issued the press release tomedical journalists in the UK and that it gavepermission for Chemist & Druggist to include itstelephone number at the end of the article.

Janssen-Cilag noted that Lilly had claimed thatRoychowdhury et al was different to Tran et alprimarily because the new analysis allowed, unlikeTran et al, a clear definition of a responder as either 20or 30% improvement in PANSS total at 8-weeks.Relapse was defined as 20-30% worsening of PANSStotal and a CGI-severity of 3 or more after 8 weeks inthe previously clearly defined responder group.

Janssen-Cilag failed to understand how this could bean explanation for the poster and publication beingdescribed as different. Both reported on the same setof data (ie data from a study that was designed toevaluate the effectiveness and safety of Zyprexa versusRisperdal, not the relative relapse potential of the twoproducts). In Tran et al a survival analysis wasperformed to estimate time maintaining response(time not exhibiting a significant symptomexacerbation after achieving response criteria at 8weeks). A significant symptom exacerbation wasdefined as a 20% or greater worsening in PANSS totalscore along with a CGI-S score of >3 after 8 weeks oftherapy. Only responders ie patients who showedimprovement in PANSS total score of at least 20% frombaseline at week 8 were included in this analysis.

Janssen-Cilag alleged that it was clear, therefore, thatTran et al had provided a clear definition of aresponder and that, effectively the same definitionwhich was used to determine maintenance ofresponse in the peer-reviewed publication of this datawas being interpreted by Roychowdhury et al asrelapse. Maintenance of response was not the same asrelapse (as ruled in Case AUTH/1325/5/02).

Janssen-Cilag noted that in Case AUTH/1325/5/02,Lilly was ruled in breach of the Code for using this‘maintenance of response’ data from Tran et al toclaim superior relapse prevention potential forZyprexa compared to Risperdal. Lilly had acceptedthis ruling. Janssen-Cilag felt strongly that the data inRoychowdhury et al was not new – it was merely a re-presentation of the data already in Tran et al. Janssen-Cilag alleged that continued use of such data to claimsuperiority in terms of relapse prevention for Zyprexaover Risperdal must therefore be considered as failureto comply with an undertaking, and the breach ofClause 22 should be upheld. Janssen-Cilag noted thatLilly had stated that this was new data and thereforeit was reasonable to issue a press release. The pressrelease was deemed non-promotional and describedas containing ‘new pertinent information’.

Janssen-Cilag noted that a press release should befactual and not misleading in its content and should


generally relate to new pertinent information.Janssen-Cilag alleged that the contents of the pressrelease were unbalanced, misleading and neither newnor pertinent.

Janssen-Cilag alleged that as described above,issuance of a press release, which allegedly described‘relapse rates’, derived from the Tran data should beconsidered as failing to adhere to the previousundertaking and therefore in breach of Clause 22.

Janssen-Cilag stressed that no employee had posed asa hospital pharmacist in order to obtain informationfrom another company. The employee who contactedLilly’s medical information department was not askedwhere they were calling from or their profession. Ifthey had been asked, naturally they would havedisclosed this information.

Janssen-Cilag noted that before publication of thearticle in Chemist & Druggist, Lilly agreed to the rider‘For more information: Lilly Medical Information Tel[number supplied]’ being placed at the foot of thearticle. The Janssen-Cilag employee did not requestthe poster per se; they made a request ‘for moreinformation’ as per the footnote on the article; at thistime Lilly was aware that the only additionalinformation available was the poster and that theposter contained information previously ruled inbreach of the Code; Lilly must have anticipated thatthe poster would be sent out on request. To maintainhigh standards this should have been anticipated; Theposter was not a peer reviewed article – all authorswere Lilly employees ie all information containedwithin the poster was generated internally with noexternal review.

Janssen-Cilag alleged that in order to comply with thespirit of Clause 1.2, any response should not bemisleading. The contents and conclusions in theposter were undoubtedly misleading and thereforesupplying it through medical information(particularly when it was not directly requested andsufficient explanation of its misleading nature was notgiven) was subject to the Code and represented afailure to maintain the high standards expected of thepharmaceutical industry and to comply with theprevious undertaking.

Janssen-Cilag agreed with Lilly’s submission thatthere was still no universally accepted criteria todefine relapse. However, extreme care must be takenespecially when addressing a post-hoc analysis.Janssen-Cilag alleged that if a study was notspecifically designed to address a question it waspossible that the definition of relapse used was theone most likely to result in the desired conclusion.Janssen-Cilag noted that Glick and Berg (2002)concluded that ‘Using the measures of studydiscontinuation, relapse and non-compliance, in onetrial the atypical antipsychotic olanzapine wassuperior to haloperidol, while in a second (Tran et al)there were no differences between olanzapine andrisperidone’. It was therefore possible to exploit thefact that there was no one definitive definition forrelapse and post-hoc analyses of such should bereviewed appropriately.

Janssen-Cilag alleged that with regard to thecomparative relapse prevention potential of Risperdal

and Zyprexa, Roychowdhury et al was not new data. Itwas a new representation of the analysis that wasactually in the original publication (where it wascorrectly referred to as maintenance of response).Maintenance of response was not the same as relapse(as ruled in Case AUTH/1325/5/02). The data in itselfwas misleading, especially given the published dataavailable for Risperdal with regard to relapseprevention, but more importantly it was an analysis ofdata that had already been ruled unsuitable for makingclaims of superior relapse prevention potential.

Janssen-Cilag maintained that Lilly’s use of the poster(in terms of producing a press release) and the supplyof it from medical information was failure to complywith an undertaking and strongly considered thatClause 22 had been breached.

Janssen-Cilag noted that Lilly had stated that it wasnot its intention to promote the comparative efficacyof Zyprexa and Risperdal to prevent the relapse ofschizophrenia based on Tran et al. Lilly claimed it wasa new analysis of the data set used for Tran et al.

Janssen-Cilag failed to accept this as grounds forappeal. As described above this was merely a newrepresentation of old data (with methodological flaws)that was not designed to address relapse. The data itwas based upon and the conclusions made wereaccepted by Lilly to be in breach of the Code in CaseAUTH/1325/5/02. It was therefore particularlyirresponsible of Lilly to issue a press release when ithad already been found in breach of the Code formaking a claim of superior relapse prevention basedon Tran et al.

Furthermore, by issuing a press release there was theimplication that this was a new study worthy ofpublic interest. Janssen-Cilag alleged that it was notnew data so it was inappropriate for a press release tobe issued. Doing so, especially in light of theprevious ruling, was indeed failing to maintain thehigh standards expected of the pharmaceuticalindustry. Janssen-Cilag therefore alleged that thebreach of Clause 9.1 should be upheld.

Janssen-Cilag noted that Lilly had issued a pressrelease and supplied a poster which containedstatements previously found in breach of the Code.Janssen-Cilag therefore maintained that Clauses 22and 9.1 had been breached. In the original complaint,Janssen-Cilag welcomed the Panel’s views on whetherClause 2 of the Code had been breached. The Panelconsidered that by not complying with anundertaking Lilly had brought discredit upon andreduced confidence in the pharmaceutical industry.The Panel thus ruled a breach of Clause 2 of the Code.Janssen-Cilag supported the ruling of the Panel.

APPEAL BOARD RULING

The Appeal Board considered that an undertakingwas an important document. It included an assurancethat all possible steps would be taken to avoid similarbreaches of the Code in future. It was very importantfor the reputation of the industry that companiescomplied with undertakings.

The Appeal Board noted the parties’ submissions onthe debate in the scientific community with regard to


accepted definitions of relapse in schizophrenia. TheAppeal Board further noted that the source datawhich had formed the basis of Tran et al had beenreanalysed and presented by Roychowdhury et al. Itwas not a reanalysis of the data produced by Tran et albut a reanalysis of the data used by that group in itscomparison of olanzapine and risperidone. In theAppeal Board’s view reanalysis of source data was avalid scientific methodology. Roychowdhury et al hadapplied different definitions than those used by Tranet al. Tran et al had defined a significant symptomexacerbation as a 20% or greater worsening in thePANSS total score along with a CGI-S score ≥ 3 after 8weeks’ therapy; Roychowdhury et al defined relapse

as a 20% or 30% worsening on PANSS total score anda CGI-S score of ≥ 3 after 8 weeks in responders. TheAppeal Board considered that this new analysis wassufficiently different from Tran et al such that use ofRoychowdhury et al did not represent a breach of theundertaking given in Case AUTH/1325/5/02. Nobreach of Clause 22 was ruled. Consequently theAppeal Board also ruled no breaches of Clauses 9.1and 2 of the Code. The appeal was successful.


Case completed 17 June 2004


CASE AUTH/1572/4/04

NOVARTIS v ROCHEBondronat journal advertisement

Novartis complained about two journal advertisements, onean abbreviated advertisement, for Bondronat (ibandronate)issued by Roche.

Bondronat (tablets and a concentrate solution for intravenousadministration (IV)) was indicated for the prevention ofskeletal events (pathological fractures, bone complicationsrequiring radiotherapy or surgery) in patients with breastcancer and bone metastases. In addition, Bondronat IV wasalso indicated for the treatment of tumour-inducedhypercalcaemia with or without metastases.

Novartis supplied Zometa (zoledronic acid) which hadsimilar indications to Bondronat. Both products belonged toa class of medicines known as bisphosphonates.

Novartis stated that the claim ‘The first 3rd generationbisphosphonate with equivalent oral and IV efficacy’ whichappeared as a heading to the advertisement, referenced toBody et al (2003), implied that there was head-to-head datadirectly comparing the efficacy of Bondronat IV andBondronat tablets. There had been no head-to-head studiesof Bondronat versus any agent other than placebo and thedata for both formulations came from three placebo-controlled trials, so only indirect comparisons could be made.

Novartis further stated that since Bondronat tablets were notindicated for tumour-induced hypercalcaemia, it failed to seehow the efficacy could be similar to Bondronat IV, andalleged that the claim was misleading and inconsistent withthe particulars listed in the summary of productcharacteristics (SPC). Although the phrase ‘For patients withbreast cancer and bone metastases’ appeared later in theadvertisement, this was in much smaller type further downthe page and so not obvious to the reader. Novartis allegedthat the claim was not in accordance with the marketingauthorizations for the two formulations, it was not factuallycorrect, was misleading and could not be substantiated.

The Panel noted that immediately beneath the claim ‘Thefirst 3rd generation bisphosphonate with equivalent oral andIV efficacy’ appeared an illustration of three skeletonscrossing the finishing line in a running race. The Panelconsidered that the claim implied that a direct comparison of

Bondronat IV with Bondronat tablets had concludedthat the two formulations had equivalent efficacy.This was not so. The comparable efficacy claim hadcome from a study (Body et al) which had analysedresults across three different studies, two comparingoral Bondronat with placebo and one comparingBondronat IV with placebo. The illustration of onerace being run added to the impression that thecomparative data was from one study. The Panelconsidered that the claim was misleading and notcapable of substantiation. Breaches of the Codewere ruled.

The Panel considered that the advertisementimplied that the two formulations had equivalentefficacy in all indications. The advertisement waspublished in Hospital Doctor and would thereforebe seen by doctors who would treat hypercalcaemiaof malignancy and patients with breast cancer andbone metastases. In the Panel’s view some doctorsmight think that Bondronat was the first thirdgeneration bisphosphonate which could be givenorally in the treatment of hypercalcaemia ofmalignancy which was not so. Bondronat tabletswere not so licensed. The Panel did not considerthat the impression given by the headline that oralBondronat could be given to the same patients asBondronat IV was negated by the inclusion of theclaim beneath the illustration ‘For patients withbreast cancer and bone metastases’. The headlineclaim needed to be read in conjunction with thequalifying text in order for its clinical implicationsto be understood. The Panel considered that theclaim on its own was inconsistent with theparticulars listed in the SPC for Bondronat tabletsand a breach of the Code was ruled.

Upon appeal by Roche, the Appeal Boardconsidered that the claim ‘The first 3rd generationbisphosphonate with equivalent oral and IVefficacy’ was a strong, unequivocal statement. Theclaim was referenced to Body et al which had taken

the results from three different placebo controlledstudies using two different formulations. In none ofthe studies were IV and oral Bondronat directlycompared. The study authors had concluded, interalia, that their results suggested that both IV andoral Bondronat were equally effective. The AppealBoard noted that such caution was not reflected inthe claim at issue. The Appeal Board consideredthat the claim gave the impression that a directclinical comparison of IV and oral Bondronat hadproven that the two were equally effective whichwas not so. The Appeal Board upheld the Panel’srulings of breaches of the Code.

The Appeal Board noted that Bondronat tablets,unlike the IV formulation, could not be used to treathypercalcaemia of malignancy. The claim at issuereferred to equivalent IV and oral efficacy. TheAppeal Board noted, however, that theadvertisement had appeared in Hospital Doctor; itwas thus aimed at a specialist audience which in theAppeal Board’s view would not consider oraltherapy for hypercalcaemia of malignancy. TheAppeal Board also noted that the main text of theadvertisement began ‘For patients with breast cancerand bone metastases …’. Given the intendedaudience and the main text of the advertisement, theAppeal Board did not consider that the claim ‘Thefirst 3rd generation bisphosphonate with equivalentoral and IV efficacy’ was inconsistent with theparticulars listed in the oral Bondronat SPC asalleged. No breach of the Code was ruled.

Novartis noted the claim ‘… renal safety profilecomparable to placebo in trials’ and stated thatbisphosphonates were associated withnephrotoxicity. This major organ toxicity had beenrecognised within the licence for both formulationsof Bondronat. Both SPCs stated:

‘Clinical studies have not shown any evidence ofdeterioration in renal function with long termBondronat therapy. Nevertheless, according toclinical assessment of the individual patient, it isrecommended that renal function, serum calcium,phosphate and magnesium should be monitored inpatients treated with Bondronat.’

The SPC for oral Bondronat further stated that foradverse drug reactions occurring at a frequency of<1%, azotaemia (uraemia) occurred more frequentlywith Bondronat tablets than with placebo. TheBondronat IV SPC stated that creatinine increaseoccurred in 2% of Bondronat patients compared with0.6% of placebo patients. Novartis stated that thesepercentages might appear small but the potentialclinical sequelae of renal impairment and renalfailure could result in significant morbidity andmortality. Novartis alleged that the claim impliedthat unlike other bisphosphonates renal toxicity wasnot a potential concern for Bondronat.

The Panel noted that the Bondronat SPCs bothstated: ‘Clinical studies have not shown anyevidence of deterioration in renal function with longterm Bondronat therapy. Nevertheless according toclinical assessment of the individual patient it isrecommended that renal function, serum calcium,

phosphate and magnesium should be monitored inpatients treated with Bondronat’.

The Panel accepted that there might be differencesbetween the Bondronat and Zometa SPCs in relationto monitoring renal function as submitted by Roche.However the claim at issue implied that the risk ofrenal side effects was so small that clinicians neednot consider them and this was not so given the SPCrecommendations for renal monitoring and theinclusion of uraemia as an uncommon adverse eventfor oral Bondronat. The Panel considered the claim‘… renal safety profile comparable to placebo inclinical trials’ was a misleading comparison andthus ruled a breach of the Code.

Upon appeal by Roche, the Appeal Board noted thatthe SPCs for both IV and oral Bondronat stated‘Clinical studies have not shown any evidence ofdeterioration in renal function with long termBondronat therapy’ and went on to state‘Nevertheless, according to clinical assessment ofthe individual patient, it is recommended that renalfunction, serum calcium, phosphate and magnesiumshould be monitored in patients treated withBondronat’. The Appeal Board considered thatnotwithstanding this second statement, which in itsview was a class warning, the renal profile ofBondronat was different to that of otherbisphosphonates. The Appeal Board thusconsidered that the claim ‘… renal safety profilecomparable to placebo in trials’ was notunreasonable. It was sufficiently clear that the renalsafety profile data was derived from clinical trials.The Appeal Board ruled no breach of the Code.

Novartis noted the claim ‘So with equivalentefficacy and a small once-daily tablet, compared toIV, Oral Bondronat offers all the convenience andflexibility you could want from today’sbisphosphonate therapy’ and stated that the SPC forBondronat tablets required that the tablets be takenonce daily, after an overnight fast (at least 6 hours)and before the first food or drink of the day. Fastingshould be continued for at least 30 minutes aftertaking the tablet and patients should remain uprightfor 60 minutes. In addition, patients were advisednot to chew or suck the tablets.

Novartis noted that the SPC of another oralbisphosphonate, clodronate (Bonefos, BoehringerIngelheim) tablets, stated that the tablets could betaken as a single dose, at least 1 hour before or 1hour after food. Novartis alleged that the allencompassing claim of convenience and flexibilityfor oral Bondronat was not factually correct,misleading, exaggerated and not capable ofsubstantiation.

The Panel noted that the claim was a comparison oforal and IV Bondronat. In that regard the Panelconsidered that oral therapy would usually be moreconvenient than IV treatment. The claim, however,also referred to ‘today’s bisphosphonate therapy’and in that regard the Panel noted that there werethree oral bisphosphonates indicated for thetreatment of patients with breast cancer and bonemetastases; Bonefos, Loron and Bondronat. Bonefosand Loron were to be taken in a single dose or two


divided doses each day, at least one hour before andone hour after food. Bondronat tablets were to betaken after an overnight fast of at least six hours andat least 30 minutes before the first food or drink ofthe day. The Panel considered there was thus lessflexibility with regard to the time of day that apatient could take Bondronat compared with theother oral bisphosphonates. The Panel notedRoche’s submission about the small tablet size butnoted that there was no data to show whetherpatients found these more or less convenient thanother bisphosphonate tablets. The Panel thusconsidered that in the context of ‘today’sbisphosphonate therapy’ oral Bondronat was lessconvenient and flexible in terms of timing of dosagethan other oral bisphosphonates. The Panel thusruled breaches of the Code.

Upon appeal by Roche, the Appeal Board noted thatthe claim in question appeared thus in theadvertisement:

‘So with equivalent efficacy and a small once-daily tablet, compared to IV, Oral Bondronatoffers all the convenience and flexibility youcould want from today’s bisphosphonate therapy’

The use of a capital O for Oral Bondronat gave theimpression that Oral Bondronat was the start of theclaim and it was this second half of the sentencewhich Novartis had referred to in its complaint andresponse to Roche’s appeal.

The Appeal Board considered that the claim wasmore than a comparison between IV and oral; thereference to ‘today’s bisphosphonate therapy’ turnedit into a comparison of oral Bondronat with all otherbisphosphonates. The Appeal Board thusconsidered that by stating oral Bondronat offered all(emphasis added) the convenience and flexibility aprescriber could want the claim was misleading, notcapable of substantiation and exaggerated asalleged. The Appeal Board upheld the Panel’srulings of breaches of the Code.

Novartis alleged that the claim ‘The first 3rdgeneration bisphosphonate with equivalent oral andIV efficacy’ which appeared beneath the heading‘New in metastatic bone disease due to breastcancer’ in the abbreviated advertisement was inbreach of the Code.

The Panel considered that its rulings above ofbreaches of the Code regarding the comparison oforal and IV Bondronat applied here to theabbreviated advertisement and ruled accordingly.This was confirmed upon appeal.

The Panel considered that unlike the advertisementconsidered above, the abbreviated advertisementmade it clear from the outset that the indication wasmetastatic bone disease due to breast cancer as thisappeared as a heading and would be read before theclaim at issue. The Panel thus did not consider thatthe impression was given that oral Bondronat andBondronat IV had equivalent indications. Nobreach of the Code was ruled.

Novartis Pharmaceuticals UK Ltd complained aboutthe promotion of Bondronat (ibandronate) by RocheProducts Limited. The material at issue was an

advertisement published in Hospital Doctor, 4 March2004 (ref J116053), and an abbreviated advertisementpublished in MIMS March 2004 (ref J116083).

Bondronat was available as film coated tablets and asa concentrate solution for intravenous administration(IV). Both products were indicated for the preventionof skeletal events (pathological fractures, bonecomplications requiring radiotherapy or surgery) inpatients with breast cancer and bone metastases. Inaddition, Bondronat IV was also indicated for thetreatment of tumour-induced hypercalcaemia with orwithout metastases.

Novartis supplied Zometa (zoledronic acid) whichhad similar indications to Bondronat. Both productsbelonged to a class of medicines known asbisphosphonates.

A Hospital Doctor advertisement

1 Claim ‘The first 3rd generation bisphosphonatewith equivalent oral and IV efficacy’

The claim appeared as a heading to the A3advertisement and was referenced to Body et al (2003).

COMPLAINT

Novartis stated that the claim gave the impressionthat there was head-to-head data directly comparingthe efficacy of Bondronat IV and Bondronat tablets.There had been no head-to-head studies of Bondronatversus any agent other than placebo and the data forboth formulations of Bondronat came from threeplacebo-controlled trials. There was no head-to-headtrial data comparing the two formulations ofBondronat, so only indirect comparisons could bemade.

Novartis stated that since Bondronat tablets were notindicated for tumour-induced hypercalcaemia, itfailed to see how the efficacy could be similar toBondronat IV, and alleged that the claim wasmisleading and inconsistent with the particulars listedin the summary of product characteristics (SPC).

Novartis stated that although the phrase ‘For patientswith breast cancer and bone metastases’ appearedlater in the advertisement, this was in significantlysmaller font further down the page and hence was notobvious to the reader.

Novartis alleged that the claim was not in accordancewith the marketing authorizations for the twoformulations, it was not factually correct, wasmisleading and could not be substantiated. Breachesof Clauses 3.2, 7.2, 7.3 and 7.4 of the Code werealleged.

RESPONSE

Roche submitted that the claim ‘The first 3rdgeneration bisphosphonate with equivalent oral andIV efficacy’ was factually correct, clear and could besubstantiated.

Three pivotal double-blind, placebo-controlled, phaseIII studies (two using oral Bondronat and one using


IV Bondronat) were the basis for the SPCs. Thesetrials used identical inclusion and exclusion criteria.The SPCs for the IV and oral formulations withrespect to metastatic bone disease, the subject of theadvertisement, had identical indications. Section 5.1of the Bondronat IV SPC described a 40% reduction inthe primary endpoint of skeletal related events overthe placebo control group (p=0.003). The oral SPCdescribed a 38% reduction in the primary endpoint ofskeletal related events over the placebo control group(p=0.003). Bone pain was a common and distressingsymptom of metastatic bone disease. Bone pain wassignificantly improved compared to placebo as statedin the IV SPC (p<0.001) and the oral SPC (p=0.001). Asignificant improvement was also seen for bothformulations for quality of life (IV p=0.004, oralp=0.032). A reader of the IV and oral SPCs forBondronat could not differentiate the advantages ordisadvantages of either formulation based on efficacyalone. They were equally effective. That was not toimply that both formulations were equally suitable fora given patient. For example, a patient might beunable to swallow and IV was preferred. Suchdecisions were, of course, implicit in the managementof the patient and this was where Bondronat couldprovide such flexibility unhampered bycompromising efficacy between formulations.

Body et al described a multivariate Poisson regressionanalysis of new bone events in patients from the threepivotal trials. This analysis showed significant andcomparable risk reductions for both formulationscompared to placebo including significant pain scorereduction from baseline. The authors also found aconsistent and statistically significant effect of the50mg oral dose which was comparable to the effect of6mg intravenous dose of ibandronate.

Roche stated that in suggesting that the claim misledthe reader about hypercalcaemia of malignancy,Novartis chose to take the whole advertisement out ofcontext and failed to recognise the expertise of theprescriber who treated hypercalcaemia of malignancyand metastatic bone disease. This entireadvertisement related to metastatic bone disease. Thiswas obvious as it was clearly cited in the next line‘For patients with breast cancer and bone metastases…’. Nowhere in the advertisement (including theprescribing information) was any other indicationmentioned. Hypercalcaemia of malignancy oftenpresented as a medical emergency and urgent IVrehydration and IV bisphosphonate therapy waswarranted. The expert prescribers who usedbisphosphonates in hypercalcaemia of malignancywould know this and that oral medicines were notused to reduce serum calcium levels in the required24-48 hour period.

PANEL RULING

The Panel noted that immediately beneath the claim’The first 3rd generation bisphosphonate withequivalent oral and IV efficacy’ appeared anillustration of three skeletons crossing the finishingline in a running race.

The Panel considered that the claim at issue impliedthat a direct comparison of Bondronat IV with

Bondronat tablets had concluded that the twoformulations had equivalent efficacy. This was not so.The reference, Body et al, examined three studies, twocomparing oral Bondronat with placebo and onecomparing Bondronat IV with placebo. Body et al hadundertaken a multivariate Poisson regression analysisto determine whether IV and oral Bondronat weresimilar in the reduction of the risk for developingskeletal events and stated that the results suggestedthat both formulations were equally effective. Theillustration of one race being run added to theimpression that the comparative data was from onestudy. The Panel considered that the claim wasmisleading and not capable of substantiation.Breaches of Clauses 7.2, 7.3 and 7.4 of the Code wereruled.

The Panel considered that the advertisement impliedthat the two formulations had equivalent efficacy inall indications. The advertisement was published inHospital Doctor and would therefore be seen bydoctors who would treat hypercalcaemia ofmalignancy and patients with breast cancer and bonemetastases. In the Panel’s view some doctors mightthink that Bondronat was the first third generationbisphosphonate which could be given orally in thetreatment of hypercalcaemia of malignancy whichwas not so. Bondronat tablets were not licensed forthe treatment of tumour-induced hypercalcaemia.The Panel did not consider that the impression givenby the headline that oral Bondronat could be given tothe same patients as Bondronat IV was negated by theinclusion of the claim beneath the illustration ‘Forpatients with breast cancer and bone metastases’. Thesupplementary information to Clause 7 of the Codestated that it should be borne in mind that claims inpromotional material must be capable of standingalone as regards efficacy etc. In general claims shouldnot be qualified by the use of footnotes and the like.The headline claim needed to be read in conjunctionwith the qualifying text in order for its clinicalimplications to be understood. The Panel consideredthat the claim on its own was inconsistent with theparticulars listed in the SPC for Bondronat tablets anda breach of Clause 3.2 of the Code was ruled.

APPEAL BY ROCHE

Roche submitted that the claim ‘The first 3rdgeneration bisphosphonate with equivalent oral andIV efficacy’ was made in the context of the wholeadvertisement. There was no mention ofhypercalcaemia of malignancy. Hypercalcaemia ofmalignancy was a medical emergency treated byexperienced clinicians none of whom would consideranything other than IV therapy. There was nosuggestion that oral Bondronat could be used forhypercalcaemia of malignancy and the claim shouldnot be considered in breach of Clause 3.2.

Roche noted that the word ‘equivalent’ was defined inthe Concise Oxford Dictionary as, inter alia, ‘equal invalue’ and ‘having the same result’. It did not imply adirect head-to-head comparison.

Roche noted that the SPC for oral Bondronat cited a38% reduction in the risk of skeletal related eventscompared with placebo – this was clinically


equivalent to the figure of 40% cited in the SPC for IVBondronat. This claim was, therefore, not misleading,was substantiated by the SPCs, and was not in breachof Clauses 7.2, 7.3, and 7.4.

Roche submitted that the image of three skeletonsrunning with one winning related to the advantagesof a third generation bisphosphonate and a readerwould have to be very well versed in the details of thestudy programme to draw the false conclusion thatthe skeletons represented the three pivotal trials.

Roche submitted that with regard to the Panel’scomment about differences in the individualcomponents of the primary endpoints between IV andoral formulations, the studies were not powered todetermine statistically significant differences at thelevel of individual components. This was reflected inthe SPCs of Bondronat and other bisphosphonateswhich were licensed to reduce skeletal related events(made up of several components).

Roche submitted that the primary endpoint of thetrials was the overall reduction in skeletal morbiditynot the individual components. In addition, in eachtrial very strict precautions were taken not to countmultiple events occurring in the 12 week evaluationperiods as these could be related – so that multipleevents would only be recorded as one event. Withsuch strict criteria for analysing events, it was clearlynot relevant to expect significant differences in anyone particular event. However, both in the IV andoral studies, the reduction in the skeletal morbidityperiod rates was driven by a statistically significantdecrease in the need for radiotherapy. Statisticallysignificant differences or trends seen with fracturesand surgery were identified despite the low numbersof such events and the trends were all in the clinicallyappropriate direction. The overall efficacy profile ofIV and oral Bondronat was the same.

COMMENTS FROM NOVARTIS

Novartis agreed with the Panel’s ruling that the claim‘The first 3rd generation bisphosphonate withequivalent oral and IV efficacy’ implied a directcomparison of Bondronat IV with Bondronat tabletswhich was not the case.

Novartis alleged that Roche’s assertion that there wasno mention of hypercalcaemia of malignancy did notabrogate the fact that IV Bondronat was licensed forthis indication while oral Bondronat was not andtherefore the two formulations could not betherapeutically equivalent. In addition, Roche’sstatement that clinicians would not consider anythingother than IV therapy to treat hypercalcaemia ofmalignancy was spurious since its own oralbisphosphonate, Loron 520 was indicated for ‘Themanagement of osteolytic lesions, hypercalcaemia andbone pain associated with skeletal metastases inpatients with carcinoma of the breast or multiplemyeloma’ and a competitor oral bisphosphonate,Bonefos, was indicated for ‘The management ofosteolytic lesions, hypercalcaemia and bone painassociated with skeletal metastases in patients withcarcinoma of the breast or multiple myeloma’. Incertain malignancies at least, clinicians therefore hadthe option to use oral therapy for the management of

hypercalcaemia, but this was not true of oralBondronat which was not licensed in this indication.

Novartis noted that Roche stated that the dictionarydefinition of ‘equivalent’ meant ‘equal in value’ and‘having the same result’ and this was clearly not thecase for the two formulations of Bondronat since thelicensed indications were different.

Novartis considered that Roche’s explanation that thethree skeletons running represented a third generationbisphosphonate was obscure in the extreme.

APPEAL BOARD RULING

The Appeal Board considered that the claim ‘The first3rd generation bisphosphonate with equivalent oraland IV efficacy’ was a strong, unequivocal statement.The claim was referenced to Body et al which hadtaken the results from three different placebocontrolled studies using two different formulations.In none of the studies were IV and oral Bondronatdirectly compared. The study authors had concluded,inter alia, that their results suggested that both IV andoral Bondronat were equally effective. The AppealBoard noted that such caution was not reflected in theclaim at issue. The Appeal Board considered that theclaim gave the impression that a direct clinicalcomparison of IV and oral Bondronat had proven thatthe two were equally effective which was not so. TheAppeal Board upheld the Panel’s rulings of breachesof Clauses 7.2, 7.3 and 7.4 of the Code. The appeal onthis point was unsuccessful.

The Appeal Board noted that Bondronat tablets, unlikethe IV formulation, could not be used to treathypercalcaemia of malignancy. The claim at issuereferred to equivalent IV and oral efficacy. The AppealBoard noted, however, that the advertisement hadappeared in Hospital Doctor; it was thus aimed at aspecialist audience which in the Appeal Board’s viewwould not consider oral therapy for hypercalcaemia ofmalignancy. The Appeal Board also noted that themain text of the advertisement began ‘For patientswith breast cancer and bone metastases …’. Given theintended audience and the main text of theadvertisement, the Appeal Board did not consider thatthe claim ‘The first 3rd generation bisphosphonatewith equivalent oral and IV efficacy’ was inconsistentwith the particulars listed in the oral Bondronat SPC asalleged. No breach of Clause 3.2 was ruled. Theappeal on this point was successful.

2 Claim ‘… renal safety profile comparable toplacebo in trials’

COMPLAINT

Novartis stated that bisphosphonates were associatedwith nephrotoxicity. This major organ toxicity hadbeen recognised within the licence for bothformulations of Bondronat. The SPCs for bothBondronat IV and Bondronat tablets stated thefollowing in the special warnings section:

‘Clinical studies have not shown any evidence ofdeterioration in renal function with long termBondronat therapy. Nevertheless, according to


clinical assessment of the individual patient, it isrecommended that renal function, serum calcium,phosphate and magnesium should be monitored inpatients treated with Bondronat.’

The SPC for Bondronat tablets further stated that foradverse drug reactions occurring at a frequency of<1%, azotaemia (uraemia) occurred more frequentlywith Bondronat tablets than with placebo. The SPCfor Bondronat IV stated that creatinine increaseoccurred in 2% of Bondronat patients compared with0.6% of placebo patients.

Novartis stated that these percentages might appearsmall but the potential clinical sequelae of renalimpairment and renal failure could result insignificant morbidity and mortality.

As the claim was specific to the renal safety profile ofBondronat and not to all the adverse events with acomparable frequency to placebo in the trials, it gavethe distinct impression that unlike otherbisphosphonates renal toxicity was not a potentialconcern for Bondronat. Novartis alleged that theclaim was misleading in breach of Clause 7.3.

RESPONSE

Roche explained that serious concerns over renalsafety were emerging with Zometa and were probablythe basis for this component of Novartis’ complaint,where Bondronat had a competitive advantage.

Roche noted Novartis’ allegation that it wasmisleading to give the distinct impression that unlikeother bisphosphonates renal toxicity was not apotential concern for Bondronat. Toxicity of any kindwas a ‘potential concern’ for any medicine but thiswas not what was claimed. The true impression thatwas intended was that renal toxicity was not ofspecial clinical concern with Bondronat. This wasborne out by the following facts.

Roche agreed that the Bondronat SPC stated that‘Clinical studies have not shown any evidence ofdeterioration in renal function with long termBondronat therapy’. No other bisphosphonate couldmake that claim from its SPC. All patients withmetastatic bone disease should be monitored for renalfunction with a bisphosphonate, but this need only bedone ‘according to clinical assessment of theindividual patient’ with Bondronat. The Committeeon Proprietary Medicinal Products approvedBondronat after Zometa yet did not find it necessaryto stipulate the need to monitor renal function beforeevery dose of Bondronat (unlike Zometa). Uraemiawas an uncommon (<1%) finding in trials with oralBondronat. Only three patients on Bondronat IVcompared with one on placebo had an increasedserum creatinine (which was not a good indicator ofrenal function – creatinine clearance was preferred).Indeed, there were many reasons for changes tocreatinine levels which were not due to renaldeterioration. Variations in levels occurred frequentlyin healthy individuals after protein meals and/orexercise. The SPC merely reflected changes increatinine which were incidental findings, and whichwere not incompatible with the statement that norenal deterioration was seen.

Roche noted Novartis’ statement that thesepercentages might appear small but potential clinicalsequelae of renal impairment and renal failure couldresult in significant morbidity and mortality. This waswithout substantiation for Bondronat. For the IVpivotal study ‘There was no evidence of renal toxicityassociated with ibandronate treatment: the incidenceof renal adverse events was low and did not differbetween placebo and ibandronate groups’. For theoral pivotal studies, ‘The incidence of renal [adverseevents] was comparable between ibandronate (5.2%)and placebo (4.7%), and there were no reports ofserious [adverse events] (renal failure) in the activetreatment group’.

No other bisphosphonate had four-year follow onrenal safety data to establish no renal toxicityconcerns over long term therapy. According to theSPCs, both the oral and IV Bondronat formulationscould be used with a dose adjustment in severe renalfailure (creatinine clearance less than 30ml/min),unlike Zometa which was contraindicated. There wasno caution about Bondronat with nephrotoxic agents(unlike Zometa). Indeed, in over 500,000 patientexposures in Europe since 1996, and unlike any otherIV bisphosphonate, Bondronat IV had had nopublications raising concerns over renal toxicity.

PANEL RULING

The Panel noted that the SPCs for Bondronat IV andoral Bondronat both stated: ‘Clinical studies have notshown any evidence of deterioration in renal functionwith long term Bondronat therapy. Neverthelessaccording to clinical assessment of the individualpatient it is recommended that renal function, serumcalcium, phosphate and magnesium should bemonitored in patients treated with Bondronat’.

The Panel accepted that there might be differencesbetween the SPCs in relation to monitoring renalfunction as submitted by Roche. However the Panelconsidered that the claim at issue implied that the riskof renal side effects was so small that clinicians neednot consider them and this was not so given the SPCrecommendations for renal monitoring and theinclusion of uraemia as an uncommon adverse eventfor oral Bondronat.

The Panel considered the claim ‘… renal safety profilecomparable to placebo in clinical trials’ was amisleading comparison and thus ruled a breach ofClause 7.3 of the Code.

APPEAL BY ROCHE

Roche submitted that the claim ‘… renal safety profilecomparable to placebo in trials’ simply stated a fact,given the results of the placebo comparator incontrolled phase III trials, it was not a misleadingcomparison and was not a breach of Clause 7.3. Thiswas supported by the SPC statements that ‘Clinicalstudies have not shown any evidence of deteriorationin renal function with long term Bondronat therapy’.

Roche noted that uraemia had occurred in one 92 yearold woman with ischaemic heart disease, peripheralvascular disease, and hypothyroidism whilst takingoral Bondronat in one of the two pivotal trials. This


was a chance finding, given that the oral formulationwas unlikely to achieve the peak plasmaconcentration required to exceed the renal toxicitythreshold (≥ 1000ng/ml).


Novartis agreed with the Panel’s ruling that the claim‘… renal safety profile comparable to placebo in trials’was misleading given the SPC recommendations andinclusion of renal adverse effects in Section 4.8.

Novartis noted that the whole sentence containing theclaim read: ‘Both IV and new ORAL Bondronat areequally effective in reducing risk of skeletal eventsand reducing bone pain – with a renal safety profilecomparable to placebo in trials’.

Novartis noted that although this claim clearlyreferred to both formulations of Bondronat, Rochehad chosen only to comment on the oral formulationin its appeal.

Novartis also noted that the SPCs for oral and IVBondronat listed, inter alia, the frequency of thoserenal adverse events which had occurred morefrequently with Bondronat than with placebo. Therelevant adverse events listed in the oral BondronatSPC was azotaemia (uraemia) (< 1%) and for IV it wasincreased creatinine (0.6% placebo, n=157; 2%Bondronat n=152).

Thus both SPCs were unequivocal in stating thatrecognised measures of renal dysfunction occurredmore frequently in Bondronat-treated patients thanplacebo-treated patients and to claim that the renalsafety profile of either formulation was comparable toplacebo was not only misleading but potentiallythreatened patient safety.

APPEAL BOARD RULING

The Appeal Board noted that the SPCs for both IVand oral Bondronat stated ‘Clinical studies have notshown any evidence of deterioration in renal functionwith long term Bondronat therapy.’ and went on tostate ‘Nevertheless, according to clinical assessment ofthe individual patient, it is recommended that renalfunction, serum calcium, phosphate and magnesiumshould be monitored in patients treated withBondronat’. The Appeal Board considered thatnotwithstanding this second statement, which in itsview was a class warning, the renal profile ofBondronat was different to that of otherbisphosphonates. The Appeal Board thus consideredthat the claim ‘… renal safety profile comparable toplacebo in trials’ was not unreasonable. It wassufficiently clear that the renal safety profile data wasderived from clinical trials. The Appeal Board ruledno breach of Clause 7.3 of the Code. The appeal onthis point was successful.

3 Claim ‘So with equivalent efficacy and a smallonce-daily tablet, compared to IV, OralBondronat offers all the convenience andflexibility you could want from today’sbisphosphonate therapy’

COMPLAINT

Novartis stated that the SPC for Bondronat tabletsrequired that the tablets be taken once daily, after anovernight fast (at least 6 hours) and before the firstfood or drink of the day. Fasting should be continuedfor at least 30 minutes after taking the tablet andpatients should remain upright for 60 minutes aftertaking the tablet. In addition, patients were advisednot to chew or suck the tablets.

Novartis noted that the SPC of another oralbisphosphonate, clodronate (Bonefos, BoehringerIngelheim Ltd) tablets, stated that the tablets could betaken as a single dose, at least 1 hour before or 1 hourafter food.

Novartis alleged that this all-encompassing claim ofconvenience and flexibility for oral Bondronat was notfactually correct, misleading, exaggerated and notcapable of substantiation in breach of Clauses 7.2, 7.3,7.4 and 7.10 of the Code.

RESPONSE

Roche stated that expert prescribers knew of theproblems of previous oral bisphosphonates. Thisrelated to clodronate in the UK. It was commonknowledge that the size of the clodronate tabletcaused problems in swallowing and, together withgastrointestinal (GI) intolerance, the dose ofclodronate often had to be fractionated. This requiredmultiple fasting periods throughout the day to allowfor absorption. This was complicated for theelderly/confused and disrupted normal livingpatterns.

In an abstract presented at a recent internationalbisphosphonate workshop, and with similar datapresented in Novartis’ own satellite symposium, itwas shown that GI toxicity could cause early studydiscontinuation, with reports of 11-47% of patientsreporting upper GI adverse events. These data didnot include oral Bondronat. In a long term study of1,079 patients, GI disorders were significantly morecommon with clodronate (66%) than placebo (56.2%).One might speculate the high placebo level reflectedthe size of the tablet required to match the active.Diarrhoea was also significantly more common forclodronate (15.1%) than placebo (6.8%). Complicatedregimes and compliance were cited as problems.

Oral Bondronat was small (the size of a ‘Tic Tac’mint). On waking (an overnight fast of at least 6hours) one tablet was taken each day with a tumblerof water and the patient might only take water for thenext half hour. This was a simple regime. Non-compliance had not featured in the pivotal studies.The SPC cited levels of GI intolerance (dyspepsia,nausea, abdominal pain and oesophagitis) similar toplacebo and low and they were classified as mild.

In relation to the claim ‘Oral Bondronat offers all theconvenience and flexibility you could want fromtoday’s bisphosphonate therapy’, Roche could do nobetter than cite the comment made in the publishedpaper: ‘… oral ibandronate could offer treatmentflexibility for physicians and convenience for patients.Oral ibandronate might be prescribed alongside other


oral agents (particularly hormone treatment) for at-home dosing (eg when hospital care was not beingreceived). Patients would no longer have to spendtime travelling to and from the hospital solely forbisphosphonate infusion, allowing them to maintaintheir lifestyle without disruption. The dosing regimenof oral Bondronat was convenient for patients.Adequate adherence was important in real-lifesituations, where dosing instructions were not closelymonitored, unlike clinical trials’.

PANEL RULING

The Panel noted that the claim was a comparison oforal and IV Bondronat. In that regard the Panelconsidered that oral therapy would usually be moreconvenient than IV treatment. The claim, however,also referred to ‘today’s bisphosphonate therapy’ andin that regard the Panel noted that there were threeoral bisphosphonates indicated for the treatment ofpatients with breast cancer and bone metastases:Bonefos, Loron and Bondronat. Bonefos and Loronwere to be taken in a single dose or two divided doseseach day, at least one hour before and one hour afterfood. Bondronat tablets were to be taken after anovernight fast of at least six hours and at least 30minutes before the first food or drink of the day. ThePanel considered there was thus less flexibility withregard to the time of day that a patient could takeBondronat compared with the other oralbisphosphonates. If a patient forgot to takeBondronat first thing in the morning, before breakfast,it would be difficult to take it at any other time of daygiven the need to fast for at least six hours beforehandand 30 minutes after. Patients who forgot to takeeither Bonefos or Loron could take it later in the dayas long as there was a period of at least two hourswhere they did not eat; to take Bondronat later in theday required a period of at least 61/2 hours of no food.The Panel noted Roche’s submission about the smalltablet size but noted that there was no data to showwhether patients found these more or less convenientthan other bisphosphonate tablets. The Panel thusconsidered that in the context of ‘today’sbisphosphonate therapy’ oral Bondronat was lessconvenient and flexible in terms of timing of dosagethan other oral bisphosphonates. The Panel thusruled breaches of Clauses 7.2, 7.3, 7.4 and 7.10 of theCode.

APPEAL BY ROCHE

Roche submitted that to consider a small, once-a-daytablet less convenient than the larger clodronatetablets, which often required fractionated dosing dueto compliance and tolerability problems, did not relateto clinical experience or feedback from prescribers.Non-compliance had not been reported in the pivotaltrials. The issue of ‘flexibility’ related to the choice ofan IV or oral formulation with equivalent efficacy andsafety profiles.

Roche submitted that with respect to other oralbisphosphonates, most patients would not choose tohave a midday fast. Due to the nature of thecondition and the pharmacokinetics of oralBondronat, it was unlikely that a patient would suffer

harm from missing one tablet that day. The Panel’spoint about a patient forgetting to take tablets relatedto compliance and was not part of the claim.

Roche noted that there were two brands of oralclodronate available in the UK. Each had a differenttablet size and dosage recommendations. Loron wasa 520mg tablet whilst Bonefos was available as a800mg tablet and a 400mg gelatin capsule. UnlikeBondronat, the number of tablets required was morefor clodronate, the dose might need to be divided ordoubled, and clodronate was contraindicated insevere renal failure (depriving patients of thecontinued oral clodronate cover for their metastaticbone disease). There was only one dose forBondronat (which was modified for those with severerenal failure).

Roche did not consider there had been a breach ofClauses 7.2, 7.3, 7.4, and 7.10.


Novartis agreed with the Panel’s ruling that in thecontext of today’s bisphosphonate therapy, whichincluded three oral bisphosphonates indicated for thetreatment of patients with breast cancer and bonemetastases, oral Bondronat was less flexible in termsof timing of dosage than other oral bisphosphonates.

The claim made no reference to compliance andNovartis stated that the comments to this effect inRoche’s appeal were irrelevant. In addition, thestatement that ‘Due to the nature of the condition andthe pharmacokinetics of oral Bondronat, it wasunlikely that a patient would suffer harm frommissing one tablet that day’ was entirely spurious andoutside the terms of the marketing authorization forBondronat tablets.

Novartis noted that Roche had described the differentbrands of oral bisphosphonate on the market butfailed to take account of the fact that the marketingauthorizations for all of them, stated that the dailydose might be taken at one time after a one hour fast;oral Bondronat had to be taken after a six hour fast.

APPEAL BOARD RULING

The Appeal Board noted that the claim in questionappeared thus in the advertisement:

‘So with equivalent efficacy and a small once-dailytablet, compared to IV, Oral Bondronat offers allthe convenience and flexibility you could wantfrom today’s bisphosphonate therapy’

The use of a capital O for Oral Bondronat gave theimpression that Oral Bondronat was the start of theclaim and it was this second half of the sentencewhich Novartis had referred to in its complaint andresponse to Roche’s appeal.

The Appeal Board considered that the claim was morethan a comparison between IV and oral. Thereference to ‘today’s bisphosphonate therapy’ turnedthe claim into a comparison of oral Bondronat with allother bisphosphonates.

The Appeal Board thus considered that by stating oralBondronat offered all (emphasis added) the


convenience and flexibility a prescriber could wantthe claim was misleading, not capable ofsubstantiation and exaggerated as alleged. TheAppeal Board upheld the Panel’s rulings of breachesof Clauses 7.2, 7.3, 7.4 and 7.10 of the Code. Theappeal on this point was unsuccessful.

B MIMS abbreviated advertisement

Claim ‘The first 3rd generation bisphosphonatewith equivalent oral and IV efficacy’

This claim appeared beneath the heading ‘New inmetastatic bone disease due to breast cancer’.

COMPLAINT

Novartis alleged that the claim ‘The first 3rdgeneration bisphosphonate with equivalent oral andIV efficacy’ was in breach of Clauses 3.2, 7.2, 7.3 and7.4 of the Code as alleged in point A1 above.

RESPONSE

Roche noted that the claim was prefixed by theheading ‘New in metastatic bone disease due to breastcancer’. Novartis had taken the claim out of context.The abbreviated advertisement, as with theadvertisement at issue in point A1, clearly and solelyrelated to metastatic bone disease.

PANEL RULING

The Panel considered that its rulings of breaches ofClauses 7.2, 7.3 and 7.4 of the Code in point A1regarding the comparison of oral and IV Bondronat

applied here to the abbreviated advertisement andruled accordingly.

The Panel considered that unlike the advertisementconsidered at point A above, the abbreviatedadvertisement made it clear from the outset that theindication was metastatic bone disease due to breastcancer as this appeared as a heading and would beread before the claim ‘The first 3rd generationbisphosphonate with equivalent oral and IV efficacy’.The Panel thus did not consider that the impressionwas given that oral Bondronat and Bondronat IV hadequivalent indications. No breach of Clause 3.2 wasruled. This ruling was not appealed.

APPEAL BY ROCHE

Roche did not specifically appeal the Panel’s rulingsof breaches of the Code but its appeal at point A1above was taken to apply here.


Novartis made no further comment.

APPEAL BOARD RULING

The Appeal Board considered that its comments atpoint A1 above regarding the implied direct clinicalcomparison of oral and IV Bondronat applied here.The Panel’s rulings of breaches of Clauses 7.2, 7.3 and7.4 of the Code were upheld. The appeal on this pointwas unsuccessful.

Complaint received 2 April 2004

Case completed 2 August 2004


Pfizer complained about a leavepiece and a journaladvertisement for Crestor (rosuvastatin) issued byAstraZeneca. Pfizer supplied Lipitor (atorvastatin).

The front cover of the leavepiece resembled a passport andbore a coat of arms which included the brand name Crestor.Pfizer considered that this, and not the Cresor logo on theinside page, was the most prominent display of the brandname and therefore the non- proprietary name should beimmediately adjacent to it.

The Panel considered that the first mention of Crestor, on thefront cover of the leavepiece, was the most prominent andtherefore the non-proprietary name should have appearedimmediately adjacent to this mention of the brand. A breachof the Code was ruled.

The journal advertisement showed a man jumping into aswimming pool alongside which was the claim ‘“Eureka”Discover a whole new level of cholesterol control’. The claim‘GET IT RIGHT FIRST TIME’ appeared beneath the productlogo in the bottom right hand corner.

Pfizer alleged that the claim ‘Discover a whole new level ofcholesterol control’ could not be substantiated. The claimdid not specify what was being compared eg 10mg of Crestordid not have superior cholesterol control to 80mg ofatorvastatin. Even across the full dose range of Crestor therewas no evidence of superiority to combination treatmentssuch as simvastatin plus ezetimibe. Pfizer also alleged thatthe claim ‘Get it right first time’ was ambiguous andunqualified. Pfizer assumed that it referred to the use of10mg of Crestor but at this dose Crestor did not have ‘awhole new level’ of control when compared to the doseranges of other statins.

Pfizer alleged that ‘cholesterol control’ was ambiguous andunqualified, it did not know if it referred to total cholesterol,LDL, HDL or HDL/LDL ratio.

Prescribers would expect that ‘whole new level’ meant thatthe cholesterol control achieved with Crestor was associatedwith clinically significant improvements in cholesterolcontrol. While AstraZeneca artificially selected a mg for mgcomparison to demonstrate statistically significant differencesin selected lipid parameters, there were no endpoint data todemonstrate that any differences were of clinical significance.

The Panel noted that Crestor was indicated inter alia forprimary hypercholesterolaemia or mixed dyslipidaemia as anadjunct to diet when response to diet and other non-pharmacological treatments was inadequate.

With regard to Pfizer’s allegation that the claim ‘Discover awhole new level of cholesterol control’ was misleading as itwas not clear what was being compared, the Panel did notconsider that readers would be confused or expect Crestor10mg (the starting dose) to have superior cholesterol controlto 80mg atorvastatin or that Crestor had superior cholesterolcontrol to combination therapies. No other products werementioned in the advertisement.

The Panel did not accept that the claim ‘Get it right first time’was ambiguous and unqualified as alleged. The Panel noted

AstraZeneca’s submission with regard to thesuperiority of Crestor 10mg in reducing LDL over arange of start doses of other statins. The summary ofproduct characteristics (SPC) stated that the majorityof patients would be controlled at 10mg per day.

The Panel considered that although it might not beclear whether the claim ‘Get it right first time’referred to the starting dose of Crestor, this was notnecessarily a problem. AstraZeneca had datashowing advantages for Crestor at 10mg and at40mg. The achievement of targets at start dose wasan advantage. In this regard the Panel noted thatAstraZeneca had provided data with regard to thetreatment of raised cholesterol and the underachievement of cholesterol targets with statinsgenerally. AstraZeneca also had data showingadvantages for 40mg Crestor compared to 80mgatorvastatin.

The Panel did not consider that the failure to definewhich type of cholesterol was meant in the term‘cholesterol control’ was ambiguous and misleadingas alleged. The term would be understood by theaudience.

The Panel noted Crestor’s licensed indication asstated above. The consequences of loweringcholesterol, ie endpoint data such as a reduction incoronary heart disease, were not licensed indicationsfor Crestor. The Panel did not consider that thephrase ‘whole new level’ was a superlative norwould it be read in isolation as meaning that Crestorwould be associated with clinically significantimprovements in endpoint data as alleged. Thedifference would be the fact that more patients weretreated to target with the starting dose than wouldbe achieved by other statins.

The Panel did not accept that the claim ‘Discover awhole new level of cholesterol control’ wasmisleading, exaggerated or not capable ofsubstantiation as alleged and thus ruled no breachof the Code.

Upon appeal by Pfizer, the Appeal Board notedAstraZeneca’s submission that Crestor 10mg reducedLDL more than atorvastatin 10-20mg, simvastatin 20-40mg and pravastatin 10-40mg. Further that 82% ofpatients achieved a recognized European cholesteroltarget of <3mmol/L on Crestor 10mg compared with51%, 48% and 16% of patients treated withatorvastatin 10mg, simvastatin 20mg and pravastatin20mg respectively. The Crestor SPC stated that themajority of patients would be controlled at 10mg perday. The Lipitor SPC stated that ’The usual startingdose was 10mg. Doses should be individualisedaccording to baseline LDL-C levels, the goal oftherapy and patient response’.

In the Appeal Board’s view ‘cholesterol control’ wasa long-term outcome. Crestor received its UK


CASE AUTH/1574/4/04

PFIZER v ASTRAZENECAPromotion of Crestor

marketing authorization on 21 March 2003 and solong-term data on UK dosage patterns was not yetavailable. The Appeal Board noted AstraZeneca’ssubmission at the appeal that it presently expected80% of patients to achieve LDL control at 10mgdaily. The Appeal Board noted that AstraZenecahad also cited three studies showing advantages forCrestor 40mg compared with atorvastatin 80mg; theresults from two of these studies however were notavailable to AstraZeneca when the claim at issuewas first used and the Appeal Board thus decidedthat neither would be taken into account during itsconsideration on this point. The Appeal Boardconsidered that the achievement of LDL targets atstart dose was an advantage: more patients weretreated to target with the starting dose of Crestorthan would be achieved by other statins. TheAppeal Board noted, however, that the samemagnitude of reduction in LDL observed withCrestor could be achieved with one or other of theother statins, albeit by upward titration from thestarting dose if necessary.

The Appeal Board considered that the claim‘Discover a whole new level of cholesterol control’was a broad, unqualified claim. The lipid loweringability of Crestor was not such as to constitute thesignificant improvement implied by the claim. TheAppeal Board considered that the claim wasmisleading, exaggerated and not capable ofsubstantiation as alleged and thus ruled breaches ofthe Code.

Pfizer considered that ‘Eureka’ implied a novelty forCrestor which could not be justified. Crestor’snovelty with regard to efficacy and mode of actionwas one of potency alone; AstraZeneca had failed todemonstrate a clinical benefit of this claimedadditional potency. Pfizer alleged that the use ofEureka could not be substantiated.

The Panel noted that the term ‘Eureka’ referred to amajor discovery and meant ‘I have found it’. ThePanel did not consider that the discovery of Crestorwould be seen as a major discovery similar toArchimedes’ discovery of displacement. There wasdata showing advantages for Crestor over otherstatins but this was not of the degree of magnitudethat would be implied by the use of the term‘Eureka’. The Panel considered that this aspect wasmisleading, incapable of substantiation andexaggerated as alleged. Breaches of the Code wereruled which were upheld on appeal by AstraZeneca.

Pfizer Limited complained about the promotion ofCrestor (rosuvastatin) by AstraZeneca UK Limited.The items at issue were a passport style leavepiece(ref CRES020413576) and a journal advertisement (refCRES120313340).

Pfizer supplied Lipitor (atorvastatin).

A Passport style leavepiece (ref CRES020413576)

The front cover of the leavepiece resembled a passportand bore a coat of arms which included the brandname Crestor. The ten page leavepiece, foldedconcertina style, was the same size as a passport.

COMPLAINT

Pfizer stated that the brand name Crestor appearedprominently as part of the crest on the front page.Pfizer disagreed with AstraZeneca’s view that theCrestor logo on the inside page was the mostprominent display of the brand name. Pfizer believedthat the most prominent display of the brand namewas on the front page and therefore that the non-proprietary name should be immediately adjacent tothat. Pfizer alleged a breach of Clause 4.3 of the Code.

RESPONSE

AstraZeneca stated that as indicated by Pfizer, therehad been inter-company discussions about theprominence of the brand name Crestor. AstraZenecamaintained that the first mention of the brand namewas not necessarily the most prominent appearance ofit and that clearly was the case with this leavepiece.

The passport carried an intricate crest with the nameCRESTOR faded into the design. The most prominentfeatures of the front cover were ‘YOUR PASSPORT’and ‘TO STATIN PRESCRIBING’ which appearedabove and below the crest. This encouraged thereader to open the item to reveal the inside spread.

Once inside the reader saw the familiar Crestorimagery and a highly prominent Crestor logoassociated with the non-proprietary name andinverted black triangle which AstraZeneca believed tobe the most prominent display of the brand name.There was no breach of Clause 4.3 of the Code.

This item had been superseded and was no longer incirculation.

PANEL RULING

The Panel noted that the first mention of the brandname was on the front cover of the leavepiece; itformed part of the coat of arms. When unfolding thepiece the second mention appeared on page two andit also appeared in logo format on page three. ThePanel accepted the principle that the first mention of abrand name was not necessarily the most prominentdisplay of it. The format of the item was a relevantfactor. In this instance the Panel considered that thefirst mention of the brand name was the mostprominent and that the non-proprietary name shouldtherefore have appeared immediately adjacent to thismention of the brand name on the front cover. ThePanel thus ruled a breach of Clause 4.3 of the Code.

B Journal advertisement (ref CRES120313340)

The advertisement featured an illustration of a manjumping into a swimming pool alongside whichappeared the claim ‘“Eureka” Discover a whole newlevel of cholesterol control’. The claim ‘GET ITRIGHT FIRST TIME’ appeared beneath the productlogo in the bottom right hand corner of theadvertisement.

1 Claims ‘Discover a whole new level ofcholesterol control’ and ‘Get it right first time’


COMPLAINT

Pfizer stated that it had serious concerns about theclaim ‘Discover a whole new level of cholesterolcontrol’. Pfizer had tried to persuade AstraZeneca tomodify or qualify this claim but without success.Pfizer disagreed with the arguments AstraZeneca hadused to substantiate this claim which was widely usedin promotional material for Crestor. Pfizer allegedthat the claim was misleading.

The claim did not specify what was being compared.For example 10mg of Crestor did not have superiorcholesterol control to 80mg of atorvastatin. Evenacross the full dose range of Crestor, there was noevidence of superiority to combination treatmentssuch as simvastatin plus ezetimibe.

Pfizer alleged that the claim ‘Get it right first time’was ambiguous and unqualified. Pfizer assumed,however, that it referred to the use of the 10mg doseof Crestor. At this dose Crestor did not have ‘a wholenew level’ of control when compared to the doseranges of other statins.

The term ‘cholesterol control’ was ambiguous andunqualified. Pfizer did not know if it referred to totalLDL or HDL cholesterol or the HDL/LDL ratio.

Prescribers would expect with such a superlative as‘whole new level’ that the cholesterol control achievedwith Crestor would be associated with clinicallysignificant improvements in cholesterol control.While AstraZeneca artificially selected a mg for mgcomparison to demonstrate statistically significantdifferences in selected lipid parameters there were noendpoint data to demonstrate that any differenceswere of clinical significance.

The claim was not referenced to allow a prescriber toclarify the numerous ambiguities above.

Pfizer believed therefore that ‘whole new level ofcholesterol control’ in association with Crestor couldnot be substantiated. Breaches of Clauses 7.2, 7.3, 7.4and 7.10 of the Code were alleged.

RESPONSE

AstraZeneca stated that Pfizer’s assumption that ‘Get itright first time’ referred to the 10mg dose was partlyaccurate as this was the licensed start dose for Crestor.However, it was also intended to indicate that Crestorshould be the right choice of statin at initiation ratherthan using it in patients who had previously receivedan alternative statin. The advertisement did not containany specific reference to the 10mg dose of Crestor.

As such, AstraZeneca did not accept that the claimimplied that the advertisement related only to Crestor10mg and therefore that AstraZeneca was creating theimpression that Crestor 10mg was a new level ofcontrol over full dose ranges of statins.

AstraZeneca explained that there were two importantelements to any comparison of cholesterol control.These were efficacy at initiation, and efficacy atmaximal dose.

It was inappropriate to make the comparisonsuggested by Pfizer that the top dose of one statin

should be compared to the start dose of another. Itwas also inappropriate to compare combinations ofmultiple treatment modalities to monotherapy.

However, AstraZeneca still proposed that thecombination of Crestor with any other suitabletreatment would still offer the potential for greatercontrol.

AstraZeneca maintained that for either start dose ormaximal dose comparisons Crestor offeredsignificantly superior cholesterol lowering over otherstatins.

Efficacy at start dose was imperative whenconsidering the requirements for effective cholesterolmanagement. There were a number of studies thatdemonstrated this importance including theEuroaspire II and Performance for Life studies. Thesedemonstrated the challenge facing the management ofhigh-risk patients in need of effective cholesterolmanagement. The Performance for Life studyhighlighted that up to December 2002 onlyapproximately 50% of patients with establishedcoronary heart disease (CHD), treated with initialdoses of statins, achieved the National ServiceFramework (NSF) for CHD cholesterol target. Evenwith additional management there was still significantunder achievement of targets. This demonstrated theneed for a new level of cholesterol control.

Efficacy at start dose had considerable clinicalrelevance for patients and prescribers in the area ofcholesterol management, which was dominated byevolving evidence-based guidelines and targets.Management of patients who did not achieve targetwas also highlighted by the Performance for Lifestudy, which showed that 51% of patients did notreceive therapy review with respect to the totalcholesterol target of <5mmol/L and 66% did notreceive review with respect to the need for a 25%reduction in total cholesterol. The importance forprescribers to effectively manage patients to thesetargets was further highlighted by the GeneralMedical Services (GMS) contract, which rewardedpractices for achieving specified cholesterol targets.

There was a wealth of data that demonstrated thestatistically significant superiority in reducing LDL ofCrestor 10mg over a range of start doses of other statins.The comparator doses included atorvastatin 10-20mg,simvastatin 20-40mg and pravastatin 10-40mg.

Therefore, the superiority of Crestor 10mg overtraditional start doses of other statins offered thesignificant benefit of more patients achievingguideline targets in one visit. Clinical datademonstrated that 82% of patients achieved theEuropean Atherosclerosis and other Societies (1998)LDL target of <3mmol/L on Crestor 10mg. Thiscompared with 51%, 48% and 16% of patients treatedwith atorvastatin 10mg, simvastatin 20mg andpravastatin 20mg respectively.

AstraZeneca believed that such achievement ofguideline targets provided the clinical relevance tosupport the claim and represented a meaningful newlevel of control, at start dose.

When considering the maximal doses of statins,Crestor offered a new level of cholesterol control.


Pfizer alleged that this was misleading becauseAstraZeneca was not specific with the term‘cholesterol control’. However, statins were generallyconsidered as medicines to lower total and LDLcholesterol and Crestor 40mg demonstratedsuperiority over atorvastatin 80mg, the next mosteffective statin on these parameters.

This was demonstrated by a number of clinical trials.Data from trials CORALL and RADAR demonstratedthat Crestor 40mg reduced LDL-C by 54% and 55%respectively compared to a reduction of 48% seen inboth trials with atorvastatin 80mg.

AstraZeneca believed that this fulfilled a fundamentalclinical need in delivering more high-risk patients toguideline targets than other statins.

Furthermore, neither of these comparisons wereartificial mg for mg as they related to the importantcontrast of the lipid lowering effectiveness ofappropriate comparative dosages.

PANEL RULING

The Panel noted that Crestor was indicated inter aliafor primary hypercholesterolaemia or mixeddyslipidaemia as an adjunct to diet when response todiet and other non-pharmacological treatments wasinadequate.

With regard to Pfizer’s allegation that the claim‘Discover a whole new level of cholesterol control’was misleading as it was not clear what was beingcompared, the Panel did not consider that readerswould be confused. It did not consider that readerswould expect Crestor 10mg (the starting dose) to havesuperior cholesterol control to 80mg atorvastatin orthat Crestor had superior cholesterol control tocombination therapies. No other products werementioned in the advertisement.

The Panel did not accept that the claim ‘Get it rightfirst time’ was ambiguous and unqualified as alleged.The Panel noted AstraZeneca’s submission withregard to the superiority of Crestor 10mg in reducingLDL over a range of start doses of other statins. Thecomparator doses included atorvastatin 10-20mg,simvastatin 20-40mg and pravastatin 10-40mg.Further that 82% of patients achieved the EuropeanAtherosclerosis and other Societies (1998) LDL targetof <3mmol/L on Crestor 10mg. This compared with51%, 48% and 16% of patients treated withatorvastatin 10mg, simvastatin 20mg and pravastatin20mg respectively. The summary of productcharacteristics (SPC) stated that the majority ofpatients would be controlled at 10mg per day.

The Panel considered that although it might not beclear whether the claim ‘Get it right first time’ referredto the starting dose of Crestor, this was not necessarilya problem. AstraZeneca had data showingadvantages for Crestor at 10mg and at 40mg. Theachievement of targets at start dose was an advantage.In this regard the Panel noted that AstraZeneca hadprovided data with regard to the treatment of raisedcholesterol and the under achievement of cholesteroltargets with statins generally. AstraZeneca also haddata showing advantages for 40mg Crestor comparedto 80mg atorvastatin.

The Panel did not consider that the failure to definewhich type of cholesterol was meant in the term‘cholesterol control’ was ambiguous and misleadingas alleged. The term would be understood by theaudience.

The Panel noted Crestor’s licensed indication asstated above. The consequences of loweringcholesterol, ie endpoint data such as a reduction incoronary heart disease, were not licensed indicationsfor Crestor. The Panel did not consider that thephrase ‘whole new level’ was a superlative nor wouldit be read in isolation as meaning that Crestor wouldbe associated with clinically significant improvementsin endpoint data as alleged. The difference would bethe fact that more patients were treated to target withthe starting dose than would be achieved by otherstatins.

The Panel did not accept that the claim ‘Discover awhole new level of cholesterol control’ wasmisleading, exaggerated or not capable ofsubstantiation as alleged. The Panel thus ruled nobreach of Clause 7.2, 7.4 and 7.10.

APPEAL BY PFIZER

Pfizer reiterated its original argument that the claim‘Discover a whole new world of cholesterol control’was ambiguous, misleading, incapable ofsubstantiation and exaggerated and appealed thePanel’s findings of no breach of Clauses 7.2, 7.4 and7.10.

Pfizer noted that AstraZeneca had stated that theadvertisement contained no specific reference to the10mg start dose of Crestor. Pfizer alleged, therefore,that AstraZeneca was claiming that it was making thisclaim for Crestor at all doses. This was a wide claimand could not be justified at all doses.

Pfizer noted that at a start dose of 10mg only, asAstraZeneca conceded, better control could beachieved with 40mg of atorvastatin. At 20mg ofCrestor, there was no advantage over 80mg ofatorvastatin. Pfizer stated that since it had submittedits complaint, the 40mg dose of Crestor had becomeunavailable in primary care for initiation withoutspecialist supervision and referred to recent letterssent by AstraZeneca to health professionals at thebehest of the Medicines and Healthcare productsRegulatory Agency and Committee on Safety ofMedicines. Even in those situations where 40mg wasused, there was no evidence to suggest that thecholesterol lowering effects of Crestor were in anywaysuperior to a combination of a statin and ezetimibe.AstraZeneca’s assertion that it was inappropriate tocompare combinations of multiple treatmentmodalities to monotherapy required justification.Pfizer alleged that if AstraZeneca was stating thatcomparisons between monotherapy statins only werejustifiable, then its advertisement must be qualifiedaccordingly.

Pfizer stated that the Panel did not appear to havenoted that the start dose of atorvastatin was notlimited to 10mg and 20mg and therefore appeared toaccept that Crestor offered specific advantages at itsstarting dose. The mg for mg comparison with regard


to percentage of patients achieving EuropeanAtherosclerosis and other Societies (1998) LDL targetwas therefore invalid. Further, the Panel hadjuxtaposed the two sentences ‘AstraZeneca had datashowing advantages for Crestor at 10mg and 40mg’and ‘The achievement of targets at start dose was anadvantage’ which suggested that there might be somemisunderstanding about the start dose of Crestor,which was 10mg (as above). The efficacy of the 40mgdose of Crestor was irrelevant in this context.

Pfizer stated that the Performance for Life study wasused to demonstrate the apparent failure of statins totreat patients to target. The ability of Crestor tochange this was speculative. It was more a reflectionof clinicians’ unwillingness to use appropriate startdoses of statins and to titrate dosage on the basis ofsubsequent cholesterol measurement. It possibly alsoreflected the inability of experts and ofpharmaceutical manufacturers to convince prescribersof the need to treat to target. This latter concept wasrelatively new in the primary care management ofhyperlipidaemia.

COMMENTS FROM ASTRAZENECA

AstraZeneca submitted that Pfizer’s appeal indicatedthat it did not accept the Panel’s opinion that healthprofessionals would intuitively understand theadvertisement and make the appropriatecomparisons. AstraZeneca submitted that with this inmind it struggled to understand which comparisonsPfizer believed were ambiguous, misleading,incapable of substantiation or exaggerated. Thisseemed to be based on a counter-intuitive premisethat it was appropriate to compare the start dose ofone medicine with various doses of another or withmultiple medicines used in combination.

AstraZeneca maintained its previous position thatthere were only two important elements to anycomparison of cholesterol control ie efficacy atinitiation (being the licensed usual start dose) andefficacy at maximal dose.

AstraZeneca submitted that efficacy in combinationwas an additional element to cholesterol control and itreferred to the example of ezetimibe suggested byPfizer. According to the licence for ezetimibe itshould be used in patients who were notappropriately controlled with a statin alone or whofailed to tolerate statin therapy.

However AstraZeneca submitted that if it wasconsidering statin usage in combination therapy, itwould still propose that the combination of Crestorwith any other suitable treatment would still offer thepotential for greater control.

AstraZeneca noted that Pfizer had questioned therelevance of data from studies such as Performancefor Life that demonstrated the challenge facingphysicians managing patients at high risk ofcardiovascular disease. Pfizer had claimed that theunder treatment demonstrated in this study was dueto physicians not choosing to use appropriate startdoses and titrate. AstraZeneca submitted that it hadreflected the accepted view that it was entirelyappropriate for physicians to initiate the licensed

usual start doses of statins and up-titrate, instead ofsecond-guessing the dose that was required.AstraZeneca submitted that it therefore endorsed thePanel’s opinion that a comparison to doses higherthan 10mg and certainly 20mg of atorvastatin shouldnot be the focus of Pfizer’s counter argument. Theeffort involved in patient review and up titration wasmore likely to be the reason behind the relative underachievement of targets.

AstraZeneca submitted that there was a wealth ofdata that demonstrated the superiority of Crestor10mg in reducing LDL compared with usual startdoses of other statins. These doses includedatorvastatin 10-20mg and simvastatin 20-40mg.Fundamentally Crestor 10mg resulted in morepatients achieving guideline targets in one visit thanother statins as generally used and such achievementwas highly relevant in a therapy area dominated bytargets.

AstraZeneca submitted that when considering themaximal doses of statins it considered that the patientgroup needed to be considered carefully. Both theCrestor and Lipitor SPCs suggested that these werelikely to be patients with severehypercholesterolaemia at high cardiovascular risk. Itwas therefore appropriate for these doses to be usedin conjunction with a specialist in order for patients tobe optimally managed. Pfizer’s statement thatCrestor 40mg had become ‘unavailable’ in primarycare without such supervision raised additionalconcerns on how it would choose to brief itssalesforce.

AstraZeneca submitted that for this important butrelatively small group of patients Crestor did offer anew level of cholesterol control and the possibility forsome of them to achieve target without combinationtherapy. This was demonstrated by a number ofclinical trials including patients with heterozygousfamilial hypercholesterolaemia and diabetes.

AstraZeneca considered that this had fulfilled thefundamental clinical need of delivering more high-risk patients to guideline targets than other statinsand justified the claim ‘Discover a whole new level ofcholesterol control’.

FURTHER COMMENTS FROM PFIZER

Pfizer alleged that the claim ‘Discover a whole newlevel of cholesterol control’ was a broad claim andcould not be used in an unqualified manner. In itsoriginal response, AstraZeneca had separated theissues of cholesterol control into efficacy at initiationand efficacy at maximal dosage. No such distinctionwas made in the advertisement. Thus the claim mustbe taken across the board, and Pfizer alleged that itdid not stand up to scrutiny in either situation.

Pfizer stated that it was surprised by AstraZeneca’sstatement that there were only two important elementsto any comparison of cholesterol control ie efficacy atinitiation and efficacy at maximal dose. This wassimplistic and failed to take account of safety,tolerability, concordance and the benefit:risk ratio.

Pfizer stated that at initiation, atorvastatin could beused at higher doses and, across its starting dose


range, offered better ‘cholesterol control’ than thestarting dose of any other statin. Moreover, thereafterit offered better cholesterol control across the doserange useable in primary care.

Pfizer stated that it had found a lack of compatibilityin AstraZeneca’s argument that most patients were tobe started on 10mg of Crestor and then the GP, byimplication, did not need to review them, safe in theknowledge that they would have their cholesterolunder control and those patients with high cholesterolshould, in any case, be under the care of a specialist.

Pfizer noted that the GMS contract and themonitoring of achievement of targets in generaldemanded measurement of cholesterol, which mustbe performed and reviewed under the auspices of theprescribing physician. To recommend such a ‘treatand hope’ philosophy was unacceptable.

Pfizer stated that the Panel had failed to acknowledgethat alternative start dosing with atorvastatin offeredsuperior cholesterol control to Crestor 10mg.AstraZeneca had compounded this by introducing, inits appeal, the word ‘usual’, to qualify this claim, intoits discussions of start dose. AstraZeneca’s did notrefer to the ‘usual’ start dose in its response. Pfizeralleged that in any case, the ‘usual’ start dose wasirrelevant in this context. Even if it were consideredrelevant, the claim would have to be modifiedaccordingly. Pfizer did not however, consider that thelicensed start dose was the point at issue.

Pfizer alleged that AstraZeneca’s statement that morepatients achieved guideline targets after one visit withCrestor 10mg than with other statins as generallyused was hypothetical, apparently based on thecomparison of separate data sets: the Performance forLife study and data derived from randomisedcontrolled trials (RCTs) of Crestor. Cholesterollowering in RCTs could not be assumed in such anunqualified way to translate into the attainment oftreatment targets in real life, or indeed in animprovement in clinical outcomes, an area in whichAstraZeneca could present no useful data.

Pfizer did not understand AstraZeneca’s penultimateparagraph which appeared to attribute a specialquality to Crestor in the treatment of high riskpatients; to Pfizer’s knowledge no such claim forsuperior outcome could be made for Crestor with thisgroup of patients.

Pfizer stated that the method by which it briefed itssales force was not at issue.

APPEAL BOARD RULING

In relation to the claim ‘Discover a whole new level ofcholesterol control’ the Appeal Board notedAstraZeneca’s submission that Crestor 10mg reducedLDL more than atorvastatin 10-20mg, simvastatin 20-40mg and pravastatin 10-40mg. Further that 82% ofpatients achieved the European Atherosclerosis andother Societies (1998) LDL cholesterol target of<3.0mmol/L on Crestor 10mg compared with 51%,48% and 16% of patients treated with atorvastatin10mg, simvastatin 20mg and pravastatin 20mgrespectively. The Crestor SPC stated that the majorityof patients would be controlled at 10mg per day. The

Lipitor SPC stated that ‘The usual starting dose was10mg. Doses should be individualised according tobaseline LDL-C levels, the goal of therapy and patientresponse’.

In the Appeal Board’s view ‘cholesterol control’ was along-term outcome. Crestor received its UKmarketing authorization on 21 March 2003 and solong-term data on UK dosage patterns was not yetavailable. The Appeal Board noted AstraZeneca’ssubmission at the appeal that it presently expected80% of patients to achieve LDL control at 10mg daily.The Appeal Board noted that AstraZeneca also haddata showing advantages for Crestor 40mg comparedwith atorvastatin 80mg; Jones et al, the CORALLstudy (Franken et al, 2004) and the RADAR study(Jukema et al, 2004). Neither the CORALL study northe RADAR study were available to AstraZenecawhen the claim at issue was first used and the AppealBoard thus decided that neither would be taken intoaccount during its consideration on this point. TheAppeal Board considered that the achievement ofLDL cholesterol targets at start dose was anadvantage: more patients were treated to target withthe starting dose of Crestor than would be achievedby other statins. The Appeal Board noted, however,that the same magnitude of reduction in LDLobserved with Crestor could be achieved with one orother of the other statins, albeit by upward titrationfrom the starting dose if necessary.

The Appeal Board considered that the claim ‘Discovera whole new level of cholesterol control’ was a broad,unqualified claim. The lipid lowering ability ofCrestor was not such as to constitute the significantimprovement implied by the claim. The AppealBoard considered that the claim was misleading,exaggerated and not capable of substantiation asalleged. The Appeal Board thus ruled breaches ofClauses 7.2, 7.4 and 7.10. The appeal on this pointwas successful.

2 Claim ‘Eureka’

COMPLAINT

Pfizer alleged that the use of the term ‘Eureka’, anattributed quote from Archimedes in ancient Greek,referring to a major discovery (of displacement),implied a novelty for Crestor, which could not bejustified. Crestor’s novelty with regard to efficacy andits mode of action was one of potency alone. AsPfizer had stated in point B1 above, AstraZeneca hadfailed to demonstrate a clinical benefit of this claimedadditional potency.

Pfizer believed that the term ‘Eureka’ could not besubstantiated. Breaches of Clauses 7.2, 7.3, 7.4 and7.10 were alleged.

RESPONSE

AstraZeneca noted that Pfizer had alleged that thenovelty of Crestor was one of mg for mg potency aloneand that no clinical benefit for this had been shown.AstraZeneca submitted that it highlighted above theclinical relevance for the superior efficacy at start dose.


Patients achieved lower cholesterol levels and morepatients achieved recommended cholesterol targets inone visit than with the recommended start doses oreven the usual doses of other statins. Current practicestill reflected a prescriber’s preference to start at lowdose and titrate upwards rather than to initiate athigher doses.

Furthermore, even with initiation at higher doses ofother statins, Crestor 10mg continued to offer superiorLDL lowering than atorvastatin 20mg, pravastatin40mg and simvastatin 40mg. Data from the STELLARstudy demonstrated that Crestor 10mg reduced LDLby 46%, which was significantly superior to thereductions of 37%, 39% and 30% seen withatorvastatin 10mg, simvastatin 40mg and pravastatin40mg respectively. Data from the CORALL andRADAR studies demonstrated LDL reductions of 46%and 44% respectively for Crestor 10mg compared to41% and 38% respectively for atorvastatin 20mg.

Additional practical advantage was granted by thefact that this superior LDL lowering was achieved at acost reduction of £11.66 against atorvastatin 20mg andpravastatin 40mg, and £2.97 against the generic DrugTariff price of simvastatin 40mg, based on treatmentfor 28 days.

In summary, AstraZeneca believed that the: additionalLDL lowering efficacy at start dose; enhancedachievement of National and International Guidelinetargets; reduced prescriber burden in terms of theneed for patient review and up-titration and;favourable cost-effectiveness comparison allunderpinned the sense of discovery a prescribermight feel when prescribing Crestor. AstraZeneca’suse of the word ‘Eureka’ was designed to highlightthis.

As such AstraZeneca did not believe the use of theterm ‘Eureka’ was misleading, exaggerated orunsubstantiated.

PANEL RULING

The Panel noted that the term ‘Eureka’ referred to amajor discovery and meant ‘I have found it’. ThePanel did not consider that the discovery of Crestorwould be seen as a major discovery similar toArchimedes’ discovery of displacement. There wasdata showing advantages for Crestor over otherstatins but this was not of the degree of magnitudethat would be implied by the use of the term ‘Eureka’.The Panel considered that this aspect was misleading,incapable of substantiation and exaggerated asalleged. Breaches of Clauses 7.2, 7.4 and 7.10 wereruled. This ruling was appealed by AstraZeneca.

APPEAL BY ASTRAZENECA

AstraZeneca noted the Panel’s comment that theexclamation was attributed to Archimedes and relatedto his discovery of displacement and should only beused in conjunction with such a major discovery.

AstraZeneca submitted that Eureka literally meant ‘Ihave found it’, derived from the greek verb, heurisk_,which meant to find. There had been many uses ofthe term since its use by Archimedes and ‘Eureka’

was now part of modern language and as such, theorigin of the word was of interest but not relevant.The word did not have to relate to a major discoveryand indeed Archimedes himself did not believe thathis discovery of the principle of displacement was hisgreatest discovery.

AstraZeneca submitted that the modern usage wasexemplified by dictionary definitions such as ‘a cry ofjoy or satisfaction when one finds or discoverssomething’ (Oxford) or ‘an exclamation of triumph ondiscovering or solving something’ (Collins).

AstraZeneca submitted that this was furthersupported by the widespread use of Eureka in thepromotion of goods. An Internet search identified1,750,000 examples of the term being usedcommercially. These varied from a children’sinteractive museum, housing and real estate, discountshopping and a tent company through to a range ofvacuum cleaners.

AstraZeneca noted that the Panel had accepted thatthere was sufficient evidence to support the claim‘Discover a whole new level of cholesterol control’and there remained a significant need for this newlevel of control. Studies had highlighted that beforeCrestor only approximately half of patients treatedwith statins achieved recommended healthycholesterol levels. As guidelines continued to drivethe recommended healthy levels to lower targetsprescribers would increasingly need to discover newlevels of control.

AstraZeneca submitted that supporting this there wasa wealth of data that demonstrated the statisticallysignificant superiority in reducing LDL and deliveringpatients to healthy cholesterol levels of Crestor 10mgcompared to a range of start doses of other statins.The comparator doses included atorvastatin 10-20mg,simvastatin 20-40mg and pravastatin 10-40mg.Crestor offered at least a one dose titration advantageover all statins with a 2 or 3 dose titration advantageover simvastatin or pravastatin.

AstraZeneca submitted, based on the modern use ofEureka, the above definitions and the clinicalevidence, that Eureka was a wholly appropriate wayto describe the feeling a prescriber or patient mightexperience on discovering the effectiveness of Crestor.As such the use of this expression was not misleading,exaggerated and unsubstantiated.

COMMENTS FROM PFIZER

Pfizer maintained that ‘Eureka’ implied a discoveryworthy of note and therefore attempted todifferentiate Crestor from other statins. Pfizer did notconsider that the commercial use of Eureka in anyway reduced the power of its meaning – that was areal ‘discovery’ of something novel and different.Pfizer alleged that the use of the expression wasfactually incorrect for the reasons outlined below.

Pfizer alleged that the claim that only approximatelyhalf of patients reached target levels of cholesterol onexisting statins was misleading and it could provideevidence to show that 96% of patients treated withatorvastatin achieved the Joint BritishRecommendations and General Medical Service’s


Contract total cholesterol target of 5mmol/L or less(Athyros et al 2002). In addition, there was datademonstrating that between 87-95% of patientstreated with atorvastatin in clinical trials reached theNational Cholesterol Education Program AdultTreatment Panel’s (NCEP ATPIII) LDL cholesteroltarget of <2.6mmol/L (McKenney et al 2004, Jones et al2003), levels that were currently lower than thoserequired by the GMS contract.

Pfizer noted that AstraZeneca had implied that astargets were lowered physicians would find theefficacy of established statins increasingly inadequateand therefore need to discover new levels of control.In support of this argument AstraZeneca had claimedthat there was a wealth of data demonstrating theclinical superiority of Crestor 10mg in reducing LDL.Pfizer alleged that this was misleading in that thecomparison was not made to the possible range ofdoses of established statins that could be initiated,dependent on the initial cholesterol levels and thereduction that was required. Pfizer stated that therewas no significant superiority of Crestor 10mg overatorvastatin 20 to 40mg (Law et al 2003, Bays et al2004).

Pfizer alleged that furthermore there was no clearindication on the advertisement as to whether thisclaim was in reference to statins used as monotherapyor whether this remained true for statins used incombination. Pfizer stated that statins used incombination with other compounds such as ezetimibeprovided cholesterol control surpassing that ofCrestor 10mg (Ballantyne et al 2004, Guadiani et al2004, AstraZeneca ‘Dear Healthcare Professional’letter, 2004). Should AstraZeneca defend this point bystating that any comparison should be made withstatins as a monotherapy only, its claim should thenbe so qualified in the advertisement.

Pfizer stated that the claim of the dose titrationadvantage of Crestor assumed a milligram formilligram comparison, rather than using doses ofequivalent efficacy and did not reflect clinical practice;if appropriate doses were used, Crestor did not offer a

superior level of control to other established statins(Law et al, Bays et al, Ballantyne et al).

Pfizer noted that AstraZeneca had not referred torecent changes in its SPC that outlined significantrestrictions on the use of Crestor. These restrictionsincluded a re-emphasis of the approved start dose of10mg and also described patient populations in whomthe use of Crestor was specifically contraindicated.The prevention of the use of the 40mg dose of Crestorin primary care and its restriction to use withinsecondary care only further underminedAstraZeneca’s right to claim a significant discovery bythe use of ‘Eureka’. In the light of the recent letterssent to all health professionals and pharmacists in theUK as well as in other countries advising them ofthese limitations, Pfizer considered that the statement‘Eureka’ was not representative of the clinicallimitations placed upon the use of Crestor, especiallyin primary care.

In summary, Pfizer restated that the use of ‘Eureka’ inproclaiming the discovery of Crestor could not bejustified and that the Panel was correct in its findingof breaches of Clauses 7.2, 7.4 and 7.10.

APPEAL BOARD RULING

In the Appeal Board’s view ‘Eureka’ referred to amajor discovery. This was reinforced by theillustration of the man jumping for joy into aswimming pool. The Appeal Board did not considerthat the discovery of Crestor would be seen as a majordiscovery; whilst there was data showing advantagesfor Crestor over other statins this was not of thedegree of magnitude that would be implied by‘Eureka’. The Appeal Board considered that the use of‘Eureka’ was misleading, incapable of substantiationand exaggerated as alleged and so it upheld thePanel’s ruling of breaches of Clauses 7.2, 7.4 and 7.10.The appeal on this point was unsuccessful.




GlaxoSmithKline complained that claims for Symbicort(formoterol/budesonide) were not substantiated by the citedreference, the SUND (Symbicort Up aNd Down) study. Theitem at issue was a four page leavepiece issued byAstraZeneca which had been sent as a mailing to healthprofessionals. GlaxoSmithKline supplied Seretidesalmeterol/fluticasone).

GlaxoSmithKline noted that in its previous complaint aboutpromotional activity in relation to the SUND study, CaseAUTH/1527/10/03, the study was not specifically reviewed,and the Panel had noted that AstraZeneca had not defendedit. AstraZeneca had continued to make superiority claims forSymbicort adjustable dosing over Seretide fixed dosing,based upon its analysis of the SUND study.GlaxoSmithKline alleged that these claims were notsubstantiable based upon the design of the study and the factthat the primary endpoint (well controlled asthma weeks)showed no difference between the study arms.

The claims of specific concern, which appeared in theleavepiece at issue, were (1) Adjustable Symbicort ahead by40% in severe exacerbation control: study confirms adjustabledosing is better than Seretide fixed dosing, (2) Symbicortsuperior to Seretide in severe exacerbation control: patientsshown to be better controlled on adjustable dosing and (3)Patients on adjustable Symbicort benefited from 40% fewersevere exacerbations (p=0.018) compared with fixed-doseSeretide according to a recent study. GlaxoSmithKline notedthat the fixed dose treatment arms in the SUND study lasted7 months; the 7 month Symbicort adjustable dose armhowever included 1 month of fixed dosing and 6 months ofadjustable dosing.

GlaxoSmithKline noted that AstraZeneca had claimed a 40%reduction in severe exacerbations for Symbicort adjustabledosing compared with Seretide fixed dosing, by calculating thenumber of exacerbations in each arm over the total studyperiod. In this period however, a combination of both fixedand flexible dosing was used in the Symbicort adjustabledosing arm. To describe 1 month of fixed dosing plus 6 monthsof adjustable dosing as ‘the adjustable dosing arm’ wasmisleading. GlaxoSmithKline alleged that the claim of a 40%reduction in severe exacerbations for adjustable dosing wasthus inaccurate, unbalanced and not capable of substantiation.

GlaxoSmithKline noted that the primary endpoint of theSUND study was defined as the odds of achieving a well-controlled asthma week. This was a composite measure ofasthma control, which included asthma exacerbations. Thestudy showed that there was no statistical significance in theprimary endpoint between any of the arms of the study, yetsuperiority had been claimed for the primary endpoint ofcontrol (‘patients shown to be better controlled on adjustabledosing’) in the second half of claim 2 above. This did notreflect the primary outcome of the study. Additionally, thedata on exacerbations was one of many secondary measuresthat the study was not appropriately powered to examine andwas at risk from statistical multiplicity. Thus the 40% claimwas not capable of substantiation and did not reflect theavailable evidence.

GlaxoSmithKline noted that exacerbations weredefined as the use of oral steroids, visits toemergency room or hospitalisations. When theirasthma worsened patients in the flexible dosing armcould increase their study medication. This,however, was not an option available to those in thefixed dose arm, who were required to take oralsteroids. The study was thus inherently biased andthis would have resulted in an over-reporting ofexacerbations in the fixed dose group as compared tothe adjustable dosing group.

In summary, GlaxoSmithKline alleged that theclaims were misleading because the fundamentalstudy design was not robust and suffered frominherent bias; the primary endpoint failed to meetstatistical significance.

The Panel noted that two of the three claims at issuehad been incorrectly cited by GlaxoSmithKline. Thefirst headline claim read ‘Symbicort ahead by 40% insevere exacerbation control:’ followed immediatelyin smaller print by ‘study confirms adjustabledosing is better than Seretide fixed dosing’.GlaxoSmithKline had incorrectly inserted‘Adjustable’ at the beginning of the claim. Thesecond claim read ‘Symbicort superior to Seretide insevere exacerbation control: patients shown to bebetter controlled on adjustable Symbicort’.GlaxoSmithKline had incorrectly replaced the final‘Symbicort’ with ‘dosing’. The final claim, ‘Patientson adjustable Symbicort benefited from 40% fewersevere exacerbations (p=0.018) compared with fixeddose Seretide according to a recent study’ had beencorrectly cited.

The Panel noted that the SUND study was designedto determine whether adjustable dosing withSymbicort had greater efficacy compared to fixeddose regimens with Seretide or Symbicort. Therewere three treatment periods: run-in, double blindand a six month open extension during whichpatients received Seretide (one inhalation bid) or afixed dose of Symbicort (two inhalations) or anadjustable dose of Symbicort (one or twoinhalations bid, depending on the level of asthmacontrol). The primary endpoint was the odds ofhaving a well controlled asthma week during thepost-randomisation period; a well controlled asthmaweek was defined as a week with no night-timeawakenings due to asthma, no exacerbations and nochange in asthma treatment due to adverse eventsplus at least two of the following: asthma symptomscore of >1 on ≤ 2 days; ≤ 2 days of relievermedication use; morning PEF ≥ 80% of the predictednormal value every day. Exacerbations were definedas oral steroid treatment for ≥ 3 days, emergencyroom visits and/or hospitalisation.

The study showed that the odds of achieving a wellcontrolled asthma week over the whole treatment


CASE AUTH/1579/4/04

GLAXOSMITHKLINE v ASTRAZENECASymbicort leavepiece

period were similar for fixed dose Seretide andadjustable dosed Symbicort. One fifth across allgroups failed to achieve a well controlled asthmaweek throughout the study period. There were notreatment differences observed for total asthmacontrol weeks.

Patients receiving adjustable dose Symbicort had40% fewer exacerbations than those receiving fixeddose Seretide (35 vs 59, p=0.018). The authors statedthat this treatment difference related to a reductionof 20 severe exacerbations per 100 patients/year(numbers needed to treat – 4.9). The total rate ofexacerbations over 7 months for Symbicort andSeretide was 0.024/month and 0.41/monthrespectively, ie a rate reduction of 39.7% (p=0.018) infavour of adjustable dose Symbicort. The resultsalso showed that 57% of those taking adjustabledose Symbicort required no step-ups in treatment.Most patients who needed a temporary step-upregained control of their asthma in 7 days (67% ofthe step-up periods).

The study authors noted that with increasing studyduration Symbicort appeared to provide betterasthma control: the favourable difference inexacerbation rates became more marked over time.However the use of well controlled asthma weeksalone only presented half the picture of a successfultreatment outcome. The results highlighted theneed for studying multiple measures of asthmacontrol before drawing conclusions on theeffectiveness of different regimens. Promptlyincreasing the dose of inhaled corticosteroid andlong acting B2 agonists at the first sign of asthmaworsening provided an early intervention strategyfor the reduction of exacerbations.

The design of the SUND study allowed Symbicortpatients to increase their dose of steroid by usingmore of the same inhaler. Adjustable dosing withSeretide was only possible by using an additionalinhaler to increase the dose of inhaled corticosteroidbecause the salmeterol dose response curve waslimited. The Panel noted that AstraZeneca hadsubmitted a report which addressed the allegationthat the study design was biased as fixed dose armsonly had the option to use oral steroids if theirasthma worsened. The report explained that thiswas not the case; oral steroids were not used for selfmanagement but were only given by clinicians as arescue medication if patients needed to consult thembecause of severe asthma attack. Symbicort patients,who increased their maintenance treatment inresponse to an increased need for relief medicationhad less unscheduled clinic visits because ofexacerbations that then resulted in less oral steroiduse and emergency treatment.

The Panel noted that the leavepiece concentratedwholly on the severe exacerbation data from theSUND study. This was only one aspect of asthmacontrol. The only reference in the leavepiece to theprimary endpoint of the study was a statement at thebottom of a bar chart, which took up the whole ofpage 3, that ‘The primary endpoint (odds of a well-controlled asthma week) showed no significantdifference between the treatment arms’. The Panelconsidered that by focussing solely on exacerbation

data the leavepiece did not give a balanced and fairoverview of the comparison of adjustable doseSymbicort and fixed dose Seretide. In the Panel’sview some readers might be misled and assume thatin all aspects of asthma control Symbicort was betterthan Seretide which was not the case. Thisimpression was compounded by a caption to aphotograph on the back page which stated ‘Shemissed the sales last year – now, after gaining controlwith adjustable Symbicort, she can enjoy shoppingwithout symptoms’. The Panel thus concluded thatgiven the context in which they appeared the claims‘Symbicort ahead by 40% in severe exacerbationcontrol: study confirms adjustable dosing is betterthan Seretide fixed dosing’, ‘Symbicort superior toSeretide in severe exacerbation control: patientsshown to be better controlled on adjustableSymbicort’ and ‘Patients on adjustable Symbicortbenefited from 40% fewer severe exacerbations(p=0.018) compared with fixed dose Seretideaccording to a recent study’ were not a fair reflectionof the outcome of the SUND study. The claims weremisleading in this regard and thus could not besubstantiated. Breaches of the Code were ruled.

GlaxoSmithKline UK Ltd complained about thepromotion of Symbicort (formoterol/budesonide) byAstraZeneca UK Limited. It was concerned thatcertain claims were not substantiated by the citedreference, the SUND (Symbicort Up aNd Down)study. The item at issue was a four page leavepiece(ref SYMB 03 13214B) which had been sent as amailing to health professionals in February 2004.GlaxoSmithKline supplied Seretide(salmeterol/fluticasone). Dialogue between thecompanies had failed to resolve the issues.

COMPLAINT

GlaxoSmithKline noted that it had previouslycomplained about promotional activity in relation tothe SUND study, Case AUTH/1527/10/03, whereinthe study was not specifically reviewed, and the Panelhad noted that AstraZeneca had not defended it.Since Case AUTH/1527/10/03 AstraZeneca hadcontinued to make superiority claims for Symbicortadjustable dosing over Seretide fixing dosing, basedupon its analysis of the SUND study.GlaxoSmithKline alleged that these claims were notsubstantiable based upon the design of the study andthe fact that the primary outcome parameter (wellcontrolled asthma weeks) showed no differencebetween the study arms. In order to address thesesuperiority claims it was necessary to critically reviewthe design and analysis of the SUND study.GlaxoSmithKline provided a copy of a report from anindependent asthma expert who had criticallyreviewed the SUND study.

The claims of specific concern, which appeared in theleavepiece at issue, were:

1 ‘Adjustable Symbicort ahead by 40% in severeexacerbation control: study confirms adjustabledosing is better than Seretide fixed dosing.’

2 ‘Symbicort superior to Seretide in severeexacerbation control: patients shown to be bettercontrolled on adjustable dosing.’


3 ‘Patients on adjustable Symbicort benefited from40% fewer severe exacerbations (p=0.018)compared with fixed-dose Seretide according to arecent study.’

In relation to claims 1 and 3 GlaxoSmithKline hadasked AstraZeneca to clarify the time periods overwhich exacerbation numbers were measured foradjustable dosing with Symbicort and fixed dosingwith Seretide. AstraZeneca had explained that alltreatment arms in the SUND study lasted 7 months;the 7 month Symbicort adjustable dose arm included1 month of fixed dosing and 6 months of adjustabledosing. The other two treatment arms were fixeddose for all 7 months.

GlaxoSmithKline noted that AstraZeneca had claimeda 40% reduction in severe exacerbations for Symbicortadjustable dosing compared with Seretide fixeddosing, by calculating the number of exacerbations ineach arm over the total study period. In this periodhowever, a combination of both fixed and flexibledosing was used in the Symbicort adjustable dosingarm. Thus, describing 1 month of fixed dosingtogether with 6 months of adjustable dosing as ‘theadjustable dosing arm’ was misleading.GlaxoSmithKline alleged that the claim of a 40%reduction in severe exacerbations for adjustabledosing was thus inaccurate, unbalanced and notcapable of substantiation.

In relation to all three claims GlaxoSmithKline wasconcerned about flawed statistical analysis andinterpretation of the SUND study.

GlaxoSmithKline noted that the primary endpoint ofthe SUND study was defined as the odds of achievinga well-controlled asthma week. This was a compositemeasure of asthma control, which included asthmaexacerbations. The study showed that there was nostatistical significance in the primary endpointbetween any of the arms of the study. Despite thislack of significance, superiority had been claimed forthe primary endpoint of control (‘patients shown to bebetter controlled on adjustable dosing’) in the secondhalf of claim 2 above. This was not reflective of theprimary outcome of the study. Additionally, the dataon exacerbations was one of many secondarymeasures that the study was not appropriatelypowered to examine and was at risk from statisticalmultiplicity. Thus the 40% claim was not capable ofsubstantiation or reflective of the available evidence.

GlaxoSmithKline also alleged that the study designwas biased towards favouring adjustable dosingwhen measuring exacerbations. Exacerbations weredefined as the use of oral steroids, visits to emergencyroom or hospitalisations. When their asthmaworsened patients in the flexible dosing arm couldincrease their study medication. This, however, wasnot an option available to those in the fixed dose arm,and as such they were required to take oral steroids.The study was thus inherently biased against fixeddosing in the evaluation of this parameter. Thiswould have resulted in an over-reporting ofexacerbations in the fixed dose group as compared tothe adjustable dosing group.

GlaxoSmithKline considered that, in reviewing thepoints above, the SUND study design was not robust,

with inherent bias, and prevented superiority claimsbeing made for Symbicort adjustable dosing overSeretide fixed dosing. It was an open label study,which compared two treatment regimens ie fixed andadjustable dosing and not two medicines directly.Despite these flaws, superiority claims had beenmade. This was seen both in claims of being ‘bettercontrolled’, and on the secondary endpoint ofexacerbations, reporting a 40% lower rate of severeexacerbations among those taking adjustable doses ofSymbicort than in patients on fixed doses of Seretide.GlaxoSmithKline noted that no statistical analysis hadbeen provided for this claim.

In summary, GlaxoSmithKline alleged that the claimswere misleading in breach of Clauses 7.2, 7.3 and 7.4of the Code because the fundamental study designwas not robust and suffered from inherent bias andthe primary endpoint failed to meet statisticalsignificance.

RESPONSE

AstraZeneca stated that the SUND study was animportant study in the context of current UK clinicalpractice. The use of combination inhalers in the UKwas increasing and represented 25% of total asthmaprescribing. Doctors needed to be able to make achoice on which combination to prescribe. The BritishThoracic Society guidelines recommended the use ofinhaled steroids and long-acting beta agonists (LABA)at step 3 of asthma management. Combinationinhalers allowed both these agents to be given in asingle inhaler and might assist in patient compliance.In the last few years there had been an increase inprescriptions in the UK for these products. Therewere currently only two combination inhalersavailable in the UK, Symbicort and Seretide.

AstraZeneca submitted that there were cleardifferences in the pharmacology of the components ofSymbicort and Seretide (Palmqvist et al 1999 andPalmqvist et al 1997). Symbicort Turbohaler waslicensed in adults to be given between the dose rangesof one inhalation daily to four inhalations twice daily.This range of adjustability within a single inhaler wasdue to the unique properties of the LABA withinSymbicort, formoterol. Formoterol had a greaterrange of dose responsiveness than the LABAconstituent (salmeterol) in Seretide (Palmqvist et al1999). This range of dose-responsiveness meant ahigher dose of formoterol would produce a higherclinical response. For the patient this meant that ifthey increased their dose they would receive anincreased effect. Increasing doses of salmeterol didnot produce this same increase in clinical response.The other difference between formoterol andsalmeterol was their onset of action. Formoterol hadan onset of action as fast as salbutamol (within 3minutes), the most widely used reliever medication,while maintaining effect for 12 hours; salmeterol’sonset of action was within 15 minutes (again beingmaintained for 12 hours)(Palmqvist et al 1997). Theseproperties allowed adjustability of the dose within asingle inhaler of Symbicort, compared with Seretidewhere a new or additional inhaler was required tomake a dosage alteration during worsening ofasthma.


AstraZeneca noted that previous studies comparingadjustable Symbicort with fixed dose Symbicort hadshown that allowing patients to increase their dose ofinhaled steroid and long-acting beta agonists via acombination inhaler when symptoms increased (aspart of an asthma action plan) led to fewer asthmaexacerbations (FitzGerald et al 2003 and Ställberg et al2003). The next important clinical question was tocompare Seretide with the adjustable dosing regimenof Symbicort.

AstraZeneca submitted that for these reasons, SUNDwas an important study that helped doctors to make adecision on which combination inhaler to prescribe.The study was clinically relevant; in terms of itsdesign and results it reflected real-life clinical practice.

In clinical practice, patients on Seretide had threeoptions when their asthma symptoms increased.They could increase the intake of reliever medicationand progress on to oral steroids if an exacerbationdeveloped; switch to an increased strength Seretideinhaler; take an additional Flixotide inhaler alongwith the Seretide dose. The basis of these options wasto increase the dose of inhaled steroid because, asdiscussed above, there was no clinical benefit toincreasing the salmeterol component. AstraZenecanoted that adjustable dosing with Seretide within asingle inhaler was outside the product licence.

AstraZeneca submitted that prescribing data fromMediplus suggested that the first option was whathappened in clinical practice; from March 2003 toMarch 2004 only 4.3% and 9.4% of patients onSeretide Accuhalers and Evohalers respectivelyreceived a prescription for more than one strength ofinhaler. During this same time period only 12.8% ofpatients received prescriptions for both Seretide andFlixotide. The data did not indicate how many ofthese were concurrent prescriptions. Mediplus wasused industry wide and was accepted as the mostreliable source of UK prescribing data. It was adatabase of 3.5 million patient records taken form theelectronic records of 800 GPs and reportedlongitudinal treatment decisions for patients.AstraZeneca submitted that this information wasbacked up by anecdotal evidence from practisingdoctors in the UK.

AstraZeneca noted that for these reasons the firstoption was the one that was available to patients inthe Seretide arm in the SUND study as it wasdesigned to reflect actual clinical practice.

Patients on Symbicort had two options when theirasthma symptoms increased: to increase the intake ofreliever medication and progress on to oral steroids ifan exacerbation developed; to increase the dose givenby twice daily Symbicort in the same inhaler (due tothe dose-responsiveness of the formoterolcomponent). Both options for Symbicort were used inthe SUND study to allow a review of the mostappropriate treatment option.

Patients who had uncontrolled asthma should bebrought under control by a period of fixed dosing andthen, if appropriate, they could be given an asthmaaction plan to allow adjustable dosing with Symbicort.AstraZeneca noted that patients in the SUND studywere given their previous inhaled steroids during the

run-in period (2 weeks) and then randomised to oneof three treatment arms for 7 months’ therapy. For theadjustable treatment arm the first month was a fixeddose regimen to reflect actual clinical practice inbringing these patients under control.

In relation to the reference to the 40% reduction insevere exacerbations in claims 1 and 3 AstraZenecanoted that the complaint was focused on the timeperiod of the study. Patients who had uncontrolledasthma should be brought under control by a periodof fixed dosing and then, if they were treated withSymbicort, they could be given an asthma action planto allow adjustable dosing (stepping up and down).

AstraZeneca submitted that the claims were made inrelation to treatment arms that were whollyappropriate and reflective of clinical practice. Itwould be misrepresentative of the data if it was not tocompare the whole of the treatment period the studytook place over.

AstraZeneca did not accept that this was in breach ofClauses 7.2, 7.3 or 7.4.

AstraZeneca noted that the primary end-point of theSUND study was the odds of achieving a well-controlled asthma week. AstraZeneca submitted thatit had not claimed superiority for the primaryendpoint of control. The claim ‘patients shown to bebetter controlled on adjustable dosing’ was part of asentence that specifically referred to severeexacerbation control. It could not be read as anindividual phrase. A statement in the leavepiece that‘the primary endpoint (odds of a well-controlledasthma week) showed no significant differencebetween the treatment arms’ appeared beside thechart of the reductions in exacerbations. The chartcould not be viewed without seeing this statement.

AstraZeneca noted that the complaint questioned ifthe study was powered to examine difference inexacerbation rates. AstraZeneca submitted that thestudy was comparable in treatment arm size (around200 patients) to the FACET study. The FACET studywas a well-accepted study comparing exacerbationrates between differing doses of inhaled budesonideand inhaled budesonide plus formoterol in a similarpatient population to the SUND study (Pauwels et al1997). AstraZeneca submitted that as the treatmentgroup sizes were similar it could be concluded that theSUND study was suitably powered for exacerbations.

The event rate for exacerbations in the SUND studywas consistent with that shown in previous studiesfor adjustable dosing with Symbicort (Ställberg et al;Ind et al 2004). (These studies compared adjustabledosing and fixed dosing of Symbicort and includedover 2,500 patients.)

AstraZeneca submitted that the manuscript of theSUND study (Aalbers et al 2004) provided statisticalanalysis for the 40% claim. A formal analysis of thetotal number of exacerbations over the full post-randomisation period (7 months) was performed byPoisson regression, a recognized analytical method forthis type of data with the time in the study as anoffset variable.

AstraZeneca noted that exacerbations were asecondary end-point of the SUND study and also


were a variable for the primary end-point: well-controlled asthma weeks. A well-controlled asthmaweek was defined as a week with: no night-timeawakenings due to asthma; no exacerbations; nochange in asthma treatment due to adverse events;AND at least two of the following: asthma symptomscore of >1 on ≤ 2 days; ≤ 2 days of relievermedication use (maximum four occasions/week);morning PEF ≥ 80% of predicted normal value everyday.

AstraZeneca submitted that the study was designedto compare two distinct paradigms of asthmamanagement (adjustable versus fixed dosing). Assuch a global measure of asthma control wasappropriate as a primary end-point. Currently themeasure used in studies such as GOAL (Busse et al2004) was well-controlled asthma weeks and it wasappropriate to the same measure. However, this hadits limitations in quantifying events that had asignificant impact on patients’ lives. Exacerbationshad a larger clinical impact on patients and healthprofessionals than other variables that completed awell-controlled asthma week such as the use ofreliever medication on 5 occasions in a week.

● In the study, the definition of exacerbations waslimited to clinically meaningful events – the needfor oral steroid courses or emergency roomvisits/hospitalisation.

● For patients, these exacerbations would be asignificant event and might result in time off workand impact to the patient and any carer.

● For doctors or practices, these asthmaexacerbations would require medical interventionand place demands on healthcare resources.

● Given the above, a reduction of 40% fewerexacerbations was clinically significant.

AstraZeneca submitted that the claim did not misleadas to the clinical importance of this reduction. Theclaim was capable of substantiation as it clearlyrelated to asthma exacerbations only and it wasreflective of the available evidence. AstraZenecasubmitted that it had also clearly stated there was nodifference between treatment arms for the primaryendpoint so as not to mislead. AstraZeneca thereforedid not accept that this breached Clauses 7.2, 7.3 or7.4.

In relation to the allegation of study bias AstraZenecanoted as above that the study was designed tocompare dosing regimens most commonly used inclinical practice and was representative of actualclinical practice based on prescribing data andanecdotal evidence.

AstraZeneca submitted that Seretide was not licensedto be used in an adjustable dosage regimen and it wasnot aware of any evidence of this being recommendedin the near future. A fixed dosage regimen forSeretide was therefore appropriate. Previous studiescomparing adjustable dosing Symbicort with fixeddose Symbicort had shown similar results with regardto a reduction in asthma exacerbations in theadjustable dosing arm. AstraZeneca did not acceptthat the study design was biased, rather that it wasdesigned to answer an important clinical question.

AstraZeneca submitted that in reviewing the pointsmade above it had shown that the SUND studydesign was robust and was designed to be clinicallyrelevant and to compare treatment regimens. Thiscomparison of treatment regimens was reflected in thepapers. AstraZeneca accepted that the study wasdesigned to compare treatment regimens; Seretidewas only licensed to be given in a fixed-dose regimen.

For the study to have been double-blind throughoutwould have required a highly complex design with atleast four regular inhalers per treatment arm andwould have raised concerns in interpretation of results.

AstraZeneca submitted that the manuscript providedstatistical analysis for the 40% claim. A formalanalysis of the total number of exacerbations of thefull post-randomisation period (7 months) wasperformed by Poisson regression, a recognizedanalytical method for this type of data with the timein the study as an offset variable. In summaryAstraZeneca considered that all the promotionalactivities related to the SUND study were accurate,balanced, fair, objective and unambiguous based onan up-to-date evaluation of all the evidence andreflected that evidence clearly.

The activities did not mislead as to the results of thestudy and were capable of substantiation.

AstraZeneca did not consider that the promotionalactivities relation to the SUND study were in breachof Clauses 7.2, 7.3 or 7.4.

In relation to the expert report submitted byGlaxoSmithKline, AstraZeneca stated that this was anevaluation of the SUND study, not a definitive clinicaljudgement; it listed personal opinion which did notconstitute judgement on the claims made. The SUNDstudy was published in a peer-reviewed journal,Current Medical Research and Opinions, andunderwent the editorial scrutiny associated withacceptance by a peer-review journal. The authors ofthe paper clearly disclosed their relationship toAstraZeneca at the end of the article. As theevaluation made was a review of the manuscript andnot a review of any promotional claims made fromthe manuscript, AstraZeneca provided a separatedocument by the lead author of the SUND study inreply to a GlaxoSmithKline expert.

AstraZeneca welcomed the opinion that ‘the studydesign appeared reasonable in the main and the dosesof drugs used seem appropriate’. AstraZenecainterpreted this as an endorsement of the studydesign in answering the clinical question the studyaimed to address. AstraZeneca accepted there was nodifference in the treatment arms for primary end-point and had stated this clearly on all promotionalmaterial relating to this study. AstraZeneca contestedthat hospitalisations were the only robust measure ofthe definition of an exacerbation.

AstraZeneca submitted that other clinical studies thathad examined the occurrence of asthma exacerbations(FACET and EDICT) included the following asdefinitions of exacerbations: an increase in reliefmedication use; night time awakenings; deteriorationof PEF; administration of additional inhaled steroidsand administration of oral steroids.


The use of oral steroids in the community or throughemergency room visits was a clinically importantmeasure of patients’ asthma control. Althoughmanaged mainly in the community, poor control wasoften referred to hospitals. Reducing exacerbationswould reduce the cases referred to hospital, althoughnot necessarily for immediate care. Only a smallnumber of patients with serious asthma wouldrequire hospital admission for immediate care.

AstraZeneca accepted that patients in the adjustablearm would be likely to use less reliever medication ifthe increase in the dose of their primary medicationresulted in a decrease in asthma symptoms.AstraZeneca did not believe this was a source of biasbut a relevant variable to be measured to determinewhether adjusting the dose of Symbicort helped toreduce asthma symptoms and so had an impact onpatients.

AstraZeneca submitted that the objective of the studywas to compare the efficacy of Symbicort Turbohaler,given as a fixed dose therapy or with an adjustabledosing regimen, with that of Seretide Diskus given asstandard therapy in asthmatic adults and adolescents.

There were two Symbicort dosages available in theadjustable arm to reflect the needs of these patientsfor differing Symbicort dose. The analysis of boththese groups together was a priori and was not doneon a post-hoc basis.

AstraZeneca noted that the use of appropriatetreatment group sizes to show a difference inexacerbation rate had been discussed above.

AstraZeneca submitted that it was implied that therewere several differences in secondary outcomes thatfavoured fixed dose regimens, in fact there was onlyone. Evening PEF was the only variable that was infavour of either fixed dose regimen compared toadjustable dosing and it was in favour of both fixeddosage regimens. No other difference was in favour ofthe Seretide arm versus either of the Symbicort arms.Symbicort fixed dose and adjustable dosing was notcompared in the analysis. A possible explanation ofwhy evening PEF might be the only variable that wentagainst the trend of the other results was given in thediscussion section of the paper.

AstraZeneca submitted that the frequency of subjectsreporting adverse events and serious adverse eventswas similar in all treatment groups. There were onlytwo patients in the adjustable arm and one patient inthe Symbicort fixed dose arm that had serious adverseevents related to asthma, this accounted for less than1% of each treatment arm.

AstraZeneca submitted that the discussion section ofthe paper discussed the limitation of the lack ofblinding in the last 6-months of the study and theappropriateness of the choice of primary end-point.AstraZeneca had reviewed recent papers published inpeer-reviewed journals on PubMed (a medicalliterature database), both with and without industrysponsorship. This review demonstrated that while itmight be an ideal for the discussion to be critical, thiswas not always the case. AstraZeneca noted that theconflict of interest was declared clearly within themanuscript according to publishing standards.

In summary, AstraZeneca strongly believed that theSUND study answered an important clinical question;it was a well-designed study that reflected actualclinical practice; the promotional activity relating tothis study was balanced, capable of substantiation bythe data and was not misleading. AstraZeneca didnot consider that it was in breach of Clauses 7.2, 7.3and 7.4 in any of the areas discussed above.

PANEL RULING

The Panel noted that there were three claims at issue.The first two claims had been incorrectly cited byGlaxoSmithKline. The first headline claim read‘Symbicort ahead by 40% in severe exacerbationcontrol:’ followed immediately in smaller print by‘study confirms adjustable dosing is better thanSeretide fixed dosing’. GlaxoSmithKline hadincorrectly inserted the word ‘Adjustable’ at thebeginning of the claim. The second claim read‘Symbicort superior to Seretide in severe exacerbationcontrol: patients shown to be better controlled onadjustable Symbicort’. GlaxoSmithKline hadincorrectly replaced the final word ‘Symbicort’ with‘dosing’. The final claim had been correctly cited byGlaxoSmithKline and read ‘Patients on adjustableSymbicort benefited from 40% fewer severeexacerbations (p=0.018) compared with fixed doseSeretide according to a recent study’.

The Panel noted that the SUND study was designedto determine whether adjustable dosing withSymbicort had greater efficacy compared to fixed doseregimens with Seretide or Symbicort. The studycomprised three treatment periods: run-in, doubleblind and a six month open extension during whichpatients received Seretide (one inhalation bid) or afixed dose of Symbicort (two inhalations twice daily)or an adjustable dose of Symbicort (one or twoinhalations bid, depending on the level of asthmacontrol). The primary efficacy variable was the oddsof having a well controlled asthma week during thepost-randomisation period; a well controlled asthmaweek was defined as a week with no night-timeawakenings due to asthma, no exacerbations and nochange in asthma treatment due to adverse eventsplus at least two of the following: asthma symptomscore of >1 on ≤ 2 days; ≤ 2 days of relievermedication use; morning PEF ≥ 80% of the predictednormal value every day. Exacerbations were definedas oral steroid treatment for ≥ 3 days, emergencyroom visits and/or hospitalisation. If oral steroidswere used for more than 10 consecutive days theeleventh day was considered to be a secondexacerbation. The study showed that the odds ofachieving a well controlled asthma week over thewhole treatment period were similar for fixed doseSeretide and adjustable dosed Symbicort. One fifthacross all groups failed to achieve a single wellcontrolled asthma week throughout the study period.Similarly no treatment differences were observed fortotal asthma control weeks.

Patients receiving adjustable dose Symbicort hadfewer exacerbations than those receiving fixed doseSeretide (35 vs 59, p=0.018). The total rate ofexacerbations over 7 months was 0.024/month and0.041/month for Symbicort and Seretide respectively.


There was a statistically significant rate reduction of39.7% (p=0.018) in favour of adjustable doseSymbicort. The results also showed that 57% ofpatients in the adjustable dose Symbicort grouprequired no step-ups in treatment. Most patients whoneeded a temporary step-up regained control of theirasthma in 7 days (67% of the step-up periods).

The study authors noted that adjustable dosing withSeretide was only possible by using a separate andadditional inhaler to increase the dose of inhaledcorticosteroid because the salmeterol dose responsecurve was limited.

The study authors explained that the definition ofexacerbations was limited to clinically meaningfulevents. With increasing study duration Symbicortappeared to provide better asthma control: thedifference in exacerbation rates in favour of Symbicortbecame more marked over time. However the use ofwell controlled asthma weeks alone only presentedhalf the picture of a successful treatment outcome.The results highlighted the need for studying multiplemeasures of asthma control before drawingconclusions on the effectiveness of different regimens.Promptly increasing the dose of inhaled corticosteroidand long acting B2 agonists at the first sign of asthmaworsening provided an early intervention strategy forthe reduction of exacerbations.

The Panel noted that AstraZeneca had submitted areport from one of the study authors which noted thatSeretide could achieve a similar dose adjustment toSymbicort but using three separate inhalers for theinhaled corticosteroid component which was beyondthe scope of the study. In relation to the allegationthat the study design was biased as fixed dose armsonly had the option to use oral steroids if their asthmaworsened the report explained that this was not thecase; oral steroids were not used for self managementbut were only given by clinicians as a rescuemedication if patients needed to consult theirclinicians because of severe asthma attack. Symbicortpatients who increased their maintenance treatment inresponse to an increased need for relief medicationhad less unscheduled clinic visits because ofexacerbations that then resulted in less oral steroiduse and emergency treatment.

The Panel noted AstraZeneca’s explanation of therationale for the design of the SUND study andfurther noted both parties’ submission on the issue ofbias.

The Panel noted the hypothesis of the SUND studywas to determine whether adjustable dosing with acombination inhaler had greater efficacy comparedwith fixed dose regimens. The Panel noted that therewas a difference regarding patients with inadequatelycontrolled asthma. Under the study design patientson Symbicort could increase their dose of steroid (andconsequently formoterol) whereas patients on Seretidecould not increase their dose of steroid. The primaryefficacy variable was the odds of having a well-

controlled asthma week during the post-randomisation period. This, as noted above, was acomposite measure. Total asthma control weeks werealso analysed as was exacerbation data. Many of theasthma variables measured showed no statisticallysignificant difference between adjustable dosedSymbicort and fixed dose Seretide. There was nodifference between the two for well-controlled asthmaweeks or total asthma control weeks, change inmorning peak expiratory flow, night-time awakeningsor daytime asthma symptom score. There washowever a difference, in favour of adjustable doseSymbicort, with regard to the amount of relievermedication required (p< 0.05). There was also a 40%reduction in the number of severe exacerbationswhich occurred in those taking adjustable doseSymbicort compared to those taking fixed doseSeretide (p=0.018). The authors stated that thistreatment difference related to a reduction of 20 severeexacerbations per 100 patients/year (numbers neededto treat – 4.9).

The Panel noted that the leavepiece at issueconcentrated wholly on the data from the SUNDstudy with regard to severe exacerbations. This wasonly one aspect of asthma control. The only referencein the leavepiece to the primary endpoint of the studywas a statement at the bottom of a bar chart, whichtook up the whole of page 3, that ‘The primaryendpoint (odds of a well-controlled asthma week)showed no significant difference between thetreatment arms’. The Panel considered that byfocussing solely on exacerbation data the leavepiecedid not give a balanced and fair overview of thecomparison of adjustable dose Symbicort and fixeddose Seretide. In the Panel’s view some readers mightbe misled and assume that in all aspects of asthmacontrol Symbicort was better than Seretide which wasnot the case. This impression was compounded by acaption to a photograph on the back page whichstated ‘She missed the sales last year – now, aftergaining control with adjustable Symbicort, she canenjoy shopping without symptoms’. The Panel thusconcluded that given the context in which theyappeared the claims ‘Symbicort ahead by 40% insevere exacerbation control: study confirms adjustabledosing is better than Seretide fixed dosing’,‘Symbicort superior to Seretide in severe exacerbationcontrol: patients shown to be better controlled onadjustable Symbicort’ and ‘Patients on adjustableSymbicort benefited from 40% fewer severeexacerbations (p=0.018) compared with fixed doseSeretide according to a recent study’ were not a fairreflection of the outcome of the SUND study. Theclaims were misleading in this regard and thus couldnot be substantiated. Breaches of Clauses 7.2, 7.3 and7.4 of the Code were ruled.


Case completed 21 July 2004


The head of a primary care trust prescribing support unitcomplained about a claim that using rosiglitazone could alsohelp lower blood pressure which appeared in a journaladvertisement for Avandia (rosiglitazone) and Avandamet(rosiglitazone/metformin) issued by GlaxoSmithKline.

The complainant could find no reference to blood pressurelowering in the Avandia summary of product characteristics(SPC), although side effects likely to cause increased bloodpressure were described. The complainant questionedwhether this supposedly additional benefit fromrosiglitazone could be advertised in this manner.

The Panel noted that the advertisement was headed‘Confront the new challenges for Type 2 diabetes’ andreferred to rosiglitazone available as Avandia and, incombination with metformin, as Avandamet. Both productswere for the treatment of Type 2 diabetes. Avandia could beused as monotherapy particularly in overweight patientsinadequately controlled by diet and exercise and for whommetformin was inappropriate. It could also be used incombination treatment in patients with insufficient glycaemiccontrol despite maximal tolerated dose of oral monotherapywith either metformin or a sulphonylurea. Avandamet wasindicated particularly for the treatment of overweightpatients who were unable to achieve sufficient glycaemiccontrol at their maximally tolerated dose of metformin alone.

The introductory paragraph of the advertisement stated thatmanaging Type 2 diabetes was no longer just aboutglycaemic control and that this was why the General MedicalServices (GMS) contract focussed ‘on both lasting glycaemiccontrol and reductions in blood pressure’. The remainder ofthe paragraph discussed tight glycaemic control and itsassociation with fewer microvascular complications and tightblood pressure control and its association with fewer majorcardiovascular events.

The following paragraph explained that rosiglitazone couldhelp meet both blood glucose and blood pressure GMStargets by targeting insulin resistance, a root cause of Type 2diabetes. A subsequent paragraph began ‘By targetinginsulin resistance, rosiglitazone also helps to achieve bloodpressure targets …’ and discussed studies which hadconsistently shown that rosiglitazone helped to significantlylower blood pressure. The effect of rosiglitazone on bloodpressure was compared to that of sulphonylureas and it wasfurther noted that the ‘UKPDS [UK Prospective DiabetesStudy] found that sulphonylureas had no significant effect oncardiovascular outcomes after a mean treatment period of 10years’. The final paragraph referred to Avandia andAvandamet. The claims ‘You really want to hit targets yearafter year’ and ‘Using the right oral antidiabetic agent canalso help lower blood pressure’ appeared in highlightedcircles.

The Panel noted that there was evidence showing a beneficialeffect of Avandia on blood pressure in Type 2 diabetics.Whilst it was not necessarily unacceptable to refer to such a

benefit in promotional material such referencesshould comply with the Code and could only bemade within the context of treating patients for theproduct’s licensed indications. The Panelconsidered that the balance of the advertisementwas such that the reduction of blood pressure as abenefit of using Avandia or Avandamet had beengiven undue emphasis; it had not been placedsufficiently within the context of the licensedindications. The advertisement implied thatAvandia and Avandamet were indicated for bloodpressure reduction and that was not so; theadvertisement was misleading and inconsistent withthe marketing authorizations in this regard.Breaches of the Code were ruled.

The head of the prescribing support unit of a primarycare trust (PCT) complained about a journaladvertisement (AVM/FPA/04/11822/1) for Avandia(rosiglitazone) and Avandamet (rosiglitazone/metformin) issued by GlaxoSmithKline UK Limited.

COMPLAINT

The complainant was particularly concerned aboutthe claim that using rosiglitazone could also helplower blood pressure. The complainant could find noreference to this action in the summary of productcharacteristics (SPC), although side effects (weightgain, fluid retention and cardiac failure) likely tocause increased blood pressure were described.

The complainant questioned whether this supposedlyadditional benefit from rosiglitazone could beadvertised in this manner.

When writing to GlaxoSmithKline, the Authorityasked it to respond in relation to Clauses 3.2 and 7.2of the Code.

RESPONSE

GlaxoSmithKline noted that the complainantappeared to make two separate allegations: firstly,that, irrespective of any evidence, it was not permittedunder the Code to make claims concerning the effectsof Avandia on blood pressure, inasmuch as sucheffects were not mentioned in the SPC; and, secondly,that the claims made might not accurately represent atrue benefit or clinical effect of the product.

GlaxoSmithKline noted Clause 3.2 that the promotionof a medicine ‘must not be inconsistent’ with theparticulars listed in its SPC. GlaxoSmithKlinesubmitted that drawing the attention of prescribers tohighly relevant additional pharmacodynamicproperties of a product not specifically mentioned inits SPC did not contravene this provision. The final


CASE AUTH/1580/4/04

HEAD OF PRIMARY CARE TRUST PRESCRIBINGSUPPORT UNIT v GLAXOSMITHKLINEAvandia and Avandamet journal advertisement

paragraph of the advertisement in question clearlystated the groups of patients for whom Avandia wasindicated, and these were in accordance with the SPC.GlaxoSmithKline therefore did not consider that theadvertisement sought to promote Avandia outwiththe terms of its marketing authorization.

GlaxoSmithKline noted that by its nature, an SPCcould not act as a repository of all clinical informationpertinent to a medicine. Indeed, the ‘Guideline onSummary of Product Characteristics’ issued by theEuropean Commission stated that, for the‘Pharmacodynamic properties’ section of an SPC, ‘Ingeneral, no information is expected’. It wouldevidently be impracticable to apply for an SPCamendment on each occasion that a new piece ofevidence about a product became available. Tointerpret Clause 3.2 in the highly restrictive senseapparently advocated by the complainant would havea deleterious effect on education and scientificinformation relating to medicines; and would deprivehealth professionals of easy access to research findingsthat could potentially be of great benefit to themselvesand to their patients.

GlaxoSmithKline submitted that in this respect, theimportance of vigorously addressing raised bloodpressure in Type 2 diabetic patients was indisputable.The United Kingdom Prospective Diabetes Study(UKPDS), the only major prospective outcome studyin this condition conducted to date – demonstratedthat tight blood pressure control was the single mostimportant factor in reducing the incidence ofmacrovascular complications, including myocardialinfarction, stroke, and sudden death. There was a34% reduction in adverse cardiovascular outcomes inthe tight blood pressure control group compared withthe ‘standard’ control group. However, the study alsodemonstrated the difficulty of achieving optimumcontrol: nearly 45% of patients in the tight controlgroup failed to maintain their target blood pressure;and 60% of hypertensive patients needed two or moreantihypertensive agents, and 29% three or moreagents, to maintain adequate control. In this context,the ancillary antihypertensive effects of anantidiabetic agent such as Avandia were highlyrelevant, particularly given that the main alternatives,the sulphonylureas, had no consistent effect on bloodpressure.

GlaxoSmithKline noted that the Medicines andHealthcare products Regulatory Agency (MHRA) hadrecently completed a review of promotion of theglitazones. GlaxoSmithKline provided a copy of arecent letter from the MHRA which stated that ‘Theevidence shows that glitazones may have a secondaryeffect on other parameters such as…blood pressure, indiabetic patients…’ and went on to allow promotionof such secondary effects, provided that they were notgiven undue prominence relative to theantihyperglycaemic effects, and that it was made clearthat they resulted from the primary mode of action ofthe glitazones, ie improving insulin resistance. Bothof these provisos were met in the advertisement inquestion. In reaching these conclusions the MHRAimplicitly acknowledged that promotion of the effectsof glitazones on blood pressure was consistent withthe marketing authorization for these agents and,

explicitly, that the evidence base was sufficient tojustify such promotion.

GlaxoSmithKline submitted that to assess whether theadvertisement was in breach of Clause 7.2 of theCode, it was necessary to examine this evidence base.Notwithstanding the complainant citing severaluncommon side-effects of glitazones, there was alarge, consistent and growing body of evidence thatAvandia had clinically and statistically significanteffects in lowering blood pressure. These effects hadbeen noted in practically all trials with Avandiaconducted to date in which blood pressure had beenexamined. GlaxoSmithKline provided a tablesummarising blood pressure changes seen withAvandia in eleven clinical and observational trials:eight in diabetics (n > 7,500), and three in non-diabetics (only the trials in diabetics were referencedin the advertisement). GlaxoSmithKline alsopresented a bar chart setting out the blood pressuredrops seen in these studies. GlaxoSmithKlinesubmitted that despite variations in studymethodology, duration and design, the results wereclearly completely consistent. Without exception,there was a statistically significant reduction in bothsystolic (3.5 – 20mmHg) and diastolic (2.7-17mmHg)blood pressure with Avandia.

GlaxoSmithKline submitted that the reality andsignificance of the blood pressure effects of glitazoneshad been attested to by several independent expertsin clinical reviews of the cardiovascular effects ofglitazones. Bakris et al (2003) stated ‘Glucose controlwith traditional oral hypoglycemic agents, such assulphonylureas, has failed to show any reduction inblood pressure. Insulin sensitization with[glitazones], however, has demonstrated a reductionof elevated blood pressure…’. Likewise, Greenberg etal (2003), stated ‘[Glitazone] therapy has significanteffects on the traditional elements of the metabolicsyndrome, including dyslipidemia and hypertension’and ‘The [glitazones] also reduce elevated bloodpressure in patients with type 2 diabetes, androsiglitazone has been shown to lower the expressionand secretion of the angiotensin II precursor,angiotensinogen’. Viberti et al (2003) stated ‘Animportant component of the [metabolic syndrome],hypertension is linked with insulin resistance, hence ithas been proposed that agents that reduce insulinresistance such as the [glitazones] may have beneficialeffects on blood pressure in patients with type 2diabetes. Preliminary evidence indicates that this isthe case, and small but significant decreases in bloodpressure have been reported in patients treated withrosiglitazone’. GlaxoSmithKline noted that this reportwas written prior to publication of several of theeleven clinical and observational trials on Avandia inwhich blood pressure had been examined and whichwere referred to above, in which much larger dropswere observed. Finally, as noted above, the MHRAhad recognised that the evidence on the bloodpressure effects of glitazones was sufficient to justifypromotional claims.

In summary, GlaxoSmithKline maintained that theadvertisement in question was not inconsistent withthe Avandia SPC and that it was permissible to makepromotional claims relating to the secondary


pharmacodynamic effects of a medicine, providedthat the effects were relevant (which they mostcertainly were in this case) and were supported by thebalance of the evidence. In the case of the action ofAvandia on blood pressure, the existing evidence wasoverwhelmingly in favour of a clinically andstatistically significant beneficial effect. This wasendorsed by numerous independent experts. TheMHRA had also concluded that the evidence base wassufficient to justify promotional claims and(implicitly) that such claims might be made, subject tocertain conditions, within the terms of the existingmarketing authorization for Avandia.

As such, GlaxoSmithKline did not consider that theadvertisement was in breach of Clauses 3.2 or 7.2 ofthe Code.

PANEL RULING

The Panel noted that the advertisement was headed‘Confront the new challenges for Type 2 diabetes’ andreferred to rosiglitazone available as Avandia and, incombination with metformin, as Avandamet. ThePanel noted that Avandia was indicated as oralmonotherapy treatment of Type 2 diabeticsparticularly in overweight patients inadequatelycontrolled by diet and exercise and for whommetformin was inappropriate because ofcontraindications or intolerance. Avandia was alsoindicated in oral combination treatment in patientswith insufficient glycaemic control despite maximaltolerated dose of oral monotherapy with eithermetformin or a sulphonylurea: in combination withmetformin particularly in overweight patients; incombination with a sulphonylurea only in patientswho showed intolerance to metformin or for whommetformin was contraindicated. Avandamet wasindicated for the treatment of Type 2 diabetics,particularly overweight patients, who were unable toachieve sufficient glycaemic control at their maximallytolerated dose of metformin alone.

The Panel noted that the introductory paragraph ofthe advertisement stated that managing Type 2diabetes was no longer just about glycaemic controland that this was why the GMS contract focussed ‘onboth lasting glycaemic control and reductions in bloodpressure’. The remainder of the paragraph discussedtight glycaemic control and its association with fewermicrovascular complications and tight blood pressure

control and its association with fewer majorcardiovascular events.

The following paragraph explained that rosiglitazonecould help meet both blood glucose and bloodpressure GMS targets by targeting insulin resistance, aroot cause of Type 2 diabetes. Reference was made tohitting ‘targets year after year’ within the context ofrosiglitazone’s ‘proven lasting effectiveness’. Asubsequent paragraph began ‘By targeting insulinresistance, rosiglitazone also helps to achieve bloodpressure targets …’ and discussed studies which hadconsistently shown that rosiglitazone helped tosignificantly lower blood pressure. The effect ofrosiglitazone on blood pressure was compared to thatof sulphonylureas and it was further noted that the‘UKPDS found that sulphonylureas had no significanteffect on cardiovascular outcomes after a meantreatment period of 10 years’. The final paragraphreferred to Avandia and Avandamet. The claims ‘Youreally want to hit targets year after year’ and ‘Usingthe right oral antidiabetic agent can also help lowerblood pressure’ appeared in highlighted circles.

The Panel considered there was a difference betweenpromoting a product for a licensed indication andpromoting the benefits of treating a condition.

The Panel noted that there was evidence showing abeneficial effect of Avandia on blood pressure in Type2 diabetics. Whilst it was not necessarilyunacceptable to refer to such a benefit in promotionalmaterial such references should comply with the Codeand could only be made within the context of treatingpatients for the product’s licensed indications. ThePanel considered that the balance of theadvertisement was such that the reduction of bloodpressure as a benefit of using Avandia or Avandamethad been given undue emphasis. The advertisementdid not place reduction in blood pressure sufficientlywithin the context of the licensed indications for theproducts. The advertisement gave the impression thatAvandia and Avandamet were indicated for bloodpressure reduction and that was not so; theadvertisement was misleading and inconsistent withthe marketing authorizations in this regard. Breachesof Clauses 3.2 and 7.2 were ruled.


Case completed 23 June 2004


Novo Nordisk complained about the promotion of Lantus(insulin glargine) by Aventis Pharma. Lantus was indicatedfor the treatment of diabetes mellitus where treatment withinsulin was required. It should be administered once daily atany time but at the same time each day. The materials atissue, a four page booklet and a six page booklet, included asa heading on the front covers ‘For Type 1 and Type 2diabetes, treat to A1c target with 24-hour control’. ‘Treat toA1c with 24-hour control’ also appeared as a straplinebeneath the product logo in both booklets. Novo Nordiskconsidered that the claim for ‘24-hour control’ was notsupported by sufficient clinical data. Novo Nordisk supplieda range of insulins.

Novo Nordisk noted that the Medicines and Healthcareproducts Regulatory Agency had recently stated that ‘claimsfor 24-hour relief need to be supported by clinical effectivenessover a full 24-hour period’ (emphasis added by Novo Nordisk).In Novo Nordisk’s view the claim of ‘24-hour control’ was aclaim of clinical effectiveness and needed to be supported byclinical data. However, data cited in support of the claim wasderived from a pharmacodynamic study (Lepore et al 2000).Novo Nordisk did not consider that such data could beextrapolated to support a claim of ‘24-hour control’, which wasa clinical effectiveness claim. In intercompany correspondenceAventis had agreed that Lepore et al was an ‘artificialsituation’, and that ‘repeated dosing is required for adequateclinical management of diabetes’. Aventis referred to Fanelliet al (2002) which was a pharmacodynamic study and was notreferred to in either booklet.

Novo Nordisk was also concerned about over-claiming fromthe evidence. Aventis had stated that plasma insulin levelsfollowing injection of glargine plateaued at a concentrationof 18.9 +/- 0.3µU between 3 and 24 hours. Novo Nordisknoted that plasma insulin levels did not necessarily translateinto pharmacodynamic activity (ie glucose lowering effect).

Furthermore, Aventis had stated that ‘glucose infusion ratefollowing injection of glargine stabilised at 3 hrs and wasnearly constant to 24 hours’, and ‘plasma glucose followinginjection of glargine remained at the target value until 15hrs’. However Lepore et al showed that duration of action ofthe 0.3U/kg of subcutaneous injection of Lantus was 20.5 +/-3.7 hours. In Novo Nordisk’s view this was over-claiming theduration of action of insulin glargine.

Novo Nordisk alleged that the booklets were misleading andcould not be supported by the cited papers.

The Panel noted that Lepore et al compared thepharmacokinetics and pharmacodynamics of one dose ofLantus with other insulins in 20 patients. Lepore et alconcluded that glargine was a peakless insulin which lastednearly 24 hours.

Fanelli et al examined the effect of a daily dose of Lantus fora week on 20 patients and concluded that after 7 days ofadministration onset of action was earlier, the duration ofaction closer to 24 hours, the action profile flatter, the insulinaction greater and inter-individual variability lower ascompared to its first injection. The duration of action for day

1 of the study was 20.5 ± 3.7 hours and for day 7 was23.2 + 1.3 hours. There was a statisticallysignificantly different result for day 7 compared today 1 with regard to onset of action, end of actionand duration of action.

The Panel noted that the Lantus summary of productcharacteristics (SPC) stated that it should beadministered once a day. The Panel also noted theresults from Lepore et al and Fanelli et al. ThePanel considered that the reference to 24-hourcontrol in the claim at issue ‘Treat to A1c target with24-hour control’ was not unreasonable. Data hadbeen provided to support the claim which the Panelconsidered was not misleading as alleged. ThePanel thus ruled no breaches of the Code.

Novo Nordisk Limited complained about thepromotion of Lantus (insulin glargine) by AventisPharma Ltd. The materials at issue were a four pagebooklet (ref LAN2780403) and a six page booklet (refLAN3420703). The front covers of both were headed‘For Type 1 and Type 2 diabetes, treat to A1c targetwith 24-hour control’. ‘Treat to A1c with 24-hourcontrol’ also appeared as a strapline beneath theproduct logo in both booklets.

Lantus was indicated for the treatment of diabetesmellitus where treatment with insulin was required.It should be administered once daily at any time butat the same time each day.

Novo Nordisk supplied a range of insulins.

COMPLAINT

Novo Nordisk considered that the claim for ‘24-hourcontrol’ was not supported by sufficient clinical data.Breaches of Clauses 7.2 and 7.4 of the Code werealleged.

Novo Nordisk noted that a recent announcement fromthe Medicines and Healthcare products RegulatoryAgency (MHRA) stated that ‘claims for 24-hour reliefneed to be supported by clinical effectiveness over a full24-hour period’ (emphasis added by Novo Nordisk).In Novo Nordisk’s view the claim of ‘24-hour control’was a claim of clinical effectiveness and needed to besupported by data from phase 2 to 4 clinical trials.However, data cited in support of the claim wasderived from a pharmacodynamic study (Lepore et al2000). Novo Nordisk did not consider that such datacould be extrapolated to support a claim of ‘24-hourcontrol’, which was essentially a clinical effectivenessclaim.

In intercompany correspondence Aventis agreed thatLepore et al was an ‘artificial situation’, and that‘repeated dosing is required for adequate clinicalmanagement of diabetes’. Aventis referred to Fanelliet al (2002) which was a pharmacodynamic study andwas not referred to in either booklet.



NOVO NORDISK v AVENTIS PHARMALantus booklets

Novo Nordisk was also concerned about over-claiming from the evidence. Aventis had stated inintercompany correspondence that plasma insulinlevels following injection of glargine plateaued at aconcentration of 18.9 +/- 0.3µU between 3 and 24hours. Novo Nordisk noted that plasma insulin levelsdid not necessarily translate into pharmacodynamicactivity (ie glucose lowering effect).

Furthermore, Aventis had stated that ‘glucose infusionrate following injection of glargine stabilised at 3 hrsand was nearly constant to 24 hours’, and ‘plasmaglucose following injection of glargine remained at thetarget value until 15 hrs’. However a closer scrutinyof Lepore et al revealed that duration of action of the0.3U/kg of subcutaneous injection of Lantus was 20.5+/- 3.7 hours. In Novo Nordisk’s view this was over-claiming the duration of action of insulin glargine.

Novo Nordisk therefore concluded that the bookletswere misleading and could not be supported by thecited papers. Breaches of Clauses 7.2 and 7.4 of theCode were alleged.

RESPONSE

In relation to the claim ‘Treat to A1c target with 24-hour control’ Aventis noted the MHRA advice stated:‘For 24 hour relief, data must show clinical effect thatover the 24 hour period’ and ‘Evidence of blood levelsalone is unlikely to be sufficient to support a claim’.In this context Aventis further noted that the clinicaleffect of all insulins lay in their ability to lower bloodglucose. Therefore Aventis considered that to make aclaim of 24-hour control for Lantus, fulfilling thecriteria that the MHRA had advised, it was necessaryto show that it exerted a clinically relevant glucoselowering effect over a 24-hour period. Theestablished gold standard method of showing theduration of action of any insulin accurately was anisoglycaemic clamp study that measured both thepharmacokinetic and pharmacodynamic properties ofthe insulin in question. Novo Nordisk was wrong toconsider that data from such studies wasinappropriate. Moreover, the MHRA advice did notmake reference to ‘clinical effectiveness’, nor did itmandate that data from phase 2 to 4 clinical trials,was required in order to make a promotional claim, asstated by Novo Nordisk.

Lepore et al reported the pharmacokinetic andpharmacodynamic response in the 24-hours followinga single subcutaneous injection 0.3U/kg of Lantus intwenty subjects with Type 1 diabetes (in comparisonto isophane insulin, ultralente insulin and acontinuous subcutaneous infusion of insulin lispro).The study concluded that the duration of action ofinsulin glargine, defined as the length of time betweenthe onset of action (the time after injection that therate of intravenous insulin decreased by 50%compared to the pre-injection time period) and theend of action (the time at which plasma glucose ineach subject consistently increased above 150mg/dl)was 20.5 +/- 3.7hrs. Moreover the authors reflectedthat the duration of action was underestimated usingthe above definition of end of action, as in a Type 1subject who had an absolute insulin deficiency, aplasma glucose above 150mg/dl reflected that the

insulin was continuing to exert activity (the plasmaglucose would be considerably higher if no insulinactivity was present). The study also noted that in 6out of 20 subjects, the end of action wasunderestimated because when a study terminated atthe 24-hour point, plasma glucose concentrationsremained below 150mg/dl in those subjects. Plasmainsulin levels following the injection of insulinglargine increased to a plateau concentration of 18.9+/- 0.3 µU/ml between 3 and 24-hours (studytermination).

Fanelli et al reported the pharmacodynamic responsefollowing the subcutaneous administration of0.3U/kg Lantus in twenty subjects with Type 1diabetes. This differed from Lepore et al as subjectswere studied on two occasions, once following thefirst injection of Lantus and seven days later, havingreceived a once daily injection of Lantus on each ofthe intervening days. Lantus levels reached steadystate in an individual after 2 to 4 days. Therefore theisoglycaemic clamp study on the seventh day showeda duration of action of Lantus at steady state. Thisstudy reflected the real-life situation where a diabeticrequired repeated insulin doses each day to managetheir disease. The results showed that the duration ofaction of insulin glargine on day 7 (using the samedefinitions as in the Lepore study et al) was 23.9 +/-1hrs.

In addition, the glucose continued to be infused up to32 hours after study start, which was a reflection thatLantus continued to exert a metabolic effect up to thatpoint.

In conclusion, Lepore et al showed that following afirst single injection of Lantus of 0.3U/kg, theduration of action using pre-defined parameters was20.5hrs +/- 3.7hrs. However at the end of the study,clear indication of continued Lantus activity waspresent (plasma insulin levels and controlled plasmaglucose levels in 16 subjects) though this could not befurther quantified as the study terminated at thispoint. Fanelli et al developed the evidence further,showing that when Lantus had reached steady state,its duration of action using the same definitions was23.9 +/- 1.0hrs, with clear evidence of continuedmetabolic action well beyond the 24-hour point.Aventis submitted that these two studies clearlydemonstrated that Lantus showed clinical effect overthe 24-hour period and were sufficient to substantiatethe claim in question.

In its complaint Novo Nordisk alleged that Aventishad ‘over-claimed’ with reference to Lepore et al;however no mention was made of the data fromFanelli et al. Aventis noted that when asked tosubstantiate the claim, it clearly made reference toboth studies and that both were used assubstantiation. The suggestion of ‘over claiming’ onLepore et al, was therefore incorrect.

The isoglycaemic clamp studies presented above werethe gold standard technique for establishing thepharmacokinetics and pharmacodynamics of Lantus.Randomised controlled clinical studies also reportedpharmacodynamic end points. However, thedisadvantage of such studies was that more thaninsulin was usually required to control blood glucose


in clinical practice. For example, a ‘basal bolus’regimen included a basal insulin to provide abackground level of insulin and a short acting insulinor ‘bolus’ to provide extra insulin to lower the raisedblood glucose that occurred after each meal. Theresults thus reflected the pharmacodynamics of thecombined regime of insulin and precise assessment ofthe duration of action of each specific insulin wasdifficult to determine. However, despite this caveat,clinical studies confirmed the findings from theisoglycaemic clamp studies presented aboveregarding the duration of action of Lantus.

Hamann et al (2003) reported a clinical study in which378 patients with Type 1 diabetes were treated withonce daily Lantus together with insulin lispro given atmeal-times, over a 24-week period. Patients wererandomised into three groups, with each groupreceiving insulin glargine either at breakfast, dinner orbedtime. The glucodynamic profile of each patientwas examined at the end of each study using 8 self-monitored blood glucose measurements over a 24hour period. The authors reported that ‘the 24 hourblood glucose profiles were comparable, regardless ofthe time of insulin glargine administration andconfirmed the flat, reproducible glucodynamic profilefollowing once-daily administration of insulinglargine’.

In summary, isoglycaemic clamp studies were theappropriate method to show the duration of clinicaleffect of an insulin. The data presented from Leporeet al and Fanelli et al showed that Lantus exerted aclinical effect in lowering blood glucose that extendedto 24-hours and beyond. These findings wereconfirmed by clinical data from Hamann et al wheninsulin glargine was combined with insulin lispro in abasal bolus regimen for the practical treatment ofdiabetes. In addition Lantus had been approved foronce daily dosing by the European MedicinesEvaluation Agency following consideration of just

such data; this was reflected in the Lantus summaryof product characteristics (SPC). Therefore Aventiswas confident that the claim in question had beenclearly substantiated and was not in breach of Clauses7.2 and 7.4 of the Code.

PANEL RULING

The Panel noted that Lepore et al compared thepharmacokinetics and pharmacodynamics of one doseof Lantus with other insulins in 20 patients. Lepore etal concluded that glargine was a peakless insulinwhich lasted nearly 24 hours.

Fanelli et al examined the effect of a daily dose ofLantus for a week on 20 patients. Fanelli et al whichwas presented as an abstract concluded that after 7days of administration onset of action was earlier, theduration of action closer to 24 hours, the action profileflatter, the insulin action greater and inter-individualvariability lower as compared to its first injection.The duration of action for day 1 of the study was 20.5± 3.7 hours and for day 7 was 23.2 ± 1.3 hours. Therewas a statistically significantly different result for day7 compared to day 1 with regard to onset of action,end of action and duration of action.

The Panel noted that the Lantus SPC stated that itshould be administered once a day. The Panel alsonoted the results from Lepore et al and Fanelli et al.The Panel considered that the reference to 24-hourcontrol in the claim at issue ‘Treat to A1c target with24-hour control’ was not unreasonable. Data hadbeen provided to support the claim which the Panelconsidered was not misleading as alleged. The Panelthus ruled no breach of Clauses 7.2 and 7.4 of theCode.




A diabetes specialist nurse complained about a posteradvertising a meeting at which it was stated that arepresentative from Aventis Pharma would give a talk to a localgroup of Diabetes UK on Lantus insulin (insulin glargine).

The complainant understood that the Code prohibited theadvertising of prescription only medicines to the public andwas concerned that the representative was prepared toadvertise her company’s insulin to a group of patients. Thecomplainant firmly believed that insulin treatment forpatients should be on an individual basis and whilst Lantuswas a very useful insulin, it was not appropriate for all.

The Panel noted that the poster announced that a namedrepresentative from Aventis would be giving a talk on Lantusinsulin on Wednesday, 19 May, at 7pm. All were welcome.The Diabetes UK logo appeared in the top right hand cornerand further details about the charity appeared at the bottom.

The Panel was concerned that the representative was going totalk to members of the public at a local branch meeting ofDiabetes UK. The main role of a representative was topromote medicines. The Panel noted that the chair of thelocal Diabetes UK group had mistakenly assumed that therepresentative was going to talk about Lantus. Whilst it wasnot necessarily unacceptable for representatives to talk to thepublic the company should exercise extreme caution wheninstructing them on such activity.

The Panel noted Aventis’ submission that during a routinesales call in 2003 the representative met a person fromDiabetes UK who invited her to give a talk at its localmeeting on 19 May 2004. The content of the talk wasdiscussed. The representative believed she had made it clearthat she was not permitted to discuss any diabetes productmade by Aventis. There had been no further contact betweenthe parties in the intervening months. The representativehad been unaware of the title of the talk and the steps takenby Diabetes UK to advertise it.

The Panel noted that there had been no contact between therepresentative and Diabetes UK since 18 June 2003, when themeeting was arranged, until shortly after 5 May 2004 whenAventis was notified of the complaint, two weeks before themeeting was scheduled to take place. The Panel notedAventis’ conclusion that this matter arose as a direct result ofthe absence of communication between the representativeand Diabetes UK during this time. The Panel considered thatwhen meetings were arranged the company ought to ensure,at the outset, that the respective roles and responsibilities ofall parties involved were discussed and agreed and that thirdparties were aware of the relevant requirements of the Code.

The Panel noted the company’s submission that therepresentative was going to talk about the range of non-promotional materials produced by Aventis for patients. ThePanel ruled no breach of the Code. The Panel was concernedabout the overall arrangements for the meeting, the role ofthe representative and the impression given. The Panelnoted Aventis’ submission that it had nothing to do with theposter. On balance, however, given the particularcircumstances of this case the Panel did not consider that

either the representative or the company had failedto maintain a high standard of ethical conduct. Nobreach of the Code was ruled. Nor did the Panelconsider that the company had brought discreditupon or reduced confidence in the pharmaceuticalindustry. No breach of Clause 2 was ruled.

A diabetes specialist nurse complained about a posteradvertising a meeting at which it was stated that arepresentative from Aventis Pharma Ltd would give atalk to a local group of Diabetes UK on Lantus insulin(insulin glargine).

COMPLAINT

The complainant understood that Clause 20 of theCode prohibited the advertising of prescription onlymedicines to the public and was concerned that therepresentative was prepared to advertise hercompany’s insulin to a group of patients. Thecomplainant firmly believed that insulin treatment forpatients should be on an individual basis and whilstLantus was a very useful insulin, it was notappropriate for all.

When writing to Aventis the Authority asked it torespond in relation to Clauses 2, 9.1, 15.2 and 20.1 ofthe Code.

RESPONSE

Aventis stated that during a routine sales call with ahospital diabetes specialist nurse on 18 June 2003, theAventis representative was introduced to arepresentative of a local branch of Diabetes UK (acharity for people with diabetes). The representativewas asked if she would attend one of the group’sforthcoming meetings, to which she agreed. Sheplanned to talk at the meeting about the range of non-promotional patient materials that Aventis producedand supplied for diabetics and their carers (titles in therange included, ‘Understanding type 1 diabetes’,‘Understanding type 2 diabetes’ and ‘What is a hypo?’).Though the content of the talk was discussed and thedate of 19 May 2004 set, no firm title for the talk wasdecided. The representative believed that she hadmade it clear that she was not permitted to discuss anyproducts made by Aventis for the treatment of diabetes.

The representative had not been in contact with thelocal Diabetes UK group during the interveningmonths and the first knowledge that she had of thetitle of the talk and the arrangements that DiabetesUK had made to advertise it, was when Aventisreceived notice of this complaint. It went withoutsaying that as an experienced representative shewould neither have undertaken, not agreed toundertake, any activity that could be interpreted aspromoting Lantus, or any other productsmanufactured by Aventis, to patients.



DIABETES SPECIALIST NURSE v AVENTIS PHARMAAlleged promotion of Lantus to diabetes group

Upon receipt of the complaint, Aventis contacted thechair of the local Diabetes UK group. Shecorroborated the above account of events and hadwritten to the Authority to clarify matters.

Aventis explained that the meeting was to be held atthe initiative of the local Diabetes UK group and thatthe representative had not prepared a presentation.Aventis was not aware of the exact list of invitees butassumed that it would have been the members ofDiabetes UK affiliated to the local branch. Aventiswas not aware where the poster was displayed.

In summary, Diabetes UK had set the title of the talkand produced and posted the posters without theknowledge of Aventis. The representative had nointention of presenting information about specificproducts that Aventis manufactured for the treatmentof diabetes and was well aware of the constraints ofthe Code in this regard. Aventis concluded that thisunfortunate episode came about as a direct result ofthe absence of communication between therepresentative and Diabetes UK over the interveningten months. This was most certainly not a meetingthat was planned by Aventis to promote Lantus directto members of the general public. As a result Aventisdid not consider this episode represented a breach ofthe Code on the part of Aventis.

* * * * *

The chair of the local Diabetes UK voluntary groupwrote to the Authority and explained that the talk,which had been verbally and informally arranged inJune 2003, was erroneously entitled ‘A talk on thesubject of Lantus Insulin’. This title had beenmistakenly assumed to be correct without properconsultation or agreement with the representativewho was completely unaware of it until publication –a communication failure.

The group was very concerned that this unfortunateincident had occurred and for any distress caused.There was never any intention to contravene theCode. The group could only apologise for what was agenuine and innocent mistake, and one that that itwould endeavour to avoid in future. The subject ofthe talk had been cancelled and all posters wereimmediately requested to be removed.

PANEL RULING

The Panel noted that Clause 20.1 prohibited theadvertising of prescription only medicines to thegeneral public. Clause 20.2 of the Code permittedinformation to be supplied directly or indirectly to thegeneral public but such information had to be factualand presented in a balanced way. It must not raiseunfounded hopes of successful treatment or bemisleading with respect to the safety of the product.

The Panel noted that the poster at issue announcedthat a named representative from Aventis would begiving a talk on Lantus insulin on Wednesday, 19 May,at 7pm. All were welcome. The Diabetes UK logoappeared in the top right hand corner and furtherdetails about the charity appeared at the bottom.

The Panel was concerned that the representative was

going to give a talk to members of the public at a localbranch meeting of Diabetes UK. The main role of arepresentative was to promote medicines. The Panelnoted that the chair of the local Diabetes UK grouphad mistakenly assumed that the representative wasgoing to give a talk about Lantus. Whilst it was notnecessarily unacceptable for representatives to talk tothe public, the company should exercise extremecaution when instructing representatives on suchactivity and take great care to ensure that all of thearrangements complied with the Code, especially theprovisions of Clause 20.

The Panel noted Aventis’ submission that during aroutine sales call last year the representative wasintroduced to a person from Diabetes UK who invitedher to give a talk at its local meeting on 19 May. Thecontent of the talk was discussed. The representativebelieved she had made it clear that she was notpermitted to discuss any diabetes product made byAventis. There had been no further contact betweenthe parties in the intervening months. Therepresentative had been unaware of the title of the talkand the steps taken by Diabetes UK to advertise it.

The Panel was concerned about the overallarrangements for the meeting. The Panel noted thatthere had been no contact between the representativeand Diabetes UK since 18 June 2003, when themeeting was arranged until shortly after 5 May 2004when Aventis was notified of the complaint, twoweeks before the meeting was scheduled to take placeon 19 May. The Panel noted Aventis’ conclusion thatthis matter arose as a direct result of the absence ofcommunication between the representative andDiabetes UK during this time. The Panel consideredthat when meetings were arranged the companyought to ensure, at the outset, that the respective rolesand responsibilities of all parties involved werediscussed and agreed and that third parties wereaware of the relevant requirements of the Code so thattheir actions would not render companies in breach ofthe Code. When patients were involved the Panelconsidered that it was especially important that thesearrangements were recorded between the parties.

The Panel noted the company’s submission about thecontent of the presentation; the representative wasgoing to talk about the range of non-promotionalmaterials produced by Aventis for patients. The Panelruled no breach of Clause 20.1 of the Code. The Panelwas concerned about the overall arrangements for themeeting, the role of the representative and theimpression given. The Panel noted Aventis’submission that it had nothing to do with the poster.On balance, however, given the particularcircumstances of this case the Panel did not considerthat the representative had failed to maintain a highstandard of ethical conduct. No breach of Clause 15.2was ruled. Nor did the Panel consider that theseparticular circumstances meant that the company hadfailed to maintain high standards or brought discreditupon or reduced confidence in the pharmaceuticalindustry. No breach of Clauses 9.1 and 2 was ruled.

Complaint received 4 May 2004



The lead prescribing support pharmacist at a primary caretrust alleged that a journal advertisement for Plavix(clopidogrel) issued jointly by Bristol-Myers Squibb andSanofi-Synthelabo was misleading. The advertisementstated: ‘Imagine you’ve had a heart attack, stroke or havePAD [peripheral arterial disease], Imagine you’ve beenprescribed aspirin, imagine improving on that. Plavixdelivers significant protection above and beyond aspirin’.

The complainant stated that the advertisement was basedentirely upon the outcomes of the CAPRIE study in whichpatients with a history of heart attack, stroke or PAD wererandomised to aspirin or Plavix and followed up for acomposite primary outcome of ischaemic stroke, heart attackor vascular death. The study showed a significant reductionin risk in the Plavix group. However, in a pre-definedsubgroup analysis statistically significant benefit was onlydemonstrated in the PAD subgroup. In the stroke subgroupa non-significant trend towards benefit was shown and in theheart attack subgroup the trend was towards harm but againthis was not significant.

The complainant stated that the advertisement could beinterpreted as Plavix being significantly better than aspirin inpreventing ischaemic stroke, heart attack or vascular death inany patient who had had either a heart attack or a stroke.The CAPRIE study did not show this to be the case.

When writing to the companies the Authority noted that thecomplaint appeared to be closely similar to CasesAUTH/889/6/99 and AUTH/890/6/99. This raised thepossibility of a breach of undertaking which was taken up bythe Director as it was the responsibility of the Authorityitself to ensure compliance with undertakings. This accordedwith advice given by the Code of Practice Appeal Board.

The Panel noted that CAPRIE was designed to assess therelative efficacy of Plavix and aspirin in reducing the risk of acomposite outcome cluster of ischaemic stroke, heart attack orvascular death. The population studied comprisedsubgroups of patients with atherosclerotic vascular diseasenamely recent ischaemic stroke, recent heart attack orsymptomatic PAD. Most of the patients who had had arecent heart attack received aspirin for the first few daysimmediately following their heart attack. The study waspowered to detect a realistic treatment effect in the wholestudy cohort but not in each of the three clinical subgroups.The primary endpoint showed a statistically significantrelative risk reduction in favour of Plavix. The study authorsstated that the long-term administration of Plavix to patientswith atherosclerotic vascular disease was more effective thanaspirin in reducing the combined risk of ischaemic stroke,heart attack or vascular death. Analyses of the heart attack,stroke, and PAD subgroups showed a relative risk reductionof –3.7%, 7.3% and 23.8% respectively. The study authorsstated that a test for heterogeneity suggested that theobserved differences in these relative treatment effects were

greater than might be due to chance. The‘Pharmacodynamic properties’ section of the Plavixsummary of product characteristics (SPC) stated thatin patients who were enrolled in the trial on the solebasis of a recent heart attack, Plavix was numericallyinferior, but not statistically different from aspirin.It was further stated that since the CAPRIE trial wasnot powered to evaluate efficacy in individualsubgroups, it was not clear whether the differencesin relative risk reduction across qualifyingconditions were real, or a result of chance.

The Panel thus did not consider that the results ofthe CAPRIE study demonstrated a clear outcomesbenefit for patients when analysed by qualifyingcondition ie patients who had had a recent stroke orheart attack or PAD if treated with Plavix instead ofaspirin; the study was not powered to evaluateefficacy in individual subgroups. The Panelconsidered that the advertisement was misleading inthat regard and that the implied claim for benefitcompared with aspirin in subgroups of patientscould not be substantiated. Breaches of the Codewere thus ruled.

Upon appeal by Bristol-Myers Squibb and Sanofi-Synthelabo the Appeal Board noted that Plavix waslicensed for the prevention of atherothromboticevents in patients who had had a recent heart attack,ischaemic stroke or who had established PAD.These were all clinical manifestations ofatherosclerotic vascular disease. The CAPRIE studyassessed the relative long-term efficacy of Plavix andaspirin in patients with atherosclerotic vasculardisease. Plavix was shown to be more effective thanaspirin in reducing the combined risk of ischaemicstroke, myocardial infarction or vascular death.Patients were enrolled into the study if they had hada recent ischaemic stroke, a recent heart attack orhad symptomatic PAD. The study was powered todetect an effect in the whole patient cohort but notin each of the three clinical subgroups. The AppealBoard noted that the CAPRIE study was animportant study and although Plavix preventedatherothrombotic events in patients who had had aheart attack, stroke or who had PAD, as per thelicensed indications, it had not shown it to be moreefficacious than aspirin in each of these threeseparate patient subgroups, only in the patientpopulation as a whole.

The Appeal Board noted that the advertisementstated ‘Imagine you’ve had a heart attack, stroke orhave PAD, imagine you’ve been prescribed aspirin,imagine improving on that. Plavix deliverssignificant protection above and beyond aspirin’.



PRIMARY CARE TRUST LEAD PRESCRIBINGSUPPORT PHARMACIST/DIRECTOR v SANOFI-SYNTHELABO and BRISTOL-MYERS SQUIBBPlavix journal advertisement

The Appeal Board accepted that patients with onemanifestation of atherosclerotic vascular diseasewould often develop another and that there wasthus an overlap between the clinical subgroups.Nonetheless, the Appeal Board considered that theadvertisement implied that any patient whopresented with a heart attack or with a stroke orwith PAD would have a better outcome on Plavixthan on aspirin. This had not been proven. TheAppeal Board considered that the advertisement wasmisleading in this regard and upheld the Panel’sruling of breaches of the Code.

With regard to the possible breach of undertakingthe Panel noted that in Cases AUTH/889/6/99 andAUTH/890/6/99 breaches of the Code had been ruledbecause of claims, based on the results of theCAPRIE study, that compared to aspirin, Plavix wassignificantly more effective at reducing heart attack,reducing stroke and reducing vascular death, whichwas not so. The Panel considered that theadvertisement now at issue was sufficiently differentfor it not to be in breach of the undertaking given inCases AUTH/889/6/99 and AUTH/890/6/99. Nobreaches of the Code were ruled.

The lead prescribing support pharmacist at a primarycare trust complained about a journal advertisement(ref PLA03/257) for Plavix (clopidogrel) issued jointlyby Bristol-Myers Squibb Pharmaceuticals Limited andSanofi-Synthelabo Limited.

When writing to the companies the Authority notedthat the complaint appeared to be closely similar to aprevious complaint (Cases AUTH/889/6/99 andAUTH/890/6/99). This raised the possibility of abreach of undertaking which was taken up by theDirector as it was the responsibility of the Authorityitself to ensure compliance with undertakings. Thisaccorded with advice given by the Code of PracticeAppeal Board.

COMPLAINT

The complainant noted that the body of theadvertisement stated:

‘Imagine you’ve had a heart attack, stroke or havePAD [peripheral arterial disease], Imagine you’vebeen prescribed aspirin, imagine improving on that.Plavix delivers significant protection above andbeyond aspirin’.

The complainant had contacted Sanofi-Synthelabo toconfirm that the advertisement was based entirelyupon the outcomes of the CAPRIE study in whichpatients with a history of heart attack, stroke or PADwere recruited and randomised to aspirin or Plavixand followed up for a composite primary outcome ofischaemic stroke, heart attack or vascular death. Inthis instance there was a significant reduction in riskin the Plavix group. However, a pre-definedsubgroup analysis looked at the recruited diseasetypes separately. In these subgroups, statisticallysignificant benefit was only demonstrated in the PADgroup. In the stroke group a trend towards benefitwas shown but this was not significant and in theheart attack group the trend was towards harm butagain this was not significant.

The complainant alleged that the advertisement wasmisleading in that it could be interpreted as Plavixbeing significantly better than aspirin in preventingischaemic stroke, heart attack or vascular death in anypatient who had had either a heart attack or a stroke.The study upon which this advertisement was baseddid not show this to be the case in the subgroupanalysis.

When writing to the companies the Authority askedthem to respond in relation to Clauses 2, 7.2, 7.4, 9.1and 22.

RESPONSE

Bristol-Myers Squibb and Sanofi-Synthelabosubmitted a joint response. The companies stated thatCases AUTH/889/6/99 and AUTH/890/6/99involved the outcomes from CAPRIE (heart attack,ischaemic stroke or peripheral arterial disease),whereas the complaint now at issue (CasesAUTH/1588/5/04 and AUTH/1589/5/04) involvedpatient populations included in CAPRIE. The Plavixsummary of product characteristics (SPC) stated thatPlavix was indicated for the prevention ofatherothrombotic events in patients suffering from aheart attack (from a few days until less than 35 days),ischaemic stroke (from 7 days until less than 6months) or established peripheral vascular disease.These were the populations referred to in the text inthe body of the advertisement. The prescribinginformation at the bottom of the advertisement read‘Indication: Reduction of atherothrombotic events inpatients with a history of symptomatic atheroscleroticdisease defined by ischaemic stroke, myocardialinfarction (MI) [heart attack] or established peripheralarterial disease …’. Patients presented to their doctorwith either stroke, heart attack or PAD as amanifestation of atherothrombotic disease and ifprescribed Plavix, rather than aspirin, had asignificantly reduced risk of either further stroke,heart attack and PAD. The licence for use of Plavixwas not confined to patients presenting with all threeconditions and it was therefore difficult to understandhow this advertisement could be construed asmisleading, given the current understanding of riskacross all clinical presentations.

The companies submitted that the text was consistentwith the SPC and prescribing information and as suchthe advertisement was not misleading, therefore nobreach of Clauses 7.2 and 7.4 could be ruled.

The companies stated that as a result of CasesAUTH/889/6/99 and AUTH/890/6/99 all materialswere removed and the copy had subsequently beenaltered to be consistent with the ruling made in thosecases and consistent with the SPC. The companiesthus denied breaches of Clauses 2, 9.1 and 22.

PANEL RULING

The Panel considered that the advertisement impliedthat any patient who had had a heart attack or astroke or who had PAD, would have a better outcomeif they were treated with Plavix instead of aspirin.This claim had been made on the basis of the resultsof the CAPRIE study.


The Panel noted that CAPRIE was a randomisedblinded trial designed to assess the relative efficacy ofPlavix (75mg once daily) and aspirin (325mg oncedaily) in reducing the risk of a composite outcomecluster of ischaemic stroke, heart attack or vasculardeath. The population studied comprised subgroupsof patients with atherosclerotic vascular disease namelyrecent ischaemic stroke, recent heart attack orsymptomatic peripheral arterial disease. Most of thepatients who had had a recent heart attack receivedaspirin for the first few days immediately followingtheir heart attack. The study was powered to detect arealistic treatment effect in the whole study cohort butnot in each of the three clinical subgroups. Theprimary endpoint showed a statistically significantrelative risk reduction in favour of Plavix. The studyauthors stated that the long-term administration ofPlavix to patients with atherosclerotic vascular diseasewas more effective than aspirin in reducing thecombined risk of ischaemic stroke, heart attack orvascular death. Analyses of the heart attack, stroke,and PAD subgroups showed a relative risk reduction of–3.7%, 7.3% and 23.8% respectively. The study authorsstated that a test for heterogeneity suggested that theobserved differences in these relative treatment effectswere greater than might be due to chance. The‘Pharmacodynamic properties’ section of the PlavixSPC stated that in patients who were enrolled in thetrial on the sole basis of a recent heart attack, Plavixwas numerically inferior, but not statistically differentfrom aspirin. It was further stated that since theCAPRIE trial was not powered to evaluate efficacy inindividual subgroups, it was not clear whether thedifferences in relative risk reduction across qualifyingconditions were real, or a result of chance.

The Panel thus did not consider that the CAPRIEstudy demonstrated a clear outcomes benefit forpatients when analysed by qualifying condition iepatients who had had a recent stroke or heart attackor PAD if treated with Plavix instead of aspirin; thestudy was not powered to evaluate efficacy inindividual subgroups. The Panel considered that theadvertisement was misleading in that regard and thatthe implied claim for benefit compared with aspirin insubgroups of patients could not be substantiated.Breaches of Clauses 7.2 and 7.4 were thus ruled. Thisruling was appealed by Bristol-Myers Squibb andSanofi-Synthelabo.

The Panel noted that in Cases AUTH/889/6/99 andAUTH/890/6/99 breaches of the Code had been ruledbecause a detail aid and an advertisement featuredclaims, based on the results of the CAPRIE study, thatcompared to aspirin, Plavix was significantly moreeffective at reducing heart attack, reducing stroke andreducing vascular death, which was not so. The Panelconsidered that in that regard the advertisement nowat issue was sufficiently different for it not to be inbreach of the undertaking given in CasesAUTH/889/6/99 and AUTH/890/6/99. No breach ofClauses 2, 9.1 and 22 was ruled.

APPEAL BY BRISTOL-MYERS SQUIBB ANDSANOFI-SYNTHELABO

The indications for Plavix in the SPC were ‘…theprevention of atherothrombotic events in patients

suffering from myocardial infarction (from a few daysuntil less than 35 days), ischaemic stroke (from 7 daysuntil less than 6 months) or established peripheralarterial disease’.

The advertisement stated ‘Imagine you’ve had a heartattack, stroke or PAD [peripheral arterial disease] …’.

The companies noted that the patient groups in theadvertisement were consistent with the licensedindication and the order in which they werementioned was the same as in the SPC. Thecompanies further noted that the indications (heartattack, stroke or PAD) were listed in one line ratherthan being split into three lines (ie ‘imagine you’vehad a heart attack, imagine you’ve had a stroke,imagine you have peripheral arterial disease’). Thisaccurately represented those groups of patients thatwere recruited into the CAPRIE study, and reflected inthe SPC, and also combined them in a single cohort bylisting them on one line. By the format of the wordingadopted the advertisement did not invite an analysisof subgroups. The claim was, therefore, consistentwith the SPC and as the wording reflected the SPC inthe format laid out in the SPC, it was not misleading.

The companies stated that CAPRIE was designed tostudy a cohort of atherothrombotic patients andevaluate efficacy by assessing differences in acomposite endpoint (atherothrombotic events:myocardial infarction, ischaemic stroke and vasculardeath) between Plavix and aspirin. The SPC (Section5.1) stated that ‘since the CAPRIE trial was notpowered to evaluate efficacy of individual subgroups,it is not clear whether the differences in relative riskreduction across qualifying conditions are real, or aresult of chance’.

The companies submitted that conclusions from thesubgroup analyses were limited by the smallernumbers analysed. The most robust and validinterpretation of the CAPRIE study therefore was toconsider the whole cohort recruited and the primaryendpoint (the outcome cluster of reduction ofatherothrombotic events) and, in doing so, it wasshown that Plavix was significantly superior toaspirin in reducing atherothrombotic events(myocardial infarction, ischaemic stroke and vasculardeath) in patients with vascular disease (myocardialinfarction, ischaemic stroke and peripheral arterialdisease).

The companies submitted that the advertisement wasthus consistent with the conclusion drawn fromCAPRIE and, importantly, consistent with theparticulars listed in the SPC.

The companies disagreed that the wording in theadvertisement was not substantiable as they hadhighlighted that the advertisement was based onCAPRIE and the conclusion was drawn from thestudy. Furthermore, as demonstrated above, thewording of the advertisement reflected the licensedindications stated in the SPC and, as stated in Clause7.5 of the Code, substantiation did not need to beprovided ‘in relation to the validity of indicationsapproved in the marketing authorization’.

The companies submitted that the complainant hadmisinterpreted the advertisement, especially in the


light of evidence that emphasised the risk of futurevascular events in multiple vascular beds in patientssuch as those studied in CAPRIE and the nature of theglobal vascular disease represented by such a study.

COMMENTS FROM THE COMPLAINANT

The complainant agreed that the advertisement was inkeeping with the SPC and accurately reflected theprimary study group of CAPRIE. However hedisagreed with the submission that the advertisementdid not invite a subgroup analysis just because it usedthe same wording and same ordering as both the SPCand the CAPRIE study.

The complainant noted that the companies had basedthe advertisement on the CAPRIE study and the SPCreferenced this study. The study had fully detailed asubgroup analysis under the method heading. Theoriginal trial might not have been powered to detectdifferences at the subgroup level, but in this case whydefine these analyses in the design of the trial andallow them to dominate the content of the paper?

The complainant submitted that medical practitionerswho chose to look up the reference in the SPC wouldfind it plain to read that the data were presentedrepeatedly through the paper in subgroup categories.Therefore, to suggest that an advertisement based onCAPRIE did not invite an analysis of subgroupsseemed to be a strange argument, perhaps readers ofthe advertisement were not expected to look at thepaper at all!

The complainant noted that on the basis of the wholestudy population Plavix was statistically better thanaspirin, but stated that during a patient consultation amedical practitioner would assess a patient with asingle diagnosis from the list of three included in theadvertisement. By implication the advertisementstated that Plavix was better than aspirin in these singledisease areas even though, by the companies’ ownadmission, they could not substantiate these claims asthe CAPRIE study was not powered to detectdifferences in the subgroups detailed in the paper.

The complainant alleged that purely listing thedisease areas together on a single line, in accordancewith the SPC, would not stop readers seeing the threeindividual diseases. There was no individual patientthat was representative of the primary trial cohort andtherefore the advertisement invited a subgroupanalysis.

The complainant noted that the companies haddisagreed that the wording of the advertisement wasnot substantiable. Again the complainant noted thatby their own admission the companies could notdemonstrate significantly better outcomes fromaspirin for individuals with single disease diagnoses.

The complainant considered that the companies’statement that ‘the complainant had misinterpretedthe advertisement’ was an admission that theadvertisement was misleading. As he had managedto read something into the advertisement that was notintended to be stated without any extrapolation of

information on his part proved that the advertisementwas misleading.

The complainant stated that the companies wereentitled to advertise and promote Plavix within thebounds of its SPC. The original trial design for theCAPRIE was to recruit patients with a history ofischaemic events. Since the study looked atsubgroups and a test of heterogenicity was performedthat suggested that the benefit of Plavix might not beidentical across the three groups, claims could not andshould not be made for a list of conditions. Thisinferred equivalent benefit for each of the diseasesstated in the list, and the complainant restated thatthis could not be substantiated.

The complainant stood by his original complaint thatthe advertisement was misleading.

APPEAL BOARD RULING

The Appeal Board noted that Plavix was licensed forthe prevention of atherothrombotic events in patientswho had had a recent heart attack, ischaemic stroke orwho had established PAD. These were all clinicalmanifestations of atherosclerotic vascular disease.The CAPRIE study assessed the relative long-termefficacy of Plavix and aspirin in patients withatherosclerotic vascular disease. Plavix was shown tobe more effective than aspirin in reducing thecombined risk of ischaemic stroke, myocardialinfarction or vascular death. Patients were enrolledinto the study if they had had a recent ischaemicstroke, a recent heart attack or had symptomatic PAD.The study was powered to detect an effect in thewhole patient cohort but not in each of the threeclinical subgroups. The Appeal Board noted that theCAPRIE study was an important study and althoughPlavix prevented atherothrombotic events in patientswho had had a heart attack, stroke or who had PAD,as per the licensed indications, it had not shown it tobe more efficacious than aspirin in each of these threeseparate patient subgroups, only in the patientpopulation as a whole.

The Appeal Board noted that the advertisement stated‘Imagine you’ve had a heart attack, stroke or havePAD, imagine you’ve been prescribed aspirin, imagineimproving on that. Plavix delivers significantprotection above and beyond aspirin’. The AppealBoard accepted that patients with one manifestation ofatherosclerotic vascular disease would often developanother and that there was thus an overlap betweenthe clinical subgroups. Nonetheless, the Appeal Boardconsidered that the advertisement implied that anypatient who presented with a heart attack or with astroke or with PAD would have a better outcome onPlavix than on aspirin. This had not been proven. TheAppeal Board considered that the advertisement wasmisleading in this regard and upheld the Panel’sruling of breaches of Clauses 7.2 and 7.4 of the Code.The appeal was unsuccessful.


Case completed 7 October 2004


The director of clinical governance at a primary care trustcomplained about a journal advertisement issued byGlaxoSmithKline which discussed rosiglitazone and itsavailability as Avandia and, with metformin, as Avandamet.Both products were indicated for glycaemic control in certaingroups of type 2 diabetics.

The complainant believed that a statement that rosiglitazonehelped to control blood pressure compared withsulphonylureas, which had no such effect, was misleadingand was not substantiated by clinical evidence.

The Panel noted that whilst the advertisement did notcontain a discrete statement that ‘rosiglitazone helped tocontrol blood pressure compared with sulphonylureas’, asimplied by the complainant, it nonetheless directly comparedthe two with regard to blood pressure control.

The Panel noted GlaxoSmithKline had referred to CaseAUTH/1580/4/04 wherein the same advertisement was thesubject of a recent adjudication by the Code of Practice Panel;GlaxoSmithKline had not been informed of the outcome ofthat case before it had submitted its response to this case.The complainant in Case AUTH/1580/4/04 had beenconcerned about the claim that using rosiglitazone could helpto lower blood pressure and queried whether this supposedlyadditional benefit could be advertised in this manner. ThePanel had noted that the advertisement was headed‘Confront the new challenges for Type 2 diabetes’ andreferred to rosiglitazone available as Avandia and, incombination with metformin, as Avandamet. Avandia couldbe used as monotherapy particularly in overweight patientsinadequately controlled by diet and exercise and for whommetformin was inappropriate. It could also be used incombination treatment in patients with insufficient glycaemiccontrol despite maximal tolerated dose of oral monotherapywith either metformin or a sulphonylurea. Avandamet wasindicated for the treatment of type 2 diabetics, particularlyoverweight patients, who were unable to achieve sufficientglycaemic control at their maximally tolerated dose ofmetformin alone.

The Panel had noted in Case AUTH/1580/4/04 that theintroductory paragraph of the advertisement stated thatmanaging type 2 diabetes was no longer just about glycaemiccontrol and that this was why the General Medical Services(GMS) contract focussed ‘on both lasting glycaemic controland reductions in blood pressure’. The remainder of theparagraph discussed tight glycaemic control and itsassociation with fewer microvascular complications and tightblood pressure control and its association with fewer majorcardiovascular events.

The following paragraph had explained that rosiglitazonecould help meet both blood glucose and blood pressure GMStargets by targeting insulin resistance, a root cause of type 2diabetes. A subsequent paragraph began ‘By targetinginsulin resistance, rosiglitazone also helps to achieve bloodpressure targets …’ and discussed studies which had

consistently shown that rosiglitazone helped tosignificantly lower blood pressure. The effect ofrosiglitazone on blood pressure was compared tothat of sulphonylureas and it was further noted thatthe ‘UKPDS [UK Prospective Diabetes Study] foundthat sulphonylureas had no significant effect oncardiovascular outcomes after a mean treatmentperiod of 10 years’. The final paragraph referred toAvandia and Avandamet. The claims ‘You reallywant to hit targets year after year’ and ‘Using theright oral antidiabetic agent can also help lowerblood pressure’ appeared in highlighted circles. ThePanel considered that there was a differencebetween promoting a product for a licensedindication and promoting the benefits of treating acondition.

The Panel had noted that there was evidenceshowing a beneficial effect of Avandia on bloodpressure in type 2 diabetics. Whilst it was notnecessarily unacceptable to refer to such a benefit inpromotional material such references should complywith the Code and could only be made within thecontext of treating patients for the product’s licensedindications. The Panel considered that the balanceof the advertisement was such that the reduction ofblood pressure as a benefit of using Avandia orAvandamet had been given undue emphasis; suchan effect had not been placed sufficiently within thecontext of the licensed indications for the products.The advertisement implied that Avandia andAvandamet were indicated for blood pressurereduction and that was not so; the advertisementwas misleading and inconsistent with the marketingauthorizations in this regard. Breaches of the Codehad been ruled.

Turning to the present case, Case AUTH/1590/4/04,the Panel considered that whilst the allegation wasdifferent to that considered previously, its commentsin Case AUTH/1580/4/04 were nonetheless relevant.

The Panel considered that the balance of theadvertisement was such that undue emphasis hadbeen given to the reduction of blood pressure as abenefit of using Avandia and Avandamet; it impliedthat Avandia and Avandamet were so licensedwhich was not so. Whilst it was not necessarilyunacceptable to compare the blood pressurelowering effect of sulphonylureas and rosiglitazoneany such comparisons could only be made withincontext of treating patients for the products’licensed indications. The Panel considered thatgiven the balance of the advertisement thecomparison at issue compounded the overallmisleading impression that Avandia andAvandamet were licensed for reduction of bloodpressure. A breach of the Code was ruled.


CASE AUTH/1590/5/04

PRIMARY CARE TRUST DIRECTOR OF CLINICALGOVERNANCE v GLAXOSMITHKLINERosiglitazone (Avandia and Avandamet) journal advertisement

The director of clinical governance at a primary caretrust complained about a journal advertisement (refAVM/FPA/04/11822/1) issued by GlaxoSmithKlineUK Ltd which appeared in Pulse 12 April. Theadvertisement discussed rosiglitazone and itsavailability as Avandia and, with metformin, asAvandamet. Both products were indicated forglycaemic control in certain groups of type 2diabetics.

COMPLAINT

The complainant believed that a statement thatrosiglitazone helped to control blood pressurecompared with sulphonylureas, which had no sucheffect, was misleading and was not substantiated byclinical evidence.

When writing to GlaxoSmithKline, the Authorityinvited it to respond in relation to Clause 7.2 of theCode of Practice.

RESPONSE

GlaxoSmithKline explained that in a recent review ofthe glitazones, the Medicines and Healthcare productsRegulatory Agency (MHRA) had acknowledged thatpromotion of the effects of glitazones on bloodpressure was consistent with the marketingauthorization for these agents; and explicitly that theevidence base was sufficient to justify suchpromotion. Specifically it stated that ‘The evidenceshows that glitazones may have a secondary effect onother parameters such as modifying blood lipids andblood pressure, in diabetic patients, though it does notconclude whether these effects are due to a direct oran indirect (through its insulin-sensitising) action’.The advertisement in question did not fall outside theMHRA guidelines, a copy of which was provided.

The importance of vigorously addressing raised bloodpressure in type 2 diabetics was indisputable. TheUnited Kingdom Prospective Diabetes Study(UKPDS) – the only major prospective outcome studyin this condition conducted to date – demonstratedthat tight blood pressure control was the single mostimportant factor in reducing the incidence ofmacrovascular complications, including myocardialinfarction, stroke and sudden death. Thus there was a34% reduction in adverse cardiovascular outcomes inthe tight blood pressure control group compared withthe ‘standard’ control group. However, the study alsodemonstrated the difficulty of achieving optimumcontrol: nearly 45% of patients in the tight controlgroup failed to maintain their target blood pressure;and 60% of hypertensive patients needed two or moreantihypertensive agents, and 29% three or moreagents, to maintain adequate control. In this context,the ancillary antihypertensive effects of anantidiabetic agent such as rosiglitazone contained inboth Avandia and Avandamet were highly relevant.

The Oxford Handbook of Endocrinology and Diabetes(2002 edition) stated that hypertension in type 2diabetes was associated with both insulin resistanceand hyperinsulinaemia. Hyperinsulinaemia mightdirectly cause hypertension by increasing sympatheticnervous system activity, stimulating proximal tubule

sodium resorption and stimulating vascular smoothmuscle cell proliferation. Sulphonylureas, whichstimulated release of insulin from pancreatic betacells, would therefore not be expected to positivelyaffect blood pressure, and this was borne out in theconclusions of a number of articles eg Inzucchi (2002)and Fonseca (2003). In contrast, agents that reducedinsulin resistance such as rosiglitazone might beexpected to have positive effects on blood pressure(Viberti et al 2003) and this was borne out by clinicaldata.

The UKPDS demonstrated that sulphonylureas hadno significant effect on blood pressure. In UKPDS 33‘systolic and diastolic blood pressure weresignificantly higher throughout the study in patientsassigned chlorpropamide than in those assigned anyof the other therapies’.

Evidence that sulphonylureas as a class had no effecton blood pressure compared to rosiglitazone wasbacked up by data from a comparative study ofglibenclamide with rosiglitazone (St John Sutton et al2002) wherein rosiglitazone was associated withsignificant reductions in blood pressure compared toglibenclamide (drops of 3.7/2.8mmHg vglibenclamide at a mean dose of 10.5mg over 1 year).A double-blind, placebo controlled trial designed tomeasure changes in blood pressure with the additionof rosiglitazone therapy demonstrated blood pressurereductions of 12/6mmHg (Honisett et al 2003). Thesetwo studies, together with a number of others,provided a growing body of evidence relating to theblood pressure lowering effects of targeting insulinresistance. GlaxoSmithKline provided details of thereductions seen with rosiglitazone in 11 studies.

GlaxoSmithKline submitted that as this case wassimilar to Case AUTH/1580/4/04 it seemed sensiblefor any ruling to be considered in the light of theruling in the earlier case. In summaryGlaxoSmithKline did not agree that Clause 7.2 of theCode had been breached. The benefits of bloodpressure lowering were clear from the UKPDS studyand agents such as rosiglitazone that had ancillaryblood pressure lowering effects in addition to bloodglucose lowering offered important clinicaladvantages. The UKPDS study had demonstratedthat sulphonylureas had no significant blood pressurelowering effects. St John Sutton et al confirmed thatrosiglitazone offered advantages over sulphonylureatherapy with respect to blood pressure control, and anumber of other studies now added to the body ofevidence on the blood pressure lowering effects ofrosiglitazone.

GlaxoSmithKline stated that the advertisement towhich the complainant referred had been withdrawnin the week commencing 10 May as part of a plannedcampaign update.

PANEL RULING

The Panel noted that whilst the advertisement did notcontain a discrete statement that ‘rosiglitazone helpedto control blood pressure compared withsulphonylureas’, as implied by the complainant, itnonetheless directly compared the two with regard toblood pressure control. The Panel also noted that


GlaxoSmithKline had not been notified of theoutcome of the previous case, CaseAUTH/1580/4/04, when it submitted its response tothe present complaint.

Case AUTH/1580/4/04

The Panel noted GlaxoSmithKline had referred toCase AUTH/1580/4/04 wherein the sameadvertisement was the subject of a recent adjudicationby the Code of Practice Panel; the complainant hadbeen concerned about the claim that usingrosiglitazone could help to lower blood pressure andqueried whether this supposedly additional benefitfrom rosiglitazone could be advertised in this manner.The Panel had noted that the advertisement washeaded ‘Confront the new challenges for Type 2diabetes’ and referred to rosiglitazone available asAvandia and, in combination with metformin, asAvandamet. Avandia was indicated as oralmonotherapy treatment of type 2 diabeticsparticularly in overweight patients inadequatelycontrolled by diet and exercise and for whommetformin was inappropriate because ofcontraindications or intolerance. Avandia was alsoindicated in oral combination treatment in patientswith insufficient glycaemic control despite maximaltolerated dose of oral monotherapy with eithermetformin or a sulphonylurea: in combination withmetformin particularly in overweight patients; incombination with a sulphonylurea only in patientswho showed intolerance to metformin or for whommetformin was contraindicated. Avandamet wasindicated for the treatment of type 2 diabetics,particularly overweight patients, who were unable toachieve sufficient glycaemic control at their maximallytolerated dose of metformin alone.

The Panel had noted that the introductory paragraphof the advertisement stated that managing type 2diabetes was no longer just about glycaemic controland that this was why the GMS contract focussed ‘onboth lasting glycaemic control and reductions in bloodpressure’. The remainder of the paragraph discussedtight glycaemic control and its association with fewermicrovascular complications and tight blood pressurecontrol and its association with fewer majorcardiovascular events.

The following paragraph explained that rosiglitazonecould help meet both blood glucose and bloodpressure GMS targets by targeting insulin resistance, aroot cause of type 2 diabetes. Reference was made tohitting ‘targets year after year’ within the context ofrosiglitazone’s ‘proven lasting effectiveness’. Asubsequent paragraph began ‘By targeting insulinresistance, rosiglitazone also helps to achieve bloodpressure targets …’ and discussed studies which hadconsistently shown that rosiglitazone helped tosignificantly lower blood pressure. The effect ofrosiglitazone on blood pressure was compared to thatof sulphonylureas and it was further noted that the‘UKPDS found that sulphonylureas had no significanteffect on cardiovascular outcomes after a meantreatment period of 10 years’. The final paragraphreferred to Avandia and Avandamet. The claims ‘Youreally want to hit targets year after year’ and ‘Using

the right oral antidiabetic agent can also help lowerblood pressure’ appeared in highlighted circles.

The Panel had considered there was a differencebetween promoting a product for a licensed indicationand promoting the benefits of treating a condition.

The Panel had noted that there was evidence showinga beneficial effect of Avandia on blood pressure intype 2 diabetics. Whilst it was not necessarilyunacceptable to refer to such a benefit in promotionalmaterial such references should comply with the Codeand could only be made within the context of treatingpatients for the product’s licensed indications. ThePanel considered that the balance of theadvertisement was such that the reduction of bloodpressure as a benefit of using Avandia or Avandamethad been given undue emphasis. The advertisementdid not place reduction in blood pressure sufficientlywithin the context of the licensed indications for theproducts. The advertisement gave the impression thatAvandia and Avandamet were indicated for bloodpressure reduction and that was not so; theadvertisement was misleading and inconsistent withthe marketing authorizations in this regard. Breachesof Clauses 3.2 and 7.2 had been ruled.

* * * * *

Case AUTH/1590/4/04

Turning to the present case, Case AUTH/1590/4/04,the Panel considered that whilst the allegation wasdifferent to that considered previously its commentsin Case AUTH/1580/4/04 were nonetheless relevant.The Panel noted the licensed indications of Avandiaand Avandamet as set out above. The Panel notedthat sulphonylureas were indicated for the treatmentof type 2 diabetes (ref BNF March 2004).

The Panel noted GlaxoSmithKline’s submission aboutthe importance of addressing raised blood pressure intype 2 diabetics and that the UKPDS demonstratedthat sulphonylureas had no significant blood pressurelowering effects.

The Panel considered that the balance of theadvertisement was such that undue emphasis hadbeen given to the reduction of blood pressure as abenefit of using Avandia and Avandamet; it gave theimpression that Avandia and Avandamet were solicensed. That was not so. Whilst it was notnecessarily unacceptable to compare the bloodpressure lowering effect of sulphonylureas androsiglitazone any such comparisons could only bemade within the context of treating patients for theproducts’ licensed indications. The Panel consideredthat given the balance of the advertisement thecomparison at issue compounded the overallimpression that Avandia and Avandamet werelicensed for reduction of blood pressure. Thecomparison was misleading in this regard. A breachof Clause 7.2 was ruled.




Janssen-Cilag complained about a detail aid and a leavepiecefor Transtec (buprenorphine transdermal patch) issued byNapp. Transtec was indicated for moderate to severe cancerpain and severe pain which did not respond to non-opioidanalgesics. Janssen-Cilag supplied Durogesic (fentanyltransdermal patch). Durogesic was indicated for themanagement of chronic intractable pain due to cancer orotherwise. Section 4.2 of the Durogesic summary of productcharacteristics (SPC) stated that in strong opioid naïvepatients, the lowest dose 25µg/hr should be used as the initialdose.

Janssen-Cilag noted the claim ‘Transtec matrix patches can beused sooner than [Durogesic]’ was followed by anapproximation to the morphine equivalence of each medicineand another claim ‘Transtec’s low starting dose means that itmay be appropriate to use before fentanyl in strong opioidnaïve patients’. Janssen-Cilag alleged that to imply that therewere some patients for whom the lowest dose of Transtec(35mg/hr) was suitable but the lowest dose of Durogesic(25µg/hr) was not suitable, was misleading, incapable ofsubstantiation and disparaged Durogesic.

The Panel noted that according to their respective SPCs thelowest strength Transtec patch (35µg/hr) was equivalent to 30-60mg oral morphine per day and the lowest strengthDurogesic patch (25µg/hr) was equivalent to oral doses ofmorphine of less than 135 mg/day. Under the heading dosetitration the Durogesic SPC stated that Durogesic 25µg/hrwas approximately equivalent to 90mg/day of oral morphine.The Panel acknowledged that there was a difference betweenthe products in that the lowest strength Transtec patch wasless potent than the lowest strength Durogesic patch. TheTranstec SPC indicated that the product could be used inpatients who had previously not received any analgesicswhereas the Durogesic SPC stated that the initial dose shouldbe based, inter alia, on the patient’s opioid history. ThePanel noted, however, that both the detail aid and theleavepiece referred, on their front covers, to Transtec as ‘Yournext step after a weak opioid in severe, chronic pain’ and itwas in this context that the claims at issue were considered.

Both the detail aid and the leavepiece stated that ‘Transtecmatrix patches can be used sooner than [Durogesic] patches’.There then followed a description of the oral morphineequivalent of the lowest strength of both products. This wasfollowed by the claim ‘Transtec’s low starting dose means itmay be appropriate to use before [Durogesic] in strongopioid naïve patients’. The Panel noted Napp’s submissionwith regard to the difference between the equivalent dailyoral morphine dose for the two products and clinical practice.Nonetheless, Durogesic 25µg/hr was licensed for use inpatients who had not previously received a strong opioid.This was not made sufficiently clear in the materials. ThePanel considered that use of the word ‘may’ in the claim thatTranstec ‘may (emphasis added) be appropriate to use before[Durogesic]’ did not negate the impression that Transtec wasappropriate to use before Durogesic. Given the licensedindications for both products with regard to patients whoneeded more than a weak opioid, the Panel considered that,

in the context in which they appeared, the claims‘Transtec matrix patches can be used sooner thanfentanyl reservoir patches’ and ‘Transtec’s lowstarting dose means that it may be appropriate touse before fentanyl in strong opioid naïve patients’were misleading and could not be substantiated.Breaches of the Code were ruled. The Panel furtherconsidered that the claims disparaged Durogesic. Abreach of the Code was ruled.

Janssen-Cilag Ltd complained about the promotion ofTranstec (buprenorphine transdermal patch) by NappPharmaceuticals Limited. The items at issue were aleavepiece (ref UK/TR-03052) and a detail aid (refUK/TR-03048) which had been used with bothprimary and secondary care health professionalsbetween 1 January and 30 April 2004. Transtec wasindicated for moderate to severe cancer pain andsevere pain which did not respond to non-opioidanalgesics. Janssen-Cilag supplied Durogesic(fentanyl transdermal patch). Durogesic wasindicated for the management of chronic intractablepain due to cancer or otherwise. Contact between thecompanies had failed to resolve the matter.

COMPLAINT

Janssen-Cilag noted that Napp had made severalclaims on the ‘theme’ that Transtec could be usedbefore Durogesic. The claims started with ‘Transtecmatrix patches can be used sooner than fentanylreservoir patches’. This was then followed by anapproximation to the morphine equivalence of eachmedicine, and another claim stating ‘Transtec’s lowstarting dose means that it may be appropriate to usebefore fentanyl in strong opioid naïve patients’.Janssen-Cilag alleged that these claims weremisleading, incapable of substantiation anddisparaged Durogesic in breach of Clauses 7.2, 7.4 and8.1 of the Code.

The summary of product characteristics (SPC) clearlystated that Durogesic was indicated in themanagement of chronic intractable cancer and non-cancer pain. Section 4.2 of the SPC stated that instrong opioid naïve patients, the lowest Durogesicdose 25µg/hr should be used as the initial dose.

The key question that needed to be addressed was:was there a patient population where Transtec couldbe used before/sooner than Durogesic?

Having compared the SPCs of both productsJanssen-Cilag did not consider that such a patientpopulation existed in either strong opioid naïvepatients or opioid tolerant patients. Initiation oftreatment with Durogesic 25µg/hr was whollyappropriate as long as the patient had chronicintractable cancer or non-cancer pain. The patient’scurrent pain status was primarily determinedclinically, taking into account their pre-existing


CASE AUTH/1591/5/04

JANSSEN-CILAG v NAPPPromotion of Transtec

analgesic requirements. Durogesic treatment couldbe initiated in strong opioid naïve patients, and thisby definition included patients who had notpreviously been exposed to morphine.

Transdermal buprenorphine was licensed formoderate to severe cancer pain and severe pain,which did not respond to non-opioid analgesics.Transdermal buprenorphine was contra-indicated forthe treatment of acute pain.

Strong opioid naïve patients:

When a clinician had decided to initiate treatmentwith a strong opioid in a strong opioid naïve patient,there was no clinical instance where Transtec 35µg/hrcould be used before/sooner than Durogesic 25µg/hr,which was a licensed dose for this patient group.

Opioid tolerant patients:

There were several guides to help clinicians who haddecided to initiate treatment with a strong opioid inopioid tolerant patients. The Durogesic SPC statedthat in patients requiring less than 135mg of oralmorphine a day, Durogesic 25µg/hr was appropriate.The SPC further stated that subsequent doseadjustments should be made in 25µg/hr increments,although the supplementary analgesic requirements(oral morphine 90mg/day was approximatelyDurogesic 25µg/hr) and the pain status of the patientshould be taken into account.

In patients who might have required, for example,either 10mg or 60mg of morphine previously per day,Durogesic 25µg/hr was an appropriate initialtreatment dose. Although as previously stated themorphine conversion could serve as a guide, the keyquestion to ask when a physician was decidingwhether to commence therapy with Durogesic25µg/hr in an opioid tolerant patient was: did thepatient currently have chronic intractable cancer ornon-cancer pain? If the answer was yes thenDurogesic 25µg/hr was appropriate in patients whoseprevious oral morphine requirements were up to135mg of morphine a day.

In conclusion, the overall decision to prescribeDurogesic 25µg/hr was based primarily on theclinical pain state of the patient. For opioid tolerantpatients, the oral morphine conversion charts werethere as a guide only. Accordingly, Napp’s claimswere misleading. Janssen-Cilag did not believe thatNapp could substantiate its claim that there was apatient group where Transtec 35µg/hr could be usedsooner/before Durogesic 25µg/hr in either strongopioid naïve patients or in opioid tolerant patients.Additionally, by implying that there were patients forwhom Durogesic 25µg/hr was not suitable butTranstec 35µg/hr was, Napp disparaged Durogesic.

RESPONSE

Napp considered that the comparison made betweenTranstec and Durogesic complied with the Code. Itwas accurate, balanced, fair, objective, unambiguous,based on clear, up-to-date clinical recommendations tobe found in a number of reputable publications andsupported by leading authorities in painmanagement.

Napp noted that Janssen-Cilag’s complaint was basedexclusively on what its SPC stated. In the DurogesicSPC the overriding principle in initial dose selectionwas to take account of the patient’s opioid history,their current general condition and medical status.Subject to that, the 25µg/hr patch was recommendedas the initial dose for both strong opioid naïvepatients and for opioid tolerant patients who hadbeen taking up to 135mg of oral morphine a day. Thesection on dose titration, however, stated that theDurogesic 25µg/hr patch was equal to approximately90mg of oral morphine per day.

The Transtec SPC advised that the lowest possibledose providing adequate pain relief should be given.For opioid naïve patients, this was the 35µg/hr patch.For those patients switching from an opioid analgesic,the guideline for conversion from oral morphine wasas follows:

35µg/hr patch: 30-60mg of morphine.52.5µg/hr patch: 90mg of morphine.70µg/hr patch: 120mg of morphine.

A comparison of the data in the SPCs of the twoproducts showed:

1 The lowest Transtec patch was equivalent to 30-60mg of oral morphine per day, whilst the loweststrength Durogesic patch was equivalent to 90mg oforal morphine per day. This compared to therecommended starting dose for MST Continus tabletsof 60mg of morphine per day. A potency 50% greaterthan the starting dose for morphine was a clinicallysignificant higher dose.

2 The 25 µg/hr Durogesic patch had the samemorphine equivalence as the 52.5µg/hr Transtec patchie the middle, not the lowest strength. This wasfurther substantiated by Twycross et al (2003)Palliative Care Formulary which stated that‘buprenorphine 52.5 microgram/h is approximatelyequivalent to fentanyl TD 25 microgram/h’.

3 The highest strength Transtec patch had amorphine equivalence lower than the 135mg ofmorphine stated in the Durogesic SPC as the upperend of the range for which the 25µg/hr patch couldbe used.

Napp’s first point was, therefore, that its claim, whichwas clearly referenced to the SPCs, did no more thandraw a very obvious conclusion from a comparison ofthe morphine conversion rates for the two products.

This conclusion was further supported by whathappened in clinical practice. Doctors were advisedto carefully titrate patients on strong opioids to theoptimum dosage level, and all the more so in opioidnaïve, frail or vulnerable patients. ‘Start low, go slow’was the principle. The aim was to minimise adverseeffects, which was especially important when usingcontrolled release products with prolonged retentiontimes within the body. In other words, if too high adose was given, resulting in side effects, the sideeffects would continue for many hours until the levelof medicine in the body had reduced.

This was further supported in the introduction to the1996 World Health Organisation (WHO) guidelines oncancer pain relief which stated ‘the right drug in the


right dose at the right time intervals’ and ‘Lowstarting doses should be used in elderly people, whomay have an increased response because of changes inthe pharmacokinetics of opioids’. Perhaps the BritishNational Formulary (BNF) provided the mostcommonly used guidance on current, recommendedclinical practice. The preface to the BNF emphasisedthat it ‘aims to provide prescribers, pharmacists andother healthcare professionals with sound up-to-dateinformation about the use of medicines’. It was‘constructed from clinical literature and reflects,wherever possible, an evaluation of the evidence’ and‘the Joint Formulary Committee receives expertclinical advice on all therapeutic areas in tune withcorrect best practice; this ensures that the BNF’srecommendations are relevant to practice’. The BNFset out clear guidance on starting doses for strongopioids. In the section headed ‘Prescribing inpalliative care’ the starting dose of twice dailymodified release morphine preparations wasdescribed as ‘10-20mg every 12 hours if no otheranalgesic (or only paracetamol) has been takenpreviously, but to replace a weaker opioid analgesic(such as coproxamol) the starting dose is usually 20-30mg every 12 hours’. The BNF further stated underthe heading ‘Transdermal Route’ that ‘Carefulconversion from oral morphine to transdermalfentanyl is necessary’. It then quoted a morphineequivalence of 90mg daily for the Durogesic 25µg/hrpatch. This was consistent with the conversion levelgiven in the titration section of the Durogesic SPC,and significantly higher than the starting dose for oralmorphine.

Napp noted that the BNF guidance in theTransdermal Route section changed to the currentwording in the September 2000 edition. Previously, inthe March 2000 edition, it had stated that ‘a 25micrograms/hour patch is equivalent to a total doseof morphine up to 135mg/24 hours’. The reason forthe change was unclear, but one reasonable inferencewas that in 2000, 5 years after launch, clinical practicerecognised the need for a more precise conversionlevel between morphine and fentanyl than theprevious statement (which reflected the SPC) that thelower strength fentanyl patch was equivalent toanything from 0.1mg to 135mg of morphine per day.This was not surprising given that this was aremarkably wide range of dosage of morphine whichwould be used to treat moderate pain at the lowerend and severe pain at the higher end.

The current on-line version of Martindale, TheComplete Drug Reference, also provided currentclinical use for Transtec and Durogesic patches. ForTranstec the ‘Use of a patch providing 35micrograms/hour of buprenorphine is approximatelyequivalent to the oral administration of 30 to 60 mg ofmorphine sulfate daily’. In contrast, for Durogesic,‘Use of a patch providing 25 micrograms of fentanylper hour is approximately equivalent to oraladministration of 90 mg of morphine sulfate daily’.

So, both the BNF and Martindale indicated that, inaccordance with the SPCs, clinicians treated thelowest strength Transtec patch as being equivalent toa significantly lower dose of morphine than thelowest strength of the Durogesic patch. The Transtec

lowest strength was considered to be approximatelyequivalent to the starting dose for modified releasemorphine, whilst the lowest strength Durogesic patchwas considered to be 50% more potent and on a parwith the middle strength Transtec patch.

The clinical significance of this could be seen fromtalking with experts in palliative care. Janssen-Cilagstated that there was no patient population in whichTranstec patches could be used in preference toDurogesic. A senior lecturer in palliative medicine ata local cancer centre had provided the followingcomment based on her clinical experience. She cited,two important factors about Transtec in clinicalpractice:

1 ‘It is an opioid with clinical properties which aredifferent from other opioids and we find useful inpatients who are susceptible to opioid side effects’.

2 ‘It can be started at a relatively lower dose thansome other opioids which is particularly useful inpatients who cannot tolerate Step 2 analgesics butwho have severe pain and problems with opioidside effects and need to be titrated gently. Such adrug is enormously helpful in clinical practice’.

A professor of anaesthesia, critical care and painmedicine at a local university stated that ‘it is anadvantage to patients and their clinicians to haveavailable to them, in Transtec, a skin patch that can beused to provide a lower ‘morphine equivalent’ dosethan the lowest dose Durogesic patch. Both areexcellent preparations that can alleviate pain andsuffering, but some patients can attain analgesia withminimal side-effects at lower opioid doses thanothers’.

In conclusion, there was nothing in the detail aid orleavepiece which denigrated Durogesic. The claimsimply compared the SPCs of the two products anddrew the obvious conclusion that the lowest strengthTranstec patch was less potent than the loweststrength Durogesic patch. This conclusion wassupported and further substantiated by clinicalpractice as evidenced by support from experts incancer and non-cancer pain management, the BNF,Martindale and Twycross et al. This information wasparticularly relevant to a doctor seeking to carefullytitrate a patient starting on a strong opioid patch, toassist him or her in achieving the optimum dose forthe patient with the minimum side effects. The claimwas accurate, fair and balanced. It reflected up-to-date clinical practice, as substantiated by clinicians,the BNF, Martindale and Twycross et al. Nappsubmitted that there was no breach of the Code.

PANEL RULING

The Panel noted that according to its SPC the loweststrength Transtec patch (35µg/hr) was equivalent to30-60mg oral morphine per day. The lowest strengthDurogesic patch (25µg/hr) was equivalent to oraldoses of morphine of less than 135 mg/day accordingto part of section 4.1 of its SPC. Under the headingdose titration the SPC stated that Durogesic 25µg/hrwas approximately equivalent to 90mg/day of oralmorphine. The Panel acknowledged that there was adifference between the products in that the lowest


strength Transtec patch was less potent than thelowest strength Durogesic patch. The Transtec SPCindicated that the product could be used in patientswho had previously not received any analgesicswhereas the Durogesic SPC stated that the initial doseshould be based, inter alia, on the patient’s opioidhistory. The Panel noted, however, that both thedetail aid and the leavepiece referred, on their frontcovers, to Transtec as ‘Your next step after a weakopioid in severe, chronic pain’ and it was in thiscontext that the claims at issue were considered.

Both the detail aid and the leavepiece stated that‘Transtec matrix patches can be used sooner than[Durogesic] patches’. There then followed adescription of the oral morphine equivalent of thelowest strength of both products. This was followedby the claim ‘Transtec’s low starting dose means itmay be appropriate to use before [Durogesic] instrong opioid naïve patients’. The Panel notedNapp’s submission with regard to the differencebetween the equivalent daily oral morphine dose forthe two products and clinical practice. Nonetheless,

Durogesic 25µg/hr was licensed for use in patients whohad not previously received a strong opioid. This wasnot made sufficiently clear in the materials. The Panelnoted that the claim stated that Transtec ‘may(emphasis added) be appropriate to use before[Durogesic]’ but considered that use of the word ‘may’did not negate the impression that Transtec wasappropriate to use before Durogesic. Given the licensedindications for both products with regard to patientswho needed more than a weak opioid, the Panelconsidered that, in the context in which they appeared,the claims ‘Transtec matrix patches can be used soonerthan fentanyl reservoir patches’ and ‘Transtec’s lowstarting dose means that it may be appropriate to usebefore fentanyl in strong opioid naïve patients’ weremisleading and could not be substantiated. Breaches ofClauses 7.2 and 7.4 were ruled. The Panel furtherconsidered that the claims disparaged Durogesic. Abreach of Clause 8.1 was ruled.




Gilead Sciences complained about a leavepiece produced byGlaxoSmithKline which promoted Epivir (lamivudine) andZiagen (abacavir) as an effective alternative nucleosidereverse transcriptase inhibitor (NRTI) backbone in treatment-naïve HIV patients. Gilead supplied two NRTIs, Viread(tenofovir) and Emtriva (emtricitabine).

Gilead alleged that the statement ‘Oranges are not the onlyfruit. Choose something fresh in naïve therapy’, on the frontpage of the leavepiece beneath a depiction of one apple at theend of four rows of oranges, implied that the use of Epivirplus Ziagen in treatment-naïve HIV patients was a ‘new’alternative; ‘fresh’ was synonymous with ‘new’, ‘recent’ and’latest‘. Both Epivir and Ziagen had been available for manyyears for use in combination as part of a therapeutic regimen.

The Panel considered that, in combination with the visual,the majority of readers would assume that ‘fresh’ meant thatthere was an alternative option available for treatment-naïvepatients to those commonly used. ‘Fresh’ did not necessarilyimply that the option was new. The statement at issue didnot contain the word ‘new’ and the Panel did not considerthat the statement would be interpreted as such. No breachof the Code was ruled.

Gilead noted that the heading ‘Choose Epivir + Ziagen aneffective alternative NRTI backbone in naïve therapy’appeared on a page of the leavepiece which detailed theresults of DeJesus et al. Two bullet points beneath thesubheading ‘The CNA 30024 study conclusions’ read‘Equivalent virological response to Combivir*’ and‘Significantly greater increase than Combivir* in medianCD4+ count from baseline’. A footnote to each bullet pointin small print at the bottom of the page stated ‘Combivirgiven as its separate components lamivudine andzidovudine’. Gilead stated that, despite the footnote, thebullet points misleadingly implied that Combivir (acombination tablet containing lamivudine and zidovudine)had been used in DeJesus et al, whereas its components hadbeen given separately.

The Panel noted that DeJesus et al compared Epivir plusZiagen to lamivudine plus zidovudine, the constituents ofCombivir. The Combivir summary of product characteristics(SPC) stated that when discontinuation of therapy with oneof the active substances of Combivir or dose reduction wasnecessary separate preparations of lamivudine andzidovudine were available. It was recommended thatseparate preparations be administered to patients with renalor hepatic impairment and haematological adverse reactions.The SPC contained the warnings and precautions relevant toboth lamivudine and zidovudine and stated that there wereno additional precautions and warnings relevant to thecombination Combivir. Section 5.1 stated that Combivir wasshown to be bioequivalent to lamivudine 50mg andzidovudine 300mg given as separate tablets whenadministered to fasting subjects. The Panel also notedGlaxoSmithKline’s submission of data regardingbioequivalence, clinical equivalence and tolerability.

The Panel considered that given the data and the statementsin the Combivir SPC the two bullet points ‘Equivalent

virological response to Combivir’ and ‘Significantlygreater increase than Combivir in median CD4+count from baseline’ were not misleading as alleged;no breach of the Code was ruled.

Gilead noted the claim ‘Choose Epivir + Ziagen abackbone with established tolerability’ hadappeared as a heading to a page of the leavepiecewhich discussed DeJesus et al and featured twobullet points which favourably compared thetolerability of Epivir plus Ziagen with Combivir. Afootnote to each bullet point, at the bottom of thepage in small print, read ‘Combivir given as itsseparate components lamivudine and zidovudine’.Gilead noted that once again two bullet pointscompared Epivir plus Ziagen with Combivir whenin fact Combivir had been given as its separatecomponents lamivudine and zidovudine.

The Panel considered that its comments aboveapplied here. The Panel did not consider that eitherbullet point: ‘Nausea and vomiting is 50% lesscommon with Epivir + Ziagen than with Combivir’or ‘Grade 3-4 neutropenia, anaemia, leukopenia andthrombocytopenia are significantly less commonwith Epivir + Ziagen than with Combivir (3% vs7%)’ was misleading as alleged. No breach of theCode was ruled.

Gilead alleged that the heading ‘Choose Epivir +Ziagen to maximise subsequent therapy options’, ona page which highlighted the effect of resistancemutations on the sensitivity of individual NRTIs,implied that by starting therapy with Epivir plusZiagen patients were offered more alternatives thanother combinations if therapy needed to be altereddue to the development of resistance. Readerswould assume that the claim meant that theEpivir/Ziagen combination offered the widest rangeof potential second-line therapy options of anycombination that might be used in treatment-naïvetherapy. Gilead alleged that the word ‘maximise’was being used as a superlative, and that the claimthat Epivir and Ziagen in combination maximisedsubsequent therapy options could not besubstantiated.

Gilead also alleged that this broad claim was notsupported by the references cited. The assessmentof future options was best made on the basis ofregimens proved to be clinically effective in theevent of initial regimen failure. No clinical data wascited for the efficacy of Epivir plus Ziagen inpatients who had failed their initial antiretroviraltherapy. All the arguments provided were based onin-vitro resistance testing.

The Panel noted that one definition of maximize was‘increase to the highest possible degree; enhance tothe utmost’. The Panel disagreed withGlaxoSmithKline’s submission that the claim didnot intimate that other regimens could not also


CASE AUTH/1592/5/04

GILEAD SCIENCES v GLAXOSMITHKLINEEpivir and Ziagen leavepiece

increase subsequent therapy options. The Panelconsidered that most readers would assume that theclaim ‘Choose Epivir + Ziagen to maximizesubsequent therapy options’ meant that by usingEpivir plus Ziagen in treatment-naïve patients theprescriber would have more subsequent therapyoptions compared to any other combinationtreatment option and thus implied that Epivir plusZiagen had some special merit; no evidence hadbeen provided that this was so. The Panel thusruled a breach of the Code.

The Panel further noted Gilead’s submission thatthe assessment of further treatment options was bestmade on the basis of regimens proved to beclinically effective. The Panel notedGlaxoSmithKline’s submission that in vitro testingwas standard practice and was supported by theBritish HIV Association treatment guidelines whichalso stated that in medicine-naïve patients resistancetesting prior to therapy might be of crucial value fora proportion of patients who carried mutations,especially in the context of demonstrabletransmitted medicine resistance. Resistance testingwas recommended for all medicine-naïve patientsprior to commencing treatment. The Panelconsidered that it was important to assess not onlythe efficacy of HIV treatment options but also theloss of subsequent treatment options. In theabsence of long-term clinical trial data showing theimpact of mutations developed during first linetherapy on subsequent therapy, in vitro resistantdata would provide estimates of remaining optionsfollowing treatment failure. The Panel thus did notconsider that the claim ‘Choose Epivir + Ziagen tomaximize subsequent therapy options’ wasincapable of substantiation solely because theassessment of future therapy options was based onin vitro resistance testing as alleged and on thisnarrow point ruled no breach of the Code.

Gilead noted that a table entitled ‘Effect ofresistance mutations on the sensitivity of individualNRTIs’ appeared beneath the headline claim at issueabove and showed the sensitivity of M184V, K65Rand M184V+K65R resistance mutations to thefollowing medicines; ddI, ddC, AZT [zidovudine],d4T, ABC [Ziagen], TDF [tenofovir] and 3TC[Epivir]. The sensitivity data was obtained fromPhenoSense reports for median phenotypes of thesegenotypic patterns. The heading to the table wasreferenced to Lanier et al (2003) and Nadler et al(2003).

Gilead alleged that in the context of the heading‘Choose Epivir + Ziagen to maximise subsequenttherapy options’, the table implied that the drugresistance mutuations which might develop as aresult of treatment with Ziagen and Epivir weresensitive to subsequent therapy with other NRTIs.However, the table did not give a comprehensive listof possible mutations which might result fromtreatment with Ziagen. When the leavepiece wasprepared, there was information available from aGlaxoSmithKline sponsored clinical study, Gazzardet al (2003), which showed that a regimen containingEpivir and Ziagen was associated with significantnumbers of M184V and L74V resistant mutations

(quoted as accounting for 48% and 26% ofvirological failures respectively). The SPC forZiagen also listed the possible resistant mutationwhich might occur with treatment, and includedM184V, L74V and Y115F; none of which werementioned in the leavepiece at issue.

The significance of the M184V and L74V mutationswas further emphasised by the conclusions of Lanieret al ‘Mutational patterns involving (K)65R and/or(L)74V in conjunction with M184V are associatedwith resistance to multiple NRTSs’, yet the table atissue did not refer to M184V and L74V, despite thefact that it was adapted from a similar table inLanier et al. Gilead alleged that the data presentedin the table was selective, and therefore neitherbalanced nor fair, and did not represent availableevidence.

The Panel noted that the table at issue wasreferenced to Lanier et al and Nadler et al. Lanier etal, which featured a similar table to the one at issue,sought to predict NRTI options by assessingresistance data. Data for, inter alia, the L74Vmutation in combination with M184V werepresented. It was unclear whether the data relatedsolely to treatment-naïve patients. The authorsnoted that in treatment-naïve patients any singlemutation probably pre-existed therapy and doublemutations might also be present. The authorsconcluded that K65R and/or 74V mutations inconjunction with M184V were associated withresistance to multiple NRTIs. These pathwaysrequired substantially fewer mutations to causebroad spectrum cross-resistance than thymidineanalogue mutations. First line therapy should bechosen in part to minimize the potential for rapidselection of broadly cross-resistant mutants thatmight reduce future treatment options.

The Ziagen SPC, pharmacodynamic properties,identified Ziagen resistant mutations as M184V,K65R, L74V and Y115F. The Epivir SPC,pharmacodynamic properties, referred to thedevelopment of M184V mutation and explained thatM184V mutants displayed greatly reducedsusceptibility to Epivir. It mentioned that Ziagenmaintained its retroviral activities against Epivirresistant HIV1 harbouring only the M184Vmutation.

The Panel considered that this was a complexmatter. The Panel noted its ruling above regardingthe heading ‘Choose Epivir and Ziagen to maximizetherapy options’. The Panel considered that thetable when viewed in light of the heading andsubheading ‘Effect of resistance mutations on thesensitivity of individual NRTIs’ did not make thebasis of the mutation selection sufficiently clear.There was an implication that the table listed allmutations that might develop during Ziagen andEpivir combination therapy and that was not so.The table was misleading in this regard. A breachof the Code was ruled.

Gilead noted that the section headed ‘Withvirological failure on an Epivir + Ziagen backbone’,which appeared on the same page as the claim andtable at issue in the two previous points above,


featured two bullet points, ‘The incidence of K65Rranges from 0 to < 1%’ and ‘The mutation mostcommonly seen is M184V alone’.

Gilead noted that, as explained above, Gazzard et aland Lanier et al clearly highlighted the significanceof both the M184V and L74V mutations. This hadagain been ignored in the summary. Gilead allegedthat the data presented was selective and thereforeneither balanced nor fair, nor representative of allthe evidence available in breach of the Code.

The Panel considered that its comments above wererelevant. The bullet points now at issue weredifferent to the data presented in the table; thesubheading did not imply that the subsequentbullet points would discuss each mutation whichwould develop on Epivir/Ziagen combinationtherapy. The Panel thus did not consider the sectionheaded ‘With virological failure on an Epivir andZiagen backbone’ misleading as alleged. No breachof the Code was ruled.

Gilead Sciences Limited complained about a six page,gate-folded leavepiece for Epivir (lamivudine) andZiagen (abacavir) entitled ‘Oranges are not the onlyfruit. Choose something fresh in naïve therapy’,which was produced by GlaxoSmithKline UKLimited. The leavepiece promoted Epivir plus Ziagenas an effective alternative nucleoside reversetranscriptase inhibitor (NRTI) backbone in treatment-naïve HIV patients.

The leavepiece was left with doctors following adetail from HIV representatives and had been so usedsince October 2003.

Gilead supplied two NRTIs, Viread (tenofovir) andEmtriva (emtricitabine).

1 Statement ‘Oranges are not the only fruit.Choose something fresh in naïve therapy’

This statement appeared on the front page of theleavepiece beneath a depiction of one apple at the endof four rows of oranges.

COMPLAINT

Gilead alleged that this statement implied that the useof Epivir plus Ziagen in treatment-naïve HIV patientswas a ‘new’ alternative and noted that the OxfordThesaurus (1991 Edition) described ‘fresh’ with suchsynonyms as ‘new’, ‘recent’ and ‘latest’. Both Epivirand Ziagen had been available for many years for usein combination as part of a therapeutic regimen.Gilead alleged a breach of Clause 7.11 of the Code.

RESPONSE

GlaxoSmithKline explained that in the UK, themajority of treatment-naïve HIV patients started anti-retroviral therapy (ART) on a regimen consisting of anNRTI backbone of lamivudine and zidovudine, plus athird agent. This third agent was usually a non-nucleoside reverse transcriptase inhibitor (NNRTI),although it might be a protease inhibitor (PI) or athird NRTI. In clinical practice, lamivudine pluszidovudine did not suit every patient, so alternative

NRTI backbones needed to be considered in thesecases.

Clinical trial data had previously illustrated theeffectiveness of Epivir and Ziagen in combinationwith a PI, however, limited data existed on theefficacy and safety of Epivir plus Ziagen incombination with efavirenz – an NNRTI which wasthe current UK standard of care third agent used inART.

DeJesus et al (2003) (study CNA 30024), was a largerandomised, double-blind, placebo-controlled, multi-centre study to evaluate the efficacy and safety of anEpivir and Ziagen NRTI backbone compared to alamivudine and zidovudine NRTI backbone, both incombination with efavirenz, in over 600 treatment-naïve adults. The results provided clinical datasupporting the non-inferiority of Epivir plus Ziagenas an NRTI backbone compared to the current mostwidely used NRTI backbone, lamivudine andzidovudine. GlaxoSmithKline thus considered thatthe term ‘fresh’ was appropriate, in keeping with thefruit visuals used in the leavepiece, to inform readersof this recent clinical data supporting the use of anEpivir plus Ziagen NRTI backbone in treatment-naïvepatients.

The Collins English Dictionary defined ‘fresh’ as: ’notstale or deteriorated; newly made, harvested etc’,‘newly acquired, created, found etc.: freshpublications’. There was no intention to use the term‘fresh’ as a synonym for ‘new’, but rather to emphasisthe new evidence base for an alternative approach intreatment-naïve HIV patients, for whom the currentstandard of care was not appropriate.GlaxoSmithKline strongly refuted any suggestion ofan intent to do so, and submitted therefore that therewas no breach of Clause 7.11.

PANEL RULING

The Panel noted the parties’ submissions on thevarious interpretations of ‘fresh’. The Panelconsidered that in combination with the visual on thefront page of the leavepiece the majority of readerswould assume that ‘fresh’ meant that there was analternative option available for treatment-naïvepatients to those commonly used. ‘Fresh’ did notnecessarily imply that the option was new.

The Panel noted that Clause 7.11 prohibited the use ofthe word ‘new’ to describe a product or presentationwhich had been generally available or therapeuticindication which had been generally promoted formore than twelve months in the UK. The Panel notedthat the statement at issue did not contain the word‘new’ and did not consider that the statement wouldbe interpreted as such. The Panel thus ruled nobreach of Clause 7.11 of the Code.

2 Page headed ‘Choose Epivir + Ziagen aneffective alternative NRTI backbone in naïvetherapy’

This statement appeared as a heading to page 2 of theleavepiece which detailed the results of DeJesus et al.

Two bullet points beneath the subheading ‘The CNA30024 study conclusions’ read ‘Equivalent virological


response to Combivir*’ and ‘Significantly greaterincrease than Combivir* in median CD4+ count frombaseline’. A footnote to each bullet point in smallprint at the bottom of the page read ‘Combivir givenas its separate components lamivudine andzidovudine’ and that Epivir and Ziagen was given incombination with efavirenz as was Combivir.

COMPLAINT

Gilead noted that the two bullet points werereferenced to DeJesus et al which compared a regimenof Epivir and Ziagen to lamivudine and zidovudineand not to Combivir (a combination tablet containinglamivudine and zidovudine) as stated in the piece.Despite the footnote stating that Combivir was givenas its separate components, Gilead alleged that thebullet points misled by implication in breach ofClause 7.2.

RESPONSE

GlaxoSmithKline explained that Combivir was afixed-dose combination of lamivudine 150mg andzidovudine 300mg licensed to be administered as onetablet twice daily. The separate components ofCombivir were also available as Epivir (lamivudine)and Retrovir (zidovudine), respectively. Epivir waslicensed to be administered as 300mg daily either as300mg once daily or 150mg twice daily, and Retroviras 500-600mg daily given in 2–3 divided doses (theusual adult dose being 300mg twice daily).

There was extensive data demonstrating the efficacyand safety of the lamivudine/zidovudine NRTIbackbone as a constituent of a HAART (highly activeanti-retroviral therapy) regimen – as well as datademonstrating the bioequivalence of Combivir to itsseparate components.

Moore et al (1999) had shown that Combivir wasbioequivalent to co-administration of lamivudine andzidovudine separately. Eron et al (2000) had shownthe antiretroviral activity of the fixed-doseformulation of lamivudine/zidovudine (Combivir) tobe clinically equivalent to the conventionallamivudine and zidovudine regimen. There were nodifferences in medicine-related adverse eventsbetween the two arms. Eron et al also confirmed thefindings of Rozenbaum and Chauveau (1998), whichshowed that Combivir taken twice daily had anequivalent safety profile to that of lamivudine (150mgbid) plus zidovudine (200mg tid).

In view of the well-known interchangeability andbioequivalence of Combivir and its components,GlaxoSmithKline submitted that the statements madeon page 2 were not designed to mislead byimplication. A footnote clearly stated that Combivirwas administered as its separate components inDeJesus et al and provided additional clarifyinginformation. GlaxoSmithKline submitted that thebullet points were reasonable and therefore there wasno breach of Clause 7.2.

PANEL RULING

The Panel noted that DeJesus et al compared Epivir

plus Ziagen to lamivudine plus zidovudine, theconstituents of Combivir.

The Combivir summary of product characteristics(SPC) stated that when discontinuation of therapywith one of the active substances of Combivir or dosereduction was necessary separate preparations oflamivudine and zidovudine were available. The SPCrecommended that separate preparations beadministered to patients with renal or hepaticimpairment and haematological adverse reactions.Section 4.4 of the SPC contained the warnings andprecautions relevant to both lamivudine andzidovudine and stated that there were no additionalprecautions and warnings relevant to the combinationCombivir. Section 5.1 of the SPC, Pharmacokineticsproperties, stated that Combivir was shown to bebioequivalent to lamivudine 50mg and zidovudine300mg given as separate tablets when administered tofasting subjects. The Panel also notedGlaxoSmithKline’s submission regardingbioequivalence, clinical equivalence and tolerabilitystudies; Moore et al, Eron et al.

The Panel considered that given the data and thestatements in the Combivir SPC the two bullet points‘Equivalent virological response to Combivir’ and‘Significantly greater increase than Combivir inmedian CD4+ count from baseline’ were notmisleading as alleged; no breach of Clause 7.2 wasruled.

3 Page headed ‘Choose Epivir + Ziagen abackbone with established tolerability’

This claim appeared as a heading to page 5 of theleavepiece which discussed DeJesus et al (2003) andfeatured two bullet points which favourablycompared the tolerability of Epivir plus Ziagen withCombivir. A footnote to each bullet point, at thebottom of the page in small print read ‘Combivirgiven as its separate components lamivudine andzidovudine’.

COMPLAINT

Gilead noted that similar misleading statements tothose at issue at point 2 above were also made on thispage. Once again, two bullet points compared Epivirplus Ziagen with Combivir when in fact Combivirhad been given as its separate componentslamivudine and zidovudine. A breach of Clause 7.2was alleged.

RESPONSE

GlaxoSmithKline referred to its comments at point 2above.

PANEL RULING

The Panel considered that its comments at point 2above applied here. The Panel did not consider thateither bullet point: ‘Nausea and vomiting is 50% lesscommon with Epivir + Ziagen than with Combivir’ or‘Grade 3-4 neutropenia, anaemia, leukopenia andthrombocytopenia are significantly less common withEpivir + Ziagen than with Combivir (3% vs 7%)’ was


misleading as alleged. No breach of Clause 7.2 wasruled.

4 Claim ‘Choose Epivir + Ziagen to maximisesubsequent therapy options’

This claim headed page 3 which highlighted the effectof resistance mutations on the sensitivity of individualNRTIs.

COMPLAINT

Gilead stated that this claim implied that by startingtherapy with a combination of Epivir and Ziagen,patients were offered more alternatives than othercombinations if therapy needed to be altered due tothe development of resistance.

Readers would assume that the claim meant that theEpivir and Ziagen combination offered the widestrange of potential second-line therapy options of anymedicine combination that might be used intreatment-naïve therapy. Consequently, the word‘maximise’ was being used as a superlative. Gileadfurther alleged that the claim that Epivir and Ziagenin combination maximised subsequent therapyoptions could not be substantiated in breach of Clause7.10.

Gilead also alleged that this broad claim was notsupported by the references quoted. The assessmentof future options was best made on the basis ofregimens proved to be clinically effective in the eventof initial regimen failure. No clinical data wasreferenced for the efficacy of Epivir plus Ziagen inpatients shown to have failed their initialantiretroviral therapy. All the arguments providedwere based on in-vitro resistance testing. Gileadalleged a breach of Clause 7.4 of the Code.

RESPONSE

GlaxoSmithKline did not accept that ‘maximise’ wasbeing used as a superlative as there was no intimationthat other regimens could not also increasesubsequent therapy options. It did not accept thatthere had been a breach of Clause 7.10.

GlaxoSmithKline explained that in clinical practice,virological failure arose as a consequence ofdevelopment of resistant mutations. Duringdevelopment it was therefore important tocharacterise those mutations associated with aparticular medicine. Virologists conducted a series ofin vitro experiments where wild type virus wascultured with increasing concentrations of a newmedicine in an attempt to drive the development ofthese mutations, which could then be characterised.From this data phenotypic resistance data could bedeveloped which would suggest when the efficacy ofa medicine might be impacted by certain mutations.

Whilst it might be optimal to use clinical data toinform future treatment options following thevirological failure of a HAART regimen, it was notalways possible to do so. In the absence of such datait was disingenuous to state that the use of in vitrophenotypic and genotypic resistance testing to help

predict the viral response of patients was not a validand widely used methodology. Furthermore, as databecame available from clinical trials it was often seenthat when virological failure occurred the mutationsthat developed in vivo were similar to those thatdeveloped in vitro, although some mutations mightoccur more commonly than others. The use of in vitroresistance testing was standard practice and wasfurther supported by the current HIV treatmentguidelines issued by The British HIV Association(BHIVA). In a section of the guidelines which dealtwith which medicines to use following failure ofinitial therapy it was stated: ‘Wherever possible oneor two different drugs of the NRTI/PI/NNRTI classesshould be included in such a switch regimen.Resistance testing should be used to inform the choiceof regimen, particularly for those with priorexperience of NAs and PIs or NNRTIs. Patientswhose therapy fails with adherence problems maybenefit from simpler but effective regimens to whichtheir virus is still sensitive’.

GlaxoSmithKline submitted that, for the intendedaudience of HIV clinicians, it was not misleading touse the results of phenotypic and genotypic resistancetesting to substantiate the claims made, and thereforethere was no breach of Clause 7.4.

PANEL RULING

The Panel noted that Clause 7.10 prohibited the use ofsuperlatives except for those limited circumstanceswhere they related to a clear fact about a medicine.Claims should not imply that a medicine had somespecial merit, quality or property unless this could besubstantiated.

The Panel noted that maximize was defined, inter alia,as ‘increase to the highest possible degree; enhance tothe utmost’ (ref New Shorter Oxford EnglishDictionary (1993)).

The Panel disagreed with GlaxoSmithKline’ssubmission that the claim did not intimate that otherregimens could not also increase subsequent therapyoptions. The Panel considered that most readerswould assume that the claim ‘Choose Epivir + Ziagento maximize subsequent therapy options’ meant thatby using Epivir and Ziagen in combination intreatment-naïve patients the prescriber would havemore subsequent therapy options compared to anyother combination treatment option and thus impliedthat Epivir plus Ziagen had some special merit; noevidence had been provided that this was so. ThePanel thus ruled a breach of Clause 7.10.

The Panel further noted Gilead’s submission that theassessment of further treatment options was bestmade on the basis of regimens proved to be clinicallyeffective. The Panel noted GlaxoSmithKline’ssubmission that in vitro testing was standard practiceand was supported by the BHIVA treatmentguidelines which also stated that in medicine-naïvepatients resistance testing prior to therapy might be ofcrucial value for a proportion of patients who carriedmutations, especially in the context of demonstrabletransmitted medicine resistance. Resistance testingwas recommended for all medicine-naïve patientsprior to commencing treatment. The Panel considered


that it was important to assess not only the efficacy ofHIV treatment options but also the loss of subsequenttreatment options. In the absence of long-term clinicaltrial data showing the impact of mutations developedduring first line therapy on subsequent therapy, invitro resistant data would provide estimates ofremaining options following treatment failure. ThePanel thus did not consider that the claim ‘ChooseEpivir + Ziagen to maximize subsequent therapyoptions’ was incapable of substantiation solelybecause the assessment of future therapy options wasbased on in vitro resistance testing as alleged and onthis narrow point ruled no breach of Clause 7.4 of theCode.

5 Table entitled ‘Effect of resistance mutationson the sensitivity of individual NRTIs’

This table appeared beneath the headline claim atissue at point 4 above and showed the sensitivity ofM184V, K65R and M184V+K65R resistance mutationsto the following medicines; ddI, ddC, AZT[zidovudine], d4T, ABC [Ziagen], TDF [tenofovir] and3TC [Epivir]. The sensitivity data was obtained fromPhenoSense reports for median phenotypes of thesegenotypic patterns. The heading to the table wasreferenced to Lanier et al (2003) and Nadler et al(2003).

COMPLAINT

Gilead alleged that in the context of the heading‘Choose Epivir + Ziagen to maximise subsequenttherapy options’, the table implied that the drugresistance mutuations which might develop as a resultof treatment with Ziagen and Epivir were sensitive tosubsequent therapy with other NRTIs. However, thetable did not give a comprehensive list of possiblemutations which might result from treatment withZiagen. When the leavepiece was prepared (15September 2003), there was information availablefrom a GlaxoSmithKline sponsored clinical study,Gazzard et al 2003 (the ZODIAC study), whichshowed that a regimen containing Epivir and Ziagenwas associated with significant numbers of M184Vand L74V resistant mutations (quoted as accountingfor 48% and 26% of virological failures respectively).The SPC for Ziagen (18 March 2004) also listed thepossible resistant mutation which might occur withtreatment, and included M184V, L74V and Y115F;none of which were mentioned in the leavepiece atissue.

The significance of the M184V and L74V mutationswas further emphasised by the conclusions from aposter by Lanier et al which stated: ‘Mutationalpatterns involving (K)65R and/or (L)74V inconjunction with M184V are associated withresistance to multiple NRTSs’, and yet, the table atissue made no reference of M184V and L74V, despitethe fact that it was adapted from a similar table (table2) in the Lanier poster.

The data presented in the table at issue was selectiveand therefore neither balanced nor fair, norrepresentative of all the evidence available. Gileadalleged a breach of Clause 7.2 of the Code.

RESPONSE

GlaxoSmithKline disagreed with Gilead’s statementthat the table implied that the drug resistancemutations which might develop as a result oftreatment with Ziagen plus Epivir were sensitive tosubsequent therapy with other NRTIs. The tableclearly illustrated that virus was not sensitive toEpivir in the presence of the M184V mutation alone,and that virus was not sensitive to ddI, ddC, tenofovirand Epivir in the presence of the K65R mutationalone, and that virus was not sensitive to ddI, ddC, orEpivir in the presence of the M184V + K65Rmutations. The table illustrated that virus might bepartially sensitive to Ziagen and tenofovir in thepresence of the M184V + K65R mutations.

PhenoSense was a virological database widely usedby laboratories to provide clinical guidance tophysicians for the selection of new agents when thepatient’s regimen had failed due to resistancemutations.

The table in question made no claim to be acomprehensive listing of the effects of all resistancemutations on all NRTIs. The mutations chosen werethose of particular interest (because they occurred inthe greatest numbers) when considering the studies inquestion and cited in the leavepiece – namely fortenofovir, Miller et al (2002) and for Epivir/Ziagen,DeJesus et al.

GlaxoSmithKline noted Gilead’s comment regardingthe lack of data presented for the L74V resistancemutation. When the leavepiece was prepared none ofthe data available for DeJesus et al noted thedevelopment of the L74V mutation. More recentlyavailable data from a poster presentation, Irlbeck et al(2004), noted that the L74V mutation wassubsequently found to have developed in one subject12 weeks after failure with the M184V and G190Smutations. Even at this later time point, no cases ofthe K65R mutation were found to have developed.

GlaxoSmithKline summarised virology results for thecited studies DeJesus et al and Miller et al whichinvestigated the use of either Ziagen or tenofovir(Viread) in combination with Epivir and efavirenz(Sustiva).

GlaxoSmithKline noted that genotypic typing of theHIV virus in subjects experiencing virological failureenabled the presence or absence of specific virologicalmutations to be confirmed. Definitions of whatconstituted virological failure could vary from trial totrial – in DeJesus et al it was based on a new FDArequirement; the time to loss of virological responsealgorithm, which defined virological failure as either:

● Rebound: Confirmed two consecutive plasma HIV-1 RNA values greater than the lower limit ofquantification (50copies/ml) after achieving aconfirmed level of <50copies/ml during thetreatment phase

● Never Suppressed: Plasma HIV-1 RNA levels neverachieve confirmed suppression (<50copies/ml)with at least 48 weeks of randomised treatment

● Insufficient Virological Response: Plasma HIV-1RNA levels never achieving confirmed


suppression (<50copies/ml) and investigatoridentified the reason for treatment discontinuationprior to week 48 due to insufficient viral loadresponse.

Miller et al defined it as patients with >400copies/mlof HIV-1 RNA at week 48, week 96 or at earlydiscontinuation for any reason.

It was possible for patients to be defined as failingvirologically and yet to have a viral load that was stilltoo low to enable genotypic analysis to be successfullyperformed with current techniques – this was the casefor some subjects in DeJesus et al. For this reason thedata was presented as the number of cases of eachspecific mutation as a percentage of the number thatcould be genotyped successfully.

Of the 33 virological failures observed in DeJesus et al,20 were seen in the Epivir/Ziagen/efavirenz arm and13 in the zidovudine/lamivudine/efavirenz arm, withgenotyping available for 16 of 33 virological failures.The reason for this was that there was difficulty inestablishing genotype for those virological failureswith plasma HIV-1 levels <200copies/ml.

Of the 16 subjects with genotype available, 8 subjectsdemonstrated wild type virus (suggesting pooradherence to treatment rather than lack of efficacy ofthe ART regimen) and 8 had mutant virus. In theEpivir/Ziagen/efavirenz arm, 6 subjects had wildtype virus and 4 had mutant virus (all 4 had NNRTIassociated mutations and two also had M184V andM184I). In the zidovudine/lamivudine/efavirenzarm, 2 subjects had wild type virus and 4 mutantvirus (all had NNRTI associated mutations andM184V). No subjects were demonstrated to have theL74V or K65R mutation at time of failure.

GlaxoSmithKline did not understand why Gilead hadreferred to the ZODIAC study since this studyincluded Ziagen being administered in a once dailyregimen. Ziagen was currently licensed for twicedaily administration only, and it would beinappropriate to include data supporting anunlicensed dosage schedule in promotional material.Gilead’s repeated references in its letter to studiesusing Ziagen in a once daily regimen were thereforemisleading and irrelevant.

However, for completeness and as backgroundinformation GlaxoSmithKline provided a table whichsummarized the virology results for the ZODIACstudy, which investigated the use of Ziagen in a oncedaily or twice daily regimen in combination withEpivir and efavirenz.

In the ZODIAC study there was a slightly higherincidence of the L74V mutation than in DeJesus et al.Upon examination of those subjects experiencingvirological failure (that could be genotyped), 23%were found to have already possessed virologicalmutations at baseline, which might have impacted onthe subsequent mutation selection process.

If GlaxoSmithKline had chosen to include a widerrange of clinical studies, where an Epivir/ZiagenNRTI backbone (at currently licensed doses) had beenstudied in treatment-naïve HIV patients, this wouldhave further supported the company’s premise thatM184V was the most commonly produced NRTI

associated mutation following therapy with thesemedicines. However, as Miller et al was currently theonly published study where a tenofovir/Epivirbackbone had been used in treatment-naïve patients,GlaxoSmithKline considered that a comparison ofthese two large similarly designed trials (Miller et aland DeJesus et al) provided the most balanced rangeof data.

In the leavepiece at issue, virological data for theMiller et al study at 48 weeks was used, butGlaxoSmithKline for completeness provided 96 weekdata (Miller et al 2002 and Miller et al 2003).

GlaxoSmithKline provided a copy of an extract fromThe Stanford HIV Drug Resistance Database, anindependent and internationally respected database,which showed that the impact of the K65R mutationon subsequent NRTI treatment options was muchgreater than that of the L74V and Y115F mutations.Following virological failure with the K65R mutation,only ziclovudine was left fully sensitive. Followingfailure with Y115F, all nucleosides except Ziagenremained fully sensitive. Following failure with L74V,zidovudine, d4T, kenofovir, FTC and Epivir remained.

In summary therefore, GlaxoSmithKline refuted thatthe data presented in the table at issue was selectiveand that there had been any breach of Clause 7.2.

PANEL RULING

The Panel noted Gilead’s allegation that in the contextof the heading ‘Choose Epivir + Ziagen to maximizesubsequent therapy options’ the table implied that thedrug resistance mutations which might develop as aresult of treatment with Ziagen plus Epivir weresensitive to subsequent therapy with other NRTIs.Gilead alleged that the data presented was selective.

The Panel also noted GlaxoSmithKline’s submissionthat the table did not purport to be a comprehensivelisting of the effects of all resistance mutations on allNRTIs. The mutations chosen were those of particularinterest because they were particularly prevalent inDeJesus et al and Miller et al. Miller et al wascurrently the only published study where a tenofovir/Epivir backbone had been used in treatment-naïvepatients. GlaxoSmithKline thus submitted that acomparison of these similarly designed trialsprovided the most balanced range of data. The Panelnoted GlaxoSmithKline’s comments upon the studies’design and results.

The Panel noted GlaxoSmithKline’s submission thatwhen the leavepiece was prepared the available datafor DeJesus et al did not mention the L74V mutation.The Panel noted that material had to comply with theCode not only when it was prepared but alsothroughout the period when it was used.

The table at issue was referenced to Lanier et al (2003)and Nadler et al (2003). Lanier et al, which featured asimilar table to the one at issue, sought to predictNRTI options by assessing resistance data. Data for,inter alia, the L74V mutation in combination withM184V were presented. It was unclear whether thedata related solely to treatment-naïve patients. Theauthors noted that in treatment-naïve patients anysingle mutation probably pre-existed therapy and


double mutations might also be present. The authorsconcluded that K65R and/or 74V mutations inconjunction with M184V were associated withresistance to multiple NRTIs. These pathwaysrequired substantially fewer mutations to cause broadspectrum cross-resistance than thymidine analoguemutations. First line therapy should be chosen in partto minimize the potential for rapid selection ofbroadly cross-resistant mutants that might reducefuture treatment options.

The Ziagen SPC, pharmacodynamic propertiesidentified Ziagen resistant mutations as M184V, K65R,L74V and Y115F. The Epivir SPC, pharmacodynamicproperties referred to the development of M184Vmutation and explained that M184V mutantsdisplayed greatly reduced susceptibility to Epivir. Itmentioned that Ziagen maintained its retroviralactivities against Epivir resistant HIV1 harbouringonly the M184V mutation.

The Panel considered that this was a complex matter.The Panel noted its ruling at point 4 above regardingthe heading ‘Choose Epivir and Ziagen to maximizetherapy options’. The Panel considered that the tablewhen viewed in light of the heading and subheading‘Effect of resistance mutations on the sensitivity ofindividual NRTIs’ did not make the basis of themutation selection sufficiently clear. There was animplication that the table listed all mutations thatmight develop during Ziagen and Epivir combinationtherapy and that was not so. The table wasmisleading in this regard. A breach of Clause 7.2 wasruled.

6 Section headed ‘With virological failure on anEpivir + Ziagen backbone:’

This section, which appeared on page 3, the samepage as the claim and table at issue at points 4 and 5above, featured two bullet points which read ‘Theincidence of K65R ranges from 0 to < 1%’ and ‘Themutation most commonly seen is M184V alone’.

COMPLAINT

Gilead noted that, as explained above, the ZODIACstudy and Lanier et al clearly highlighted thesignificance of both the M184V and L74V mutations.This had again been ignored in the summary. Gilead

alleged that the data presented was selective andtherefore neither balanced nor fair, nor representativeof all the evidence available in breach of Clause 7.2 ofthe Code.

RESPONSE

GlaxoSmithKline noted that Gilead appeared to havebased its argument on data referring to Ziagen use inan unlicensed dosage schedule, and again, this wasirrelevant.

With regard to the L74V mutation, the references citedgave the incidence of this mutation in studies withZiagen administered at licensed doses as a percentageof those failing ranging from 0.9% to 5%. Based oninformation contained in The Stanford HIV DrugResistance Database GlaxoSmithKline contended that,in terms of future NRTI sequencing options available,the consequences were less limiting than would be thecase with the development of the K65R mutation.Thus, GlaxoSmithKline denied that the significance ofthe L74V mutation had been ignored.

With regard to the K65R mutation, the references citedgave the incidence of this mutation as a percentage ofthose failing ranging from 0% to 2.1%, whichcontrasted with the 22% incidence observed in Milleret al. Again, GlaxoSmithKline refuted that thesignificance of the K65R mutation had been ignored,and did not consider that there had been a breach ofClause 7.2.

PANEL RULING

The Panel considered that its comments at point 5above were relevant. The Panel considered that thebullet points now at issue were different to the datapresented in the table; the subheading did not implythat the subsequent bullet points would discuss eachmutation which would develop on Epivir/Ziagencombination therapy. The Panel thus did not considerthe section headed ‘With virological failure on anEpivir and Ziagen backbone’ misleading as alleged.No breach of Clause 7.2 was ruled.




Roche complained about a Zometa (zoledronic acid) detail aidissued by Novartis. Zometa was licensed for the prevention ofskeletal related events (pathological fractures, spinalcompression, radiation or surgery to bone, or tumour-inducedhypercalcaemia) in patients with advanced malignanciesinvolving bone. It could also be used to treat tumour-inducedhypercalcaemia. Roche marketed Bondronat which wasavailable as film coated tablets and as a concentrate for solutionfor intravenous administration. Both formulations wereindicated for the prevention of skeletal events (pathologicalfractures, bone complications requiring radiotherapy orsurgery) in patients with breast cancer and bone metastases. Inaddition, Bondronat IV was also indicated for the treatment oftumour-induced hypercalcaemia with or without metastases.Zometa and Bondronat were bisphosphonates.

Roche stated that the headline claim ‘Licensed for bonemetastases in more tumour types than any otherbisphosphonate’ on the front cover of the detail aid did notspecify that the product was licensed for the prevention ofskeletal related events in patients with advancedmalignancies involving bone. Zometa was not licensed toprevent or clear bone metastases as this claim suggested.Roche alleged that the claim was misleading.

The Panel noted the licensed indication for Zometa andconsidered that the claim ‘Licensed for bone metastases inmore tumour types than any other bisphosphonate’ was notsufficiently clear in this regard; there was an implication thatthe product could be used to treat the metastases per se andthat was not so. The Panel considered that the claim wasmisleading. A breach of the Code was ruled. This rulingwas appealed.

On appeal by Novartis, the Appeal Board, although notingthat Zometa would have an effect on bone metastases and theproduct was licensed to prevent five specific skeletal relatedevents in patients with advanced malignancies involvingbone, nonetheless considered the claim was not sufficientlyclear. The Appeal Board upheld the Panel’s ruling of abreach of the Code.

Roche alleged that the claim ‘Broad protection from thethreat of skeletal complications’ which appeared as astrapline below the product logo on the front cover of thedetail aid and also on other pages was all-embracing.

The Panel noted that the strapline and product logo, togetherwith the claim at issue above, was all the promotional copythat appeared on page 1. The Panel noted its comments andruling above and considered that, given the context in whichit appeared, the claim now at issue, ‘Broad protection fromthe threat of skeletal complications’ was exaggerated and all-embracing; it reinforced the impression that Zometa could beused to treat the metastases per se or otherwise protectpatients from developing bone metastases which was not so.A breach of the Code was ruled. This ruling was appealed.

Upon appeal by Novartis the Appeal Board considered that,given the context in which it appeared, the claim wasexaggerated and all-embracing. The Appeal Boardconsidered that the claim gave the impression that Zometacould provide protection from the formation of new

metastases which was not so. Skeletal relatedevents as referred to in the summary of productcharacteristics (SPC) was not the same as skeletalcomplications. The Appeal Board upheld thePanel’s ruling of a breach of the Code.

With regard to other uses of the claim the Panelnoted that the product logo and strapline alsoappeared at the bottom of pages 3, 8, 9, 12 and 14.Page 3 was part of a double-page spread headed‘Zometa – meeting the challenges of treatingmetastic bone disease’ and included details of themost common skeletal related events in patientswith metastatic bone disease. Pages 8 and 9 togetherwere headed ‘Zometa – a new standard for thetreatment of hypercalcaemic cancer patients’, page12 dealt with the tolerability of Zometa and theprescribing information and references were givenon page 14. The Panel considered that given thecontent of these pages the claim ‘Broad protectionfrom the threat of skeletal complications’ was notunreasonable; there was no implication that Zometaprevented the patient developing metastases. ThePanel considered that, other than on page 1 of thedetail aid, given the context in which it appeared,the claim was not exaggerated or all-embracing. Nobreach of the Code was ruled.

Roche noted a bar chart on page 3 of the detail aid,adapted from Green et al (1994), depicted thepotency of seven bisphosphonates relative topamidronate disodium in vivo (hypercalcaemic rat)on a linear scale. Six of the seven medicines shownhad a relative potency of less than 44. Of those sixibandronate (Bondronat) had the highest relativepotency of 43.6. The relative potency of Zometa wasgiven as 847.

Roche alleged that the bar chart misled,misrepresented and exaggerated the difference inpotencies between Bondronat and Zometa. It wasnot possible to see how the bar chart had beengenerated from the cited reference. In addition, atthe time the detail aid was produced Bondronat didnot have a product licence for metastatic bonedisease and, hence the medicine was promoted priorto the grant of its marketing authorization.

Roche stated that the footnote on the table of databelow the chart stating that ‘potency is notnecessarily related to clinical efficacy’ could not beused to ameliorate the impact of the clinical messageat the claim ‘Broad protection from the threat ofskeletal complications’.

Roche stated that the use of the bar chart entitled‘Zometa – meeting the challenges of treatingmetastatic bone disease’ and with a strapline –‘Broad protection from the threat of skeletalcomplications’ misled the reader into unfairlyassuming greater efficacy for Zometa thanBondronat when no such data existed.


CASE AUTH/1594/6/04

ROCHE v NOVARTISZometa detail aid

The Panel considered that as the page was headed‘Zometa – meeting the challenges of treatingmetastatic bone disease’, it would be viewed interms of the clinical situation. Although the barchart at issue showed that in terms of in vivopotency Zometa was many times more potent thanthe other bisphosphonates, given the context, somereaders would assume that it also meant that Zometawas the most efficacious. The Panel further notedthat although the page heading referred tometastatic bone disease the bar chart related to thetreatment of hypercalcaemia. Overall the Panelconsidered that the bar chart was misleading andexaggerated the differences between Zometa andBondronat as alleged. Breaches of the Code wereruled which were upheld on appeal from Novartis.

The Panel considered that although the bar chartreferred to Roche’s product ibondronate, regardlessof what it was licensed for Novartis could not beaccused of promoting it. No breach of the Code wasruled.

The Panel considered that the bar chart wasmisleading with regard to the implied relativeefficacy of Bondronat and Zometa but consideredthat this was covered by its ruling above. The Paneldid not, however, consider that the bar chartdisparaged Bondronat. No breach of the Code wasruled.

Roche noted a table of data below the bar chart atissue above compared the relative potency (in vivo),infusion time, bioavailability and route ofadministration of Zometa, pamidronate and oralclodronate. It was noted that with oral preparations,patients had to adhere to a strict dosing scheduleand that the potential for poor compliance andtreatment failure was high.

Roche alleged that the omission of Bondronat fromthe table was unbalanced. Roche further noted thatalthough comments were made about the posologyof other bisphosphonates, no caution was discussedabout Zometa and its use related to renal function(ie it could not be used in a patient with a creatinineclearance < 30ml/min and there were concerns overconcomitant use with other potentially nephrotoxicagents).

The Panel noted that the leavepiece pre-datedBondronat’s licence for use in metastatic bonedisease. The Panel thus ruled no breach of the Codewith regard to the omission of Bondronat from thetable.

The Panel noted that the table detailed relativepotency (in vivo), infusion time (minutes),availability % and route of administration. None ofthese headings related to the use of thebisphosphonates in patients with impaired renalfunction. The Panel therefore did not consider thatomission of such data was misleading. No breach ofthe Code was ruled.

Roche alleged that the claim ‘Statistically significanteffects were achieved at low concentration’ whichappeared beneath a statement that pre-clinicalstudies had shown significant effects of Zometa oncancer cells and its ability to interfere with the

metastatic process in bone in animal models was all-embracing. Such effects were commonly seen withbisphosphonates and the page imputed special meritfrom pre-clinical data where there might be none.

The Panel noted that the page detailed Zometa’smode of action and featured a diagram showing thatit mediated osteosclerotic bone formation andinhibited osteolytic bone resorption. The Panel didnot consider, given the context in which it appeared,that the claim at issue, ‘Statistically significanteffects were achieved at low concentration’ wasexaggerated, all-embracing or that it implied specialmerit from pre-clinical data where there might benone. No breach of the Code was ruled.

Roche alleged that the headline claim ‘Zometa –superior to pamidronate in reducing the risk of bonecomplications in advanced breast cancer’ was allembracing; it implied that all patients with advancedbreast cancer would benefit which not true. The datareferred to a highly selected subset ie patients whowere undergoing hormonal therapy and who hadsuffered from hypercalcaemia of malignancy. Thedata on file to support the claim consisted of fourtables from a confidential report. The data had beensupplied on request with a few hand scribbledcalculations but without explanation. Roche allegedthis failed to adequately substantiate the claim.

Roche added that apart from radiation to bone (asecondary endpoint), the original publicationshowed that the primary endpoint of non-inferioritywas reached, ie Zometa was no worse thanpamidronate (Rosen et al 2001). The SPC also stated‘Zometa 4mg showed comparable efficacy to 90mgpamidronate in the prevention of SREs [SkeletalRelated Events]’. Although the SPC included astatement of benefit over pamidronate, this wasbased on a secondary endpoint of the trial. Theclaim that Zometa was superior to pamidronate wastherefore not consistent with the SPC.

The Panel noted that the claim at issue ‘Zometa –superior to pamidronate in reducing the risk of bonecomplications in advanced breast cancer’ wasreferenced to data on file published as Rosen et al(2003) and Rosen et al (2004). The data did not, assubmitted by Roche, refer only to those who wereundergoing hormonal therapy. Rosen et al (2003)looked at the treatment of skeletal complications inpatients with advanced multiple myeloma or breastcancer. Rosen et al (2004) looked at the treatment ofbone metastases in breast cancer patients with atleast one osteolytic lesion. Rosen et al (2003) statedthat in patients with breast cancer Zometa 4mg wassignificantly more effective than pamidronate,reducing the risk of skeletal related events by anadditional 20% (p=0.025) compared withpamidronate and by an additional 30% in patientsreceiving hormonal therapy (p=0.009).

Rosen et al (2004) stated that multiple-event analysisshowed a 20% additional reduction in the risk ofskeletal events (p=0.037) for Zometa-treated patientscompared with those taking pamidronate. Inpatients with lytic lesions although the primaryendpoint (the proportion of patients with a skeletalevent) did not achieve statistical significance,


multiple-event analysis demonstrated that thebenefit of Zometa was even greater compared withpamidronate with an additional 30% reduction inthe risk of skeletal events, a secondary endpoint,being observed (p=0.01). The Panel noted that thediscussion section of Rosen et al (2004) stated thatthe data strongly suggested that Zometa might bemore effective clinically compared withpamidronate in patients with breast cancer and atleast one osteolytic lesion and in the overallpopulation of patients with breast carcinoma. Suchcaution was not reflected in the claim at issue. ThePanel considered that the headline claim was not afair reflection of the study results and wasmisleading and exaggerated in that regard. Breachesof the Code were ruled.

Upon appeal by Novartis the Appeal Board notedthat the data from Rosen et al (2003) was a pre-planned, prospective analysis whereas Rosen et al(2004), was a post-hoc retrospective analysis of thedata. The Appeal Board considered that theheadline claim was a fair reflection of the data andas such was not misleading or exaggerated. Nobreach of the Code was ruled.

The Panel noted that at the time the claim was madethe Rosen et al papers had not been published; onlythe four pages of data on file, which comprisedtables showing hazard ratios, p values and robust pvalues for the various treatments were available.Some handwritten calculations were included ontwo of the tables. The Panel considered that thepresentation of the data on file was such that it wasdifficult to understand and inadequate tosubstantiate the claim at issue. A breach of theCode was ruled.

The Panel noted that the Zometa SPC stated that in acombined patient group of those with multiplemyeloma or breast cancer with at least one bonelesion, Zometa and pamidronate had comparableefficacy in prevention of skeletal related events. Theclaim at issue related only to patients with breastcancer. In that regard the Panel did not considerthat the claim was inconsistent with the SPC. Nobreach of the Code was ruled.

The claim ‘Zometa – effective bone protection inbreast cancer’ appeared below a chart which showedthat breast cancer patients treated with Zometa had a20% lower risk of developing skeletal complicationscompared with pamidronate. Roche noted thatZometa was not licensed for breast cancer per se, noradjuvant use to prevent bone metastases, as thisclaim promoted. The data on file referred to abovewas supplied on request. There was no mention ofbone pain scores. Roche alleged that the data didnot substantiate the claim.

The Panel noted that the claim ‘Zometa – effectivebone protection in breast cancer’ appeared on a pageon which the heading referred to ‘advanced breastcancer’. The page tag, however, stated ‘Zometa – inbreast cancer’. In that context the Panel consideredthat the claim implied that Zometa was authorizedfor use in all breast cancer patients which was notso. The claim was inconsistent with the SPC. ThePanel ruled a breach of the Code as alleged.

Upon appeal by Novartis, the Appeal Board onbalance considered that the claim at issue impliedthat Zometa was authorized for use in all breastcancer patients which was not so. The claim wasthus inconsistent with the SPC. The Appeal Boardupheld the Panel’s ruling of a breach of the Code.

Roche noted that the claim ‘Zometa consistentlyreduces the incidences of all types of skeletal-relatedevents (SREs)’ and associated bar chart werereferenced to the data on file referred to above. Thebar chart showed numerical values for Zometaversus pamidronate in terms of the percentage ofpatients with fracture (all types), radiation to bone,surgery to bone and spinal cord compression. Apartfrom radiation to bone (a secondary end point), theprimary end point showed non-inferiority, ieZometa was no worse than pamidronate. The SPCalso stated ‘Zometa 4mg showed comparable efficacyto 90mg pamidronate in the prevention of SREs’. Inthe absence of values of significance on the barchart, the reader could not evaluate this claim, whichwas misleading and all-embracing.

The Panel noted that the statement in the SPC thatZometa was comparable to pamidronate in theprevention of skeletal related events referred to astudy of patients with multiple myeloma or breastcancer with at least one bone lesion. The bar chartshowed only the breast cancer data and that,compared with pamidronate, Zometa reduced thepercentage of patients with each skeletal relatedevent. The clinical significance of the differencebetween the two medicines was not mentioned. ThePanel considered that the claim and the bar chartwere misleading; a breach of the Code was ruled.The Panel also considered that the claim was all-embracing. A breach of the Code was ruled. Theserulings were appealed.

Upon appeal by Novartis the Appeal Board notedthat although the claim at issue referred to allskeletal related events the incidence of tumourrelated hypercalcaemia was not shown on the barchart. Although there was a numerical advantagefor Zometa with regard to each skeletal related eventthere was no indication as to the statisticalsignificance of any of the data; all of the advantagesshown for Zometa could thus have been chancefindings. The Appeal Board considered that theclaim was misleading and all-embracing as alleged.The Panel’s rulings of breaches of the Code wereupheld.

Roche drew attention to a claim ‘Consistently lowerpain scores reported throughout the study’ andassociated bar chart which showed eight studyperiods over the 24 months of the study. Bone painscores were statistically significantly different toplacebo at only half of those study periods and,even then, the actual ‘p’ number was not given – just‘p<0.05’. Roche alleged that the claim wasmisleading and all-embracing.

The Panel noted that the visual impression of thebar chart was that at every time point Zometa-treated patients had lower pain scores than thosetreated with placebo and that such differences weremeaningful. This was not so. At months 6, 12, 15


and 18, although there was a trend to a lower painscore with Zometa, the results were not statisticallysignificant. The Panel did not consider that use ofthe word ‘consistently’ served to negate theotherwise misleading impression. A breach of theCode was ruled. The Panel ruled that the claim wasall-embracing in breach of the Code. This rulingwas appealed.

Upon appeal by Novartis the Appeal Board notedthat the claim was based on a long-term study whichhad shown a difference in pain scores for Zometaand placebo. Although only four of the eight timepoints were statistically significant, these wereclearly marked and a p value given. By defaultthere must have been no statistically significantdifferences at the other time points. The AppealBoard considered that the bar chart was clear andwas not misleading and no breach of the Code wasruled. The Appeal Board did not consider that theclaim was all-embracing. No breach of the Codewas ruled.

Roche alleged a breach of the Code with regard tothe use of the word ‘new’ in the claim ‘Zometa – anew standard for the treatment of hypercalcaemiccancer patients’ as Zometa was launched more than12 months ago. Roche also alleged that the claimwas all-embracing as it suggested Zometa could beused to treat any cause of hypercalcaemia in cancerwhereas it was only licensed for ‘tumour-induced’hypercalcaemia. There were other causes ofhypercalcaemia and although it was highly likelythat a patient’s hypercalcaemia was due to theirmalignancy, it was not automatically the case. Thisclaim was therefore all-embracing and outside of themarketing authorization.

The Panel noted that in the claim at issue ‘new’ wasused to describe the standard of care, not Zometathus the Panel ruled no breach of the Code.

The Panel noted that, in cancer patients,hypercalcaemia was likely to be tumour-induced asopposed to due to any other cause. The page tags read‘Zometa-tumour induced hypercalcaemia’. The Panelthus did not consider the claim ‘Zometa – a newstandard for the treatment of hypercalcaemic cancerpatients’ was all-embracing. No breach of the Codewas ruled. The claim did not promote Zometa for anunlicensed indication and thus no breach was ruled.

Roche alleged that the claim ‘Zometa decreases therisk of a skeletal complication in multiple myelomacompared to pamidronate’ was misleading. Theclaim was referenced to Rosen et al (2001). This wasfollowed by a chart showing the relative risk ofZometa versus pamidronate in multiple myeloma.The p value was p=0.593. The claim implied anadvantage for Zometa whereas there was nosignificant difference between it and pamidronate.

The Panel noted that, there was no statisticallysignificant difference between Zometa andpamidronate. The Panel considered that the claimwas misleading as alleged. A breach of the Codewas ruled which was upheld on appeal by Novartis.

Roche stated that the claim ‘Zometa has superiorefficacy to pamidronate disodium in hypercalcaemic

cancer patients’ implied that all hypercalcaemiccancer patients would benefit. The data (Major et al2001) only referred to breast cancer patients whowere undergoing hormonal therapy and who hadsuffered from hypercalcaemia of malignancy – ahighly selected subset. Also, as noted above, not allhypercalcaemic cancer patients would have tumour-induced hypercalcaemia. Roche alleged that theclaim was all-embracing and not true.

The Panel noted that Major et al, recruited patients≥ 18 years of age with histological or cytologicalconfirmation of cancer and severe hypercalcaemia ofmalignancy. Patients were not limited to those withbreast cancer undergoing hormonal therapy asalleged; patients had a wide range of primary cancersites. The Panel noted its comments above that, inpatients with cancer, hypercalcaemia was likely tobe tumour-induced as opposed to due to any othercause. The Panel considered that, in the context inwhich it appeared, ie on a page summarising all thathad gone before, the claim was not misleading orall-embracing as alleged. No breach of the Codewere ruled.

Roche noted the claim ‘Zometa is quick andconvenient to deliver’, referenced to the ZometaSPC, and alleged that ‘quick’ was not a medicalterm; it was vague and without substantiation.‘Quick’ did not appear in the SPC. It also misledthe reader as patients required a pre-dose renal testas, according to the SPC Zometa was notrecommended in patients with severe renal failureand the dose should be withheld if renal functionhas deteriorated. A 15 minute infusion was not‘quick’ and the claim was thus misleading.

Roche noted that the patient must usually: attendhospital as an out patient, have bloods taken tocheck renal function, have a vein cannulated and aninfusion given, have medical and nursingattendance, have the intravenous line taken downand be checked to ensure they could safely be senthome. The whole process could not be described as‘convenient’ especially when the only reason to visithospital was to receive a bisphosphonate.Intravenous care at home also carried difficultiesand risks. Roche alleged that the claim wasmisleading.

The Panel noted that, the claim at issue appeared ona page which summarized the Zometa data andcompared it with other bisphosphonates. The claim‘Zometa is quick and convenient to administer’would be read in that context.

Compared with Bondronat or Aredia, Zometa couldbe infused in smaller volumes over a shorter periodof time. The Panel thus considered that Zometacould be administered quickly. No breach of theCode was ruled in that regard.

The Panel considered that the claim that Zometa wasconvenient to use implied an advantage over othersimilar therapies. This was not so. As with otherintravenous bisphosphonates, patients had to havetheir renal function and plasma electrolytesmeasured. Prescribers must also ensure thatpatients treated with Zometa were adequatelyhydrated. This was not the case for other


bisphosphonates. The Panel considered that Zometawas no more convenient to administer than otherbisphosphonates and in that regard the impliedadvantage was misleading. A breach of the Codewas ruled.

Upon appeal by Novartis the Appeal Board did notconsider that, within the overall context of treating apatient with cancer, Zometa would be seen asinconvenient. Zometa could be administered by a15 minute infusion, which was faster than other IVbisphosphonates. The Appeal Board considered thatthis advantage was in itself a convenient aspect ofZometa therapy. The Appeal Board did not considerthat the claim was misleading and no breach of theCode was ruled.

Roche noted the claim ‘Zometa is well tolerated’ andstated that of all the issues raised by the detail aid,the fact that Novartis had not fully informedprescibers about the issues surrounding Zometa andrenal toxicity was of greatest concern. Renal toxicitywas described as ‘common’ in the Zometa SPC andyet was not even mentioned in the detail aid whichgave prominence to details only of efficacy.

References were not made to the letter to the NewEngland Journal of Medicine (Chang et al 2003) fromthe Food and Drug Administration (FDA) discussingrenal toxicity concerns about zoledronic acid. Rochenoted that no such concerns were raised in this letterabout any other bisphosphonates. Otherpublications had referred to Zometa’s renal toxicity(Markowitz et al 2003 and Johnson et al 2003).

No reference was made to the important safetyrequirement of withholding Zometa treatment inpatients with severe renal impairment. Theobligation to discontinue therapy put the patient atfurther risk of skeletal events in the absence ofbisphosphonate cover from Zometa. No mentionwas made of the need for caution with the use ofZometa with other potentially nephrotoxic agents.Roche alleged that Novartis had failed to give dueemphasis to these important safety matters whendiscussing safety issues and this might be seriousenough to constitute a breach of Clause 2.

The Panel noted that the Zometa SPC stated that theproduct must only be used by clinicians experiencedin the administration of intravenousbisphosphonates. In the Panel’s view thesephysicians would be well aware that such medicineshad to be used with care in patients with renalimpairment and that renal function should bemonitored during therapy. The Zometa SPC statedthat the adverse reactions to the medicine weresimilar to those reported for other bisphosphonatesand could be expected to occur in approximately onethird of patients. The Panel did not consider thatthe omission of data regarding the renal toxicity ofZometa gave a misleading impression of the safetyof the product. There was no implication that renaltoxicity was not a problem with Zometa. The Panelthus considered that the claim ‘Zometa is welltolerated’ was not misleading. No breach of theCode was ruled. The Panel consequently also ruledno breach of Clause 2 of the Code. These rulingswere appealed.

Upon appeal by Roche the Appeal Board notedstatements in the Zometa SPC with regard to whocould use the product and the incidence of adverseevents compared with other bisphosphonates. TheAppeal Board noted that there were some concernsregarding the renal tolerability profile of Zometa butconsidered that these had been exaggerated byRoche. The Appeal Board did not consider that thefailure to refer to the renal tolerability profile of theproduct rendered the claim ‘Zometa is welltolerated’ misleading and unbalanced as alleged.The Panel’s rulings of no breach of the Code wereupheld.

Roche noted the claim ‘Zometa has a fast andconvenient administration’, referenced to the SPC,and stated that the same issues arose here as aboveregarding the claim ‘Zometa is quick and convenientto deliver’.

The Panel noted its comments and rulings abovewith regard to ‘quick’ and ‘convenient’ andconsidered that they applied here. The Panel thusruled no breach of the Code with regard to fast anda breach of the Code with regard to convenient. Theruling of a breach of the Code was overturned onappeal by Novartis for the reasons given above.

Roche Products Limited complained about a Zometa(zoledronic acid) detail aid (ref ZOM03001303) issuedby Novartis Pharmaceuticals UK Ltd. Zometa waspresented as a concentrate for solution for infusionand licensed for the prevention of skeletal relatedevents (pathological fractures, spinal compression,radiation or surgery to bone, or tumour-inducedhypercalcaemia) in patients with advancedmalignancies involving bone. It could also be used totreat tumour-induced hypercalcaemia. Rochemarketed Bondronat which was available as filmcoated tablets and as a concentrate for solution forintravenous administration. Both formulations wereindicated for the prevention of skeletal events(pathological fractures, bone complications requiringradiotherapy or surgery) in patients with breastcancer and bone metastases. In addition, BondronatIV was also indicated for the treatment of tumour-induced hypercalcaemia with or without metastases.Both Zometa and Bondronat belonged to a class ofmedicines known as bisphosphonates.

1 Claim ‘Licensed for bone metastases in moretumour types than any other bisphosphonate’

This claim appeared as the headline on the front cover(page 1) of the detail aid.

COMPLAINT

Roche stated that the claim was vague and did notspecify for what the product was being used, ie theprevention of skeletal related events (pathologicalfractures, spinal compression, radiation or surgery tobone, or tumour-induced hypercalcaemia) in patientswith advanced malignancies involving bone.Zometa was not licensed to prevent or clear bonemetastases as this claim suggested. Roche allegedthat the claim was misleading in breach of Clause 7.2of the Code.


RESPONSE

Novartis disagreed that the claim was vague. Zometawas licensed for ‘Prevention of skeletal related events(pathological fractures, spinal compression, radiationor surgery to bone, or tumour-inducedhypercalcaemia) in patients with advancedmalignancies involving bone’. The companyconsidered that as ‘advanced malignancies involvingbone’ was synonymous with ‘bone metastases’ and‘skeletal related events’ were the consequence of bonemetastases the meaning of the claim was clear. Therewas no implication that Zometa could either preventthe occurrence of bone metastases, or clear them;given that the target audience was oncology/haematology specialists it was unimaginable that theywould infer this. Novartis did not consider that theclaim was misleading and thus denied a breach ofClause 7.2.

PANEL RULING

The Panel noted that Zometa was licensed to preventskeletal related events in patients with advancedmalignancies involving bone. The Panel consideredthat the claim ‘Licensed for bone metastases in moretumour types than any other bisphosphonate’ was notsufficiently clear in this regard; there was animplication that the product could be used to treat themetastases per se and that was not so. The Panelconsidered that the claim was misleading. A breachof Clause 7.2 was ruled.

APPEAL BY NOVARTIS

Novartis referred to the licensed indications forZometa. Bone was one of the most common locationsto which cancer metastasised. The major cancer typeswhich tended to metastasise to bone includedmultiple myeloma, breast, prostate, lung, kidney andthyroid cancers. All of these were covered by theZometa license, unlike the other bisphosphonatescurrently on the market which were all restricted tobreast cancer +/- multiple myeloma.

Bone metastases damaged bone making it moresusceptible to complications such as: pathologicalfractures due to intrinsic weakening of the bonecaused by the metastasis; spinal cord compressionleading to paralysis due to pressure on the cord froma growing metastasis, or collapse of a vertebra;hypercalcaemia due to release of bone calcium fromover-activity in the skeleton caused by the growth ofthe metastasis. These sequelae of bone metastaseswere defined as ‘skeletal related events’. Bydefinition, it was not possible to have a skeletalrelated event without at least one bone metastasis.Researchers concluded that once these metastasesappeared, sequelae would ensue which complicatedthe course of the disease and adversely affectedquality of life.

The goals of treatment of bone metastases were toreduce morbidity and so improve quality of life.Such treatment might involve chemotherapy,hormonal therapy, radiotherapy, surgery to stabilise aweakened bone, for instance in the spine, andbisphosphonates.

Novartis noted that the term ‘treatment of bonemetastases’ with reference to bisphosphonates was incommon use in the clinical community, as it wasequally applied to the use of radiotherapy in thissetting. The company noted that in Rosen et al (2003)and Rosen et al (2004), the term ‘treatment’ was usedto describe the use of zoledronic acid, or pamidronate,in patients with bone metastases. Novartis providedfurther examples of the use of this terminology in themedical literature (Lacerna and Hohneker 2003 andMaxwell et al 2003). Therefore in common parlance inthe clinical community, the term ‘treatment’ in thiscontext was not only well understood, but appearedto be the preferred term.

Thus, Zometa was used to treat bone metastases inorder to prevent these complications, hence thewording of the licence ‘Prevention of skeletal relatedevents’ in patients who already had one or more bonemetastases: ‘Advanced malignancies involving bone’meant the presence of bone metastases.

Novartis disagreed with the Panel’s statement that‘there was an implication that the product could beused to treat the metastases per se and this was not so’.On the contrary, the product was used precisely totreat bone metastases as demonstrated above.

Novartis noted that Roche had alleged that the claimsuggested that Zometa was licensed to prevent orclear bone metastases (which was quite distinct fromtreating them). However, there was no indication ofthis. ‘Licensed for bone metastases …’ implied thatthe condition was already present, as in ‘licensed forhypertension’. It did not imply that the licence wasfor prevention. It also did not state that treatmentwould ‘clear’ or cure bone metastases, againanalogous to ‘licensed for hypertension’ which didnot claim a cure, merely a treatment.

Novartis did not consider that the claim wasmisleading or in breach of Clause 7.2.

COMMENTS FROM ROCHE

Roche stated that ‘common parlance’ in medicine wasnot a substitute for unambiguous and definitestatements, as set out in the marketing authorization.The Panel was correct in its ruling of this major firstclaim at its face value – it implied that Zometa couldbe used to treat metastatic bone cancer per se, forwhich it was not licensed.

APPEAL BOARD RULING

The Appeal Board noted that the Panel had stated thatZometa could not be used to treat the metastases perse. The Appeal Board disagreed with this; Zometawould have an effect on bone metastases and theproduct was licensed to prevent five specific skeletalrelated events in patients with advanced malignanciesinvolving bone. The Appeal Board considered,however, that the claim ‘Licensed for bone metastasesin more tumour types than any other bisphosphonate’was not sufficiently clear in this regard; there was animplication that the product could be used to preventor clear the metastases, and that was not so. TheAppeal Board considered that the claim was


ambiguous and misleading. The Panel’s ruling of abreach of Clause 7.2 was upheld. The appeal on thispoint was unsuccessful.

2 Claim ‘Broad protection from the threat ofskeletal complications’

This claim appeared as a strapline below the productlogo on the front cover of the detail aid and also onpages 3, 8, 9, 12 and 14.

COMPLAINT

Roche alleged that the claim was all-embracing inbreach of Clause 7.10.

RESPONSE

Novartis stated that the claim clearly appeared in thecontext of the licence for bone metastases and wasconsistent with the summary of productcharacteristics (SPC) wording ‘Prevention of skeletalrelated events’. The marketing authorization wassupported by several large randomized trials in awide array of solid tumour types and multiplemyeloma. Novartis did not consider that the claimwas all-embracing and thus denied a breach of Clause7.10.

PANEL RULING

The Panel noted that the claim ‘Broad protection fromthe threat of skeletal complications’ appeared as astrapline beneath the Zometa product logo on thefront cover of the detail aid. That, together with theclaim at issue in point 1 above, was all thepromotional copy that appeared on page 1. The Panelnoted its comments and ruling in point 1 andconsidered that, given the context in which itappeared, the claim now at issue was exaggerated andall-embracing; it reinforced the impression thatZometa could be used to treat the metastases per se orotherwise protected patients from developing bonemetastases which was not so. A breach of Clause 7.10was ruled. This was appealed by Novartis.

The product logo and strapline also appeared at thebottom of pages 3, 8, 9, 12 and 14. Page 3 was part ofa double-page spread headed ‘Zometa – meeting thechallenges of treating metastic bone disease’ andincluded details of the most common skeletal relatedevents in patients with metastatic bone disease. Pages8 and 9 together were headed ‘Zometa – a newstandard for the treatment of hypercalcaemic cancerpatients’, page 12 dealt with the tolerability of Zometaand the prescribing information and references weregiven on page 14. The Panel considered that giventhe content of these pages the claim ‘Broad protectionfrom the threat of skeletal complications’ was notunreasonable; there was no implication that Zometaprevented the patient developing metastases. ThePanel noted from the licensed indication for Zometathat it could be used to prevent a number of skeletalrelated events (pathological fractures, spinalcompression, radiation or surgery to bone, or tumour-induced hypercalcaemia). The Panel considered that,other than on page 1 of the detail aid, given the

context in which it appeared the claim was notexaggerated or all-embracing. No breach of Clause7.10 was ruled.

APPEAL BY NOVARTIS

Novartis stated that as described in point 1 above,Zometa was used for the treatment of patients withbone metastases, the claim ‘Broad protection from thethreat of skeletal complications’ further clarified thepurpose of treatment, which was to protect againstskeletal complications in this disease. In addition, asit was not possible to have a skeletal complicationwithout underlying bone metastases, this claim couldnot imply that Zometa protected against developingbone metastases.

Novartis did not consider that the claim wasexaggerated or all-embracing or in breach of Clause7.10.

COMMENTS FROM ROCHE

Roche stated that the claim implied that Zometa had abroad range of protection against all skeletalcomplications. Sustained quality of life maintenanceand bone pain control had not been demonstratedover 2 years. Patients might still sustain fractures; theSPC showed a non-significant difference compared toplacebo for the proportion of patients with fractureswith prostate (p=0.052), breast and myeloma(p=0.653), or other solid tumours (p=0.064). Radiationtherapy might not be avoided; the SPC showed non-significant differences compared to placebo for theproportion of patients with radiation to bone withprostate (p=0.119), and solid tumours other thanbreast and prostate (p=0.173). The claim remained abreach of Clause 7.10.

APPEAL BOARD RULING

The Appeal Board noted that the claim ‘Broadprotection from the threat of skeletal complications’appeared as a strapline beneath the Zometa productlogo on the front cover of the detail aid. That,together with the claim at issue in point 1 above, wasall the promotional copy that appeared on page 1.The Appeal Board noted its comments and ruling inpoint 1 and considered that, given the context inwhich it appeared, the claim now at issue wasexaggerated and all-embracing. The Appeal Boardconsidered that the claim gave the impression thatZometa could provide protection from the formationof new metastases which was not so. Skeletal relatedevents as referred to in the SPC was not the same asskeletal complications. The Appeal Board upheld thePanel’s ruling of a breach of Clause 7.10 of the Codein relation to the claim as it appeared on page 1. Theappeal on this point was unsuccessful.

3 Bar chart adapted from Green et al (1994)

A bar chart on page 3 of the detail aid depicted thepotency of seven bisphosphonates relative topamidronate disodium in vivo (hypercalcaemic rat) ona linear scale. Six of the seven medicines shown had a


relative potency of less than 44. Of those sixibandronate (Bondronat) had the highest relativepotency of 43.6. The relative potency of Zometa wasgiven as 847.

COMPLAINT

Roche alleged that the bar chart misled,misrepresented and exaggerated the difference inpotencies between Bondronat and Zometa in breachof Clause 7.2, 7.3 and 7.10. It was not possible to seehow the bar chart had been generated from the citedreference and if it was not capable of substantiation itwould breach Clause 7.5. In addition, in September2003 (the date on which the detail aid was produced),Bondronat did not have a product licence formetastatic bone disease and, hence the chart, at thattime, promoted a medicine prior to the grant of itsmarketing authorization. A breach of Clause 3.1 wasalleged.

Roche stated that the footnote on the table of databelow the chart (see point 4 below) stating that‘potency is not necessarily related to clinical efficacy’,could not be used to ameliorate the impact of theclinical promotional message that was repeated at thebottom of page 3 in bold red lettering – ‘Broadprotection from the threat of skeletal complications’.

Roche noted the prominent use of the bar chart on thesecond page of a double-page spread entitled, in boldred lettering, ‘Zometa – meeting the challenges oftreating metastatic bone disease’ and with a bold redstrapline – ‘Broad protection from the threat ofskeletal complications’. It misled the customer intounfairly assuming greater efficacy for Zometa thanBondronat when no such data existed in breach ofClauses 7.2 and 8.1.

RESPONSE

Novartis submitted that the y axis on the bar chartwas clearly labelled ‘Potency relative to pamidronatedisodium in vivo (hypercalcaemic rat), linear scale’.Green et al only contained one hypercalcaemic ratmodel (the other model was mouse calvaria and wasin vitro), and only one table of relative potencies inthis model. Relative potencies were derived from theED50 (µg/kg SC) figures taking pamidronate as thestandard. Thus, the ED50 for clodronate was 1,200compared to pamidronate of 61, giving a relativepotency of 0.05 (61/1,200) and so on. This was furtherhighlighted by the authors in the ‘Results’ sectionwhere they stated ‘[Zometa], with an ED50 of 0.072µg/kg SC, was the most potent of all thebisphosphonates tested to date in our laboratory’ and‘Thus, [Zometa] was 850 times more potent thanpamidronate …’.

Novartis submitted that the bar chart did not mislead,misrepresent or exaggerate the difference in potenciesas it was clear that the figures were not a generalcomparison but were all derived from a single in vivostudy as stated in the heading ‘Zometa is the mostpotent bisphosphonate in this in vivo study’. Novartisdenied breaches of Clauses 7.2, 7.3 or 7.10; the barchart could be substantiated from the reference givenand was not in breach of Clause 7.5.

Novartis added that the use of an in vivohypercalcaemic rat model to demonstrate relativepotencies could not be considered to promoteBondronat prior to its marketing authorization formetastatic bone disease, especially since, at this timepoint, Bondronat already had a marketingauthorization for tumour-induced hypercalcaemia.Thus the bar chart could not be in breach of Clause3.1.

Novartis stated that the general heading on page 3,‘Zometa is a highly potent bisphosphonate’, was astatement of fact and not a comparison. There wasalso a footnote about potency and efficacy whichrelated to the potency figures given. The strapline‘Broad protection from the threat of skeletalcomplications’ was repeated from page 1 and referredonly to the licensed indication for Zometa and did notinfer comparison to other bisphosphonates. Inaddition, the heading on pages 2 and 3 ‘Zometa –meeting the challenges of treating metastatic bonedisease’ also referred only to Zometa and did notmake any comparison to other bisphosphonates. Itdid not therefore mislead the customer into assuminggreater efficacy for Zometa over Bondronat and wasnot in breach of Clause 7.2, nor did it disparageBondronat and so it was thus not in breach of Clause8.1.

PANEL RULING

Page 3 was part of a double-page spread headed‘Zometa – meeting the challenges of treatingmetastatic bone disease’; the Panel thus consideredthat the information given on page three would beviewed in terms of the clinical situation. Althoughthe bar chart at issue showed that in terms of in vivopotency Zometa was many times more potent thanthe other bisphosphonates, given the context in whichit appeared, some readers would assume that suchrelative potency translated into similar relativeefficacy and that Zometa was the most efficaciousbisphosphonate. The Panel further noted thatalthough the page heading referred to metastatic bonedisease the bar chart related to the treatment ofhypercalcaemia. Overall the Panel considered that thebar chart was misleading and exaggerated thedifferences between Zometa and Bondronat asalleged. Breaches of Clauses 7.2, 7.3 and 7.10 wereruled.

The Panel noted Novartis’ explanation as to how thedata had been generated for the bar chart. The Panelconsidered that the bar chart per se could besubstantiated. The Panel noted, however, that Rochehad alleged a breach of Clause 7.5 which requiredsubstantiation for any claim etc to be providedwithout delay at the request of members of the healthprofessions or appropriate administrative staff. Therewas no indication that data to substantiate the claimat issue had been requested or that such a request hadnot been complied with. No breach of Clause 7.5 wasruled.

The Panel noted that Clause 1.2 of the Code defined‘promotion’ as any activity undertaken by apharmaceutical company, or with its authority whichpromoted the prescription, supply, sale or


administration of its medicines (emphasis added). Itwas thus an established principle under the Code thatone company could not be accused of promotinganother company’s products. The Panel noted thatnonetheless references to competitor products had tocomply, inter alia, with Clause 7.2. There washowever, no allegation in this regard. The Panelconsidered, therefore, that although the bar chartreferred to Roche’s product ibandronate, regardless ofwhat it was licensed for Novartis could not beaccused of promoting it. No breach of Clause 3.1 wasruled.

The Panel considered that the bar chart wasmisleading with regard to the implied relative efficacyof Bondronat and Zometa but considered that thiswas covered by its ruling of a breach of Clause 7.2above. The Panel did not, however, consider that thebar chart disparaged Bondronat. No breach of Clause8.1 was ruled.

APPEAL BY NOVARTIS

Novartis noted that the bar chart appeared under abanner heading ‘Zometa – meeting the challenges oftreating metastatic bone disease’. The clear andunambiguous heading ‘Zometa is the most potentbisphosphonate in this in vivo study’, referred veryspecifically to Green et al and gave no opportunity tomislead that the evidence presented was in a clinicalsetting. The chart also had an over-arching statement‘Zometa is a highly potent bisphosphonate’. This wasa matter of fact. The chart then explained the pre-clinical basis for the claim. The fact that the pre-clinical rat model was in hypercalcaemia (not bonemetastases) was not relevant as it was a model forpotency alone, not for clinical efficacy.

Novartis stated that the detail aid was aimed atoncologists and haematologists, a specialist ratherthan generalist audience. These doctors generallyworked in tertiary referral centres, and many wereacademics. Clinicians of this calibre found scientificdata – including pre-clinical data – useful as it addedto the overall information on a product allowing themto make an informed decision.

Novartis disagreed that the chart misled the reader,given the very clear heading, and therefore did notconsider it to be in breach of Clause 7.2. Novartisconsidered that, in the context of the clearly labelledin vivo study, the comparison of products – in thisnarrow definition was acceptable and therefore not inbreach of Clause 7.3. Equally, in this narrowdefinition, the difference between Zometa andibandronate was not exaggerated, but an accuratereflection of the study, and therefore not in breach ofClause 7.10.

COMMENTS FROM ROCHE

Roche stated that putting this misleading chart(adapted by Novartis to exaggerate the potency ofZometa) amidst a discussion of clinical efficacy wasclearly designed to imply clinical relevance. Rochesubmitted that the chart could not be read in isolationon the page. Roche concurred with the Panel’s ruling.

APPEAL BOARD RULING

The Appeal Board noted that page 3 was part of adouble-page spread headed ‘Zometa – meeting thechallenges of treating metastatic bone disease’ andthus considered that the information on both pageswould be viewed in terms of the clinical situation.Although the bar chart at issue showed that the invivo potency of Zometa was many times greater thanthe other bisphosphonates, given the context in whichit appeared, some readers would assume that suchrelative potency translated into similar relativeefficacy and the bar chart showed that Zometa wasthe most clinically efficacious bisphosphonate.Overall the Appeal Board considered that the barchart was misleading and exaggerated the differencesbetween Zometa and Bondronat as alleged. TheAppeal Board upheld the Panel’s rulings of breachesof Clauses 7.2, 7.3 and 7.10 of the Code. The appealon this point was unsuccessful.

4 Table of data on page 3

A table of data below the bar chart at issue in point 3above compared the relative potency (in vivo),infusion time, bioavailability and route ofadministration of Zometa, pamidronate and oralclodronate. It was noted that with oral preparations,patients had to adhere to a strict dosing schedule andthat the potential for poor compliance and treatmentfailure was high.

COMPLAINT

Roche complained that Bondronat had not beenincluded in the table. Bondronat had beencommercially available for metastatic bone diseasesince March 2004. To not include reference to theproduct in the detail aid was unbalanced in breach ofClause 7.2 of the Code.

Roche further noted that although comments weremade about the posology of other bisphosphonates,no caution was discussed about Zometa and its userelated to renal function ie it could not be used in apatient with a creatinine clearance < 30ml/min andthere were concerns over concomitant use with otherpotentially nephrotoxic agents. This was unbalancedin breach of Clause 7.2.

RESPONSE

Novartis stated that the detail aid had beenwithdrawn in January 2004 to coincide with thelaunch of a new formulation of Zometa (from the oldfreeze dried powder to the new solution for infusion).The detail aid was thus withdrawn prior to themarketing authorization for Bondronat in metastaticbone disease in breast cancer, therefore failure tomention the product in the clinical context of treatingmetastatic bone disease was hardly unreasonable atthat time and could not be considered unbalanced orin breach of Clause 7.2.

Novartis disagreed with Roche’s comments in relationto the posology of other bisphosphonates in this table.The table had a bold heading about bioavailabilityand the table clearly related to this. There was a


single comment at the bottom of the table aboutcompliance with oral agents which had directrelevance to the issue of bioavailability and thetimings (from the SPC) required for oral clodronate tobe taken were given and again were directly relevantto its bioavailability. Novartis failed to see therelevance of Roche’s comments about the use ofZometa in patients with severely impaired renalfunction in the context of a table about bioavailability,particularly when Roche had not indicated thatsimilar cautions for the other agents discussed shouldbe mentioned. Novartis therefore disagreed that, inthe context of bioavailability, the table wasunbalanced and thus denied a breach of Clause 7.2.

PANEL RULING

The Panel noted that the leavepiece pre-datedBondronat’s licence for use in metastatic bone disease.The Panel thus ruled no breach of Clause 7.2 of theCode with regard to the omission of Bondronat fromthe table of data at issue.

The Panel noted that the table of data detailed relativepotency (in vivo), infusion time (minutes), availability% and route of administration. None of theseheadings related to the use of the bisphosphonateslisted in patients with impaired renal function. ThePanel therefore did not consider that omission of suchdata with regard to Zometa from the table in questionwas misleading. No breach of Clause 7.2 was ruled.

5 Claim ‘Statistically significant effects wereachieved at low concentration’

This claim appeared at the bottom of page 4 beneath astatement that pre-clinical studies had shownsignificant effects of Zometa on cancer cells and itsability to interfere with the metastatic process in bonein animal models.

COMPLAINT

Roche alleged that the claim, offered without furtherexplanation or references, was all-embracing in breachof Clause 7.10 and possibly Clause 7.5. Such effectswere commonly seen with bisphosphonates and thepage imputed special merit from pre-clinical datawhere there might be none.

RESPONSE

Novartis noted that the claim was the last point on apage entitled ‘Zometa – a potent inhibitor of osteolyticbone resorption and osteosclerotic bone formation’which was referenced and described how Zometaworked. It was not a stand-alone statement and couldnot be considered to be all-embracing in this context.It was not in breach of Clause 7.10, and since it wasclearly referenced, nor was in breach of Clause 7.5.

Novartis did not entirely understand Roche’s pointabout these effects being seen commonly withbisphosphonates and this implying some special meritfrom pre-clinical data. The mechanism of actionshown was consistent with the references cited, andalso with Section 5.1 of the Zometa SPC and therefore

it was not an exaggerated claim or in breach of Clause7.10.

PANEL RULING

Page 4 detailed Zometa’s mode of action and featureda diagram showing that it mediated osteoscleroticbone formation and inhibited osteolytic boneresorption. The Panel did not consider, given thecontext in which it appeared, that the claim at issue,‘Statistically significant effects were achieved at lowconcentration’ was exaggerated, all-embracing or thatit implied special merit from pre-clinical data wherethere might be none. No breach of Clause 7.10 wasruled.

The Panel noted that Roche had also alleged a breachof Clause 7.5. Clause 7.5 required substantiation forany claim or comparison to be provided withoutdelay at the request of members of the healthprofessions or appropriate administrative staff. Therewas no indication that data to substantiate the claimat issue had been requested or that such a request hadnot been complied with. No breach of Clause 7.5 wasruled.

6 Claim ‘Zometa – superior to pamidronate inreducing the risk of bone complications inadvanced breast cancer’

This claim appeared as the headline to page 5 andwas referenced to data on file.

COMPLAINT

Roche stated that the claim implied that all patientswith advanced breast cancer would benefit. This wasan all-embracing claim in breach of Clause 7.10 andwas not true in breach of Clause 7.2. These datareferred to patients who were undergoing hormonaltherapy and who had suffered from hypercalcaemiaof malignancy – hence, a highly selected subset. The‘data on file’ used to support this claim consisted offour tables from a confidential report. This data hadbeen supplied on request with a few hand scribbledcalculations but without explanation. Rocheconsidered that this failed to adequately substantiatethe claim in breach Clause 7.4.

Roche added that apart from radiation to bone (asecondary endpoint), the original publication showedthat the primary endpoint of non-inferiority wasreached, ie Zometa was no worse than pamidronate(Rosen et al 2001). The SPC also stated ‘Zometa 4mgshowed comparable efficacy to 90mg pamidronate inthe prevention of [Skeletal Related Events]’.Although the SPC included a statement of benefitover pamidronate, this was based on a secondaryendpoint of the trial. The claim that Zometa wassuperior to pamidronate was therefore not consistentwith the SPC in breach of Clause 3.2.

RESPONSE

Novartis disagreed with Roche’s interpretation ofwhat it considered to be a fairly straightforward claimbased on the results cited in Section 5.1 of the ZometaSPC as follows: ‘In a third phase III randomised,


double-blind trial, 4mg Zometa or 90mg pamidronateevery 3 to 4 weeks were compared in patients withmultiple myeloma or breast cancer with at least onebone lesion. The results demonstrated that Zometa4mg showed comparable efficacy to 90mgpamidronate in the prevention of SREs. The multipleevent analysis revealed a significant risk reduction of16% in patients treated with Zometa 4mg incomparison with patients receiving pamidronate’.

Novartis submitted that this showed superiority (a16% risk reduction) of Zometa over pamidronate forthe entire patient population including both multiplemyeloma and breast cancer patients. Roche’sstatement that these data only referred to breastcancer patients who were undergoing hormonaltherapy and who had suffered from hypercalcaemiaof malignancy was wrong. Not only was Zometasuperior to pamidronate in the study population as awhole, taking the group of patients with breast cancer(including those with and without hypercalcaemiaand those treated with either chemotherapy orhormonal therapy) the risk reduction on Zometa was20% compared to pamidronate, and 30% in the subsetof patients with breast cancer who received hormonaltherapy. Therefore the claim was not in breach ofeither Clause 7.10 or Clause 7.2.

The data on file supporting this claim was supplied toRoche on request and adequately supported the claimif the figures given in the tables supplied wereanalysed (the hand written calculations showed howthe analysis was derived). Therefore the claim couldbe substantiated and was not in breach of Clause 7.4.The data on file related to the 25 month follow-updata which had subsequently been published (Rosenet al, 2003 and Rosen et al 2004). These papers bothconcluded that ‘Zoledronic acid 4mg is more effectivethan pamidronate 90mg in reducing the risk ofdeveloping skeletal complications in the overallpopulation and in patients with breast carcinoma’ and‘[Zoledronic acid] appeared to be more effective thanpamidronate in patients with breast carcinoma and atleast one osteolytic lesion’. Novartis stated that sincethese data had now been published, it no longer usedthe data on file as a reference document.

Novartis submitted that the statement was consistentwith Section 5.1 of the Zometa SPC and was thereforenot in breach of Clause 3.2.

PANEL RULING

The Panel noted that the claim at issue ‘Zometa –superior to pamidronate in reducing the risk of bonecomplications in advanced breast cancer’ wasreferenced to data on file. That data had now beenpublished as Rosen et al (2003) and Rosen et al (2004).These data did not, as submitted by Roche, refer onlyto those who were undergoing hormonal therapy.

Rosen et al (2003) looked at the treatment of skeletalcomplications in patients with advanced multiplemyeloma or breast cancer. Rosen et al (2004) looked atthe treatment of bone metastases in breast cancerpatients with at least one osteolytic lesion. Rosen et al(2003) stated that in patients with breast cancerZometa 4mg was significantly more effective thanpamidronate, reducing the risk of skeletal related

events by an additional 20% (p=0.025) compared withpamidronate and by an additional 30% in patientsreceiving hormonal therapy (p=0.009).

Rosen et al (2004) stated that multiple-event analysisshowed a 20% additional reduction in the risk ofskeletal events (p=0.037) for Zometa-treated patientscompared with those taking pamidronate. In patientswith lytic lesions although the primary endpoint (theproportion of patients with a skeletal event) did notachieve statistical significance, multiple-event analysisdemonstrated that the benefit of Zometa was evengreater compared with pamidronate with anadditional 30% reduction in the risk of skeletal events,a secondary endpoint, being observed (p=0.01). ThePanel noted that the discussion section of Rosen et al(2004) stated that the data strongly suggested thatZometa might be more effective clinically comparedwith pamidronate in patients with breast cancer andat least one osteolytic lesion and in the overallpopulation of patients with breast carcinoma. Suchcaution was not reflected in the claim at issue. ThePanel considered that the headline claim was not afair reflection of the study results and was misleadingand exaggerated in that regard. Breaches of Clauses7.2 and 7.10 were ruled.

The Panel noted that at the time the claim was madethe two papers by Rosen et al had not been published;all that was available was the data on file whichconsisted of 4 pages of tables showing hazard ratios, pvalues and robust p values for the various treatments.Some handwritten calculations were included on twoof the tables. The Panel noted that the breast cancerdata were given according to whether patientsreceived chemotherapy or hormonal therapy. ThePanel considered that the presentation of the data onfile was such that it was difficult to understand andwas inadequate to substantiate the claim at issue. Abreach of Clause 7.4 was ruled.

The Panel noted that the Zometa SPC stated that in acombined patient group of those with multiplemyeloma or breast cancer with at least one bonelesion, Zometa and pamidronate had comparableefficacy in prevention of skeletal related events. Theclaim at issue related only to patients with breastcancer. In that regard the Panel did not consider thatthe claim was inconsistent with the particulars listedin the SPC. No breach of Clause 3.2 was ruled.

APPEAL BY NOVARTIS

Novartis stated that bone metastases were present in60 – 80% of patients with metastatic (advanced) breastcancer ie the most common site of tumour metastasesin these patients. In addition, to reduce the risk ofbone complications (specifically, not to reduce the risk ofdeveloping bone metastases), it was implicit that bonemetastases were present (and, of course, in themajority of advanced disease, they were).

The claim was based on a study of 1,648 patients withat least one bone lesion secondary to multiplemyeloma or advanced breast cancer. The primaryendpoint was to demonstrate non-inferiority ofZometa to pamidronate, an active control, in theproportion of patients experiencing at least oneskeletal related event (pathological fracture, spinal


cord compression, radiation to bone and surgery tobone, ie complications of bone metastases). Thatendpoint was achieved at the initial 13 month analysisand the final 25 month analysis (Rosen et al 2003).

As stated in Rosen et al (2003) ‘For the primaryefficacy analysis, HCM [hypercalcaemia ofmalignancy] was not included in the definition ofSREs [skeletal related events], because zoledronic acidhas already demonstrated efficacy in treating HCM.However, HCM is a clinically important event thatcan be life threatening; therefore, some secondaryefficacy analyses included HCM, defined as a serumcalcium ≥ 12mg/dL. Secondary efficacy endpointsincluded the proportion of patients experiencing anSRE, the proportion of patients experiencing each typeof SRE, time to first SRE, time to each type of SRE,skeletal morbidity rate, multiple-event analysis,overall survival, and ECOG [Eastern CooperativeOncology Group] performance status changes’.

Novartis stated that these secondary endpoints wereboth clinically relevant and important, whereas theprimary endpoint was a statistical one to demonstratenon-inferiority. Rosen et al (2003) further stated that a‘pre-planned multiple-event analysis was performedusing the Andersen-Gill approach, and the robustestimate of variance was used to calculate P values’.This multiple event analysis was the most sensitiveand statistically robust measure of skeletal morbidityand also clinically very useful as it ‘…captures dataon all clinically relevant SREs and the time to eachevent, thus providing a comprehensive assessment ofskeletal morbidity’ (Rosen et al 2004).

Novartis noted that Rosen et al (2003) stated, withregard to the multiple event analysis ‘Treatment with4mg zoledronic acid reduced the risk of developing askeletal complication by an additional 16% comparedwith pamidronate in the overall patient population’.This fact was reflected in Section 5.1 of the ZometaSPC. Turning to the subset analysis in patients withbreast carcinoma ie excluding those with multiplemyeloma, the multiple event analysis showed that‘among all breast cancer patients, 4mg zoledronic acidsignificantly reduced the risk of developing anyskeletal complications (including HCM) by anadditional 20% compared with pamidronate (riskratio, 0.799; 95% CI, 0.657 – 0.972; P = 0.025)’. Thisdata was demonstrated graphically beneath the claim‘Zometa – superior to pamidronate in reducing therisk of bone complications in advanced breast cancer’.

Rosen et al (2004) described a retrospective subsetanalysis ie unplanned, unlike the multiple eventanalysis described above, of the breast cancer patientsfrom the same study separated by radiologicappearance of their bone lesions (lytic, blastic ormixed). This post hoc analysis determined that in thegroup of patients with lytic lesions, Zometa reducedthe risk of a skeletal complication by an additional 30%compared with pamidronate. Unfortunately, the Panelhad concentrated on Rosen et al (2004), the post hocanalysis, rather than Rosen et al (2003) which reportedthe pre-planned analyses that clearly demonstratedthat Zometa was superior to pamidronate in the studypopulation as a whole, and in particular in all patientswith breast cancer included in the trial on the clinicallyrelevant multiple event analysis.

Novartis did not consider that the claim was an unfairreflection of the study results nor misleading andtherefore it was not in breach of Clauses 7.2 or 7.10.

COMMENTS FROM ROCHE

Roche noted that Novartis stated that ‘secondaryendpoints were both clinically relevant andimportant’. According to the SPC, superiority wasnot demonstrated for patients with breast cancer ormyeloma in the following analyses: proportion ofpatients with SREs (p=0.198); proportion of patientswith fractures (p=0.653); median time to SRE(p=0.151); median time to fracture (p=0.672); skeletalmorbidity rate for SREs (p=0.084) and skeletalmorbidity rate for fractures (p=0.614).

Roche stated that the Panel had taken a balanced viewof the two Rosen papers. Multiple event analysis wascriticised by the Council of the American Society ofClinical Oncology as a statistical tool in its latestguidelines: ‘Analysis based on multiple event datamust be interpreted with care … and require makingsomewhat arbitrary decisions about how to representevents …’ They ‘may be subject to after the factassumptions, and ideally, should be independentlyvalidated. The panel concluded there was insufficientevidence to conclude that the effectiveness ofzoledronic acid was superior to pamidronate.’

Roche alleged that the claim misled and exaggeratedthe SPC position as set out in table 4 of the SPC.

APPEAL BOARD RULING

The Appeal Board noted that the claim at issue‘Zometa – superior to pamidronate in reducing therisk of bone complications in advanced breast cancer’was referenced to data on file which had now beenpublished as Rosen et al (2003) and Rosen et al (2004).Rosen et al (2003) described a pre-planned,prospective analysis of the data and stated that inpatients with breast cancer Zometa 4mg wassignificantly more effective than pamidronate,reducing the risk of skeletal related events by anadditional 20% (p=0.025) compared withpamidronate and by an additional 30% in patientsreceiving hormonal therapy (p=0.009). Rosen et al(2004), which was a post-hoc retrospective analysis ofthe data, stated that multiple-event analysis showed a20% additional reduction in the risk of skeletal events(p=0.037) for Zometa-treated patients compared withthose taking pamidronate. In patients with lyticlesions although the primary endpoint (theproportion of patients with a skeletal event) did notachieve statistical significance, multiple-eventanalysis demonstrated that the benefit of Zometa waseven greater compared with pamidronate with anadditional 30% reduction in the risk of skeletalevents, a secondary endpoint, being observed(p=0.01). The Appeal Board considered that theheadline claim was a fair reflection of the data and assuch was not misleading or exaggerated. Nobreaches of Clauses 7.2 and 7.10 were ruled. Theappeal on this point was successful.


7 Claim ‘Zometa – effective bone protection inbreast cancer’

This claim appeared on page 5 below a chart whichshowed that breast cancer patients treated withZometa had a 20% lower risk of developing skeletalcomplications compared with pamidronate. Theclaim was referenced to data on file.

COMPLAINT

Roche alleged that the claim was inconsistent with thelicensed indication ‘Prevention of skeletal relatedevents (pathological fractures, spinal compression,radiation or surgery to bone, or tumour-inducedhypercalcaemia) in patients with advancedmalignancies involving bone’ (emphasis added).Zometa was not licensed for breast cancer per se, noradjuvant use to prevent bone metastases, as this claimpromoted. Roche alleged a breach of Clause 3.1. Inaddition, this claim was supported by data on filefrom a confidential report. Again, it was supplied onrequest with a few hand scribbled calculations butwithout explanation. These data did not readilydemonstrate statistically how this claim wasgenerated, as there was no mention of bone painscores. Roche considered that the data did notsubstantiate the claim in breach of Clause 7.4.

RESPONSE

Novartis noted that the claim appeared on a pagewhich was headlined ‘Zometa – superior topamidronate in reducing the risk of bonecomplications in advanced breast cancer’ and abovethe statement ‘Zometa consistently reduces theincidence of all types of skeletal-related events (SREs)’and was therefore clearly in the context of breastcancer with bone metastases. Zometa was notlicensed for breast cancer per se, nor for adjuvant useto prevent bone metastases and in context this claimdid not promote these indications and was not inbreach of Clause 3.1.

Novartis noted that, as in point 6 above, the data onfile was supplied to Roche on request and gave thetables of figures from which the claim was derived.Therefore it was not in breach of Clause 7.4. Asabove, since these data had now been published,Novartis no longer used the data on file as a referencedocument.

PANEL RULING

The Panel noted that the claim ‘Zometa – effectivebone protection in breast cancer’ appeared on a pageon which the heading referred to ‘advanced breastcancer’. The page tag, however, stated ‘Zometa – inbreast cancer’. In that context the Panel consideredthat the claim at issue implied that Zometa wasauthorized for use in all breast cancer patients whichwas not so. The claim was inconsistent with theparticulars listed in the SPC. The Panel ruled a breachof Clause 3.1 as alleged.

The Panel noted its comments in point 6 above withregard to the data on file and considered that itsruling of a breach of Clause 7.4 also applied here.

APPEAL BY NOVARTIS

Novartis noted that the claim appeared below theheading ‘Zometa – superior to pamidronate inreducing the risk of bone complications in advancedbreast cancer’ and the sub-heading ‘Multiple eventanalysis showed patients treated with Zometa had a20% lower risk of developing skeletal complicationscompared to pamidronate (p = 0.025). Both theheading and sub-heading were in very large type. Incontext, the claim seemed reasonable. It could not beread in isolation on the page, which includedstatements about advanced breast cancer and skeletalcomplications. Moreover, the entire detail aid wasabout skeletal complications.

Novartis noted that the Panel implied that the pagetag ‘Zometa – in breast cancer’, which was inconsiderably smaller font than the heading or sub-heading (and rotated through 90°), negated thecontext of the entire page. However, on opening thepage (having seen the front of the detail aid whichwas about bone metastases), and starting to read fromthe top it was immediately apparent that the contextwas advanced breast cancer.

Novartis disagreed that the claim, in the context inwhich it appeared, was inconsistent with the SPC andthus denied a breach of Clause 3.1.

COMMENTS FROM ROCHE

Roche stated that this large, bold claim (on a pagetabbed ‘Zometa – in breast cancer’) implied adjuvantuse, for which Zometa was not licensed. Rocheconcurred with the Panel.

APPEAL BOARD RULING

The Appeal Board noted that the claim ‘Zometa –effective bone protection in breast cancer’ wasunqualified with regard to the severity of breastcancer although it appeared on a page on which theheading referred to ‘advanced breast cancer’. Thepage tag, however, was also unqualified and stated‘Zometa – in breast cancer’. Given the context inwhich it appeared the Appeal Board on balanceconsidered that the claim at issue implied that Zometawas authorized for use in all breast cancer patientswhich was not so. The claim was thus inconsistentwith the particulars listed in the SPC. The AppealBoard upheld the Panel’s ruling of a breach of Clause3.1 of the Code. The appeal on this point wasunsuccessful.

8 Claim ‘Zometa consistently reduces theincidences of all types of skeletal-relatedevents (SREs)’ and associated bar chart

The claim and bar chart appeared on page 5 and werereferenced to the data on file referred to at points 6and 7 above. The bar chart showed numerical valuesfor Zometa versus pamidronate in terms of thepercentage of patients with fracture (all types),radiation to bone, surgery to bone and spinal cordcompression.


COMPLAINT

Roche noted that, apart from radiation to bone (asecondary end point), the original showed that theprimary end point of non-inferiority was reached, ieZometa was no worse than pamidronate. The SPCalso stated ‘Zometa 4mg showed comparable efficacyto 90mg pamidronate in the prevention of SREs’. Inthe absence of values of significance on the bar chart,the reader could not evaluate this claim, which wasmisleading in breach of Clause 7.2 and all-embracingin breach of Clause 7.10.

RESPONSE

Novartis submitted that the claim was an accuratereflection of the conclusions of the study in question.It made no reference to the significance, or otherwise,of each individual end point but demonstratedgraphically that, in absolute terms, in all cases(consistently) the percentage of patients with each ofthe skeletal related events shown was indeed reducedin the Zometa arm compared with the pamidronatearm. Therefore this claim was neither misleading norall-embracing. Novartis denied breaches of Clauses7.2 and 7.10.

PANEL RULING

The Panel noted that the statement in the SPC thatZometa was comparable to pamidronate in theprevention of skeletal related events referred to astudy of patients with multiple myeloma or breastcancer with at least one bone lesion. The bar chartshowed only the breast cancer data. The Panel notedthat although the bar chart showed that, comparedwith pamidronate, Zometa reduced the percentage ofpatients with each skeletal related event, there was noinformation given to whether there were statisticallysignificant differences between the two medicines.The clinical significance of the differences was notmentioned. The Panel considered that the claim andthe bar chart were misleading; a breach of Clause 7.2was ruled. The Panel also considered that the claimwas all-embracing. A breach of Clause 7.10 wasruled.

APPEAL BY NOVARTIS

Novartis noted that the claim and bar chart were onthe same page as considered at point 7 above. Thechart showed the absolute percentages of patientsexperiencing various types of skeletal related eventson either Zometa or pamidronate. None of thedifferences were statistically significant (and this wasobvious in the graph), but in every case (consistently),the absolute reduction in incidence was greater in theZometa group compared to the pamidronate group.The clinical significance again needed to be put incontext of the whole page which described the overallsuperiority – including statistical significance in theclinically relevant multiple event analysis of Zometato pamidronate. The claim and bar chart would notbe seen in isolation.

Novartis did not consider that the claim and bar chartwere misleading as it gave actual percentages, or all

embracing, and therefore denied a breach of Clause7.2 or 7.10.

COMMENTS FROM ROCHE

Roche stated that only non-significant trends existed.The company concurred with the Panel.

APPEAL BOARD RULING

The Appeal Board noted that although the claim atissue referred to all skeletal related events theincidence of tumour related hypercalcaemia was notshown on the bar chart. Although there was anumerical advantage for Zometa with regard to eachskeletal related event there was no indication on thebar chart as to the statistical significance of any of thedata; all of the advantages shown for Zometa couldthus have been chance findings. The Appeal Boardconsidered that the claim was misleading and all-embracing as alleged. The Panel’s rulings of breachesof Clauses 7.2 and 7.10 were upheld. The appeal onthis point was unsuccessful.

9 Claim ‘Consistently lower pain scores reportedthroughout the study’ and associated bar chartshowing an advantage for Zometa comparedwith placebo over the course of two years

This claim and bar chart appeared on page 7 of thedetail aid. The claim was referenced to Saad et al(2003) and Saad et al (2002).

COMPLAINT

Roche noted that the bar chart showed eight studyperiods over the 24 months of the study. Bone painscores were statistically significantly different toplacebo at only half of those study periods and, eventhen, details of the actual ‘p’ number were not given –just ‘p<0.05’. Roche alleged that the claim wasmisleading in breach of Clause 7.2 and all-embracingin breach of Clause 7.10.

RESPONSE

Novartis submitted that, as in the bar chartconsidered in point 8 above, the use of the word‘consistently’ did not imply statistical significance, butindicated that at all time points the pain scores werelower on Zometa than on placebo. The points whichwere statistically significant, at the accepted p value of<0.05, were indicated with an asterisk. Hence thisclaim was not misleading or all-embracing and not inbreach of Clause 7.2 or 7.10.

PANEL RULING

The Panel noted that it had not been provided with acopy of the cited references by either party. Thevisual impression of the bar chart was that at everytime point Zometa-treated patients had lower painscores than those treated with placebo and that suchdifferences were meaningful. This was not so. Atmonths 6, 12, 15 and 18, although there was a trend toa lower pain score with Zometa, there was no


statistically significant difference between it andplacebo. The Panel did not consider that use of theword ‘consistently’ served to negate the otherwisemisleading impression. A breach of Clause 7.2 wasruled. The Panel considered that the claim was all-embracing. A breach of Clause 7.10 was ruled.

APPEAL BY NOVARTIS

Novartis noted that the bar chart showed various timepoints throughout a two year study and at every oneof these time points, the difference in pain scoresfavoured Zometa, with the difference achievingstatistical significance at some points, most notably, atthe end of the study. Novartis noted that at the timepoints when statistical significance was reached, thiswas not marginal (at 3 months p=0.003; 9 monthsp=0.03; 21 months p=0.014 and 24 months p=0.024).

Novartis noted the Panel’s statement ‘The visualimpression of the bar chart was that at every timepoint Zometa-treated patients had lower pain scoresthan those treated with placebo and that suchdifferences were meaningful. This was not so’.

Novartis submitted that ‘consistently’ had nostatistical meaning. Various definitions of ‘consistent’were: in agreement; compatible, being in agreementwith itself; coherent and uniform, reliable, steady, inmathematics as having at least one common solution,as of two or more equations or inequalities andholding true as a group; not contradictory.

Therefore it was not inappropriate to describe thepain scores throughout the study as ‘consistentlylower’ in the Zometa group.

COMMENTS FROM ROCHE

Roche stated that Novartis had answered the issuewith the given definitions of ‘consistent’ in its appeal.Bearing in mind only half the data points showedstatistically relevant differences, the results were not‘in agreement’, ‘uniform’, or ‘holding true’.

In addition, pain scores progressively increased in thisstudy as shown by this chart (presumably due todisease progression) – certainly, the scores were not‘consistent’ between months 3 and 24.

APPEAL BOARD RULING

The Appeal Board noted that the claim was based ona long-term study which had shown a difference inpain scores for Zometa and placebo. Although onlyfour of the eight time points were statisticallysignificant, these were clearly marked and a p valuegiven. By default there must have been nostatistically significant differences at the other timepoints. The Appeal Board considered that this barchart was different to the one at issue in point 8above. The Appeal Board considered that the barchart was clear and was not misleading and no breachof Clause 7.2 was ruled. The Appeal Board did notconsider that the claim was all-embracing. No breachof Clause 7.10 was ruled. The appeal on this pointwas successful.

10 Claim ‘Zometa – a new standard for thetreatment of hypercalcaemic cancer patients’

This claim appeared as a headline across pages 8 and9 of the detail aid.

COMPLAINT

Roche alleged that as Zometa was launched for thetreatment of hypercalcaemia in April/May 2001,which was more than 12 months ago, the use of ‘new’was in breach of Clause 7.11. Roche also alleged thatthe claim was all-embracing in breach of Clause 7.10as it suggested Zometa could be used to treat anycause of hypercalcaemia in cancer. The Zometa SPCstated that the use of this medicine in this indicationwas limited to ‘tumour-induced’ hypercalcaemia.Other causes of hypercalcaemia included endocrinedisorders (eg hyperparathyroidism), medicines (egthiazide diuretics, excessive calciumsupplementation), granulomatous disorders (egtuberculosis), immobilisation and miscellaneous (egphaeochromocytoma). These were not within thelicensed indications for Zometa.

Roche stated that although it was highly likely that apatient’s hypercalcaemia was due to their malignancy,it was not automatically the case. This claim wastherefore all-embracing in breach of Clause 7.10, andoutside of the marketing authorization in breach ofClause 3.1.

RESPONSE

Novartis denied a breach of Clause 7.11 because ‘new’clearly referred to the standard and not to the productor presentation.

The claim was not all-embracing when viewed in aclinical setting bearing in mind that the targetaudience was oncologists and haematologists.Novartis submitted that the other causes ofhypercalcaemia listed by Roche were exceedinglyrare. If a patient with known malignancy presentedwith hypercalcaemia, as a matter of common clinicalpractice they would be treated for assumed tumour-induced hypercalcaemia in the first instance, whateverthe actual cause, since this was by Roche’s ownadmission, ‘highly likely’. Therefore, this claim wasnot in breach of Clause 7.10 or 3.1.

PANEL RULING

The Panel noted that Clause 7.11 of the Code statedthat the word ‘new’ must not be used to describe anyproduct or presentation which had been generallyavailable, or any therapeutic indication which hadbeen generally promoted, for more than 12 months inthe UK. In the claim at issue ‘new’ was used todescribe the standard of care, not Zometa. In thatregard the Panel considered that there had been nobreach of Clause 7.11 and ruled accordingly.

The Panel noted both parties’ submission that, inpatients with cancer, hypercalcaemia was likely to betumour-induced as opposed to due to any othercause. The page tags of pages 8 and 9 read ‘Zometa-tumour induced hypercalcaemia’. The Panel thus didnot consider the claim ‘Zometa – a new standard for


the treatment of hypercalcaemic cancer patients’ wasall-embracing. No breach of Clause 7.10 was ruled.The Panel also did not consider that the claimpromoted Zometa for an unlicensed indication. Nobreach of Clause 3.1 was ruled.

11 Claim ‘Zometa decreases the risk of a skeletalcomplication in multiple myeloma compared topamidronate’

This claim appeared on page 10 of the detail aid. Theclaim was referenced to Rosen et al (2001). This wasfollowed by a chart showing the relative risk ofZometa versus pamidronate in multiple myeloma.The p value was p=0.593.

COMPLAINT

Roche alleged that the claim was misleading, in breachof Clause 7.2 of the Code, as implied an advantage forZometa whereas there was no significant differencebetween it and pamidronate (p=0.593).

RESPONSE

Novartis submitted that Zometa did have anadvantage over pamidronate as demonstrated in thechart below the statement. The p value was givenand was not significant, but there was a reduction inrelative risk and therefore the statement, which madeno mention of statistical significance, was notmisleading or in breach of Clause 7.2.

PANEL RULING

The Panel noted that, statistically, there was nosignificant difference between Zometa andpamidronate; both were equally effective indecreasing the risk of skeletal complications inmultiple myeloma. The fact that numerically theresults favoured Zometa could have been a chancefinding. The Panel thus considered that the claim wasmisleading as alleged. A breach of Clause 7.2 wasruled.

APPEAL BY NOVARTIS

Novartis noted that the claim ‘Zometa decreases therisk of a skeletal complication in multiple myelomacompared to pamidronate’ was based on the sametrial as the breast cancer data discussed above andpublished by Rosen et al. As already discussed,‘Treatment with 4mg zoledronic acid reduced the riskof developing a skeletal complication by an additional16% compared with pamidronate in the overallpatient population’. This group included patientswith multiple myeloma, although the differencebetween zoledronic acid and pamidronate was notstatistically significant in these patients. However, p=0.593 was printed in large, bold type on the chartaccompanying this claim, and no mention was madeof significance. In addition, this item was used with aspecialist audience well versed in the significance, orotherwise, of given p values.

Novartis did not consider that the claim was in breachof Clause 7.2.

COMMENTS FROM ROCHE

Roche made no further comment.

APPEAL BOARD RULING

The Appeal Board noted that, statistically, there wasno significant difference between Zometa andpamidronate; both were equally effective indecreasing the risk of skeletal complications inmultiple myeloma. The fact that numerically theresults favoured Zometa could have been a chancefinding. The Appeal Board thus considered that theclaim was misleading as alleged. The Appeal Boardupheld the Panel’s ruling of a breach of Clause 7.2.The appeal on this point was unsuccessful.

12 Claim ‘Zometa has superior efficacy topamidronate disodium in hypercalcaemiccancer patients’

This claim appeared as one of five bullet points onpage 11 of the detail aid which was headed ‘Zometa –summary’. The claim was referenced to Major et al(2001).

COMPLAINT

Roche stated that the claim implied that allhypercalcaemic cancer patients would benefit. Thedata only referred to breast cancer patients who wereundergoing hormonal therapy and who had sufferedfrom hypercalcaemia of malignancy – a highlyselected subset. Also, as noted in point 10 above, notall hypercalcaemic cancer patients would havetumour-induced hypercalcaemia. Roche allegedtherefore that the claim was all-embracing in breach ofClause 7.10 and was not true in breach of Clause 7.2.

RESPONSE

Novartis noted that Major et al reported on the twopivotal hypercalcaemia trials. Patients taking parthad the following primary cancer sites: lung, breast,multiple myeloma, head and neck, renal, unknown,haematologic and other. The Zometa SPC reflectedthese trial data in Section 5.1. Roche’s assertion thatthese data only referred to breast cancer patients wastherefore inaccurate.

For the same reasons given in point 10 above ie theclinical assessment of cancer patients withhypercalcaemia (which were the inclusion criteria forthe studies) the claim was not all-embracing and notin breach of Clause 7.10 or Clause 7.2.

PANEL RULING

The Panel noted that Major et al had recruited patients≥ 18 years of age with histological or cytologicalconfirmation of cancer and severe hypercalcaemia ofmalignancy. Patients were not limited to those withbreast cancer undergoing hormonal therapy asalleged; demographic details showed that patientshad a wide range of primary cancer sites. With regardto the cause of hypercalcaemia, the Panel noted itscomments in point 10 above that, in patients withcancer, hypercalcaemia was likely to be tumour-


induced as opposed to due to any other cause. ThePanel considered that, in the context in which itappeared, ie on a page summarising all that had gonebefore, the claim was not misleading or all-embracingas alleged. No breach of Clauses 7.2 and 7.10 wereruled.

13 Claim ‘Zometa is quick and convenient todeliver’

This claim appeared as the last of the five bulletpoints on page 11 of the detail aid which was headed‘Zometa – summary’. The claim was referenced to theZometa SPC.

COMPLAINT

Roche stated that ‘quick’ was not a medical term; itwas vague and without substantiation. ‘Quick’ didnot appear in the SPC and so it was in breach ofClause 7.5. It also misled the reader in breach ofClause 7.2 as patients required a pre-dose renal test tocomply with the SPC requirement that ‘Zometa is notrecommended in patients with severe renal failure’and for ‘the measurement of renal function prior toeach dose. In all patients with bone metastases, thedose should be withheld if renal function hasdeteriorated’. Roche noted that the pivotal trial wasset up to show that a bolus injection could be usedwith Zometa which could reasonably be described asquick. However, this was toxic and had to beabandoned in favour of a 15 minute infusion. A 15minute infusion was not ‘quick’ and the claim wasthus misleading.

With respect to ‘convenient to deliver’, Roche notedthat the patient must usually: attend hospital as anout patient (which necessitated transportation); havebloods taken to check for renal function; have a veincannulated and an infusion given; have medical andnursing attendance; have the intravenous line takendown; be checked to ensure they can safely be senthome and require transportation to get home. Thewhole process could not be described as ‘convenient’for the healthcare staff or the patient, especially wherethe only reason to visit hospital was to receive abisphosphonate. Intravenous care at home alsocarried difficulties and risks. Roche alleged that theclaim was misleading in breach of Clause 7.2.

RESPONSE

Novartis noted that ‘quick’ could be defined as‘capable of rapid movement or action’ (CollinsEnglish dictionary). It was not an absolute term, waswell understood and could hardly be consideredvague. Most clinicians would accept that a 15 minuteinfusion was ‘quick’. By comparison Novartis notedthat the infusion times for other bisphosphonatesrange from 1 hour (Bondronat) to 4 hours (single doseclodronate). The claim at issue was consistent withthe Zometa SPC and therefore capable ofsubstantiation and not in breach of Clause 7.5. Thefact that renal function monitoring was recommendedbefore each dose of Zometa was irrelevant, as this testcould be done at the patient’s leisure at their local GPsurgery if desired. Therefore the statement was not

misleading in this respect and not in breach of Clause7.2.

Novartis submitted that ‘convenient’ could be definedas ‘suitable or opportune, easy to use’ (Collins Englishdictionary). Thus insofar as any medicine, perhapsparticularly those for patients with cancer, wasinconvenient, the administration of Zometa couldreasonably be described as ‘convenient’. This claimwas not misleading in that regard or in breach ofClause 7.2.

PANEL RULING

The Panel noted that, the claim at issue appeared on apage which summarized the data on Zometa andcompared the product with other bisphosphonates.The claim ‘Zometa is quick and convenient toadminister’ would be read in that context.

Compared with Bondronat or Aredia, Zometa couldbe infused in smaller volumes (100ml) over a shorterperiod of time (not less than 15 minutes). The Panelthus considered that Zometa could be administeredquickly; there was no implication from the claim inquestion that ‘quick’ referred to a bolus injection. Nobreach of Clause 7.2 was ruled in that regard.

The Panel considered that the claim that Zometa wasconvenient to use implied an advantage over othersimilar therapies. This was not so. As with otherintravenous bisphosphonates, patients had to havetheir renal function and plasma electrolytes measured.Prescribers must also ensure that patients treated withZometa were adequately hydrated. This was not thecase for other bisphosphonates. The Panel consideredthat Zometa was no more convenient to administerthan other bisphosphonates and in that regard theimplied advantage was misleading. A breach ofClause 7.2 was ruled.

APPEAL BY NOVARTIS

Novartis noted that Zometa was given by 15 minuteintravenous infusion every 3 – 4 weeks for bonemetastases. Many of these patients would beattending outpatient clinics regularly to receivechemotherapy and would receive Zometa at the sametime. Ensuring that such patients were adequatelyhydrated before giving a dose of Zometa would take amember of the medical team a matter of seconds, andso Novartis did not consider that this alone singledZometa out from other intravenous bisphosphonates.

Section 4.4 of all bisphosphonate SPCs recommendedmonitoring of renal function during treatment asfollows:

Bondronat (ibandronic acid) oral and IV: ‘Nevertheless,according to clinical assessment of the individualpatient, it is recommended that renal function, serumcalcium, phosphate and magnesium should bemonitored in patients treated with Bondronat’.

Loron 520 (clodronate, oral): ‘It is recommended thatappropriate monitoring of renal function with serumcreatinine be carried out during treatment’.

Bonefos (clodronate) oral and IV: ‘It is recommendedthat appropriate monitoring of renal function with


serum creatinine measurement be carried out duringtreatment’.

Aredia (pamidronate): ‘As with other i.v.bisphosphonates renal monitoring is recommended,for instance, measurement of serum creatinine prior toeach dose of Aredia’.

Zometa: ‘As with other bisphosphonates renalmonitoring is recommended, for instance,measurement of serum creatinine prior to each doseof Zometa’.

In terms of ‘convenience’ therefore, Zometa hadsimilar requirements for monitoring of renal functionas other bisphosphonates, both oral and IV and hadthe advantage over other IV preparations of aconsiderably shorter infusion time (15 minutes versus1-2 hours). Efficacy issues apart, this must beweighed against the ‘convenience’ of oralpreparations which could obviously be taken at home,once or twice a day (versus once every 3-4 weeks), butall of which required a variable fast beforehand (dueto poor absorption) and the patient to remain uprightfor a time after dosing (to avoid oesophagealulceration).

Novartis did not consider that the claim ‘Zometa isquick and convenient to administer’ wasinappropriate as it did not imply that it was more orless convenient than other bisphosphonates, only thatit was convenient. The company denied a breach ofClause 7.2 with regard to ‘convenient’.

COMMENTS FROM ROCHE

Roche stated that Novartis was incorrect to state that‘Zometa had similar requirements for monitoring ofrenal function as other bisphosphonates’. Novartishad omitted the preceding sentence to its citedquotation from the Bondronat SPC, ie ‘Clinical studieshave not shown any evidence of deterioration in renalfunction with long term Bondronat therapy’. Thisomission altered and misled the context of thesubsequent monitoring statement.

Roche noted that Zometa must be withheld ‘if renalfunction has deteriorated’. The only way to ensurethat was the accepted practice of testing renal functionbefore every dose of Zometa. This was not arequirement of IV or oral Bondronat, where routinerenal function tests occurred as part of the overallmanagement of a patient with metastatic bone diseaseand were not dictated before every dose. TheAmerican Society of Clinical Oncology (ASCO) panelrecommended that: ‘serum creatinine should bemonitored prior to each dose of pamidronate orzoledronic acid’ and recognised that ‘it may bedifficult or inconvenient for some clinics to obtainresults of renal function tests before pamidronate orzoledronic acid administration’ and recommendedthat ‘the FDA-approved monitoring guidelines befollowed.’ The ASCO panel also noted: ‘A time andmotion study at three outpatient chemotherapyinfusion sites participating in the zoledronic acid vspamidronate clinical trial found an average visit timefor zoledronic acid patients was 1 hour 6 minutes … .’

Roche questioned the convenience of a patient havingZometa therapy withheld (and hence, losing the

benefits of continued treatment of their metastaticbone disease). IV medicines carried inherent safetyrequirements that did not make them convenient for apatient when oral, at home, alternative medicinesmight be available. In addition, it was not convenientto have to exercise caution ‘when Zometa is used withother potentially nephrotoxic agents.’ Roche allegedthat the claim was misleading in breach of Clause 7.2.

APPEAL BOARD RULING

The Appeal Board did not consider that, within theoverall context of treating a patient with cancer,Zometa would be seen as inconvenient. Zometacould be administered by a 15 minute infusion, whichwas faster than other IV bisphosphonates. The AppealBoard considered that this advantage was in itself aconvenient aspect of Zometa therapy. The AppealBoard did not consider that the claim was misleadingand no breach of Clause 7.2 was ruled. The appeal onthis point was successful.

14 Claim ‘Zometa is well tolerated’

This claim was the headline on page 12 of the detailaid.

COMPLAINT

Roche stated that of all the issues raised by this detailaid, the fact that Novartis had not fully informedprescibers about the issues surrounding Zometa andrenal toxicity was of greatest concern. Renal toxicitywas described as ‘common’ in the Zometa SPC andyet was not even mentioned in the detail aid whichgave prominence to details only of efficacy.

References were not made to the letter to the NewEngland Journal of Medicine (Chang et al 2003) fromthe Food and Drug Administration (FDA) discussingrenal toxicity concerns about zoledronic acid. Rochenoted that no such concerns were raised in this FDAletter about any other bisphosphonates. Otherpublications had cited and discussed Zometa’s renaltoxicity (Markowitz et al 2003 and Johnson et al 2003).

No reference was made to the important safetyrequirement of withholding treatment with Zometa ifpatients had severe renal impairment. The obligationto discontinue therapy put the patient at further riskof skeletal events in the absence of bisphosphonatecover from Zometa.

No mention was made of the need for caution withthe use of Zometa with other potentially nephrotoxicagents. Co-morbidities and concomitant medicationswere becoming an increasingly importantconsideration in the management of patients withadvanced cancers, especially the elderly.

Roche noted that Novartis had failed to give dueemphasis to these important safety matters whendiscussing safety issues on page 12 in breach ofClause 7.2 in being unbalanced and misleading. Aswithholding vital safety data put patients at potentialrisk, Roche considered that the Panel might view thisseriously enough to constitute a breach of Clause 2.


RESPONSE

Novartis submitted that Zometa was considered to bewell tolerated, notwithstanding the fact that it wasused in cancer patients. The trial data for Zometaconsistently showed that the adverse event profilewas similar to pamidronate or placebo.

Novartis noted Roche’s submission with regard torenal function and the Zometa SPC and stated that theSPC reflected its marketing authorization and itsposition with regard to the relevant competentauthorities, in this case the European MedicinesEvaluation Agency (EMEA). Several adverse eventswere listed in Section 4.8 as occurring ‘commonly’and indeed ‘very commonly’, but none was givenparticular prominence, and none was subject to anywarning issued by the Medicines Commission, theCommittee on Safety of Medicines (CSM) or theEMEA. Novartis noted that the statement on renalfunction read ‘There have been some reports ofimpaired renal function (2.3%), although the aetiologyappears to be multifactorial in many cases’.

Novartis was unclear therefore why Roche hadmentioned just one adverse event for particularscrutiny although it cited Chang et al from the FDA.Novartis explained that this letter to the editor wasneither an FDA letter nor an official FDA position,and contained only information which was consistentwith the US package insert and the UK SPC forZometa. It added no new information and Novartishad not been asked to amend the wording of either itsUS or European marketing authorizations as a result.

Novartis noted that the prescribing information on theback page of the detail aid listed all the adverseevents that appeared in Section 4.8 of the SPC. Thecompany submitted that it had neither misled thereader nor withheld vital safety data. Breaches ofClauses 7.2 and 2 were denied.

PANEL RULING

The Panel noted that the Zometa SPC stated that theproduct must only be used by clinicians experiencedin the administration of intravenous bisphosphonates.In the Panel’s view these physicians would be wellaware that such medicines had to be used with care inpatients with renal impairment and that renalfunction should be monitored during therapy. TheZometa SPC stated that the adverse reactions to themedicine were similar to those reported for otherbisphosphonates and could be expected to occur inapproximately one third of patients. The Panel didnot consider that the omission of data regarding therenal toxicity of Zometa gave a misleading impressionof the safety of the product. There was no implicationthat renal toxicity was not a problem with Zometa.The Panel thus considered that the claim ‘Zometa iswell tolerated’ was not misleading. No breach ofClause 7.2 was ruled. The Panel consequently alsoruled no breach of Clause 2 of the Code.

APPEAL BY ROCHE

Roche noted the Panel’s statement ‘... these physicianswould be well aware that such medicines had to beused with care in patients with renal impairment’ but

considered that one of the main functions ofpromotion was to inform prescribers. Rochedisagreed with the Panel’s assertion that ‘the omissionof data regarding the renal toxicity of Zometa [did notgive] a misleading impression of the safety of theproduct’. There were special concerns about Zometathat were not common to all other bisphosphonatesand page 12 of the detail aid on tolerability failed tobring this to the attention of that specialised audience.

Roche noted that renal toxicity was described as‘common’ in the Zometa SPC and that Chang et alfrom the FDA had discussed renal toxicity concernsabout zoledronic acid. No such concerns were raisedin this letter about any other bisphosphonate. Otherpublications had cited and discussed Zometa’s renaltoxicity (Markowitz et al and Johnson et al). A newpublication highlighted the increased risk of renaltoxicity with zoledronic acid compared withpamidronate (Mazj et al 2004). There was an SPCsafety requirement of withholding Zometa treatmentif patients had severe renal impairment. Theobligation to discontinue therapy put the patient atfurther risk of skeletal events in the absence ofbisphosphonate cover from Zometa. Roche furthernoted that the Zometa SPC advised caution with theuse of Zometa with other potentially nephrotoxicagents. Co-morbidities and concomitant medicationswere becoming an increasingly importantconsideration in the management of patients,especially elderly patients with advanced cancer.

Roche stated that whilst the majority of data in thedetail aid related to efficacy, the tolerability pagemade only two tolerability claims – ‘Zometa is welltolerated’ and ‘Adverse reactions to Zometa werecomparable to those reported for pamidronatedisodium or placebo’. This implied that all adverseeffects were at a placebo level but did not reflect theprescribing information that stated ‘Very common:Hypophosphataemia. Common: Anaemia, headache,conjunctivitis, nausea, anorexia, bone pain, myalgia,arthralgia, renal impairment, fever, flu-like syndrome,increased blood creatinine and blood urea,hypocalcaemia, generalised pain...’. Uncommon andrare undesirable effects were also listed. In addition,the pamidronate SPC also listed adverse events.

To imply that all adverse reactions were comparableto placebo failed to qualify the true profile ofZometa’s and pamidronate’s undesirable effects. Itwas misleading in breach of Clause 7.2. Thecampaign to minimise the emerging concern over therenal toxicity of Zometa was worthy of considerationof a breach of Clause 2.


Novartis noted that Roche had stated that ‘There werespecial concerns about Zometa that were not commonto all bisphosphonates’ and that page 12 of the detailaid on tolerability failed to bring this to the attentionof the target audience.

Novartis disagreed that there were ‘special concerns’about Zometa; as stated before, the SPC was notsubject to any particular warnings issued by any ofthe regulatory bodies or the CSM. In additionNovartis had submitted regular Periodic Safety


Update Reviews on Zometa, and these had not led toany change in relation to the SPC wording about renaladverse events. In particular, in Section 4.8 the SPCstated: ‘Adverse reactions to Zometa are similar tothose reported for other bisphosphonates and can beexpected to occur in approximately one third ofpatients’ as noted by the Panel in its ruling. ThusZometa did not appear to have ‘special concerns’compared to other bisphosphonates.

Novartis noted that Roche had again cited the fact thatrenal toxicity was listed on the SPC as ‘common’, andthat Chang et al as well as other publications referredto renal toxicity. Renal toxicity was listed in the SPCas common because it was present in 1-10% of patientsin clinical trials, this was reflected in Section 4.8: ‘Therehave been some reports of impaired renal function (2.3%), although the aetiology appears to be multifactorialin many cases’. This statement had not been amendedwith the post-marketing experience of Zometa, andreflected the fact that the patients treated on theclinical trial programme, and subsequently, includedsome – particularly those with multiple myeloma –who might have had a multifactorial aetiology to theirrenal impairment. Chang et al stated nothing different– it recommended renal monitoring, adequatehydration and discontinuation of treatment withZometa if renal deterioration occurred, exactly as inthe SPC. The letter from Chang et al was not anofficial FDA position.

Novartis noted that Roche had also reiterated the SPCrecommendations about not using Zometa in patientswith severe renal impairment and also the use withpotentially nephrotoxic agents. Neither of thesestatements negated the fact that Zometa was generallywell-tolerated in a population of patients withadvanced cancer.

Novartis noted that Roche had introduced a newelement to its complaint citing, for the first time, thestatement ‘Adverse reactions to Zometa werecomparable to those reported for pamidronatedisodium or placebo’. Novartis understood that nonew complaint could be introduced at this point inthe process, and so it did not comment further on thisaspect.

FURTHER COMMENTS FROM ROCHE

Roche stated that Novartis had incorrectly stated thatthe Zometa SPC was not subject to any particularwarnings. Section 4.4 of the SPC (Special warningsand precautions for use) stated that Zometa ‘shouldbe withheld if renal function has deteriorated’ and ‘…the use of Zometa is not recommended in patientswith severe renal impairment’. This was not the casewith Bondronat. Whilst the Zometa SPC might statethat ‘Adverse reactions to Zometa are similar to thosereported for other bisphosphonates and can beexpected to occur in approximately one-third ofpatients’, this must be taken into context. ‘Similar’did not mean identical. Bondronat was launched afterZometa in metastatic bone disease and this SPCstatement now represented an historical perspective.It did not match the fact that clinically relevant renaltoxicity was not a feature of Bondronat. TheBondronat SPC stated ‘Clinical studies have shown no

evidence of deterioration of renal function with longterm Bondronat therapy’. Roche contrasted this withNovartis’ admission of a 1-10% renal toxicity withZometa trials.

Roche stated that Novartis had now tempered itsclaim; its new stated position was that ‘Zometa isgenerally well tolerated’. This seemed to recognisethat Zometa had tolerability concerns and supportedRoche’s appeal that the overall claim ‘Zometa is welltolerated’ was misleading.

Roche’s stated that its comment on the claim that‘Adverse reactions to Zometa were comparable tothose reported for pamidronate disodium or placebo’was not a new complaint but was cited to reflect thefact that this was falsely used to support the claimthat ‘Zometa is well tolerated’.

Roche was concerned that important patient safetyinformation was not being shared with healthprofessionals and there were sufficient SPC andpublished data to warrant these issues being fairlypresented in promotion. Roche requested that theserious nature of suppressing such information bereconsidered. A breach of Clause 2 was alleged.

APPEAL BOARD RULING

The Appeal Board noted Roche’s original complaintwas that Novartis had not fully informed prescribersabout the issues surrounding Zometa and renaltoxicity. Further, that Novartis had failed to give dueemphasis to important safety matters relating to renaltoxicity on the page headed ‘Zometa is well tolerated’and this was unbalanced and misleading.

The SPC stated that Zometa must only be used byclinicians experienced in the administration of IVbisphosphonates. In the Appeal Board’s view thesephysicians would be well aware that such medicineshad to be used with care in patients with renalimpairment and that renal function should bemonitored during therapy. The SPC stated that theadverse reactions to Zometa were similar to thosereported for other bisphosphonates and could beexpected to occur in approximately one third ofpatients. The Appeal Board noted that there weresome concerns regarding the renal tolerability profileof Zometa but considered that these had beenexaggerated by Roche. The Appeal Board did notconsider that the failure to refer to the renaltolerability profile of the product rendered the claim‘Zometa is well tolerated’ misleading and unbalancedas alleged. The Panel’s rulings of no breach ofClauses 7.2 and 2 were upheld. The appeal on thispoint was unsuccessful.

During its consideration of this point the AppealBoard was concerned that the claim ‘Zometa is welltolerated’ was a broad, unequivocal and unqualifiedclaim. The Appeal Board also noted that anotherclaim on the same page stated that adverse reactionsto Zometa were comparable to those reported forpamidronate or placebo. The Appeal Boardconsidered these two claims implied minimal riskwith Zometa and questioned whether this was so.The Appeal Board requested that Novartis be advisedof its views in this regard.


15 Claim ‘Zometa has a fast and convenientadministration’

This claim appeared as the heading to page 13 andwas referenced to the SPC.

COMPLAINT

Roche stated that the same issues arose here as inpoint 13 above regarding the claim ‘Zometa is quickand convenient to deliver’. ‘Fast’ was a vague term.This word did not appear in the SPC and so it was inbreach of Clause 7.5. The instructions as to how toadminister Zometa which were given on page 13 alsomisled the reader in breach of Clause 7.2 as patientswould require a pre-dose renal test to comply withthe SPC requirement that ‘Zometa is notrecommended in patients with severe renal failure’and for ‘the measurement of renal function prior toeach dose. In all patients with bone metastases, thedose should be withheld if renal function hasdeteriorated’. The ‘convenience’ claim failed to takeinto account the need for pre-dose renal functiontesting and the whole inconvenience of attendinghospital and/or receiving an intravenous infusion.This was misleading in breach of Clause 7.2.

RESPONSE

Novartis stated that as for point 13 above, itconsidered that most clinicians would accept that a 15minute infusion was ‘fast’ and would understandwhat ‘fast’ meant. It was entirely consistent with theSPC and not in breach of Clause 7.5.

Novartis noted that the instructions on page 13 didnot mislead the reader as the first step was to ensurethat the patient had acceptable creatinine levels, asdefined in the SPC, prior to administering each doseof Zometa. This was therefore not in breach of Clause7.2.

As in point 13 above, the claim about convenienceseemed entirely reasonable and not in breach inClause 7.2.

PANEL RULING

The Panel noted that the claim at issue ‘Zometa has afast and convenient administration’ headed page 13which detailed the practicalities of administering themedicine. A claim at the bottom of the pagecompared the treatment time per infusion forpamidronate (152 minutes) and Zometa (59 minutes).The Panel noted its comments and rulings at point 13above with regard to ‘quick’ and ‘convenient’ andconsidered that they applied here. The Panel thusruled no breach of Clauses 7.2 and 7.5 with regard tofast and a breach of Clause 7.2 with regard toconvenient.

APPEAL BY NOVARTIS

As for the claim in point 13 above, Novartis did notconsider this to be in breach of Clause 7.2 with regardto ‘convenient’.

COMMENTS FROM ROCHE

Roche referred to its comments at point B above.

APPEAL BOARD RULING

The Appeal Board noted its comments at point 13above with regard to ‘convenient’ and considered thatthey applied here. The Appeal Board thus ruled nobreach of Clause 7.2 of the Code. The appeal on thispoint was successful.

Complaint received 4 June 2004



Bristol-Myers Squibb and Otsuka voluntarily advised theAuthority that their mailing house had, in error, sent lettersannouncing the launch of Abilify (aripiprazole) before themarketing authorization had been received. The letters hadbeen sent to 117 mental health pharmacists. Corrective actionwas taken immediately.

The Director of the Authority decided that as the matterrelated to the promotion of a medicine prior to the grant ofthe marketing authorization it was sufficiently serious for itto be taken up and dealt with as a complaint under the Code.This was consistent with advice given by the Code of PracticeAppeal Board and published in the August 1997 Code ofPractice Review.

The Panel noted that it was an established principle underthe Code that pharmaceutical companies were responsible foractivities carried out by third parties with their authority.Bristol-Myers Squibb and Otsuka were thus responsible forthe activities of their mailing house.

The explanation from the mailing house was that the boxcontaining the mailing to the pharmacists had not beenlabelled ‘hold’ pending receipt of an instruction to despatchfrom Bristol-Myers Squibb and Otsuka. All the other boxesin the mailing had been so labelled. It appeared that the boxcontaining the letters at issue fell off a pallet and wasincorrectly placed with other items which were awaitingdespatch. The mailing house apologised for the error anddescribed the steps it had taken to ensure that there was norepeat.

The Panel noted that the companies had been let down bythe mailing house resulting in a promotional letter being sentbefore the marketing authorization for Abilify had beengranted. The Panel thus ruled a breach of the Code.

RESPONSE

Bristol-Myers Squibb and Otsuka submitted a jointresponse and stated that the Commission of theEuropean Communities granted the marketingauthorization for Abilify to Otsuka PharmaceuticalsEurope Ltd on 4 June 2004. However, on 3 June amental health pharmacist contacted Bristol-MyersSquibb’s medical information department, to discussthe availability of Abilify. The pharmacist hadreceived the letter in question. The medicalinformation department immediately alerted Bristol-Myers Squibb, Otsuka and the mailing house. Anoutline plan for corrective action was verbally agreed.

The mailing house confirmed that it had sent themailing in error to 117 mental health pharmacists on 2June, despite a written instruction to ensure all suchmaterials were to be held until released by thecompanies upon receipt of the marketingauthorization. On 4 June the mailing house wrote toOtsuka and Bristol-Myers Squibb confirming the erroron its part and stating that it accepted fullresponsibility as a result of the failure of its procedure.A copy of the letter sent by the mailing house wassupplied.

Bristol-Myers Squibb and Otsuka instigated andimplemented a strategy to contact the 117 mentalhealth pharmacists as a matter of urgency starting onFriday, 4 June. The companies realised theseriousness and potential for breaching the Code andtelephoned the Authority for guidance and thensubsequently made a voluntary admission. Thecompanies also informed the Medicines andHealthcare products Regulatory Agency as the matterwas of the utmost importance.

Bristol-Myers Squibb and Otsuka gave the mailinghouse a telephone script to use to contact the mentalhealth pharmacists. This was to enable the mailinghouse to obtain fax numbers or email addresses forthe relevant pharmacists. A letter of apology wasthen faxed/emailed. One hundred and one peoplewere faxed/emailed on 4 June or over the weekend.Unfortunately sixteen people could not be contacteddue to eight fax machines not working and eightpeople not being contactable by phone.

A letter of apology was mailed to all 117 pharmacistson 4 June 2004.

Also on 4 June all relevant customer facing personnelwere informed of the mailing error. They werebriefed on how to respond to questions frompharmacists as a result of the premature mailingabout the marketing authorization.

On 8 June Bristol-Myers Squibb and Otsuka expressedtheir extreme dissatisfaction to the mailing house at



VOLUNTARY ADMISSION BY BRISTOL-MYERSSQUIBB and OTSUKAAbilify mailing

Bristol-Myers Squibb Pharmaceuticals Ltd and OtsukaPharmaceuticals (UK) Ltd voluntarily advised theAuthority that their mailing house had, in error, sentletters announcing the launch of Abilify (aripiprazole)before the marketing authorization had been received.The letters (ref ABL/04-04/0291c/03-06) had beensent to 117 mental health pharmacists. Correctiveaction was taken immediately.

The Director of the Authority decided that as thematter related to the promotion of a medicine prior tothe grant of the marketing authorization it wassufficiently serious for it to be taken up and dealt withas a complaint under the Code. This was consistentwith advice given by the Code of Practice AppealBoard and published in the August 1997 Code ofPractice Review.

The Authority requested that Bristol-Myers Squibband Otsuka respond in relation to the provisions ofClause 3.1 of the Code.

the failure of the service, sought assurance thatnothing of that kind would occur again and requesteddetails of the full review of the processes put in placeto prevent any such future occurrences. On 22 June aletter was received from the mailing house explainingthe results of its investigation into the error andidentifying improvements to the processes to preventany repetition.

The companies submitted that the prematurenotification of the Abilify marketing authorizationwas made to only a small group of pharmacists by themailing house. Neither Bristol-Myers Squibb norOtsuka had intended that this should occur, and bothcompanies had taken all reasonable precautions toprevent such an erroneous notification. Thecompanies regretted that the mailing house’s errorhad inadvertently caused the companies to breach theCode.

PANEL RULING

The Panel noted that it was an established principleunder the Code that pharmaceutical companies wereresponsible for activities carried out by third partieswith their authority. Bristol-Myers Squibb and

Otsuka were thus responsible for the activities of theirmailing house.

The explanation from the mailing house was that thebox containing the mailing to the pharmacists had notbeen correctly labelled ‘hold’ pending receipt of aninstruction to despatch from Bristol-Myers Squibb andOtsuka. All the other boxes in the mailing had beenso labelled. It appeared that the box containing theletters at issue fell off a pallet and was incorrectlyplaced on a pallet of other items which were awaitingdespatch. The mailing house apologised for the errorand described the steps it had taken to ensure thatsuch an error was not repeated.

The Panel noted that the companies had been letdown by the mailing house resulting in a promotionalletter being sent to 117 pharmacists before themarketing authorization for Abilify had been granted.The Panel thus ruled a breach of Clause 3.1 of theCode.

Proceedings commenced 15 June 2004



GlaxoSmithKline Consumer Healthcare complained about anadvertisement for Nicorette Patch issued by Pfizer ConsumerHealthcare, which was headed ‘Nicorette patch can protectpatients from unnecessary sleep disturbance’ and featured anillustration of a woman asleep in bed beneath which was aperson dressed as a cigarette. Text beneath the illustrationstarted ‘Because Nicorette 16 hour Patch is the only patchspecifically designed to mimic your patient’s regular smokingpattern, it avoids the nocturnal nicotine dosing oftenassociated with sleep disturbance. In fact, Nicorette 16 hourPatch is the only one not shown to increase levels of sleepdisturbance over and above placebo levels’. Nicorette patchesreleased nicotine over 16 hours; GlaxoSmithKline ConsumerHealthcare marketed NiQuitin CQ Patches which deliverednicotine over 24 hours.

GlaxoSmithKline Consumer Healthcare stated that theadvertisement implied that patients on Nicorette would get agood night’s sleep, and those using 24-hour patches wouldnot. Neither of these impressions was necessarily correct.The impression of Nicorette giving patients a good night’ssleep was created by the visual of a woman sleepingpeacefully in bed. The word ‘unnecessary’ in the headlinedid not negate this impression, and neither did the phrase‘not shown to increase levels of sleep disturbance over andabove placebo levels’ as no mention was made that nicotinewithdrawal itself could cause sleep disturbance. Wakingonce or twice might be equivalent to placebo but did notconstitute a good night’s sleep. Any material discussingsleep disturbance in smoking cessation should make itexplicitly clear that nicotine withdrawal itself could causesleep disturbance so that readers were not misled. A breachof the Code was alleged.

A further breach of the Code was alleged as theadvertisement failed to state that the prescribing informationappeared overleaf.

The Panel did not consider that the advertisement adequatelydistinguished between sleep disturbance caused by thetreatment and that caused by the lack of nicotine. Theadvertisement noted that nocturnal nicotine dosing was oftenassociated with sleep disturbance but did not state thatnicotine withdrawal per se was also associated with sleepdisturbance. The claim that Nicorette did not ‘increase levelsof sleep disturbance over and above placebo levels’ was notsufficient in this regard. Some readers would assume thatplacebo levels of sleep disturbance meant none. There wasthus an implication that patients using Nicorette would sleepwell whereas their sleep patterns would still be disrupteddue to nicotine withdrawal. The Panel noted that Nicorette,however, would not add to this effect. Nonetheless, thePanel considered that the advertisement gave a misleadingimpression of the sleep pattern that might be expected in apatient using Nicorette. A breach of the Code was ruled.

The Panel noted that the advertisement was a two pageadvertisement with the prescribing information appearingoverleaf. There was no reference on the first page as to the

location of the prescribing information as requiredby the Code and a breach was ruled.

GlaxoSmithKline Consumer Healthcare complainedabout a journal advertisement for Nicorette Patch(transdermal nicotine) issued by Pfizer ConsumerHealthcare Limited. The advertisement appeared inMIMS, June 2004. The advertisement, which did nothave a reference number, was headed ‘Nicorette patchcan protect patients from unnecessary sleepdisturbance’ and featured an illustration of a womanasleep in bed beneath which was a person dressed asa cigarette. The text beneath the illustration started‘Because Nicorette 16 hour Patch is the only patchspecifically designed to mimic your patient’s regularsmoking pattern, it avoids the nocturnal nicotinedosing often associated with sleep disturbance. Infact, Nicorette 16 hour Patch is the only one notshown to increase levels of sleep disturbance over andabove placebo levels’.

Nicorette patches released nicotine over 16 hours’ use.GlaxoSmithKline Consumer Healthcare marketedNiQuitin CQ Patches (transdermal nicotine) whichdelivered nicotine over 24 hours.

COMPLAINT

GlaxoSmithKline Consumer Healthcare noted that itsrecent complaint about an advertisement for NicorettePatch (Case AUTH/1563/3/04) had been upheld bythe Panel. The Panel did not consider the claim ‘helpsyour patients avoid the nocturnal nicotine dosingassociated with unnecessary sleep disturbance’adequately distinguished between the two types ofsleep disturbance [sleep disturbance that was part andparcel of quitting, and that caused by nocturnalnicotine dosing] and considered some readers wouldbe left with the impression that those taking Nicorettewould not have a disturbed night’s sleep and this wasnot necessarily so as they would continue toexperience the sleep disruption caused by nicotinewithdrawal. The footnote ‘Nicorette 16 hour Patch isthe only one not shown to cause sleep disturbanceover and above placebo levels’ did not negate theimpression given. The expectation of a good night’ssleep was strengthened by the visual of a womansleeping peacefully in bed. A breach of Clause 7.2was ruled.

GlaxoSmithKline Consumer Healthcare stated thatPfizer Consumer Healthcare had replaced theadvertisement at issue in Case AUTH/1563/3/04with one used previously and which GlaxoSmithKlineConsumer Healthcare had previously alleged was inbreach of the undertaking given in CaseAUTH/1329/6/02. The alleged breach ofundertaking was considered as Case


CASE AUTH/1598/6/04

GLAXOSMITHKLINE CONSUMER HEALTHCAREv PFIZER CONSUMER HEALTHCARENicorette Patch journal advertisement

AUTH/1380/10/02 and the Panel ruled that theundertaking given in Case AUTH/1329/6/02 had notbeen breached because the advertisement wassufficiently different from that considered in CaseAUTH/1329/6/02. However, this did not necessarilymean that the Panel approved the advertisement atissue in Case AUTH/1380/10/02. ThereforeGlaxoSmithKline Consumer Healthcare asked theAuthority to consider its concerns in this case, [CaseAUTH/1598/6/04], as a complaint rather than abreach of undertaking.

GlaxoSmithKline Consumer Healthcare stated that thecurrent advertisement implied that patients onNicorette would get a good night’s sleep, and thoseusing 24-hour patches would not. Neither of theseimpressions was necessarily correct. The impressionof Nicorette giving patients a good night’s sleep wascreated at the outset by the visual of a womansleeping peacefully in bed. The use of the word‘unnecessary’ in the headline did not negate thisimpression, and neither did use of the phrase ‘notshown to increase levels of sleep disturbance over andabove placebo levels’ as no mention was made thatnicotine withdrawal itself could cause sleepdisturbance. Waking once or twice in the night mightbe equivalent to placebo but did not constitute a goodnight’s sleep. Any material discussing sleepdisturbance in smoking cessation should make itexplicitly clear that smoking cessation (ie nicotinewithdrawal) itself could cause sleep disturbance sothat readers were not misled. A breach of Clause 7.2was alleged.

GlaxoSmithKline Consumer Healthcare also alleged abreach of Clause 4.7 as the advertisement failed tostate that the prescribing information appearedoverleaf.

RESPONSE

Pfizer Consumer Healthcare stated that the complaintwas a surprise as the company had not placed thisadvertisement; had it realised that the advertisementhad run, it would have made an immediate voluntarydisclosure to the Authority. Unfortunately the letterfrom the Authority notifying the company of thecomplaint was the first Pfizer Consumer Healthcareknew of this.

MIMS confirmed that the advertisement ran becauseof an administrative error involving MIMS’ internalbooking systems. MIMS had not received a bookingfor or authority to run the advertisement from eitherPfizer Consumer Healthcare or its booking agency.Pfizer Consumer Healthcare would not be paying forthe advertisement.

Whilst Pfizer Consumer Healthcare recognised thatunder the Code it was responsible for theadvertisement, it hoped to provide evidence ofmitigating circumstances and there was absolutely nointention to breach the Code.

Pfizer Consumer Healthcare apologised unreservedlyfor the erroneous placement of this unapprovedadvertisement. Nevertheless the company stood bythe advertisement.

Pfizer Consumer Healthcare submitted that the visualwas appropriate since it drew attention to the topicunder discussion: sleep. It did not imply no sleepdisturbance, in the same way that an image of asmiling man in an asthma product advertisement didnot imply that the product would relieve allsymptoms of asthma.

There had never been any intention to mislead thesophisticated health professional audience who wouldunderstand the phrase ‘has not been shown to increaselevels of sleep disturbance over and above placebolevels’ to mean that sleep disturbance was part andparcel of quitting smoking (placebo group) and wouldnot be exacerbated by a 16-hour patch which wasintended for removal at bedtime (Nicorette).

Pfizer Consumer Healthcare submitted that itsresponse to Case AUTH/1380/10/02 answeredGlaxoSmithKline Consumer Healthcare’s complaint.

‘Again based on the data provided for theprevious ruling, [Case AUTH/1329/6/02] thePanel accepted that several studies had shownthat sleep disturbances were not reported morefrequently in patients using an active 16-hourpatch compared to placebo. The Panel also agreedthat 16-hour patches did not cause sleepdisturbances per se. In addition, as a simplestatement of fact, Nicorette Patch was the only 16-hour patch; all other patches were designed for 24-hour administration. The Panel’s ruling statedthat sleep disturbance during smoke cessationcould also be caused by night-time dosing if apatient used a 24-hour patch. The companytherefore understood that the Panel accepted thedata provided for the previous ruling whichshowed the increased incidence of sleepdisturbances with 24-hour patches whencompared to placebo and that insomnia andabnormal dreams were listed as potential adverseeffects with NiQuitin CQ patches whereas theywere not listed for Nicorette Patch.

In the previous case, the issue was that thecompany had not made it clear that there could besleep disturbances as a consequence of nicotinewithdrawal. However the headline ‘NicorettePatch can protect patients from unnecessary sleepdisturbance’ made it clear that the subject of theadvertisement was avoidable sleep disturbances.This was supported by the amended statementwhich did not claim that there were no sleepdisturbances but that there was no increase insleep disturbances over placebo levels using 16-hour patches. This was in contrast to 24-hourpatches where the Panel accepted that nocturnalnicotine dosing can cause sleep disturbances overplacebo levels’.

Pfizer Consumer Healthcare noted the absence of aunique reference number on the advertisement andthe absence of a reference to the location of theprescribing information.

PANEL RULING

The Panel was curious with regard to what it saw asan inconsistency in Pfizer Consumer Healthcare’s


submission that had it known the advertisement hadappeared it would have made a voluntary admissionand that Pfizer Consumer Healthcare stood by itsadvertisement.

The Panel noted that the advertisement now at issuewas similar to that at issue in CaseAUTH/1380/10/02. The text and illustration werethe same although the layouts were different.

In Case AUTH/1329/6/02 the Panel had ruledbreaches of the Code as claims such as ‘For patientswho want to give up smoking, not their sleep’, ‘… byavoiding the nocturnal nicotine dosing commonlyassociated with sleep disturbance – …’ and ‘In factwhen compared to placebo Nicorette 16 hour Patch isthe only nicotine patch which has not been shown tocause sleep disturbance’ in the context of theadvertisement as a whole gave the impression thatpatients using Nicorette patch would not suffer sleepdisturbance at all. This was not necessarily so.

The advertisement subsequently at issue in CaseAUTH/1380/10/02 had been ruled not to be inbreach of the undertaking given in CaseAUTH/1329/6/02. The Panel had considered thatthe advertisement was sufficiently different; it referredto minimising the risk of unnecessary sleepdisturbance whereas the advertisement in CaseAUTH/1329/6/02 implied that patients usingNicorette Patch would not suffer sleep disturbance atall. Such patients would not avoid the sleepdisturbance caused by lack of nicotine.

The Panel noted that in Case AUTH/1563/3/04 it hadruled a breach with regard to the claim ‘[Nicorette]helps your patients avoid the nocturnal nicotinedosing commonly associated with unnecessary sleepdisturbance’ as it did not adequately distinguishbetween the two types of sleep disturbance.

Turning to the case now before it, CaseAUTH/1598/6/04, the Panel noted that theadvertisement had appeared in error. NonethelessPfizer Consumer Healthcare had to take responsibilityfor it under the Code.

The Panel did not consider that the advertisementadequately distinguished between two types of sleepdisturbance, that caused by the treatment and thatcaused by the lack of nicotine. The advertisementnoted that nocturnal nicotine dosing was oftenassociated with sleep disturbance but did not statethat nicotine withdrawal per se was also associatedwith sleep disturbance. The claim that Nicorette didnot ‘increase levels of sleep disturbance over andabove placebo levels’ was not sufficient in this regard.Some readers would assume that placebo levels ofsleep disturbance meant none. There was thus animplication that patients using Nicorette would sleepwell whereas their sleep patterns would still bedisrupted due to nicotine withdrawal. The Panelnoted that Nicorette, however, would not add to thiseffect. Nonetheless, the Panel considered that theadvertisement gave a misleading impression of thesleep pattern that might be expected in a patient usingNicorette. A breach of Clause 7.2 of the Code wasruled.

The Panel noted that the advertisement was a twopage advertisement with the prescribing informationappearing overleaf. There was no reference on thefirst page as to the location of the prescribinginformation as required by Clause 4.7. A breach ofthat clause was ruled.




Novartis complained about various articles which hadappeared in the medical and lay press about Roche’s productBondronat (ibandronate).

Bondronat was available as film-coated tablets and as aconcentrate for solution for intravenous administration (IV).Both presentations were indicated for the prevention ofskeletal events (pathological fractures, bone complicationsrequiring radiotherapy or surgery) in patients with breastcancer and bone metastases. In addition Bondronat IV wasalso indicated for the treatment of tumour-inducedhypercalcaemia with or without bone metastases. Novartismarketed Zometa (zoledronic acid) which had similarindications to Bondronat. Both products belonged to a classof medicines known as bisphosphonates.

Novartis alleged that the claim ‘Oral treatment for metastaticbone disease’ in an article in Prescriber and Future Prescriberwas misleading as Bondronat tablets were only licensed forpatients with breast cancer and bone metastases, not othermalignant types.

The Panel considered that the claim ‘Oral treatment formetastatic bone disease’ implied that Bondronat could beused to treat the metastases per se and that was not so. ThePanel noted, however, that complaints about articles in thepress were judged on the information provided by thepharmaceutical company or its agent to the journalist and noton the content of the article itself.

The Panel thus examined the material provided to themedical media. The ‘Bondronat UK Launch – Pitch Points’document featured nine bullet points: the first introducedBondronat as part of the management of advanced breastcancer. This was the only bullet point to refer to ‘breastcancer’, all of the others referred only to ‘cancer’. Theseventh point described Bondronat as the ‘bone saver’ whichworked by ‘effectively slowing the cancer’s growth in thebone’. ‘Metastatic Bone Disease – Background Information’described the pathophysiology, incidence, risk factors,complications, symptoms and goals of metastatic bonedisease management. One goal of metastatic bone diseasemanagement was ‘ideally, reduce disease progression andimprove patient survival’. Although the document concludedby discussing metastatic bone disease and breast cancer thisaspect was not mentioned at the beginning of the document,in the heading or such like. The backgrounder on Bondronatdiscussed the medicine’s mode of action, licensedindications, administration, tolerability and the convenienceof oral versus IV presentations. The document explained that‘Bondronat [was] licensed for treatment of tumour-inducedhypercalcaemia of malignancy with or without metastases.Prevention of skeletal events in patients with breast cancerand bone metastases’. The section detailing theadministration of Bondronat stated ‘Bondronat is available asintravenous and oral formulations for the treatment ofmetastatic bone disease’ and that ‘For oral use therecommended dose for metastatic bone disease is 50mg oncedaily’. The document concluded that Bondronat provided ‘animportant clinical alternative for the treatment of bonemetastases’. The medical media release ‘Improving quality

of life for advanced breast cancer patients with“bone saver”’ discussed treatment of metastatic bonedisease in breast cancer patients and explained thatthe ‘bone saver’ worked by inhibiting the spreadingcancer from growing or multiplying in the bone andtherefore reduced bone pain and bone fractures.

The Panel considered that overall the materialdirected at the medical press, apart from the medicalmedia release ‘Improving quality of life foradvanced breast cancer patients with “bone saver”’,did not make it sufficiently clear that althoughBondronat was licensed for metastatic bone diseaseit was only for metastatic bone disease secondary tobreast cancer. It was not licensed to treat metastaticbone disease resulting from any other cause. ThePanel considered that the ‘Pitch Points’ document,the Bondronat backgrounder and the MetastaticBone Disease – Background Information documentwere misleading in this regard and inconsistent withthe particulars listed in the Bondronat summary ofproduct characteristics (SPC). Breaches of the Codewere ruled. The Panel considered that this rulingalso applied to similar claims which appeared inDGNews.

Novartis alleged that the claim ‘The oral formulationhas equivalent efficacy to the IV drug’ wasmisleading as there had been no direct comparisonsof the two formulations. Any comparisons madewere indirect and inferred.

The Panel considered that the ‘Bondronat UKLaunch – Pitch Points’ document, the Bondronatbackgrounder and the medical media release gavethe impression that a direct clinical comparison ofIV and oral Bondronat had proven that the two wereequally effective and that was not so. The materialswere misleading in this regard. A breach of theCode was ruled.

Novartis alleged that the absolute statement ‘Thereare also no adverse renal effects …’ was untrue sinceSection 4.8 of the SPC stated that azotaemia(uraemia) had been reported, albeit rarely; the claimwas therefore misleading, inconsistent with theterms of the marketing authorization and misled asto the side effect profile of the medicine.

The Panel noted that a section entitled ‘What are theside effects with Bondronat’ within the Bondronatbackgrounder began by discussing the toxicitiesassociated with current bisphosphonates which, itwas stated, could limit their clinical benefit. Thefirst of three bullet points read ‘infusion ofpamidronate and zoledronate can lead to renaltoxicity, which, in rare cases, can have severe andlife-threatening consequences’. Product labellingand monitoring of patients taking zoledronate wasdiscussed. The safety profile of oral Bondronat wasdescribed as ‘comparable to placebo’. The Panel


CASE AUTH/1599/6/04

NOVARTIS v ROCHEPress articles about Bondronat

considered that the section ‘What are the side effectswith Bondronat’ implied that although renal toxicityhad been reported in association with pamidronateand zoledronate none had been reported withBondronat and that was not so. The medical mediarelease stated that Bondronat had not beenassociated with increases in renal toxicity or renaladverse events.

The Panel noted that Section 4.8 of the Bondronattablet SPC listed uraemia as an uncommon adverseevent, occurring at a frequency of <1% comparedwith placebo. The Panel thus considered that theBondronat backgrounder and the medical mediarelease were misleading with regard to the renalside effects of Bondronat and the Panel ruled abreach of the Code with respect to both. The Paneldid not consider that the matter warranted a rulingof a breach of Clause 2. The Panel considered thatthese rulings applied to a similar claim in EMIMS,April 2004.

Novartis alleged that the claim ‘… and thegastrointestinal side-effects of the oral formulationwere comparable to placebo’ was untrue and at oddswith Section 4.8 of the SPC which listed dyspepsia,nausea, abdominal pain and oesophagitis, all ofwhich were gastrointestinal side-effects which werereported commonly and greater than placebo.Novartis alleged that the claim was misleading andpotentially risked patient safety.

The Panel noted that the oral Bondronat SPC listed,inter alia, dyspepsia, nausea, abdominal pain andoesophagitis as events reported more commonlythan with placebo. A section of the Bondronatbackgrounder entitled ‘What are the side effectswith Bondronat’ discussed the side effects of otherbisphosphonates which had limited their clinicalbenefit. The third bullet point read ‘administrationof oral clodronate can cause gastrointestinaldisturbances …’. The section concluded with adiscussion of Bondronat’s side-effect profile, stating,inter alia, that the safety profile of Bondronat wascomparable to placebo. Overall, the section impliedthat Bondronat would not cause gastrointestinaldisturbance which was not so. The Panelconsidered that the Bondronat backgrounder wasnot a fair reflection of the SPC on this point and wasthus misleading. A breach of the Code was ruled.The Panel did not consider that the matterwarranted a ruling of a breach of Clause 2.

Novartis alleged that the claim which appeared in aDGNews item that ‘Bondronat was also welltolerated, with patients experiencing adverse eventssimilar to those in the placebo group’ was similar toits allegation above with regard to the claims ‘Thereare no adverse renal effects’ and ‘… and thegastrointestinal side-effects of the oral formulationwere compared to placebo’.

The Panel noted that the DGNews item referredalmost exclusively to the publication that day ofBody et al (2004). In its complaint Novartis had notquoted the whole of the claim which read, in full:‘Bondronat was also well tolerated, with patientsexperiencing adverse events similar to those in theplacebo group with the exception of a small number

of patients experiencing mild to moderate gastro-intestinal side effects’. Given the context of thenews item it was clear that the claim at issue relatedonly to the findings of one study. The Panelconsidered that the claim was a fair and accuratereflection of Body et al (2004). Given that the claimclearly related to only one cited study the Panelruled no breach of the Code. It thus followed thatthere was no breach of Clause 2 of the Code.

With regard to the claim ‘The oral drug hasadvantages over its competitor in that it is a smalltablet taken only once daily’ in Future Prescriber,Novartis assumed that the competitor was oralclodronate, but took issue with the fact that being asmall tablet, or being taken once daily offeredadvantages. Bondronat tablets must be taken afteran overnight fast (at least 6 hours) and before thefirst food or drink of the day and fasting should becontinued for at least 30 minutes after taking thetablet. Conversely, Loron capsules might be takenafter only an hour’s fast. Loron might also be takenonce daily. Novartis alleged that the claim wasmisleading.

The article in Future Prescriber referred toclodronate and zoledronic acid; both werecompetitors to Bondronat. Zoledronic acid (Zometa)was only available as an IV formulation and so thePanel assumed that the competitor referred to in theclaim at issue was clodronate.

The Panel noted that both the medical media releaseand the Bondronat backgrounder stated thatBondronat was to be taken once daily. TheBondronat backgrounder additionally noted thatBondronat was a small tablet. Neither documentreferred to the size of clodronate tablets nor to theirfrequency of administration. None of the materialscompared the tablet size or frequency ofadministration of Bondronat with clodronate; nobreach of the Code was ruled.

Novartis noted that the Code allowed advancenotification of new indications to budget holders forplanning purposes. However, Novartis alleged thatthe readership of Future Prescriber could not beassumed only to fulfil the criteria of budget holders;many would be prescribers. Thus to giveinformation to journalists about unlicensedindications constituted a breach of the Code.Novartis drew attention to a particular claim inFuture Prescriber about ongoing trials in unlicensedindications.

The Panel noted that none of the press materialsprovided by Roche referred to ongoing or futuretrials with Bondronat in unlicensed indications. Nobreach of the Code was ruled.

Novartis alleged that the claims ‘There is now adrug that could help such women to lead relativelynormal lives’ and ‘One of the other benefits ofBondronat is that it is the first drug in its class – theso-called bisphosphonates – that can be taken orallywithout the need for regular intravenous injectionsor infusions in hospital’ appeared in an articleentitled ‘A Pain-Free Future’ in The Timesnewspaper were misleading. They implied that nosuch medicine was available previously which was


clearly inaccurate, since several bisphosphonates,both oral and IV were already available fortreatment of breast cancer metastatic to bone. Loronhad been available orally for some time. Thisshould have been made clear in any briefing, inparticular to the lay press.

The Panel noted that the consumer media releasestated that Bondronat was ‘the first and onlytreatment of its kind to be available in IV and oralformulations, with the same efficacy …’. The Panelconsidered that it was unclear as to what ‘first’referred to ie ‘treatment of its kind’, ‘available in IVand oral’ or ‘with the same efficacy’. The consumermedia release was ambiguous and misleading as tothe ‘first’ that Bondronat represented. A breach ofthe Code was ruled.

With regard to the claims ‘… Bondronat, which wasoriginally developed as a treatment for osteoporosis…’ and ‘As a drug for osteoporosis, …’ whichappeared in The Times, Novartis alleged that asBondronat was not licensed for osteoporosis thesewere in breach of the Code since the introduction ofa new medicine must not be made known to thegeneral public until the medical and pharmaceuticalprofessions had been informed of its availability,which was clearly not so.

The Panel noted that none of the press materialsprovided referred to Bondronat and osteoporosis.The Panel thus ruled no breach of the Code.

With regard to the claim ‘… a frontline treatment toprevent cancer spreading beyond the breast’ whichappeared in The Times, Novartis referred to itsallegation above.

The Panel noted that the statement in The Timesarticle read, ‘Bondronat … could also have a moreimportant impact as a frontline treatment to preventcancer spreading beyond the breast’. The claim thusreferred to a possible future use of Bondronat. ThePanel noted its comments above that none of thematerials provided by Roche referred to ongoing orfuture trials with Bondronat in unlicensedindications. The Panel ruled no breach of the Code.

Novartis alleged that since Bondronat was notlicensed for this indication, the claim ‘If secondarycancer could be prevented, then many patients couldstay disease-free’ raised unfounded hopes and wasin breach of the Code.

The Panel noted that the claim was a quotation froma medical oncologist. The quotation was notincluded in any of the Bondronat press materialsprovided by Roche and nor was there any referenceto the particular medical oncologist. The Panelruled no breach of the Code.

Novartis alleged that as Bondronat was not licensedfor breast cancer, the title ‘New breast cancer drug’of an article in Bella was in breach of the Code.

The Panel did not consider that any of the pressmaterials provided by Roche gave the impressionthat Bondronat was licensed to treat breast cancer.No breach of the Code was ruled.

Novartis drew attention to the claim ‘Ibandronicacid (brand name Bondronat) is the first and only

treatment of its kind proven to offer patients up totwo years relief from the often severe and disablingpain …’ appeared in Bella and referred to a previousallegation.

The Panel noted that the claim at issue was similarto a statement in the consumer media press release.However, the Panel noted that Novartis had onlyreferred to its previous allegation it had not madeany other specific comment on what was a differentclaim to that previously considered. SimilarlyRoche had only referred to its previous response ona different claim. The Panel decided that in thelight of the complaint and the response it had nochoice other than to rule no breach of the Code.

Novartis Pharmaceuticals UK Ltd complained aboutvarious articles which had been published aboutBondronat (ibandronate) which was marketed byRoche Products Limited.

Bondronat was available as film-coated tablets and asa concentrate for solution for intravenousadministration (IV). Both products were indicated forthe prevention of skeletal events (pathologicalfractures, bone complications requiring radiotherapyor surgery) in patients with breast cancer and bonemetastases. In addition Bondronat IV was alsoindicated for the treatment of tumour-inducedhypercalcaemia with or without bone metastases.

Novartis marketed Zometa (zoledronic acid) whichhad similar indications to Bondronat. Both productsbelonged to a class of medicines known asbisphosphonates.

A Prescriber 5 April 2004 and Future Prescriber,Spring 2004

Articles in these two publications entitled ‘Oraltreatment for metastatic bone disease’ announced thelaunch of Bondronat and discussed efficacy andtolerability data.

1 Headline ‘Oral treatment for metastatic bonedisease’

COMPLAINT

Novartis alleged that this headline claim wasmisleading as Bondronat tablets were only licensedfor patients with breast cancer and bone metastases,not other malignant types. Whilst this might be amisinterpretation by the journal in question, it couldrepresent breaches of Clauses 7.2 and 3.2.

RESPONSE

Roche described its media materials and explainedthat these were part of an awareness campaign ascommonly employed by pharmaceutical companies atthe time of a product launch. The materials providedto the media were:

● ‘Metastatic Bone Disease – BackgroundInformation’, Certified for use at a media briefingevent in the UK on 21 November 2003.

● Medical media release entitled ‘Improving qualityof life for advanced breast cancer patients with


“bone saver”’. Certified for use as a mediabriefing document and embargoed until 10 March2004.

● Consumer media release entitled ‘Improvingquality of life for advanced breast cancer patientswith “bone saver”’ Certified for use as a mediabriefing document and embargoed until 10 March2004.

● ‘Backgrounder – Bondronat (ibandronic acid)’,certified for use as a media briefing document on 8January 2004 and available as required.

● ‘Bondronat UK Launch – Pitch Points’ usedverbally with journalists

Roche explained that it contacted journalists via itsUK public relations department. One of thejournalists might have been briefed at an internationalcancer meeting by Roche’s international colleagues.Discussions would also have occurred with theinvestigators and authors of the key published trials.These were eminent clinicians, experienced and wellrespected in the field of managing metastatic bonedisease with bisphosphonates. It was neither possiblenor desirable to censure the views of theseindependent opinion leaders.

Roche did not necessarily agree with all commentswritten about its medicines in the press, even whenaccurate and balanced briefing materials, backgrounddata and copies of the summary of productcharacteristics (SPC) were supplied. There were noconsistent inaccuracies as alleged by Novartis.

Roche submitted that although the content of thearticle was not subject to the Code, it would commentwithout prejudice on the complaint.

Roche stated that the claim ‘Oral treatment formetastatic bone disease’ appeared to be a journalisticoversimplification. Roche submitted that its briefingmaterials made the licensed indication clear.

PANEL RULING

The Panel noted that oral Bondronat was indicated forthe prevention of skeletal events in patients withbreast cancer and bone metastases. The headlineclaim at issue ‘Oral treatment for metastatic bonedisease’ gave the impression that Bondronat could beused to treat the metastases per se and that was not so.The Panel noted, however, that complaints aboutarticles in the press were judged on the informationprovided by the pharmaceutical company or its agentto the journalist and not on the content of the articleitself.

The Panel thus examined the material provided to themedical media. The ‘Bondronat UK Launch – PitchPoints’ document featured nine bullet points: the firstintroduced Bondronat as part of the management ofadvanced breast cancer. This was the only bulletpoint to refer to ‘breast cancer’, all of the othersreferred only to ‘cancer’. The seventh point describedBondronat as the ‘bone saver’ which worked by‘effectively slowing the cancer’s growth in the bone’.‘Metastatic Bone Disease – Background Information’described the pathophysiology, incidence, risk factors,complications, symptoms and goals of metastatic

bone disease management. One goal of metastaticbone disease management read ‘ideally, reducedisease progression and improve patient survival’.Although the document concluded by discussingmetastatic bone disease and breast cancer this aspectwas not mentioned at the beginning of the document,in the heading or such like. Whilst the document didnot mention Bondronat it was nonetheless an integralpart of the Bondronat press materials. Thebackgrounder on Bondronat discussed the medicine’smode of action, licensed indications, administration,tolerability and the convenience of oral versus IVpresentations. The document explained that‘Bondronat [was] licensed for treatment of tumour-induced hypercalcaemia of malignancy with orwithout metastases. Prevention of skeletal events inpatients with breast cancer and bone metastases’. Thesection detailing the administration of Bondronatstated ‘Bondronat is available as intravenous and oralformulations for the treatment of metastatic bonedisease’ and that ‘For oral use the recommended dosefor metastatic bone disease is 50mg once daily’. Thedocument concluded that Bondronat provided ‘animportant clinical alternative for the treatment of bonemetastases’. The medical media release ‘Improvingquality of life for advanced breast cancer patients with"bone saver"’ discussed treatment of metastatic bonedisease in breast cancer patients and explained thatthe ‘bone saver’ worked by inhibiting the spreadingcancer from growing or multiplying in the bone. Ittherefore reduced bone pain and bone fractures.

The Panel considered that overall the materialdirected at the medical press, apart from the medicalmedia release ‘Improving quality of life for advancedbreast cancer patients with "bone saver"’, did notmake it sufficiently clear that although Bondronat waslicensed for metastatic bone disease it was only formetastatic bone disease secondary to breast cancer. Itwas not licensed to treat metastatic bone diseaseresulting from any other cause. The Panel consideredthat the ‘Pitch Points’ document, the Bondronatbackgrounder and the Metastatic Bone Disease –Background Information document were misleadingin this regard and inconsistent with the particularslisted in the Bondronat SPC. Breaches of Clauses 7.2and 3.2 were ruled.

2 Statement ‘The oral formulation has equivalentefficacy to the iv drug’

COMPLAINT

Novartis alleged that this claim was misleading asthere had been no direct comparisons of the twoformulations. Any comparisons made were indirectand inferred. Novartis noted that this claim wascurrently the subject of an ongoing case; CaseAUTH/1572/4/04.

RESPONSE

Roche submitted that this was a key feature ofBondronat and the subject of an appeal in CaseAUTH/1572/4/04. In practical medical terms, theefficacy of oral Bondronat was equivalent to that ofthe IV formulation. This was borne out of the


marketing authorization and no further explanationshould be necessary. Roche referred to Clause 7.5 ofthe Code.

Roche noted that ‘equivalent’ was defined in threeonline dictionaries as: ‘corresponding or virtuallyidentical especially in effect or function’ (MerriamWebster OnLine); ‘Essentially equal’(Hyperdictionary); ‘Being essentially equal, all thingsconsidered … something that performs substantiallythe same function as another thing in substantially thesame way … corresponding or virtually identical ineffect of function < drugs that are therapeuticallyequivalent’ (Dictionary.com).

Roche noted that the IV Bondronat SPC stated thatthere was ‘a 40% reduction in the risk of SRE [SkeletalRelated Events] over placebo (relative risk 0.6,p=0.003)’. For the oral formulation the SPC statedthat there was a 38% reduction in the risk ofdeveloping an SRE when compared with placebo(relative risk 0.6, p=0.003). The trials used identicalinclusion/exclusion criteria. The indication formetastatic bone disease was identical for bothformulations. There was no direction as to which touse as both formulations were interchangeable for thisindication, all else being equal. Of course, that anindividual patient might require one formulation overthe other was dictated by their individual clinicalcircumstances. To state that 40% and 38% were‘equivalent’ was correct.

PANEL RULING

The Panel noted that Novartis had not stated a clauseof the Code which it alleged had been breached. Ithad alleged that the statement ‘The oral formulationhas equivalent efficacy to the iv drug’ was misleadingas there had been no direct comparisons of the twoproducts and referred to a previous case, CaseAUTH/1572/4/04, wherein Novartis had alleged thata closely similar claim was, inter alia, misleading andin breach of Clause 7.2 for the same reasons. CaseAUTH/1572/4/04 had also involved alleged breachesof Clauses 7.3 and 7.4 in relation to the similar claim.The Panel did not consider that it had allegationsbefore it on these points in the present case; Novartishad described the comparison as misleading: this wasadequately covered by Clause 7.2. Roche hadresponded to the present complaint in relation to therequirements of Clause 7.2 and the Panel thus ruled inrelation to the requirements of this clause.

Case AUTH/1572/4/04 concerned an allegation thatthe claim ‘The first 3rd generation bisphosphonatewith equivalent oral and IV efficacy’ was, inter alia,misleading because it gave the impression that therewas head-to-head data directly comparing the two;the Panel had upheld the complaint and upon appealby Roche the Appeal Board had considered that theclaim at issue was a strong, unequivocal statement.The claim was referenced to Body et al (2003) whichhad taken the results from three different placebocontrolled studies using two different formulations.None of the studies directly compared IV and oralBondronat. The study authors had concluded, interalia, that their results suggested that both IV and oralBondronat were equally effective. The Appeal Board

noted that such caution was not reflected in the claimat issue. The Appeal Board considered that the claimgave the impression that a direct clinical comparisonof IV and oral Bondronat had proven that the twowere equally effective which was not so. The AppealBoard thus upheld the Panel’s rulings of breaches ofClauses 7.2, 7.3 and 7.4 of the Code.

Turning to the present case, Case AUTH/1599/6/04,the Panel noted that when Roche submitted itsresponse the appeal in Case AUTH/1572/4/04 hadnot been heard. The Panel considered that thecomments and ruling in Case AUTH/1572/4/04 wererelevant here. The Panel also considered its generalcomments upon the press materials at point A1 abovewere relevant.

The Panel noted that the eighth bullet point in the‘Bondronat UK Launch – Pitch Points’ document read‘Bondronat if [sic] the first treatment available as a pillwith the same power as its IV formulation’. TheBondronat backgrounder stated ‘[oral Bondronat]combines intravenous efficacy with oral convenience’.The medical media release ‘Improving quality of lifefor advanced breast cancer patients with “bonesaver”’ stated that the IV and oral formulations hadthe same efficacy.

The Panel considered that the ‘Bondronat UK Launch– Pitch Points’ document, the Bondronatbackgrounder and the medical media release gave theimpression that a direct clinical comparison of IV andoral Bondronat had proven that the two were equallyeffective and that was not so. The materials weremisleading in this regard. A breach of Clause 7.2 wasruled.

3 Claim ‘There are also no adverse renal effects …’

COMPLAINT

Novartis alleged that this absolute statement wasuntrue since Section 4.8 of the SPC stated thatazotaemia (uraemia) had been reported, albeit rarely;the claim was therefore misleading, inconsistent withthe terms of the marketing authorization and inbreach of Clause 7.2. Since Prescriber was aimed atgeneral practitioners there was also an issue of patientsafety since it misled as to the side effect profile of themedicine and was therefore in breach of Clause 2.

RESPONSE

Roche submitted that whilst none of its materials hadever stated that Bondronat had no renal adverseeffects, it was common knowledge amongstBondronat prescribers that it had an excellent renalsafety profile. To date, an estimated 500,000 patientshad been prescribed Bondronat since its firstEuropean launch in 1995. In trials, renal adverseevents had been at a level comparable to placebo. Forthe IV pivotal study ‘There was no evidence of renaltoxicity associated with ibandronate treatment: theincidence of renal adverse events was low and did notdiffer between placebo and ibandronate groups’(Body et al 2003). For the oral pivotal studies, theincidence of renal adverse events was comparable


between ibandronate (5.2%) and placebo (4.7%), andthere were no reports of serious adverse events (renalfailure) in the active treatment group (Body et al 2004).

Roche submitted that no other bisphosphonate hadfour year follow-up renal safety data to establish norenal toxicity concerns over long-term therapy(McLachlan et al 2003, Rivkin et al 2003) and the SPCclearly stated ‘Clinical studies have not shown anyevidence of deterioration in renal function with longterm Bondronat therapy’. There were no publisheddata raising clinical concern about Bondronat’s renalsafety profile. Even Novartis had admitted that theonly cited renal adverse event occurred ‘albeit rarely’.

PANEL RULING

The Panel noted its general comments about the pressmaterials in point A1 above. In addition the Panelnoted that a section entitled ‘What are the side effectswith Bondronat’ within the Bondronat backgrounderbegan by discussing the toxicities associated withcurrent bisphosphonates which, it was stated, couldlimit their clinical benefit. The first of three bulletpoints read ‘infusion of pamidronate and zoledronatecan lead to renal toxicity, which, in rare cases, canhave severe and life-threatening consequences’.Product labelling and monitoring of patients takingzoledronate was discussed. The safety profile of oralBondronat was described as ‘comparable to placebo’.The Panel considered that the section ‘What are theside effects with Bondronat’ implied that althoughrenal toxicity had been reported in association withpamidronate and zoledronate none had been reportedwith Bondronat and that was not so. The medicalmedia release stated that Bondronat had not beenassociated with increases in renal toxicity or renaladverse events.

The Panel noted that Section 4.8 of the Bondronattablet SPC listed uraemia as an uncommon adverseevent, occurring at a frequency of <1% compared withplacebo.

The Panel considered that the Bondronatbackgrounder implied that no renal toxicity had beenreported with the medicine. The medical mediarelease stated categorically that Bondronat had notbeen associated with increases in renal adverse events.This was not so. The two documents were misleadingin this regard and the Panel ruled a breach of Clause7.2 of the Code with respect to both. The Panel didnot consider that the matter warranted a ruling of abreach of Clause 2 which was a sign of particularcensure and reserved for such. No breach of Clause 2was ruled.

4 Claim ‘… and the gastrointestinal side-effectsof the oral formulation were comparable toplacebo’

COMPLAINT

Novartis stated that this statement was untrue and atodds with Section 4.8 of the SPC which had a table ofcommon adverse drug reactions from the pooledphase III trials entitled ‘Related Adverse EventsReported Commonly and Greater than Placebo’ the

table listed dyspepsia, nausea, abdominal pain andoesophagitis, all of which were manifestlygastrointestinal side-effects which were notcomparable to placebo. Novartis alleged that theclaim was misleading about the side-effect profile ofthe medicine and potential risks to patient safety inbreach of Clauses 7.2 and 2.

RESPONSE

Roche submitted that this appeared to be a journalisticmisinterpretation. Gastrointestinal side-effects werecompared to placebo and at a very low level. Inpractice, this tablet was very well tolerated.

PANEL RULING

The Panel considered that its general comments aboveat points A1 about the media materials were relevant.

The Panel noted that the oral Bondronat SPC listeddyspepsia, nausea, abdominal pain (not otherwisespecified) and oesophagitis as events reportedcommonly (≥ 1% and <10%) and greater than placebo.Also listed were those uncommon (≥ 0.1% and <1%)adverse reactions which had occurred in two studiesmore frequently with Bondronat 50mg than withplacebo. These were abdominal pain, dry mouth,duodenal ulcer haemorrhage, dysphagia and gastritis.

The Panel noted that a section of the Bondronatbackgrounder entitled ‘What are the side effects withBondronat’ discussed the side effects of otherbisphosphonates which had limited their clinicalbenefit. The third bullet point read ‘administration oforal clodronate can cause gastrointestinal disturbances…’. The section concluded with a discussion ofBondronat’s side-effect profile, stating, inter alia, thatthe safety profile of Bondronat was comparable toplacebo. Overall, the section implied that Bondronatwould not cause gastrointestinal disturbance whichwas not so. The Panel considered that the Bondronatbackgrounder was not a fair reflection of the SPC onthis point and was thus misleading. A breach ofClause 7.2 was ruled. The Panel did not consider thatthe matter warranted a ruling of a breach of Clause 2which was a sign of particular censure and reservedfor such. No breach of Clause 2 was ruled.

B DGNews 22 March 2004

1 Heading ‘Bondronat (Ibandronate) AppearsEffective, Well-Tolerated, ConvenientTreatment for Metastatic Bone Disease’

COMPLAINT

Novartis referred to its allegation at point A1 above.

RESPONSE

Roche submitted that whilst the statement ‘Bondronat… appears effective, well-tolerated, convenient’ wascorrect, the indication cited appeared to be ajournalistic oversimplification. Roche briefingmaterial made the licensed indication quite clear.


PANEL RULING

The Panel considered that its ruling at point A1 aboveapplied here. Breaches of Clauses 3.2 and 7.2 wereruled.

2 Generic name

COMPLAINT

Novartis noted that ibandronate was not theregistered generic name for Bondronat.

RESPONSE

Roche stated that it was confused by Novartis’complaint, as it also used ‘ibandronate’ withoutqualification in its own promotional materials (CaseAUTH/1594/6/04). The registered generic name forBondronat was ibandronic acid. Ibandronate was aterm commonly used by investigators, in publications,and by many users. This issue was clarified inBondronat materials to avoid any confusion.

PANEL RULING

The Panel noted that Novartis had not stated a clauseof the Code which it alleged had been breached norhad it referred either to another part of this complaintor the previous case, Case AUTH/1572/4/04,wherein a clause was clearly stated. The situationwas thus different to point A2 above. The complaintdid not meet the requirements of Paragraph 5.2 of theConstitution and Procedure. The Panel did nottherefore consider this allegation.

3 Claim ‘Bondronat was also well tolerated, withpatients experiencing adverse events similar tothose in the placebo group’

COMPLAINT

Novartis referred to its allegation at points A3 and A4above.

RESPONSE

Roche made no additional comment on this point.

PANEL RULING

The Panel noted that the DGNews item referredalmost exclusively to the publication that day of Bodyet al (2004). In its complaint Novartis had not quotedthe whole of the claim which read, in full: ‘Bondronatwas also well tolerated, with patients experiencingadverse events similar to those in the placebo groupwith the exception of a small number of patientsexperiencing mild to moderate gastro-intestinal sideeffects’. Given the context of the news item it wasclear that the claim at issue related only to thefindings of one study. The source of the news itemwas a stated PR agency which the Panel assumed wasworking on behalf of Roche.

The Panel considered that the claim was a fair andaccurate reflection of Body et al (2004). Given that the

statement clearly related to only one cited study thePanel ruled no breach of Clause 7.2 of the Code. Itthus followed that there was no breach of Clause 2 ofthe Code.

C Article in Future Prescriber, Spring 2004

1 Statement ‘The oral drug has advantages overits competitor in that it is a small tablet takenonly once daily’

COMPLAINT

Novartis assumed that the competitor was oralclodronate, but it took issue with the fact that being asmall tablet, or being taken once daily offeredadvantages. Novartis noted that Bondronat tabletsmust be taken after an overnight fast (at least 6 hours)and before the first food or drink of the day andfasting should be continued for at least 30 minutesafter taking the tablet. Conversely, Loron capsulesmight be taken after only an hour’s fast. Novartisfurther noted that the once daily argument wasspurious since Loron might also be taken once daily.

Novartis alleged that this statement was misleadingand noted that it was currently the subject of theongoing Case AUTH/1572/4/04.

RESPONSE

Roche submitted that the convenience of oralBondronat was a key feature of Bondronat and amatter of an appeal (Case AUTH/1572/4/04). Loroncould be prescribed once daily but was commonlytaken in divided doses (as with other clodronates) dueto the large size of the tablets and gastrointestinalintolerance. This was well known and featured inNovartis’ own satellite symposium in Davos in March2004 and in the Major (2004) abstract presented at thisinternational bisphosphonate workshop. It wasshown that gastrointestinal toxicity could cause earlystudy discontinuation, with reports of 11-47% ofpatients reporting upper gastrointestinal adverseevents. These data did not include oral Bondronat. Ina long-term study of 1,079 patients, gastrointestinaldisorders were significantly more common withclodronate (66%) than placebo (56.2%) (Atula et al2003). One might speculate the high placebo levelreflected the size of the tablet needed to match theactive. Diarrhoea was also significantly morecommon for clodronate (15.1%) than placebo (6.8%).Complicated regimes and compliance were cited asproblems.

PANEL RULING

The Panel noted that Novartis had not stated a clauseof the Code which it alleged had been breached. Ithad described the statement as misleading andreferred to Case AUTH/1572/4/04 where a similarclaim was alleged to be in breach of Clause 7.2. Rochehad responded in relation to the requirements ofClause 7.2 and the Panel thus made its ruling on thisbasis.


The Panel noted that both parties had referred to theprevious case, Case AUTH/1572/4/04, wherein theclaim ‘So with equivalent efficacy and a small once-daily tablet, compared to IV, Oral Bondronat offers allthe convenience of flexibility you could want fromtoday’s bisphosphonate therapy’ had been at issue.The Panel had noted that there were three oralbisphosphonates indicated for the treatment ofpatients with breast cancer and bone metastases;Bonefos, Loron and Bondronat. Bonefos and Loronwere to be taken in a single dose or two divided doseseach day, at least one hour before and one hour afterfood. Bondronat tablets were to be taken after anovernight fast of at least six hours and at least 30minutes before the first food or drink of the day. ThePanel considered there was thus less flexibility withregard to the time of day that a patient could takeBondronat compared with the other oralbisphosphonates. If a patient forgot to takeBondronat first thing in the morning, before breakfast,it would be difficult to take it at any other time of daygiven the need to fast for at least six hours beforehandand 30 minutes after. Patients who forgot to takeeither Bonefos or Loron could take it later in the dayas long as there was a period of at least two hourswhere they did not eat; to take Bondronat later in theday required a period of at least six and a half hoursof no food. The Panel noted Roche’s submissionabout the small tablet size but noted that there was nodata to show whether patients found these more orless convenient than other bisphosphonate tablets.The Panel thus considered that in the context of‘today’s bisphosphonate therapy’ oral Bondronat wasless convenient and flexible in terms of timing ofdosage than other oral bisphosphonates. The Panelthus ruled breaches of Clauses 7.2, 7.3, 7.4 and 7.10 ofthe Code. On appeal by Roche the Appeal Boardconsidered, inter alia, that the claim was more than acomparison between IV and oral. The reference to‘today’s bisphosphonate therapy’ turned the claiminto a comparison of oral Bondronat with all otherbisphosphonates. The Appeal Board thus consideredthat by stating oral Bondronat offered all (emphasisadded) the convenience and flexibility a prescribercould want … the claim was misleading, not capableof substantiation and exaggerated as alleged. TheAppeal Board had upheld the Panel’s rulings ofbreaches of the Code.

Turning to the case now before it, CaseAUTH/1599/6/04, the Panel noted that the article inFuture Prescriber referred to clodronate andzoledronic; both were competitors to Bondronat.Zoledronic acid (Zometa) was only available as an IVformulation and so the Panel assumed that in thestatement at issue the competitor referred to wasclodronate.

The Panel noted that both the medical media releaseand the Bondronat backgrounder stated thatBondronat was to be taken once daily. The Bondronatbackgrounder additionally noted that Bondronat wasa small tablet. Neither document referred to the sizeof clodronate tablets nor to their frequency ofadministration. None of the materials compared thetablet size or frequency of administration ofBondronat with clodronate; no breach of Clause 7.2was ruled.

2 Claim ‘The manufacturers are investigating apotential inhibitory effect on bone tumours ….There are also trials underway … in [metastaticbone disease] associated with other cancers,such as lung, prostate and myeloma’

COMPLAINT

Novartis noted that the Code allowed advancenotification of new indications to budget holders forplanning purposes. However, Novartis alleged thatthe readership of Future Prescriber could not beassumed only to fulfil the criteria of budget holders;many would be prescribers. Thus to give informationto journalists about unlicensed indications constituteda breach of Clause 3.2.

RESPONSE

Roche submitted that its briefing materials did notinclude information about further areas of research.This speculation might have come from anindependent clinician.

PANEL RULING

The Panel noted that none of the press materialsprovided by Roche referred to ongoing or future trialswith Bondronat in unlicensed indications. No breachof Clause 3.2 was ruled.

D E-mims April 2004

Claim ‘For many patients with metastatic bonedisease treatment with intravenousbisphosphonates is complicated by infusion-related adverse events and the potential forrenal toxicity. Therefore, an effective oralformulation offers an important alternative’

COMPLAINT

Novartis alleged that as in point A3 above thisimplied that oral Bondronat did not have the potentialfor renal toxicity.

RESPONSE

Roche did not comment further on this point.

PANEL RULING

The Panel considered that its comments and rulings atpoint A3 above were relevant. A breach of Clause 7.2was ruled. No breach of Clause 2 was ruled.

E Article entitled ‘A Pain-Free Future’. TheTimes, Friday 19 March 2004

1 Claims ‘There is now a drug that could helpsuch women to lead relatively normal lives’and ‘One of the other benefits of Bondronat isthat it is the first drug in its class – the so-called bisphosphonates – that can be takenorally without the need for regular intravenousinjections or infusions in hospital’


COMPLAINT

Novartis alleged that these statements weremisleading since they implied that no such medicinewas available previously which was clearlyinaccurate, since several bisphosphonates, both oraland IV were already available for treatment of breastcancer metastatic to bone. Additionally, Roche’s ownproduct, Loron, had been available orally for sometime. This should have been made clear in anybriefing, in particular to the lay press. Thesestatements were misleading and in breach of Clause7.2.

RESPONSE

Roche submitted that a general comment could bemade here about the statements that appeared in thelay press. Roche stated that its briefing materials wereclear but the lay press had taken a degree of latitude,for which Roche could not be held responsible.

PANEL RULING

The Panel noted its general comments about pressmaterials at point A1 above.

The Panel noted that the consumer media releasestated that Bondronat was ‘the first and onlytreatment of its kind to be available in IV and oralformulations, with the same efficacy …’. The Panelconsidered that it was unclear as to what the firstreferred to ie ‘treatment of its kind’, ‘available in IVand oral’ or ‘with the same efficacy’. The Panelconsidered that the consumer media release wasambiguous and misleading as to the ‘first’ thatBondronat represented. A breach of Clause 7.2 wasruled.

2 Claims ‘… Bondronat, which was originallydeveloped as a treatment for osteoporosis …’and ‘As a drug for osteoporosis, …’

COMPLAINT

Novartis alleged that as Bondronat was not licensedfor osteoporosis these statements were in breach ofClause 3.2 and 20.4 since the introduction of a newmedicine must not be made known to the generalpublic until the medical and pharmaceuticalprofessions had been informed of its availability,which was clearly not the case.

RESPONSE

Roche referred to its response at point E1 above.

PANEL RULING

The Panel noted that none of the press materialsprovided referred to Bondronat and osteoporosis. ThePanel thus ruled no breach of Clauses 3.2 and 20.4 ofthe Code.

3 Claim ‘… a frontline treatment to preventcancer spreading beyond the breast’

COMPLAINT

Novartis referred to its allegation at point E2 above.

RESPONSE


PANEL RULING

The Panel noted that the statement in The Timesarticle read, ‘Bondronat … could also have a moreimportant impact as a frontline treatment to preventcancer spreading beyond the breast’. The claim thusreferred to a possible future use of Bondronat. ThePanel noted its comments at point C2 above. ThePanel ruled no breach of Clauses 3.2 and 20.4 of theCode.

4 Claim ‘(This does not affect the drug’s use forbone pain, for which it is licensed)’

COMPLAINT

Novartis alleged that clearly the journalist was awareof the licensed indication for this product.

RESPONSE


PANEL RULING

The Panel noted that Novartis had not stated a clauseof the Code which it alleged had been breached. Itappeared that in fact there was no complaint aboutthe statement. The situation was different to point A2above. The complaint did not meet the requirementsof Paragraph 5.2 of the Constitution and Procedure.The Panel did not therefore consider this matter.

5 Claim ‘If secondary cancer could be prevented,then many patients could stay disease-free’

COMPLAINT

Novartis alleged that since Bondronat was notlicensed for this indication, the claim raisedunfounded hopes and was in breach of Clause 20.2.

RESPONSE

Roche referred to its comments at point E1 above.

PANEL RULING

The Panel noted that the claim at issue was aquotation from a medical oncologist. The quotationwas not included in any of the Bondronat pressmaterials provided by Roche and nor was there anyreference to the particular medical oncologist. ThePanel ruled no breach of Clause 20.2.

F Article entitled ‘New breast cancer drug’. Bella, 11 May 2004


1 Claim ‘New breast cancer drug’

COMPLAINT

Novartis alleged that as Bondronat was not licensedfor breast cancer, this heading was in breach of Clause3.2.

RESPONSE


PANEL RULING

The Panel did not consider that any of the pressmaterials provided by Roche gave the impression thatBondronat was licensed to treat breast cancer. Nobreach of Clause 3.2 was ruled.

2 Claim ‘Ibandronic acid (brand name Bondronat)is the first and only treatment of its kindproven to offer patients up to two years relieffrom the often severe and disabling pain …’

COMPLAINT

Novartis referred to point E1 above.

RESPONSE


PANEL RULING

The Panel noted that the claims at issue at point E1above were general in nature whereas the claim nowat issue was very clear as to the feature beingdiscussed ie two year pain relief data. The Panelnoted that the article was closely similar to a claim inthe consumer media press release. However, thePanel noted that the allegation in point E1 was thatclaims were misleading and in breach of Clause 7.2 ofthe Code. Novartis had not provided any data toshow that Bondronat was not the first bisphosphonateto offer patients up to two years of pain relief. Rochehad not provided any data or response. The Paneldecided that in the light of the complaint and theresponse it had no choice other than to rule no breachof Clause 7.2.


Case completed 17 September 2004


Denfleet Pharma complained about two booklets issued byNovartis which compared Novartis’ product Clozaril(clozapine) with generic clozapine. One was entitled‘Generic clozapine – why take the risk in at risk patients?’and the other ‘WHO will pay the price for genericclozapine?’. Novartis stated that the aim was to outlineissues that needed to be considered when assessingalternative suppliers of clozapine and to provide evidenceemerging from the US regarding the use of generic clozapine.Denfleet marketed Denzapine (clozapine), a branded generic.Clozapine was an atypical antipsychotic medicine.

The claim ‘88% of patients said they would prefer to stay onClozaril rather than change to another drug’ appeared in thebooklet ‘Generic clozapine – why take the risk in at riskpatients?’. Denfleet stated that since the booklet related tothe switching of patients from Clozaril to generic clozapine,this claim was misleading; it inferred that patients wouldrather stay on Clozaril than another medicine, includinggeneric clozapine. The cited paper (Taylor et al 2000) actuallyreferred to patients’ preference for clozapine rather than theprevious antipsychotic they were taking.

The Panel noted that Taylor et al asked patients, most ofwhom had been taking clozapine for two years or more, tocompare clozapine with their previous treatment whichincluded oral typical medicines, depot typical and oralatypical; the majority (62.1%) of respondents rated clozapineas being better. The Panel considered the claim wasmisleading and had not been substantiated as it was notsufficiently clear that the comparison was with medicinesother than clozapine. Context was a contributory factor asthe purpose of the booklet was to compare generic clozapinewith Clozaril. Breaches of the Code were ruled.

The claim ‘Generally, bioequivalent drug products areconsidered to be therapeutically equivalent …’ appeared on apage headed ‘What does “bioequivalent” actually mean?’.The claim was referenced to UK regulatory guidance onbioavailability and bioequivalence and a Food and DrugAdministration (FDA) letter to health professionals regardingthe therapeutic equivalence of generic drugs.

Denfleet alleged that the use of the word ‘generally’ wasmisleading as it implied some level of variability. As far asthe FDA was concerned, a medicine was either consideredbioequivalent and therapeutically equivalent, or not. TheFDA’s letter regarding therapeutic equivalence of genericmedicines, stated that ‘For both brand-name and genericmedicines, FDA works with pharmaceutical companies toassure that all drugs marketed in the US meet specificationsfor identity, strength, quality, purity and potency. Inapproving a generic drug product, FDA requires manyrigorous tests and procedures to assure that the generic drugis interchangeable with the brand-name drug under allapproved indications’. The FDA published a list of brandname medicines and therapeutically equivalent genericproducts. Several formulations of generic clozapine werelisted as therapeutically equivalent. Therefore, the use of‘generally’ in the claim was misleading.

The Panel considered that there might be occasionswhen bioequivalent medicines were not consideredto be therapeutically equivalent, for example whensite of action was a key factor or there weredifferences in absorption rate. The UK regulatoryguidance stated ‘However, in some cases wheresimilar extent of absorption but different rates ofabsorption are observed the products can still bejudged therapeutically equivalent if thosedifferences are not of therapeutic relevance. Aclinical study to prove that the differences inabsorption rate are not therapeutically relevant willprobably be necessary’. The Panel did not considerthat the claim was misleading as alleged and thusruled no breach of the Code.

Denfleet stated that a page headed ‘What do thestudies show?’ wrongly implied that the US was theonly country in which generic clozapine wasavailable, when in fact it was also availablethroughout Europe, South Africa and Australasia.Denzapine, one of the two branded genericclozapines available in the UK, had not soughtmarketing authorization approval in the US untilthis time. No reference was made to this in thebooklet and therefore any problems due to the useof generic clozapine in the US could not apply toDenzapine. Denfleet alleged that to disseminatedata in this blanket manner to UK psychiatrists wasmisleading.

Denfleet stated that two of the three references(Kluznik et al 2001; Mofsen and Balter 2001; Price2001) which discussed relapse were presented at aseminar sponsored by an unrestricted educationalgrant from the Novartis PharmaceuticalsCorporation. This did not represent a balanced viewof the information currently available. The cases ofrelapse presented by Price were raised during asymposium discussion; no details were presented orpublished in a peer reviewed journal. The use ofthis type of reference was misleading. The bookletdid not include references to clinical studies,reported in peer-reviewed journals, where patientshad been successfully switched to generic clozapinewithout reported relapse, eg Sajbel et al (2001),Stoner et al (2003) and Makela et al (2003). Aquotation from Kelleher (2001) was referencedincorrectly.

The Panel considered that the page implied thatgeneric clozapine was only available in the US. Thiswas not so. Breaches of the Code were ruled. ThePanel did not accept that it was necessarilymisleading to present data about the US use ofgeneric clozapine to UK physicians when Denfleet’sclozapine, Denzapine, was not available in the US.No breach of the Code was ruled in this regard.

The Panel did not accept it was necessarilymisleading to use references presented at Novartis’


CASE AUTH/1600/6/04

DENFLEET PHARMA v NOVARTISClozaril booklets

sponsored seminar. No breach of the Code wasruled on this narrow point. However the Panelnoted Denfleet’s submission that there were studiesshowing switching without relapse. None had beenprovided to the Authority by either party. In thePanel’s view, given the allegation, Novartis had notdemonstrated that the data in the bookletrepresented the balance of the evidence. The Panelthus ruled breaches of the Code.

The Panel noted that the reference to Kelleher (2001)should have stated Kelleher (2002). A breach of theCode was ruled.

Denfleet alleged that the question ‘Without thesupport network associated with the CPMS (ClozarilPatient Monitoring Service), how many patients willrelapse?’ which appeared in the section headed‘Relapse’, implied that without the support of theCPMS patients might relapse more frequently. Thiswas misleading; relapse could be caused by manyfactors and could occur in patients where fulladherence to medication was confirmed.

The Panel considered that the question at issueimplied that the support network associated withthe CPMS prevented relapse. This was not so. Thequestion was misleading and its implication was notcapable of substantiation. Breaches of the Codewere ruled.

The claim ‘nearly 10% decrease in serum clozapineconcentration’ appeared as part of a description ofthe outcome of Kluznik et al which looked at theclinical effects of a randomised switch of patientsfrom Clozaril to generic clozapine. The claimappeared next to the claim ‘nearly 20mg/day increasein dose p=0.027’. Denfleet stated that Kluznik et alshowed that there was no statistically significantdifference between the mean serum clozapine levelsof patients receiving Clozaril and a genericclozapine and, therefore, no meaningful conclusioncould be drawn from the results. The claim wasmisleading and inaccurate.

The Panel noted that Kluznik et al reportedstatistically significant differences between Clozariland generic clozapine with regard to daily dose;610.17mg vs 629.5mg, p=0.027. Serum norclozapinelevels were lower for generic clozapine than Clozaril(p=0.01). The difference in serum clozapine levelsalthough lower for generic clozapine was notstatistically significant (p=0.085). The claim at issuewas not supported by a statistically significantdifference. The Panel considered that the claim wasmisleading and not capable of substantiation.Breaches of the Code were ruled.

Details of relapse in patients in a study by Mofsenand Balter were described. Denfleet noted that thestudy authors had stated that it was not possible toconduct a detailed analysis of all the variables inthis retrospective assessment. In Denfleet’s viewthis concurred with its opinion that Mofsen andBalter was based on purely anecdotal evidence, and,therefore, no meaningful comparisons could bedrawn.

The Panel noted that Mofsen and Balter concludedthat the findings suggested that brand-name

clozapine and the generic formulation might displayimportant clinical differences and a comparabletherapeutic response might not be achievabledespite adequate monitoring. Large controlledprospective trials were needed to clarify thepotential for treatment failure with the use ofgeneric clozapine. The Panel considered that thecase reports had not been presented in sufficientcontext. The limitations of the data as identified byDenfleet were not mentioned. The Panel consideredthat this was misleading and hence not capable ofsubstantiation. Breaches of the Code were ruled.

In relation to the booklet, ‘WHO will pay the pricefor generic clozapine’, Denfleet stated that on 26April it had complained to Novartis about thisbooklet which was almost identical to that referredto above. On 30 April, Novartis replied that itsbooklet had been withdrawn, revised and reissuedto the sales force. Although Denfleet did notentirely accept Novartis’ attitude, it nonethelessconsidered the matter dealt with. However, Denfleetnoted that the booklet was given to medical staff ata hospital during the week of 7 June by a Novartissales representative. The hospital pharmacydepartment was horrified that this had occurred andimmediately forwarded a copy to Denfleet. It alsonoted with concern that the Novartis representativewas on the wards without having signed the registerat the pharmacy department in contravention oflocal procedure. Denfleet stated that it appearedthat the booklet was also still being used in otherareas of the country.

The Panel noted that the parties’ accounts of eventsdiffered. Denfleet had received a copy of thebooklet ‘WHO will pay the price for genericclozapine?’ which had allegedly been recently givento hospital pharmacy staff by the Novartisrepresentative. No evidence had been provided bythe complainant to show that recently the hospitalhad a policy for visiting representatives nor that ifsuch a policy existed that it had not been followed.On the basis of the information before it the Paneldecided that it had no option other than to rule nobreach of the Code.

Denfleet referred to the section entitled ‘What do thestudies show? on a page headed ’What does“bioequivalent” actually mean ?’. This wasfollowed by ‘Evidence from several pharmacokineticstudies looking at bioequivalence have shownconflicting results’. Denfleet also alleged that thesection ‘What do the studies show?’ containedmisleading and inaccurate information.Pharmacokinetics was the study of the absorption,distribution, metabolism and excretion of medicinesyet the studies appearing on this page (Kluznik etal, Mofsen and Balter and Price) did not examine thepharmacokinetic parameters required to determinebioequivalence. Denfleet alleged that the statement‘Evidence from several pharmacokinetic studies …’was inaccurate, misleading and not supported by thestudies presented.

The Panel noted that the studies cited were notpharmacokinetic studies as such. Mofsen and Balterpresented seven case studies of patients whoexperienced a relapse of psychotic symptoms when


they were switched from branded clozapine to ageneric formulation. Kluznik et al studied theclinical effects of a randomised switch of patientsfrom Clozaril to generic clozapine. Serumconcentrations were measured. Price was takenfrom a discussion at a symposium which described aswitch of patients from Clozaril to genericclozapine. The claim ‘Evidence from severalpharmacokinetic studies looking at bioequivalencehave shown conflicting results’ followed by adescription of the three studies was thus misleadingand not capable of substantiation. Breaches of theCode were ruled.

Beneath the heading ‘How will the Clozaril PatientMonitoring Service (CPMS) support you?’ andbeneath the subheading ‘The comprehensive CPMSpackage’ appeared the claim ‘30% of the cost ofplasma drug concentration monitoring (requiredwhile titrating dose) is covered by the CPMS’ whichDenfleet alleged was misleading and inaccurate.

Denfleet stated that clozapine dosage was normallyadjusted according to clinical response and adverseeffect profile. The measurement of plasmaclozapine concentrations was useful in assessingcompliance, optimising therapy and minimisingtoxicity. Plasma drug level monitoring was notrequired whilst titrating the dose.

The Panel noted that the Clozaril summary ofproduct characteristics (SPC) stated that white bloodcell (WBC) count and differential blood counts mustbe performed within 10 days prior to initiatingClozaril treatment to ensure that only patients withWBC counts and absolute neutrophil count (ANC)within certain given parameters received themedicine. After the start of treatment the WBCcount and ANC must be monitored weekly for thefirst 18 weeks of therapy and at least every fourweeks thereafter throughout treatment. The use ofClozaril was restricted to patients, physicians andnominated pharmacists registered with the CPMS.

The only detailed information about monitoringwas in the claim at issue which implied thatmonitoring was only required when titrating thedose and only plasma drug concentrationmonitoring was necessary. This was not so. TheSPC required WBC and ANC monitoring atdifferent frequencies depending on how long thepatient had been taking Clozaril. The maximumperiod was at least every four weeks.

The Panel was very concerned that the statement inthe booklet gave a very different impression of themonitoring requirements compared to those in theSPC. The statement at issue might compromisepatient safety. The Panel considered the statementwas misleading and not capable of substantiation asalleged. Breaches of the Code were ruled.

Denfleet Pharma Ltd complained about two bookletsissued by Novartis Pharmaceuticals UK Ltd whichcompared Novartis’ product Clozaril (clozapine) withgeneric clozapine. One was entitled ‘Genericclozapine – why take the risk in at risk patients?’ andthe other ‘WHO will pay the price for genericclozapine?’. Both bore the reference CLZ/03/78.

The booklets were distributed by representatives tohospital pharmacists and hospital psychiatrists fromthe end of January 2004 until withdrawal on 30 April2004. Novartis stated that the aim was to outlineissues that needed to be considered when assessingalternative suppliers of clozapine and to provideevidence emerging from the US regarding the use ofgeneric clozapine.

Denfleet Pharma marketed Denzapine (clozapine), abranded generic. Clozapine was an atypicalantipsychotic medicine.

Denfleet alleged breaches of UK law as well as ofClauses 7.2, 7.4, 14.4, 15.2 and 15.4 of the Code. ThePanel only considered the alleged breaches of theCode. In addition to these clauses Denfleet citedsome specific clauses with some of the allegationsbelow. In such circumstances the Panel alsoconsidered the most relevant clauses from the generalallegations.

A Booklet entitled ‘Generic clozapine – why takethe risk in at risk patients?’

1 Claim ‘88% of patients said they would preferto stay on Clozaril rather than change toanother drug’

The claim appeared on page 7 as part of a two pagespread (pages 6 and 7) headed ‘How will the ClozarilPatient Monitoring Service (CPMS) support you?’ andwas referenced to Taylor et al (2000).

COMPLAINT

Denfleet stated that since the booklet related to theswitching of patients from Clozaril to genericclozapine, this quotation was misleading; it inferredthat patients would rather stay on Clozaril thananother medicine, including generic clozapine. Thereferenced paper actually referred to the patients’preference for clozapine rather than the previousantipsychotic they were taking. A breach of Clause7.2 of the Code was alleged.

RESPONSE

Novartis stated that the claim was at the end of asection highlighting the proven benefits of Clozaril andthe high standard of professional service offered by theCPMS. The claim was taken from Taylor et al 2000which evaluated patient perceptions of Clozariltreatment and was solely intended to reinforce thepositive perception patients had of Clozaril comparedto previous therapy despite some disadvantages oftreatment such as mandatory monitoring and side-effects. It was clear that the claim referred to anothermolecule and not a generic version of Clozaril.Novartis did not accept there had been a breach ofClause 7.2 of the Code. However, to enhance clarity, theclaim had now been withdrawn from future materials.

PANEL RULING

The Panel noted that the claim at issue was not aquotation as stated by Denfleet.


The Panel noted that Taylor et al surveyed perceptionsof patients most of whom had been taking clozapinefor two years or more. Patients were asked tocompare clozapine with their previous treatmentwhich included oral typical medicines, depot typicaland oral atypical with the overwhelming majority ofrespondents rating clozapine as being better (62.1%).

The Panel considered the claim was misleading andhad not been substantiated as it was not sufficientlyclear that the comparison was with medicines otherthan clozapine. Context was a contributory factor asthe purpose of the booklet was to compare genericclozapine with Clozaril. Breaches of Clauses 7.2 and7.4 of the Code were ruled.

2 Claim ‘Generally, bioequivalent drug productsare considered to be therapeutically equivalent…’

This claim appeared on page 11 headed ‘What does“bioequivalent” actually mean?’. The claim wasreferenced to a Committee for Proprietary MedicinalProducts (CPMP) Note for Guidance onBioavailability and Bioequivalence (2001) and a Foodand Drug Administration (FDA) letter to healthprofessionals sent in 1998 regarding the therapeuticequivalence of generic drugs.

COMPLAINT

Denfleet alleged that the use of the word ‘generally’was misleading as it implied some level of variability.As far as the FDA was concerned, a medicine waseither considered bioequivalent and therapeuticallyequivalent, or not. There was no grey area as far asthe FDA was concerned. To imply a degree ofvariability was misleading. The FDA’s letterregarding therapeutic equivalence of genericmedicines, sent to health professionals in January1998, stated that ‘For both brand-name and genericmedicines, FDA works with pharmaceuticalcompanies to assure that all drugs marketed in the USmeet specifications for identity, strength, quality,purity and potency. In approving a generic drugproduct, FDA requires many rigorous tests andprocedures to assure that the generic drug isinterchangeable with the brand-name drug under allapproved indications’.

The FDA identified brand name drug products andtherapeutically equivalent generic products in itspublication, ‘Approved Drug Products withTherapeutic Equivalence Evaluations’ or ‘OrangeBook’. Several formulations of generic clozapine werelisted in the Orange Book as therapeuticallyequivalent. Therefore, the use of ‘generally’ in theclaim was misleading.

RESPONSE

Novartis stated that the claim at issue, as well asbeing referenced to the FDA letter and to the CPMPguidance on bioequivalence, was followed by aquotation from Ereshefsky and Glazer (2001) in whichthe authors stated that FDA approval ofbioequivalence was not a guarantee of therapeuticequivalence, rather a statement of probability that

most patients would experience no clinicallymeaningful differences.

Novartis stated that the claim inferred that whilstbioequivalent medicines were classified as beingtherapeutically equivalent, there was debate in thepublished literature as to the exact implication of thisclassification in clinical practice. Additionally, theCPMP Guidance point 2.6 Therapeutic equivalence,stated ‘In practice, demonstration of bioequivalence isgenerally the most appropriate method ofsubstantiating therapeutic equivalence…’. Novartisdid not consider that the claim was misleading;however, for enhanced clarification, the word‘generally’ had now been removed from futurematerials.

PANEL RULING

The Panel considered that there might be occasionswhen bioequivalent medicines were not considered tobe therapeutically equivalent; for example when siteof action was a key factor or there were differences inabsorption rate.

The Panel noted that the CPMP Note for Guidancealso stated in Paragraph 2.6 ‘However, in some caseswhere similar extent of absorption but different ratesof absorption are observed the products can still bejudged therapeutically equivalent if those differencesare not of therapeutic relevance. A clinical study toprove that the differences in absorption rate are nottherapeutically relevant will probably be necessary’.

The Panel did not consider that the claim wasmisleading as alleged and thus ruled no breach ofClauses 7.2 and 7.4 of the Code.

3 Page 12 headed ‘What do the studies show?’

Page 12 stated that ‘Evidence from severalpharmacokinetic studies looking at bioequivalencehave shown conflicting results’ and ‘In the USAwhere generics are available, reports of relapse haveemerged’. This was followed by details of threestudies looking at relapse, Kluznik et al (2001), Mofsenand Balter (2001) and Price (2001).

COMPLAINT

Denfleet stated that page 12 implied that the US wasthe only country in which generic clozapine wasavailable. This was incorrect. Generic clozapine wasalso available throughout Europe, South Africa andAustralasia.

Denzapine, one of the two branded generic clozapinesavailable in the UK, had not sought marketingauthorization approval in the US until this time. Noreference was made to this anywhere in the bookletand therefore any reference to problems having arisenwith the use of generic clozapine in the US could notpossibly apply to Denzapine. Denfleet alleged that todisseminate data in this blanket manner to UKpsychiatrists was misleading in breach of the Code.

Denfleet stated that two of the three references whichdiscussed relapse were presented at a seminarsponsored by an unrestricted educational grant from


the Novartis Pharmaceuticals Corporation. This didnot represent a balanced view of the informationcurrently available. The cases of relapse presented byPrice were raised during a symposium discussion.No details of the cases were presented or published ina peer reviewed journal. The use of this type ofreference was misleading.

Denfleet stated that the booklet did not includereferences to clinical studies, reported in peer-reviewed journals, where patients had beensuccessfully switched to generic clozapine withoutreported relapse, eg Sajbel et al (2001), Stoner et al(2003) and Makela et al (2003).

Denfleet alleged that the quotation from Kelleher(2001) ‘Until more data are available, clinicians shouldweigh the potential for additional risk with genericclozapine against the moderate cost savings that canbe realised with generic products’ on page 12 wasreferenced incorrectly.

RESPONSE

Novartis submitted that the statement ‘In the USAwhere generics are available, reports of relapse haveemerged’ was not misleading. It did not imply thatthe US was the only country where generics wereavailable, merely that generics were available in theUS and evidence relating to their use had emerged.However, for enhanced clarification, for futurematerials the sentence had been amended as follows:‘In the USA, one of the countries where generics areavailable …’.

Novartis submitted that it had not stated thatDenzapine was not available in the US because thebooklet referred to issues with generic clozapine ingeneral and not to any specific brands. Novartisstated that it was not required to refer to any of thebranded generics available in the UK specifically byname and there was no breach of the Code.

With regard to Denfleet’s concerns relating to the useof references presented at a seminar sponsored by anunrestricted educational grant from Novartis and thereference in the booklets to case histories presentedduring a symposium discussion, Novartis pointed outthat Clause 7.4 stated that ‘Any information, claim orcomparison must be capable of substantiation’. Assuch, inclusion of published anecdotal evidence orcase histories or evidence obtained from sponsorededucational seminars was permitted. Therefore,Novartis submitted that no breach had occurred.

With regard to Denfleet’s concerns regarding the lackof references to clinical studies where patients hadbeen successfully switched and that the publicationsdescribed were not pharmacokinetic studies, Novartispointed out that the first sentence in the bookletrelating to the available evidence stated ‘Evidencefrom several pharmacokinetic studies looking atbioequivalence have shown conflicting results’. Thiswas a stand-alone sentence which clearly stated theavailable evidence was conflicting. It was capable ofsubstantiation. Hence, Novartis submitted that thestatement was not misleading and that no breach hadoccurred. However, for improved clarification, infuture materials the text had been expanded to state

that the evidence from studies evaluatingpharmacokinetic parameters and the switch ofpatients from branded to generic clozapine wasconflicting. Specific references to studies had alsobeen included.

Novartis stated that Kelleher publication wasincorrectly cited as 2001 instead of 2002 and thistypographical error had subsequently been corrected.

PANEL RULING

The Panel considered that the page implied thatgeneric clozapine was only available in the USA. Thiswas not so. Breaches of Clauses 7.2 and 7.4 wereruled.

The Panel did not accept that it was necessarilymisleading to present data about the USA use ofgeneric clozapine to UK physicians when Denfleet’sclozapine, Denzapine, was not available in the USA.No breach of Clauses 7.2 and 7.4 of the Code wasruled.

The Panel did not accept it was necessarily misleadingto use references presented at Novartis’ sponsoredseminar. No breach of Clauses 7.2 and 7.4 was ruledon this narrow point. However the Panel notedDenfleet’s submission that there were studies showingswitching without relapse. None had been providedto the Authority by either party. In the Panel’s viewgiven the allegation Novartis had not demonstratedthat the data in the booklet represented the balance ofthe evidence. The Panel thus ruled breaches ofClauses 7.2 and 7.4 of the Code.

The Panel noted that the reference to Kelleher (2001)was incorrect, it should have stated Kelleher (2002). Abreach of Clause 7.2 was ruled.

4 Question ‘Without the support networkassociated with the CPMS, how many patientswill relapse?’

Page 14 listed features which might contribute to thecost of switching. The question at issue appeared inthe section headed ‘Relapse’.

COMPLAINT

Denfleet alleged that the question implied thatwithout the support of the CPMS patients mightrelapse more frequently. This was misleading; relapsecould be caused by many different factors and couldoccur in patients where full adherence to medicationwas confirmed.

RESPONSE

Novartis submitted that the statement referred to thehigh standard of support health professionalsreceived from Novartis and the CPMS in themanagement of this complex and frequently difficultto manage group of patients. For example in themanagement of adverse events and the avoidance ofunnecessary treatment discontinuations. However,based on the decision to shorten the booklet page 14had been removed from future materials.


PANEL RULING

The Panel considered that the question at issueimplied that the support network associated with theCPMS prevented relapse. This was not so. Thequestion was misleading and its implication was notcapable of substantiation. The Panel ruled breaches ofClauses 7.2 and 7.4 of the Code.

5 Claim ‘nearly 10% decrease in serum clozapineconcentration’

The claim appeared on page 19 as part of adescription of the outcome of a study by Kluznik et alwhich looked at the clinical effects of a randomisedswitch of patients from Clozaril to generic clozapine.The claim appeared next to the claim ‘nearly20mg/day increase in dose p=0.027’.

COMPLAINT

Denfleet stated that the results of Kluznik et al showedthat there was no statistically significant differencebetween the mean serum clozapine levels of patientsreceiving Clozaril and a generic clozapine and,therefore, no meaningful conclusion could be drawnfrom the results. The claim was misleading andinaccurate, in breach of Clauses 7.2 and 7.4 of the Code.

RESPONSE

Novartis stated that the claim was included as part ofa diagrammatic illustration to support the statement:‘There was a significant increase in the dose ofmedication prescribed yet a decrease in serumclozapine concentrations following the switch frombranded to generic clozapine’. This was one of thefindings in Kluznik et al in conjunction with reports ofpatient relapse which led the authors to conclude thatgeneric and branded clozapine might not bebioequivalent. Novartis disagreed with thecomplainant’s view that no meaningful comparisonscould be drawn from the results; however, thedetailed description of the study had been removedfrom future materials based on the decision to shortenthe documents.

PANEL RULING

The Panel noted that Kluznik et al reportedstatistically significant differences between Clozariland generic clozapine with regard to dose; patients ona generic form of Clozaril took a mean dose of629.5mg per day, patients on Clozaril took 610.17mgper day (p=0.027) and serum norclozapine levels werelower for generic clozapine than Clozaril (p=0.01).The difference in serum clozapine levels althoughlower for generic clozapine was not statisticallysignificant (p=0.085). The claim at issue was notsupported by a statistically significant difference. ThePanel considered that the claim was misleading andnot capable of substantiation. Breaches of Clauses 7.2and 7.4 were ruled.

6 ‘Case reports of relapse’

Pages 20, 21 and 22 described details of relapse inpatients in a study by Mofsen and Balter.

COMPLAINT

Denfleet noted that the background to Mofsen andBalter stated that it was not possible to conduct adetailed analysis of all the variables in thisretrospective assessment. In Denfleet’s view thisconcurred with its opinion that Mofsen and Balter wasbased on purely anecdotal evidence, and, therefore, nomeaningful comparisons could be drawn.

RESPONSE

Novartis stated that the background to Mofsen andBalter referred to the analysis of all variables. Theauthors continued in the next sentence to state that‘However, factors other than the switch to a genericformulation of clozapine that could have caused orcontributed to patients’ deterioration (eg concomitantmedications) were actively sought’. Furthermore, theauthors, in support of their conclusions noted thestrong temporal link between relapse and the switchto generic clozapine. The authors therefore basedtheir causality assessments on the evaluation ofpossible confounders and the temporal associationwith the onset of relapse, as was standard practice inthe evaluation of adverse events. Novartis disagreedwith Denfleet’s view that no meaningful comparisonscould be drawn from this data. Use of case historiesand anecdotal evidence was permitted under theCode. However, for enhanced clarification, anintroductory paragraph documenting the authors’background information had been added to futurematerials.

PANEL RULING

The Panel noted that Mofsen and Balter concludedthat the findings suggested that brand-nameclozapine and the generic formulation might displayimportant clinical differences and a comparabletherapeutic response might not be achievable despiteadequate monitoring. Large controlled prospectivetrials were needed to clarify the potential fortreatment failure with the use of generic clozapine.

The Panel considered that the case reports had notbeen presented in sufficient context. The limitationsof the data as identified by Denfleet were notmentioned. The Panel considered that this wasmisleading and hence not capable of substantiation.Breaches of Clauses 7.2 and 7.4 of the Code wereruled.

B Booklet entitled ‘WHO will pay the price forgeneric clozapine?’

1 Alleged distribution by a representative

COMPLAINT

Denfleet stated that on 26 April, it had complained toNovartis about the above booklet which was almostidentical to that referred to in point A above,containing all of the errors noted above plus severalmore. Novartis responded on 30 April, stating that itsbooklet had been withdrawn, revised and reissued tothe sales force.


Denfleet stated that whilst not entirely acceptingNovartis’ attitude towards the errors and the fact thatit had no intention of communicating the inaccuraciesto health professionals who had received the originalpublication, Denfleet considered the matter had beendealt with. However, Denfleet noted that Novartiswas still using the booklet and had made no attemptto correct any of the errors.

Specifically the booklet was given to medical staff at ahospital during the week of 7 June by a Novartis salesrepresentative. The pharmacy department at thehospital was horrified that this had occurred andimmediately forwarded a copy to Denfleet. It wasalso horrified to note that the representative waspresent on the wards without having signed theregister at the pharmacy department, thuscontravening local hospital procedure. Denfleetstated that it appeared that the booklet was also stillbeing used in other areas of the country.

RESPONSE

Novartis stated that it had responded promptly andfully to the same issues raised by Denfleet in April;furthermore, Denfleet received written reassurancefrom Novartis, dated 30 April, that the materials inquestion had been withdrawn from use. A statementfrom the representative confirmed that he did notdistribute the materials at the hospital as alleged.

Novartis regretted that, given the full cooperationextended by it in responding to this matter, Denfleetwas unable to contain this issue at an inter-companylevel but had taken the matter not only to theAuthority but also to the Medicines and Healthcareproducts Regulatory Agency (MHRA).

Novartis stated that it took its responsibility to act in ahighly professional manner and in accordance withthe Code extremely seriously. As noted in its letter of30 April it confirmed to Denfleet that during its springsales conference, 26-30 April, the sales force had beennotified that the decision had been made to withdrawthe materials as new materials were in production.On return to the company office a further emailconfirming this withdrawal was sent to the field force.

Novartis was therefore concerned to hear that amember of its field-force had allegedly given out acopy of the withdrawn material to medical staff at ahospital during the week of 7 June, and that copies ofthe materials were still in use in other parts of thecountry in breach of company procedures. Novartisstated that the representative attended the psychiatricintensive care unit at the hospital on 10 June at theinvitation of the lead nurse; email correspondencebetween the two regarding the visit was provided.The representative confirmed that he did notdistribute copies of the withdrawn brochure duringthis visit. Other recent dates that he visited thehospital were 21 May and 2 June. On 21 May he andthe Clozaril national strategic account manager visitedthe principal pharmacist. Again, the representativestated that he did not distribute any of the withdrawnmaterials. This fact could be verified by the Clozarilnational strategic account manager. Therepresentative made a follow-up visit on his own to

the principal pharmacist on 2 June, during which sheasked for a copy of one of the booklets but was toldthat these were no longer available.

With reference to the allegation relating to therepresentative being present on the wards withoutpermission, therefore breaching local hospital policy,he stated that neither he nor any colleagues who hadworked in that region for up to 15 years were awareof any policies requiring pharmacy permission priorto visiting wards. When he had visited the wards atthe hospital this had always been with the permissionof the ward managers.

Following receipt of the allegation that copies of thematerials were still in use in other parts of thecountry, a further email requesting repeatedconfirmation of zero stock was sent out to the field-force and replies confirming zero stock were currentlybeing collated.

PANEL RULING

The Panel noted that the parties’ accounts of eventsdiffered. Denfleet had received a copy of the booklet‘WHO will pay the price for generic clozapine?’ fromstaff in the pharmacy at the hospital allegedly givento them recently by the Novartis representative.

No evidence had been provided by the complainantto show that recently the hospital had a policy forvisiting representatives nor that if such a policyexisted that it had not been followed.

On the basis of the information before it the Paneldecided that it had no option other than to rule nobreach of Clauses 15.2 and 15.4 of the Code.

2 Page 8 headed ‘What does “bioequivalent”actually mean?’

Denfleet referred to the section entitled ‘What do thestudies show?’ (Denfleet mistakenly referred to page 6whereas the section at issue appeared on page 8).This was followed by ‘Evidence from severalpharmacokinetic studies looking at bioequivalencehave shown conflicting results’.

This page was similar to the page at issue in point A3above.

COMPLAINT

Denfleet alleged that the section ‘What do the studiesshow?’ contained misleading and inaccurateinformation. By definition, pharmacokinetics was thestudy of the absorption, distribution, metabolism andexcretion of medicines. The studies appearing on thispage Kluznik et al, Mofsen and Balter and Price didnot examine the pharmacokinetic parameters requiredto determine bioequivalence. Kluznik 2001 measuredplasma concentrations of clozapine. However, thestudy did not show a significant difference in meanclozapine levels. The studies presented by Mofsenand Balter and Price did not present any of thepharmacokinetic parameters required for examiningbioequivalence. Denfleet alleged that the statement‘Evidence from several pharmacokinetic studies …’was inaccurate, misleading and not supported by thestudies presented.


RESPONSE

Novartis submitted that part of its response to pointA3 above covered this point.

PANEL RULING

The Panel noted that the studies cited on the page inquestion were not pharmacokinetic studies as such.Mofsen and Balter presented seven case studies ofpatients in long-term residential care who experienceda relapse of psychotic symptoms when their therapywas switched from branded clozapine to a genericformulation. Kluznik et al studied the clinical effectsof a randomised switch of patients from Clozaril togeneric clozapine. Serum concentrations weremeasured. Price was taken from a discussion at asymposium which described a switch of patients fromClozaril to generic clozapine. The claim ‘Evidencefrom several pharmacokinetic studies looking atbioequivalence have shown conflicting results’followed by a description of the three studies wasthus misleading and not capable of substantiation.Breaches of Clauses 7.2 and 7.4 of the Code wereruled.

3 Claim ‘30% of the cost of plasma drugconcentration monitoring (required whiletitrating dose) is covered by the CPMS’

Pages 10 and 11 provided details beneath the headingon page 10 ‘How will the Clozaril Patient MonitoringService (CPMS) support you?’ The claim at issueappeared on page 11 under the subheading ‘Thecomprehensive CPMS package’. This was similar topoint A4 above.

COMPLAINT

Denfleet alleged that one of the listed features of thecomprehensive CPMS package that ‘30% of the cost ofplasma drug concentration monitoring (required whiletitrating dose) is covered by the CPMS’ was misleadingand inaccurate in breach of Clause 7.2 and 7.4.

Denfleet stated that clozapine dosage was normallyadjusted according to clinical response and adverseeffect profile. The measurement of clozapine plasmaconcentrations was useful in assessing compliance,optimising therapy and minimising toxicity. Plasmadrug level monitoring was not required whilsttitrating the dose.

RESPONSE

Novartis stated that the text ‘required when titratingthe dose’ had been removed from future materials.

PANEL RULING

The Panel noted that the Clozaril SPC stated thatwhite blood cell (WBC) count and differential bloodcounts must be performed within 10 days prior toinitiating Clozaril treatment to ensure that onlypatients with WBC counts and absolute neutrophilcount (ANC) within certain given parameters receivedthe medicine. After the start of treatment the WBCand ANC must be monitored weekly for the first 18weeks of therapy and at least every four weeksthereafter throughout treatment. The use of Clozarilwas restricted to patients, physicians and nominatedpharmacists registered with the CPMS.

Pages 10 and 11 of the booklet referred to monitoring.The only detailed information about monitoring wasin the claim at issue which implied that monitoringwas only required when titrating the dose and onlyplasma drug concentration monitoring was necessary.This was not so. The SPC required WBC count andANC monitoring at different frequencies dependingon how long the patient had been taking Clozaril.The maximum period was at least every four weeks.

The Panel was very concerned that the statement inthe booklet gave a very different impression of themonitoring requirements compared to those in theSPC. The statement at issue might compromisepatient safety. The Panel considered the statementwas misleading and not capable of substantiation asalleged. Breaches of Clauses 7.2 and 7.4 of the Codewere ruled.

During its consideration of this case the Panel notedthat both booklets bore the same reference number(CLZ/03/78). The Guidelines on CompanyProcedures Relating to the Code of Practicerecommended that a particular reference numbershould relate to only one item of promotionalmaterial. The Panel requested that Novartis beadvised of its concerns in this regard.




The medicines management facilitator at a primary care trust(PCT) stated that a surgery had reported that at a recentpractice meeting the local Pfizer representative informedthose present that Pfizer was working with the PCT on anaudit of COX-2 medicines and comparing the prescribing ofCOX-2s with National Institute of Clinical Excellence (NICE)guidelines. Pfizer had not approached the PCT prescribingsupport team about any such activity, and the PCTprescribing support team had not agreed it; nor was it awareof the work Pfizer was seeking to undertake.

In commenting on Pfizer’s response the complainant statedthat one of her team had recently carried out an audit ofCOX-2 prescribing at the local surgery in question and wasdoing similar audits elsewhere. The PCT prescribing leadwas concerned that practices would be reluctant to work withPCT staff in a COX-2 audit if Pfizer had undertaken similarwork in their practice, particularly if they considered thatPfizer was working with the complainant’s approval.

The complainant was surprised that the representativewished to meet the PCT prescribing lead with a view topreparing local guidelines. Draft guidelines for use of COX-2s were in development and the PCT prescribing lead wasaware of this.

The complainant also asked the PCT prescribing lead tocomment on the response. The PCT prescribing lead statedthat she joined the meeting before a presentation by aconsultant surgeon. In summing up the representative statedthat Pfizer was interested in carrying out audits in practicesrelating to COX-2 and NICE guidance and was helping thePCT in this way. After the meeting the PCT prescribing leadasked the representative who she was working with in thePCT. One of the prescribing advisors was named but notnecessarily by the representative. The PCT prescribing leadarranged a follow-up meeting with the representative andcontacted the complainant to see if she had set anything upwith Pfizer, which she confirmed she had not. Hence thecomplaint.

The Panel noted that the parties’ accounts differed. Thecomplainant alleged that the representative had stated at ameeting that Pfizer was working with the PCT on a COX-2audit. The representative and the PCT prescribing lead hadspoken at the end of the meeting as the representative waspacking up. The representative asked if she and a Pfizercolleague could meet the PCT prescribing lead to discusshow Pfizer could work in partnership in producing localCOX-2 guidelines. The representative remembered themeeting as brief; a few seconds rather than minutes. Shecould not recall what exactly had been said but was sure thatshe did not state that Pfizer was doing any audits within thePCT. The Panel noted the PCT prescribing lead’s submissionthat when summing up the representative had stated thatPfizer was interested in carrying out audits and ‘was helpingthe PCT in this way’.



PRIMARY CARE TRUST MEDICINES MANAGEMENTFACILITATOR v PFIZERConduct of representative

The Panel considered that it was beholden uponrepresentatives to be abundantly clear whenexplaining the relationship between their companiesand local organisations such as PCTs to local GPs.Nonetheless, given the parties’ differing accountsthe Panel was not in a position to determine whathad happened. The Panel was thus obliged to ruleno breach of the Code.

The medicines management facilitator at a primarycare trust (PCT) complained about the conduct of arepresentative from Pfizer Limited.

COMPLAINT

The complainant stated that she had received a reportfrom a surgery that at a recent practice meeting thelocal Pfizer representative informed those present thatPfizer was working with the PCT on an audit of COX-2 medicines and comparing the prescribing of COX- 2medicines with National Institute of ClinicalExcellence (NICE) guidelines.

This surprised the PCT prescribing lead (a partner atthe practice) and the complainant. Pfizer had notapproached the PCT prescribing support team aboutany such activity. Needless to say, the PCTprescribing support team had not agreed it. If it wasto authorise this sort of activity by anypharmaceutical company the PCT team would notifypractices as appropriate and would decide on theaudit to be undertaken and the interpretation of theNICE guidance.

Not only had the PCT prescribing support team notauthorised the ‘audit’, it was not aware of the workPfizer was seeking to undertake.

When writing to Pfizer the Authority asked it torespond in relation to the requirements of Clauses 2,9.1 and 15.2 of the Code.

RESPONSE

Pfizer agreed that the representative had arranged ameeting at the surgery in question where clinicaleducation sessions were held monthly. A consultantorthopaedic surgeon spoke at the meeting about ‘Hipreshaping’ to five GPs, a nurse and a physiotherapist.

Prior to the meeting, the representative providedrefreshments and gave short presentations onCelebrex, Detrusitol XL and the Leeds Assessment ofNeuropathic Symptoms and Signs (LANSS) painscale. Everybody except the PCT prescribing lead waspresent for this part of the meeting. The PCTprescribing lead arrived at the meeting just before thepresentation commenced (at approximately 7.25 pm).

After the speaker’s presentation the representativeclosed the meeting. Whilst packing up, therepresentative spoke with the PCT prescribing lead.The representative was particularly keen to speak withthe PCT prescribing lead as she was a member of theprofessional executive committee (PEC) of the PCT.The representative wanted to discuss ways in whichshe and the Pfizer primary care account manager(PCAM) could work more closely with the PCTprescribing lead and the PCT than the representativewas able to do. The Pfizer PCAM would be able todiscuss with members of the PCT ways in whichPfizer could work with them to explore care pathwaysand guidelines, in particular the PCT’s approach toNICE guidelines on the use of COX-2 inhibitors. ThePCT prescribing lead agreed to see the representativeand the Pfizer PCAM at a later date and asked therepresentative to arrange a meeting. Therepresentative stated that, during her conversationwith the PCT prescribing lead, the representativewanted to distinguish that by having the Pfizer PCAMthere, Pfizer would be able to discuss how to work at amore strategic level with the PCT.

The following day the representative booked anappointment for the next month with the PCTprescribing lead but the meeting never occurredbecause when the representative arrived at thesurgery the PCT prescribing lead knew nothing aboutthe meeting.

The representative described the conversation withthe PCT prescribing lead at the monthly clinicalmeeting as brief and of the order of seconds ratherthan minutes. The representative did not rememberthe exact duration of the conversation or her exactwords; she might have said ‘guidelines’, ‘partnership’and ‘work at PCT level’ with reference to the possiblemeeting with the Pfizer PCAM. The representativedid not state that Pfizer was doing any audits withinthis PCT. The representative had not had previouslymet the PCT prescribing lead and she wished to makethe most of her opportunity to talk to her.

Pfizer considered that the representative’sconversation with the PCT prescribing lead wasprobably misinterpreted. The representative had notintended to attempt to mislead. The representativeknew that the PCT prescribing lead had a role withinthe PCT as a member of the PEC and clearly hadnothing to gain from implying any existingcooperative work between the PCT and Pfizer. Boththe PCT prescribing lead and the representativewould clearly have known that no such work wasgoing on. Pfizer noted that the complaint came fromthe PCT prescribing adviser, who was not present atthe meeting.

The representative considered that she had behavedappropriately and had upheld the high standardsrequired both by Pfizer and by the Code. With regardto Clauses 9.1 and 15.2, Pfizer considered that therepresentative had maintained high standards ofethical conduct and complied with all relevantrequirements of the Code and there had been nobreach of the Code. With regard to Clause 2 of theCode, Pfizer did not consider that the representativehad acted in a manner to bring discredit upon, orreduce confidence in, the pharmaceutical industry.

Pfizer concluded that this was a misunderstandingbetween both parties during a short conversation andthat there was no case to answer. Pfizer deeplyregretted that the perceived activity of therepresentative had given rise to such a complaint.

FURTHER COMMENTS FROM THE COMPLAINANT

The complainant noted that she had complainedbecause the PCT prescribing lead was concerned thatPfizer was claiming to be working with the PCT onaudits in this field when she knew that this was notthe case. Any agreements with pharmaceuticalcompanies to undertake such work in the PCT wouldbe agreed by the complainant in conjunction with themedicines management committee. One of thecomplainant’s team had recently carried out an auditof COX-2s at the surgery and was doing similar auditselsewhere. The PCT prescribing lead was concernedthat practices would be reluctant to work with PCTstaff in a COX-2 audit if Pfizer had undertaken similarwork in their practice, particularly if they consideredthat Pfizer was working with the complainant’sapproval.

The complainant was surprised that the representativewished to meet the PCT prescribing lead with a viewto preparing local guidelines. The complainantunderstood that both the Pfizer PCAM and the localrepresentatives were aware that guidelines weredrawn up collaboratively under the auspices of thearea prescribing committee and not by the individualPCTs. Draft guidelines for use of COX-2s were indevelopment and the PCT prescribing lead was awareof this. The local view was that it was not appropriatefor pharmaceutical companies to be involved in thedevelopment of guidelines.

The complainant also asked the PCT prescribing leadto comment on the response. The PCT prescribinglead agreed that she joined the meeting before thepresentation. The presentation was appropriate andwell balanced. Pfizer had missed out the fact that, insumming up to the general group, the representativestated that Pfizer was interested in carrying out auditsin practices relating to COX-2 and NICE guidance andwas helping the PCT in this way. After the meetingthe PCT prescribing lead asked the representativeabout who she was working with in the PCT. One ofthe prescribing advisor’s names was mentioned, butnot necessarily by her. The PCT prescribing leadarranged a meeting with the representative as afollow-up and contacted the complainant to confirmthat she had not set anything up with Pfizer, whichshe confirmed. Hence the complaint.

The PCT prescribing lead also stated that one of thepartners present had mentioned to the complainantthat he thought Pfizer was doing work on behalf ofthe PCT, which suggested this had been discussedwith him as well. The PCT prescribing lead was veryconcerned that these sorts of messages contravenedthe work the PCT was supporting – indeed it wasrolling out its own COX-2 audit.

PANEL RULING

The Panel noted that the parties’ accounts differed; itwas difficult in such cases to know exactly what had


transpired. A judgement had to be made on theavailable evidence bearing in mind that extremedissatisfaction was usually necessary on the part of anindividual before he or she was moved to actuallysubmit a complaint.

The complainant alleged that the representative hadstated at a meeting that Pfizer was working with thePCT on an audit of COX-2 medicines. Therepresentative and the PCT prescribing lead hadspoken at the end of the meeting as the representativewas packing up. The representative asked if she andher colleague (the Pfizer PCAM) could meet the PCTprescribing lead to discuss how Pfizer could work inpartnership in producing local COX-2 guidelines. Therepresentative’s recollection was that the meeting wasbrief; a few seconds rather than minutes. She couldnot recall the exact wording used in her conversationwith the PCT prescribing lead but was sure that shedid not make a statement that Pfizer was doing any

audits within the PCT. The Panel noted the PCTprescribing lead’s submission that when summing upto the general group the representative had stated thatPfizer was interested in carrying out audits and ‘washelping the PCT in this way’.

The Panel considered that it was beholden uponrepresentatives to be abundantly clear whenexplaining the relationship between their companiesand local organisations such as PCTs to local GPs.Nonetheless, given the parties’ differing accounts thePanel was not in a position to determine what hadhappened. The Panel was thus obliged to rule nobreach of Clauses 2, 9.1 and 15.2 of the Code.





CONSULTANT PHARMACIST v LUNDBECKCipralex journal advertisement

A consultant pharmacist complained about a journaladvertisement for the antidepressant Cipralex (escitalopram)issued by Lundbeck. Cipralex was a selective serotoninreuptake inhibitor (SSRI).

The advertisement was headed ‘Then I saw her face. NowI’m a believer’ and in the complainant’s view showed anattractive young woman with a very young child who seemeddelighted to see her general practitioner who had prescribedher Cipralex. The patient was clearly a young mother and theadvertisement thus implied that Cipralex was suitable forthis particular target group. There was clearly a possibilitythat this woman might wish to conceive especially now shewas so much better being on Cipralex. The complainantalleged that this contradicted the statements in the BritishNational Formulary – Pregnancy, ‘Antidepressant SSRI;toxicity in animal studies with escitalopram’ and in theCipralex summary of product characteristics (SPC),‘Pregnancy For escitalopram no clinical data are availableregarding exposed pregnancies. In rat reproductive toxicitystudies performed with escitalopram, embryo-fetoxic effects,but no increased incidence of malformations, were observed.The risk to humans is unknown’. In the complainant’s viewthe advertisement implied a degree of safety that was at oddswith the above statements. The complainant queriedwhether Cipralex should be used at all in women ofchildbearing age. Should it be advertised as safe in thisgroup?

The Panel noted that Cipralex SPC stated that there were noclinical data available regarding exposed pregnancies. In ratreproductive toxicity studies, reduced foetal weight and areversible delay in ossification were observed at exposures interms of AUC in excess of the exposure achieved duringclinical use. No increased frequency of malformations was

noted. The risk for humans was unknown. TheSPC further stated that Cipralex should not be usedduring pregnancy unless clearly necessary and onlyafter careful consideration of the risk/benefit.

The Panel noted that Cipralex was notcontraindicated during pregnancy and consideredthat prescribers would be very familiar with theprinciples of prescribing in women of childbearingage.

The advertisement in question showed a youngwoman with a small child apparently sitting in adoctor’s waiting room along with a mixed group ofother patients. There was no implication that theyoung woman was pregnant or might wish to be.The Panel decided that the advertisement was notmisleading with regard to the safety of Cipralexduring pregnancy as alleged. The Panel furtherconsidered that the advertisement did not promoteCipralex in a manner which was inconsistent withthe particulars listed in its SPC. No breach of theCode was ruled.

A consultant pharmacist complained about a journaladvertisement (ref 0104/ESC/501/070) for theantidepressant Cipralex (escitalopram) issued byLundbeck Ltd. Cipralex was a selective serotoninreuptake inhibitor (SSRI).

COMPLAINT

The complainant noted that the advertisement washeaded ‘Then I saw her face. Now I’m a believer’.The advertisement showed an attractive youngwoman with a very young child who seemed

delighted to see her general practitioner who hadprescribed her Cipralex. The patient was clearly ayoung mother. The advertisement therefore impliedthat Cipralex was suitable for this particular targetgroup. There was clearly a possibility that thiswoman might wish to conceive, especially now shewas so much better being on Cipralex. Thecomplainant considered that this contradicted thestatements in the British National Formulary (BNF)March 2004 Appendix 4 Pregnancy, ‘AntidepressantSSRI; toxicity in animal studies with escitalopram’and in the Cipralex summary of productcharacteristics (SPC), ‘Pregnancy For escitalopram noclinical data are available regarding exposedpregnancies. In rat reproductive toxicity studiesperformed with escitalopram, embryo-fetoxic effects,but no increased incidence of malformations, wereobserved. The risk to humans is unknown’. In thecomplainant’s view the advertisement implied adegree of safety that was at odds with the abovestatements. The complainant queried whetherCipralex should be used at all in women ofchildbearing age. Should it be advertised as safe inthis group?

When writing to Lundbeck the Authority asked it tocomment in relation to Clauses 3.2 and 7.2 of theCode.

RESPONSE

Lundbeck did not consider that its promotion ofCipralex was either misleading or inconsistent withthe Cipralex SPC. It was important to separate beingfemale and of childbearing age from being female andpregnant/or wishing to become pregnant.

Lundbeck considered that it was appropriate topromote Cipralex in the treatment of major depressiveepisodes in adults, both female and male aged 18 orolder in accordance with the terms of its marketingauthorization. The company noted a two fold greaterprevalence of major depressive disorder in womenthan in men, with an onset between the ages of 20 and50 in 50% of all patients. The use of a woman in theadvertisement was therefore not inappropriate. Theuse of Cipralex during pregnancy was notcontraindicated, and the warnings regarding such usewere clearly stated in section 4.6 of the SPC and theprescribing information ie ‘Pregnancy and Lactation:As safety during human pregnancy and lactation hasnot been established, careful consideration should begiven prior to use in pregnant women. It is expectedthat escitalopram will be excreted into breast milk.Breast-feeding women should not be treated withescitalopram’.

The advertisement did not imply that the patientmight be/or wish to become pregnant. Theadvertisement showed a woman of childbearing age.Lundbeck would not promote the use of Cipralex topatients who were, or wished to become, pregnant.The patient was not depicted in a setting that impliedthat she was wishing to become pregnant eg anantenatal clinic, nor was she, for example, holding apregnancy detection kit. The complainant made thefar-reaching premise that the patient was or wished tobecome pregnant and arrived at his own conclusion.

Lundbeck noted the important point raised by thecomplainant ie should any medicine that mightpotentially harm an unborn child be promoted towomen of childbearing age? There were perhaps only ahandful of medicines that were considered ‘safe’ to useduring pregnancy and the majority of medicines carriedwarnings and precautions for their use in pregnancy egall SSRIs, proton pump inhibitors, anti-hypertensives,anti-epileptics and analgesics including the commonlyprescribed non-steroidal anti-inflammatories.

The best way to avoid potentially harming an unbornchild as a result of treatment was for a patient not totake a medicine in the first place. A physicianprescribing any medicine to a woman of childbearingage would automatically weigh up the risk/benefitfor the patient and advise the woman on the risksinvolved were she to consider pregnancy or indeedbecome pregnant.

Lundbeck considered that it had fulfilled itsobligation of informing the prescriber of the warningconcerning pregnancy by providing the prescribinginformation. The decision and responsibility toprescribe a medicine eg Cipralex, taking intoconsideration the fact that a woman might at somefuture stage become pregnant, rested with theclinician. Furthermore, the pharmacist dispensing themedicine had an ethical obligation to perform aprofessional assessment of the prescription, includingthe suitability of the medicine for the patient ie byasking if the patient was pregnant.

If one were to make the premise that the warningsdisplayed in the prescribing information wereinsufficient, one would have to conclude that the useof a picture of a female of childbearing age in thepromotion of the majority of medicines was alsoincorrect.

In summary, Lundbeck considered that theadvertisement was neither misleading norinconsistent with the particulars listed in the CipralexSPC.

PANEL RULING

The Panel considered that it was a well establishedprinciple that medicines should be prescribed duringpregnancy only if the expected benefit to the motheroutweighed the potential risk to the foetus and that allmedicines should be avoided if possible during thefirst trimester.

The Cipralex SPC stated that there were no clinicaldata available regarding exposed pregnancies. In ratreproductive toxicity studies, reduced foetal weightand a reversible delay in ossification were observed atexposures in terms of AUC in excess of the exposureachieved during clinical use. No increased frequencyof malformations was noted. The risk for humanswas unknown. The SPC further stated that Cipralexshould not be used during pregnancy unless clearlynecessary and only after careful consideration of therisk/benefit.

The Panel noted that Cipralex was not contraindicatedduring pregnancy and considered that prescriberswould be very familiar with the principles ofprescribing in women of childbearing age.


The advertisement in question showed a youngwoman with a small child apparently sitting in adoctor’s waiting room along with a mixed group ofother patients. There was no implication that theyoung woman was pregnant or might wish to be. ThePanel decided that the advertisement was notmisleading with regard to the safety of Cipralexduring pregnancy as alleged. No breach of Clause 7.2

was ruled. The Panel further considered that theadvertisement did not promote Cipralex in a mannerwhich was inconsistent with the particulars listed inits SPC. No breach of Clause 3.2 was ruled.

Complaint received 7 July 2004



CASE AUTH/1611/8/04

MEDIA/DIRECTOR v BAYERPromotion of Avelox

An article in the Drug and Therapeutics Bulletin, entitled‘Moxifloxacin – a new fluoroquinolone antibacterial’criticized the claim ‘Rapid relief from chest infections’ madeby Bayer about Avelox (moxifloxacin). In accordance withestablished procedure the matter was taken up by theDirector as a complaint under the Code. In response to thecomplaint Bayer provided a journal advertisement, aleavepiece and a detail aid, all of which featured the claim atissue.

The Drug and Therapeutics Bulletin article began by notingthat Avelox was licensed for the oral treatment of adults withcommunity-acquired pneumonia, acute exacerbation ofchronic bronchitis or acute sinusitis. The authors furthernoted that the claim ‘Rapid relief from chest infections’ wasbased on patients’ self-reported secondary-outcome data fromone unblinded, randomised, controlled trial (Kreis et al 2000)and on unblinded, non-randomised, observational studies(Miravitlles et al 2003; Miravitlles et al 2004 and Landen andBauer 2001). The authors stated that these studies did notprovide convincing evidence that Avelox relieved respiratorytract infections as quickly as, or faster than standardantibiotics and concluded that on published clinical evidenceAvelox offered no compelling advantages over establishedtreatments. The authors considered that claims that Aveloxprovided ‘Rapid relief from chest infections’ wereunsubstantiated, potentially misleading and should bewithdrawn.

The Panel noted that the authors of each of the four studieswhich Bayer submitted supported its claim ‘Rapid relief fromchest infections’ had referred to the rapid relief of symptomsassociated with Avelox therapy. In this regard the Panelnoted the conclusion of Miravitlles et al (2004) that as Aveloxwas associated with a more rapid remission of symptomscompared with co-amoxiclav or clarithromycin then‘randomised, experimental studies need to be designed tocorroborate the hypothesis proposed in this study thatantibiotics that induce a more rapid bacteriologicaleradication are associated with a similarly more rapid clinicalcure’. Bayer had submitted that the claim was intended toinform the reader that Avelox rapidly relieved the symptomsof infection. However, as the claim did not refer tosymptomatic relief the Panel considered that it could be readto mean that Avelox rapidly cured chest infections per se iethat there was a rapid and complete eradication of micro-organisms. No data in this regard had been submitted. In

the Panel’s view, patients whose symptoms had beenrelieved could still have a chest infection. The Panelconsidered that the claim was ambiguous and thusmisleading as alleged and had not beensubstantiated. Breaches of the Code were ruled.

An article in the Drug and Therapeutics Bulletin,August 2004, entitled ‘Moxifloxacin – a newfluoroquinolone antibacterial’ criticized a claim madeby Bayer plc about Avelox (moxifloxacin). Inaccordance with established procedure the matter wastaken up by the Director as a complaint under theCode.

Bayer provided a journal advertisement (ref2AVEL87), a leavepiece (ref 4AVEL004) and a detailaid (ref 4AVEL001); all of the materials featured theAvelox product logo which incorporated the strapline‘Rapid relief from chest infections’.

COMPLAINT

The Drug and Therapeutics Bulletin article began bynoting that Avelox, the latest fluoroquinoloneantibacterial to be launched in the UK, was licensedfor the oral treatment of adults with community-acquired pneumonia, acute exacerbation of chronicbronchitis or acute sinusitis. The article, in addition toreviewing the place of Avelox in treating patients withrespiratory tract infections, noted that promotionalmaterials stated that the product provided ‘rapidrelief from chest infections’. The authors noted thatthis claim, however, was based on patients’ self-reported secondary-outcome data from oneunblinded, randomised, controlled trial (Kreis et al2000) and on unblinded, non-randomised,observational studies (Miravitlles et al 2003;Miravitlles et al 2004 and Landen and Bauer 2001).The authors stated that because of the studies’ design,they could not provide convincing evidence thatAvelox relieved respiratory tract infections as quicklyas, or faster than standard antibacterial treatments forthese conditions. The authors concluded that onpublished clinical evidence, Avelox offered nocompelling advantages over established treatmentsfor these conditions. The authors stated that in theirview, claims that Avelox provided ‘Rapid relief from

chest infections’ were unsubstantiated, might misleadprescribers and should be withdrawn.

When writing to Bayer, the Authority asked it torespond in relation to Clauses 7.2 and 7.4 of the Code.

RESPONSE

Bayer stated that Avelox, launched in the UK at theend of March 2003, was licensed for the treatment ofacute exacerbations of chronic bronchitis (AECB),community acquired pneumonia (CAP, except severecases) and acute bacterial sinusitis (adequatelydiagnosed).

The claim ‘Rapid relief from chest infections’ was astrapline, which accompanied the Avelox logo.

The intention of the claim was to succinctlycommunicate to health professionals the therapeuticarea where the product could be used along with aproduct attribute. On all the materials where theclaim appeared prescribing information was alsoprovided. The claim therefore communicated thatAvelox treated chest infections and that when it wasused the symptoms of the infection were relievedrapidly.

Bayer summarised the clinical data to support theclaim. The data had been published in peer-reviewedjournals.

Miravitlles et al (2003) was a 2 year observationalstudy in 441 outpatients with AECB. In the first yearno Avelox therapy was prescribed; in the second year,50% of patients were treated with Avelox. Onehundred and eleven exacerbations were treated withAvelox and 503 were treated with comparatorantibiotics. The mean time to recovery was 4.6 daysfor Avelox and 5.8 days for the comparators (p=0.006).The authors stated that ‘The significantly more rapidsymptom relief and time to recovery associated withmoxifloxacin therapy may be attributable to theunique aspects of moxifloxacin’s interaction with thebacteria and host’.

Landen and Bauer was a post-marketing study in2188 patients with CAP requiring hospital admission.All patients received 400mg moxifloxacin once dailyfor up to 10 days. 93.4% of patients were cured orimproved after treatment; 60.4% demonstrateddistinct improvement by day 3 of treatment (90% byday 5) and 73.7% were symptom free by day 7 (87.0%by day 10). The authors stated that ‘The results of thisstudy confirm the evidence from clinical studiesindicating that moxifloxacin 400mg once daily is aneffective and well tolerated therapy for CAPproviding rapid and comprehensive resolution ofsymptoms in a broad range of patients’.

Miravitlles et al (2004) was a primary careobservational non-randomised study in 1456 patientswith AECB or AE-COPD – Avelox 400mg once dailyfor 5 days was compared with co-amoxiclav 625mgthree times daily for 10 days or clarithromycin 500mgtwice daily for 10 days. Clinical cure rates observedon day 3 were Avelox 20%, co-amoxiclav 9.6% andclarithromycin 6.5% (p<0.001). Clinical cure ratesobserved on day 5 were; Avelox 49%, co-amoxiclav26.5% and clarithromycin 30% (p<0.001). Clinical cure

rates were similar at day 10. The authors stated thatthe ‘results of this study suggest that the antibiotictreatment of exacerbations of chronic bronchitis andCOPD with moxifloxacin is associated with a morerapid remission of the symptoms to that achievedwith co-amoxiclav or clarithromycin’.

Kreis et al was an observational study of 401 patientswith AECB. Avelox 400mg once daily for 5 days wascompared with azithromycin 500mg on day one and250mg once daily for 4 days. Avelox-treated patientsreported feeling better significantly faster thanazithromycin-treated patients (p=0.0236). Morepatients in the Avelox group reported symptomaticrelief by day 3 than did patients in the azithromycingroup (p=0.012). The authors stated that ‘Patientstreated with moxifloxacin reported faster symptomrelief and returned to normal activities more rapidly’.

Bayer stated that although these data suggested anadvantage of Avelox over a number of comparators,the claim itself did not draw a direct comparison withother therapies. Bayer considered that its use of thesestudies was a conservative interpretation of the resultsand conclusions of the authors.

Bayer noted that the Drug and Therapeutics Bulletinnoted that the claim was based on patients’ self-reported secondary-outcome data from oneunblinded, randomised, controlled trial and onunblinded, non-randomised, observational studies.However, the Code did not state that all publishedreferences must be from randomised double-blindstudies. These four studies had been conducted bythree lead authors and published in two peer-reviewed journals over the past four years andshowed that treatment with Avelox resulted in rapidsymptom relief. Furthermore, no trial had beenpublished in a peer review journal that had comparedAvelox with another agent that had shown more rapidsymptomatic relief with the other agent.

Bayer did not consider that the claim ‘Rapid relieffrom chest infections’ was in breach of Clause 7.2 or7.4 of the Code.

PANEL RULING

The Panel noted that Bayer had submitted that fourstudies supported its claim ‘Rapid relief from chestinfections’. The authors in each of the studies hadreferred to the rapid relief of symptoms associatedwith Avelox therapy. In this regard the Panel notedthe conclusion of Miravitlles et al (2004) that theresults suggested that ‘the antibiotic treatment ofexacerbations of chronic bronchitis and COPD withmoxifloxacin is associated with a more rapidremission of the symptoms to that achieved with co-amoxiclav or clarithromycin. On this basis,randomised, experimental studies need to bedesigned to corroborate the hypothesis proposed inthis study that antibiotics that induce a more rapidbacteriological eradication are associated with asimilarly more rapid clinical cure’. Bayer hadsubmitted that the claim was intended to inform thereader that Avelox rapidly relieved the symptoms ofinfection. The claim, however, did not refer tosymptomatic relief. The Panel thus considered thatthe claim could be read to mean that Avelox rapidly


cured chest infections per se ie that there was a rapidand complete eradication of micro-organisms. Nodata in this regard had been submitted. In the Panel’sview, patients whose symptoms had been relievedcould still have a chest infection. The Panelconsidered that the strapline was ambiguous and thus

misleading as alleged and had not been substantiated.Breaches of Clauses 7.2 and 7.4 were ruled.

Proceedings commenced 4 August 2004



CASE AUTH/1612/8/04

SCHWARZ PHARMA v STIEFELPromotion of Duac

Schwarz Pharma complained about the claim ‘Significantlypreferred by patients to Benzamycin’ used by Stiefel topromote Duac (clindamycin/benzoyl peroxide gel). Schwarzmarketed Benzamycin (erythromycin/benzoyl peroxide gel).Duac and Benzamycin were both indicated for the treatmentof acne.

Schwarz alleged that the claim implied that Duac waspreferred on all assessed criteria; the claim did not clarifywhat the criteria were. The data on file to which the claimwas referenced stated that ‘subjects preferred [Duac] overBenzamycin on virtually each attribute and on an overallbasis’. It appeared that ‘preference’ therefore encompassed allassessed criteria, and was not limited to the question ‘Whichproduct did you prefer overall?’. On further review of thedata on file, of the 14 questions plus sub-questions there wereno statistically significant differences for ‘feel’, ‘stinging’ and‘greasiness’ at visit 1, and for ease of make-up application atvisits 1 and 2. The reported extent of greasiness appeared tofavour Benzamycin, with statistical significance at visit 2.Therefore, not all attributes were assessed in favour of Duac.It was not clear from the claim in what ways Duac was‘significantly preferred’. Schwarz alleged that the claim didnot accurately reflect the results of the study, and thereforecould not be substantiated and was misleading.

Schwarz noted that the data on file referred to a one weekstudy with assessments being performed immediately afterfirst application and on a second visit one week later. Acnetreatment, however, normally lasted three to six months,which was not reflected by this study. The claim made noreference to the study duration, which therefore might beconsidered misleading and not accurately reflecting theevidence. Patient preference might be influenced byefficiency outcomes as well as the physical attributes ofproducts. Patients required a therapy to alleviate theirsymptoms, and this might impact on any preference for aproduct.

It only became apparent on review of the data on file that thecomparison related to practical attributes and not clinicaloutcomes. Schwarz also noted that it could not tell from thedata on file if the study had only included patients consistentwith the licensed indication.

Schwarz alleged that the information presented was notbalanced and appeared nonsensical. This highlightedfundamental issues with the design of the study. Schwarzalso alleged that the claim ‘Significantly preferred by patientsto Benzamycin’ based on the data on file, in its various

representations, was ambiguous and, as acomparative claim was misleading.

The Panel noted that Duac was indicated for thetreatment of mild to moderate acne. The objectiveof the study from which the claim at issue wasderived was to compare the consumer acceptabilityof Duac and Benzamycin on the basis of immediateperception of aesthetic attributes and after oneweek’s use. The Panel noted Stiefel’s submissionthat almost all of the 51 patients who took part inthe study had mild to moderate acne; one patientwas borderline and fell just outside the definition ofmoderate. Most but not all of the parametersmeasured showed a benefit for Duac compared withBenzamycin. The claim ‘Significantly preferred bypatients to Benzamycin’ was based on the answer tothe question ‘which product did you prefer overall?’.

In two leavepieces the claim at issue immediatelyfollowed two claims which referred to the efficacy ofDuac and its in vivo antimicrobial activityrespectively. In the printed copy of a productmonograph the claim appeared as the last of fivebullet points the first four of which referred toefficacy and tolerability. The Panel noted that therewas no indication in any of the materials that theclaim at issue was derived from a one week studyand was based only on cosmetic and practicalconsiderations and not on any measures of efficacy.In the Panel’s view some readers would assume thatthe claim referred to the longer term use of the twoproducts; given the context in which it appearedsome might also assume that a measure of efficacywas included. The unqualified claim did not allowthe reader to judge its clinical significance. ThePanel considered that the claim was misleading inthat regard and ruled breaches of the Code.

Schwarz Pharma Limited complained about thepromotion of Duac (gel containing clindamycin 1%and benzoyl peroxide 5%) by Stiefel Laboratories(UK) Ltd. The claim at issue ‘Significantly preferredby patients to Benzamycin’ and/or related claimsappeared in two leavepieces (refs D: E3128UK andD:E3130UKc) and in a product monograph (refD:E3002UK) as presented on a CD-ROM. Schwarzmarketed Benzamycin (gel containing erythromycin3% and benzoyl peroxide 5%). Duac and Benzamycinwere both indicated for the treatment of acne.

COMPLAINT

Schwarz alleged that the claim ‘Significantly preferredby patients to Benzamycin’ implied that Duac waspreferred on all assessed criteria; the claim did notclarify the criteria. The data on file to which the claimwas referenced stated that ‘subjects preferredClindoxyl Gel over Benzamycin on virtually eachattribute and on an overall basis’. It appeared that‘preference’ therefore encompassed all assessedcriteria, and was not limited to the one question‘Which product did you prefer overall?’. Of the 14questions plus sub-questions, there were nostatistically significant differences for ‘feel’, ‘stinging’and ‘greasiness’ at visit 1, and for ease of make-upapplication at visits 1 and 2. The reported extent ofgreasiness appeared to favour Benzamycin, withstatistical significance at visit 2. Therefore, not allattributes were assessed in favour of Duac. It was notclear from the claim in what ways Duac was‘significantly preferred’. Schwarz alleged that theclaim did not accurately reflect the results of thestudy, and therefore could not be substantiated andwas misleading.

Schwarz noted that the duration of the study whichcomprised the data on file was one week, withassessments being performed immediately after firstapplication and on a second visit one week later.Acne treatment, however, would be expected to last inthe order of three to six months, which was notreflected by this study. The claim made no referenceto the duration of the study, which therefore might beconsidered misleading and not accurately reflectingthe evidence. Patient preference might not be solelyinfluenced by the physical attributes of products, butmight also be influenced by efficacy outcomes.Patients required that a therapy alleviated theirsymptoms, and this might impact on any preferencefor a product. No demonstration of such an influence,or lack of influence, of efficacy was presented in thedata on file.

In intercompany correspondence, Stiefel hadsuggested that the claim was a straightforwardstatement which summarised the outcome of a well-designed study and that such ‘sensory’ studies wereusually short-term compared to the longer durationstudies for comparison of clinical efficacy. It was notapparent from the claim that this was not a clinicalstudy comparing efficacy outcomes, or that it was a‘sensory’ study. Only review of the data on file did itbecome apparent that the comparison related topractical attributes and not clinical outcomes.

Further, Stiefel had also suggested that it was ‘theearly perceptions of the cosmetic acceptability of atreatment which were likely to dictate compliance’and that ‘Compliance is an important factor in acnetreatment and we consider it appropriate to informprospective prescribers that Duac is favourablyperceived by patients, since this means that they aremore likely to use the product correctly. Of course,this in turn improves the outcomes outside the strictlyenforced regime of a clinical trial’. By Stiefel’s ownadmission, this was not a clinical trial, but consumerpatient acceptability, which should be clearly statedwith such claims. Stiefel also failed to provide anysubstantiation regarding early perceptions of cosmetic

acceptability and improved compliance, that theseperceptions might then lead to correct use of theproduct and that this might lead to improvedcompliance.

In the consumer acceptability analysis detailed in thedata on file one question asked ‘How inconvenientwas the requirement to store the product in therefrigerator and apply the product cold?’. This was aleading question that was inappropriate in such asurvey as it primed the respondent with a ‘negative’impression of one product and influenced responsesto other questions. A neutral question withappropriate choices of response would be a moreacceptable and valid approach. This leading questionthat the questionnaire design might be flawed resultsfrom the study should be interpreted with caution.

In intercompany correspondence Stiefel had statedthat the data on file study included patients consistentwith the licensed indication ie moderate tomoderately severe acne. This was not apparent fromthe data on file. However, the UK summary ofproduct characteristics (SPC) stated ‘mild to moderateacne vulgaris’ with no reference to ‘moderatelysevere’ acne. ‘Moderate’ reflected severity not‘moderately severe’. Therefore, the study did notreflect the licensed indications and should not be usedto support any claims. Stiefel’s response suggestedthat a distinction between moderate and moderatelysevere acne was not precise. However, in a well-designed study, inclusion criteria would be expectedto be sufficiently and accurately defined. Statingmoderate to moderately severe suggested adistinction in severity. The assertion that bothproducts were used in patients with the same grade ofacne ‘making the comparison fair’ was irrelevantwhen one product was not licensed in the UK formoderately severe acne. UK clinical practice wouldlikely involve patients with severe acne beingprescribed oral antibiotics. Furthermore, there was nosubstantiation to support Stiefel’s assumption thatsensory perceptions following use of either product inmoderately severe acne would be a more stringenttest of their patient acceptability than in patients withmild acne.

In the product monograph on the page entitled‘Patient acceptability’, only those attributes withfavourable or neutral outcome had been presented.Listing the attribute of greasiness as ‘low levels ofgreasy/oiliness’ was misleading as it followed thestatement ‘Duac Once Daily Gel was preferred toBenzamycin on an overall basis, as well as performingsignificantly better on all but one of the attributestested’. According to the data on file, Benzamycinwas rated as less greasy compared to Duac to astatistically significant degree at visit 2. Thepresentation of information did not account for anyimpact efficacy outcomes over standard treatmentdurations might have. It was ambiguous to claim thatDuac was ‘preferred by both men and women onvirtually every attribute and on an overall basis’.

Schwarz also alleged that the information presentedwas not balanced and appeared nonsensical. Thishighlighted fundamental issues with the design of thestudy.


Schwarz alleged that the claim at issue based on thedata on file, in its various representations, wasambiguous and, as a comparative claim wasmisleading in breach of Clauses 7.2 and 7.3 of theCode.

RESPONSE

Stiefel noted that the study in question invitedpatients to answer a number of questions concerningthe acceptability of Duac and Benzamycin. Thesewere: smell, colour, greasiness, spreadability, feel,stinging and application of make up, and thefollowing key questions:

● Which product did you prefer overall?

● Was it more convenient to apply product once aday or twice a day?

● Was it more convenient to apply product from ajar or a tube?

● If both products worked equally well and cost thesame, which one would you purchase?

The answer to all of these key questions showed asignificant preference for Duac over Benzamycin. Ofthe eight subsidiary questions yielding 16 tests, tenshowed a significant preference for Duac, five showednon-significant preference for Duac. Only one test(greasiness at visit 2) showed a significant preferencefor Benzamycin. Stiefel considered that the resultsshowed an overwhelming preference for Duac overBenzamycin. The question concerning greasiness wasone of several subsidiary questions, clearly, theanswers to the key questions confirmed that theindividuals concerned preferred Duac overall toBenzamycin. On the basis of these results Stiefel didnot consider that the claim was either misleading orambiguous and was not, therefore, in breach ofClauses 7.2 and 7.3 of the Code.

Stiefel explained that the exchange of correspondencereferred to by Schwarz took place between the twocompanies in January and February 2004. Stiefel hadnot received a response from Schwarz to its last letterof 13 February, which could be interpreted as tacitacceptance of its position. Nevertheless in theinterests of maintaining good relations with Schwarz,Stiefel had decided to revise its literature. It nowmade the claim ‘more cosmetically acceptable thanBenzamycin’. Item D:E3128UK was revised in May2004 and D:E3130UK was the only remaining item ofliterature containing the claim in question. Both itemswere used with GPs and dermatologists.

Stiefel noted that a UK Prodigy classification of acneacknowledged the difficulties in classifying acnegrades precisely, Prodigy provided the followingguideline: ‘The classification into mild, moderate orsevere acne relies heavily on a subjective assessment.In research, counts of lesions are used to assessseverity. This is not practical in general clinicalpractice, but describing this approach may help tojudge severity: mild: fewer than 20 comedones, orfewer than 15 inflammatory lesions, or total lesion

count fewer than 30, moderate: 20-100 comedones, or15-50 inflammatory lesions, or total lesion count 30-125 and severe: more than five cysts, or totalcomedone count greater than 100, or totalinflammatory count greater than 50, or total lesioncount greater than 125’.

Applying this definition to the patients in the study inquestion showed that 51 of the patients fell into theUK classification of mild to moderate acne. Onepatient was borderline and just outside this particulardefinition of moderate. Thus the patients used werewithin the terms of the licenced indication for Duacand the study was a fair and valid comparison, andthe promotional claim was valid.

In conclusion, Stiefel submitted that the claim at issuewas neither ambiguous nor misleading and it was notin breach of Clauses 7.2 and 7.3 of the Code.

PANEL RULING

The Panel noted that Duac was indicated for thetreatment of mild to moderate acne. The objective ofthe study from which the claim at issue was derivedwas to compare the consumer acceptability of Duacand Benzamycin on the basis of immediate perceptionof aesthetic attributes and after one week’s use. ThePanel noted Stiefel’s submission that almost all of the51 patients who took part in the study had mild tomoderate acne; one patient was borderline and felljust outside the definition of moderate. Most of theparameters measured showed a benefit for Duaccompared with Benzamycin although after one weekpatients rated Duac greasier than Benzamycin andthere was no difference between the two for ‘ease ofmake-up application’. The claim ‘Significantlypreferred by patients to Benzamycin’ was based onthe answer to the question ‘which product did youprefer overall?’.

In the two leavepieces the claim at issue immediatelyfollowed two claims which referred to the efficacy ofDuac and its in vivo antimicrobial activity respectively.In the printed copy of the product monograph (thecopy provided on a CD-ROM could not be read) theclaim appeared as the last of five bullet points; thefirst four bullet points referred to efficacy andtolerability. The Panel noted that there was noindication in any of the materials that the claim atissue was derived from a one week study and wasbased only on cosmetic and practical considerationsand not on any measures of efficacy. In the Panel’sview some readers would assume that the claimreferred to the longer term use of the two products;given the context in which it appeared some mightalso assume that a measure of efficacy was included.The unqualified claim did not allow the reader tojudge its clinical significance. The Panel consideredthat the claim was misleading in that regard and ruledbreaches of Clauses 7.2 and 7.3 of the Code.

Complaint received 5 August 2004



Baxter Healthcare complained that Johnson & JohnsonWound Management had promoted Quixil (human surgicalsealant) outwith its licensed indications. Quixil was licensedas supportive treatment to improve haemostasis and toreduce operative and post-operative bleeding and oozingduring liver surgery such as liver resection and reduced-sizeliver transplantation and orthopaedic surgery such as totalhip replacement and total knee replacement.

Baxter Healthcare noted that Quixil was displayed andsupporting advertising material made available at theJohnson & Johnson stand at a meeting for obstetricians andgynaecologists in Glasgow. The congress only covered topicsof interest for gynaecologists and obstetricians and thereforeno liver or orthopaedic topics were on the agenda. BaxterHealthcare further noted that similar material was displayedand distributed at the Johnson & Johnson stand during ameeting on surgical trauma skills. The meeting was clearlyaimed at trauma surgeons; no liver or orthopaedic topics wereon the agenda.

Baxter Healthcare stated that it was unacceptable for Quixilto be promoted to any surgeon outside the fields of liver ororthopaedic surgery. Indeed, such activity could beinterpreted as overt encouragement of off-label use of theproducts which was misleading and exactly the type ofactivity that reduced confidence in the pharmaceuticalindustry as a whole.

The Panel noted that Quixil was only licensed for use in liversurgery, such as liver resection and reduced-size livertransplantation, and orthopaedic surgery, such as total hip orknee replacement. In the first instance a Quixil productbrochure and administration device had been made availableat a meeting for obstetricians and gynaecologists, albeit brieflyuntil they were removed from Johnson & Johnson’s standwhen the error was noted. A large exhibition panel, headed‘Haemostasis?’, however, remained and this included a pictureof the Quixil administration device. Given that the device wasunique to Quixil and was displayed on a Johnson & Johnsonexhibition panel, the Panel considered that even in the absenceof the product name the exhibition panel promoted Quixil.The Panel considered that promotion of Quixil to obstetriciansand gynaecologists was not in accordance with the particularslisted in the summary of product characteristics (SPC). Abreach of the Code was ruled.

The Panel noted that Quixil material had also been madeavailable at a meeting of trauma surgeons. The agenda forthe meeting showed that day three began with a liver lecture.In the Panel’s view Quixil was thus relevant to the attendees;patients might undergo liver resection following trauma. Nobreach of the Code was ruled.

Baxter Healthcare Ltd complained about the promotion ofQuixil (human surgical sealant) by Johnson & Johnson WoundManagement. Quixil was used as supportive treatment toimprove haemostasis and to reduce operative and post-operative bleeding and oozing during liver surgery such as

liver resection and reduced-size liver transplantationand orthopaedic surgery such as total hip replacementand total knee replacement.

COMPLAINT

Baxter Healthcare noted that Quixil was displayedand supporting advertising material made available atthe Johnson & Johnson Gynaecare stand at a meetingfor obstetricians and gynaecologists in Glasgow inJuly. The congress only covered topics of interest forgynaecologists and obstetricians and therefore noliver or orthopaedic topics were on the agenda.

Baxter Healthcare further noted that Quixil andsupporting advertising material were displayed anddistributed at the Johnson & Johnson stand during ameeting on Definitive Surgical Trauma Skills inLondon in July. The meeting was clearly aimed attrauma surgeons. Again there were no liver ororthopaedic topics on the agenda during the time thatJohnson & Johnson promoted Quixil.

According to Section 4.1 of the summary of productcharacteristics (SPC) Quixil was licensed for thefollowing therapeutic indications:

‘Quixil is used as supportive treatment to improvehaemostasis and to reduce operative and post-operative bleeding and oozing during the followingprocedures:

● liver surgery such as liver resection and reduced-size liver transplantation

● orthopaedic surgery such as total hip replacementand total knee replacement’.

Baxter Healthcare alleged that promotion of theproduct at the above mentioned congressesconstituted promotion outwith its licensed indicationsin breach of Clause 3.2 of the Code.

The meetings in question were meetings of UKsurgical organisations, and attended primarily by UKsurgeons – it was therefore unacceptable for Quixil tobe promoted to any surgeon outside the fields of liveror orthopaedic surgery. Indeed, such activity could beinterpreted as overt encouragement of off-label use ofthe product which was misleading and exactly thetype of activity that reduced confidence in thepharmaceutical industry as a whole. BaxterHealthcare alleged a breach of Clause 2 of the Code.

RESPONSE

Johnson & Johnson stated that the meeting inGlasgow was attended by Johnson & Johnson WoundManagement as part of a cross-franchise exhibitionstand. Johnson & Johnson provided a copy of an


CASE AUTH/1613/8/04

BAXTER HEALTHCAREv JOHNSON & JOHNSON WOUND MANAGEMENTPromotion of Quixil

exhibition panel which did not refer to Quixil, but didcontain a picture of the delivery device. Johnson &Johnson submitted that this enabled the panel to beused across a wide variety of meetings.

Johnson & Johnson stated that at the start of the threeday meeting the Quixil product brochure wasavailable at the stand and a Quixil applicator was ondisplay. When the manager of the sales representativewho had organised the stand arrived he advised thatit was inappropriate to display the product in thatenvironment. The literature and product wereimmediately removed and were not displayed ordiscussed with regard to obstetric and gynaecologicalsurgery for the remainder of the three day meeting.

Johnson & Johnson agreed that display of Quixil atthis meeting was not relevant to the delegates. Thecompany regretted the error and would provideguidelines to its marketing organisation on thesuitability of conferences for future promotion ofQuixil to avoid recurrence.

Johnson & Johnson provided a copy of the agenda forthe meeting about surgical trauma skills and notedthat there was a lecture concerning trauma and liversurgery, an indicated use for Quixil. Johnson &Johnson attended this meeting with the full range ofQuixil promotional material due to the involvementof both liver and orthopaedic surgeons in thetreatment of trauma. Therefore the presence of Quixilat this meeting was appropriate, considering itsapproved indications.

Following a request for further information, Johnson& Johnson stated that the double-barrelled syringeprovided with Quixil was unique to that product.

PANEL RULING

The Panel noted that Quixil was only licensed for use

in liver surgery, such as liver resection and reduced-size liver transplantation, and orthopaedic surgery,such as total hip or knee replacement. The Panelconsidered each meeting separately. In the firstinstance a Quixil product brochure andadministration device had been made available at ameeting for obstetricians and gynaecologists, albeitbriefly until they were removed from Johnson &Johnson’s stand by the representative’s manager whenthe error was noted. A large exhibition panel, headed‘Haemostasis?’, however, remained and this includeda picture of the Quixil administration device. Giventhat the device was unique to Quixil and wasdisplayed on a Johnson & Johnson exhibition panel,the Panel considered that even in the absence of theproduct name the exhibition panel promoted Quixil.The Panel considered that promotion of Quixil toobstetricians and gynaecologists was not inaccordance with the particulars listed in the SPC asalleged. A breach of Clause 3.2 was ruled. The Panelnoted that a ruling of a breach of Clause 2 of the Codewas a sign of particular censure and reserved for suchuse. The Panel did not consider that thecircumstances warranted a breach of Clause 2.

In the second instance Quixil material had been madeavailable at a meeting of trauma surgeons. Theagenda for the meeting showed that day three beganwith a liver lecture. In the Panel’s view Quixil wasthus relevant to the attendees; patients might undergoliver resection following trauma. The Panel did notconsider that Quixil could only be promoted on theday of the liver lecture as seemed to be implied byBaxter Healthcare. No breach of Clause 3.2 was ruled.It thus followed that there was no breach of Clause 2.




It was considered during the course of routine scrutiny ofjournal advertisements that the strapline ‘POWER to relievepain and inflammation in a broad range of indications’(emphasis added) in an Arcoxia (etoricoxib) advertisementwas broader than the licensed indication for the product andthus inconsistent with the particulars listed in the summaryof product characteristics (SPC). This was not accepted byMerck Sharp & Dohme and the matter was accordinglyreferred to the Code of Practice Panel as a complaint.

Arcoxia was a selective cyclo-oxygenase 2 (COX-2) inhibitorindicated for the symptomatic relief of osteoarthritis (OA),rheumatoid arthritis (RA) and the pain and signs ofinflammation associated with acute gouty arthritis.

The Panel noted that there was nothing in the advertisementto suggest to the prescriber that Arcoxia was only licensed inOA, RA and acute gouty arthritis. The only two claims in theadvertisement ‘The power to move you’ and ‘POWER torelieve pain and inflammation in a broad range ofindications’ appeared stark against the background. ThePanel considered that, in the context in which it appeared,the phrase ‘broad range of indications’ for a COX-2 selectiveinhibitor might be read by some as meaning that the productcould be used for more than just arthritic conditions giventhat other such medicines could be used for non-arthriticconditions eg acute pain of any origin and primarydysmenorrhoea. The Panel considered that in theadvertisement in question the claim was misleading andinconsistent with the particulars listed in the SPC. Breachesof the Code were ruled.

product and thus inconsistent with the particularslisted in the SPC.

It was considered that the claim implied that Arcoxiacould be used to treat pain and inflammationgenerally and not just that caused by OE, RA or acutegouty arthritis. Arcoxia was the only COX-2 selectiveinhibitor licensed to treat these conditions; no othermedicine in the class was licensed for use in acutegout. However, Bextra (valdecoxib) was licensed totreat not only OA and RA but also primarydysmenorrhoea. Vioxx Acute could be used for acutepain and primary dysmenorrhoea. The indications forArcoxia all related to conditions involving arthritisand although wide in that regard, Bextra and VioxxAcute could both be used for non-arthritic conditions.Furthermore, although Arcoxia was a COX-2 selectiveinhibitor, it nonetheless belonged to the wider class ofnon-steroidal anti-inflammatory drugs (NSAIDs)which could be used to treat inflammation and painassociated with a very wide variety of conditions.

Merck Sharp & Dohme was asked to respond inrelation to the requirements of Clauses 3.2 and 7.2 ofthe Code.

RESPONSE

Merck Sharp & Dohme stated that the three licensedindications for Arcoxia, the symptomatic relief of OA,RA and the pain and signs of inflammation associatedwith acute gouty arthritis, although all affectingskeletal joints, varied greatly in their aetiology andpathology.

OA was largely a degenerative disease of joint tissuewith a small inflammatory component, which causedpain and disability at the time of, or following,movement. Treatment for many patients withtherapies such as Arcoxia was on an intermittent basiswhen symptoms required.

RA was a systemic autoimmune disease that affecteda variety of organs including synovial joints. It wascharacterised by destructive inflammatory ‘flares’followed by pain and disability as a result of theresidual destruction of joint and surrounding tissues.RA was treated chronically and continuously withmedicines such as Arcoxia.

Acute gouty arthritis was a crystal deposition-inducedacute inflammatory joint disorder that wasexcruciatingly painful in the acute phase. Arcoxiahad anti-inflammatory analgesic properties that wereused for the acute symptomatic period; differentmedicines with different modes of action were usedfor long-term therapy.

The three indications thus comprised a broad range ofmedical conditions. They were widely disparate inthe key areas of aetiology, pathology, symptomatologyand treatment. Arcoxia was the only COX-2 selective


CASE AUTH/1614/8/04

SCRUTINY/DIRECTOR v MERCK SHARP & DOHMEArcoxia journal advertisement

This case arose from the routine scrutiny of journaladvertisements. As the matter could not be settled, itwas referred to the Code of Practice Panel as a case inaccordance with Paragraph 18.4 of the Constitutionand Procedure.

The advertisement in question was for Arcoxcia(etoricoxib) issued by Merck Sharp & Dohme and hadappeared in Pulse, 14 June 2004. The advertisementfeatured the headline claim ‘The power to move you’superimposed onto the photograph of the bottom of alarge waterfall. Along the base of the advertisementran the strapline ‘POWER to relieve pain andinflammation in a broad range of indications’followed by the product logo. Arcoxia was a selectivecyclo-oxygenase 2 (COX-2) inhibitor.

COMPLAINT

During the course of routine scrutiny of journaladvertisements it was noted that Arcoxia wasindicated for the symptomatic relief of osteoarthritis(OA), rheumatoid arthritis (RA) and the pain andsigns of inflammation associated with acute goutyarthritis (summary of product characteristics (SPC)).The advertisement claimed ‘POWER to relieve painand inflammation in a broad range of indications’(emphasis added). The unqualified claim appeared tobe broader than the licensed indication for the

inhibitor with a marketing authorization coveringthese widely differing conditions, as no othermedicine in this class was licensed for use in acutegout. For these reasons, Merck Sharp & Dohmesubmitted that this range of indications was indeed‘broad’ and that describing the product in this mannerwas not inconsistent with the particulars listed in theSPC. Furthermore, this term had been used todescribe this range of indications for two years, andthere was no evidence, in terms of adverse commentfrom prescribers, other health professionals orcompetitor companies, that this wording wasmisleading.

Merck Sharp & Dohme did not agree that the claimwas broader than the licensed indications for theproduct and thus inconsistent with the marketingauthorization. It noted that the claim was notcomparative. It made no assertions about the‘broadness’ of the indications of other selective COX-2inhibitors or the NSAIDs, indeed those who marketedthe other medicines referred to would probablyequally feel that their products were also licensed in ‘abroad range of indications’, given the significantnumber of indications noted. The strapline might alsobe true for those products.

The claim had been carefully worded. It did not statethat any or all painful or inflammatory conditions ingeneral were indications for the use of Arcoxia.Responsible prescribers would be expected to confirmthe indication of Arcoxia before prescribing it. Thisclaim had been in use with the current range ofindications for about two years in the UK and it wasalso used in other countries with the same indications.The company knew of no instances where the claimhad caused confusion or concern amongst prescribers,nor was it aware that the claim had resulted in anyinappropriate prescribing.

Merck Sharp & Dohme stated it was not promotingindications not covered by the marketingauthorization. All Merck Sharp & Dohmeadvertisements stated that the SPC must be referredto before the medicine was prescribed. Physicianswould not prescribe a medicine based on a three pageadvertisement stating a ‘broad range of indications’without looking to see what those indications were.Reference to the SPC was essential.

Merck Sharp & Dohme submitted that the definitionof ‘broad’ covered OA, gout and RA, three separateclinical entities with different aetiologies as notedabove. These three conditions required separatelicensing authorizations. They were not simplyhomogenous rheumatological disorders. They wereas different as if the three indications had been acutepain, dysmenorrhoea and gout. There had been nocomparison with other products or use of the terms‘broader’ or ‘broadest’.

Merck Sharp & Dohme submitted that it wasimportant to assess the claim in terms of the overallmarketing of Arcoxia. All of the representativespromoted only the three indications for Arcoxia (OA,RA and gout). This was the message received bydoctors in conjunction with the claim ‘broad range ofindications’ and the advertisement merely served toremind them of the existence of the medicine.

Merck Sharp & Dohme noted that there was noevidence to suggest that prescribing practise, in termsof the ‘broadness’ of Arcoxia usage had beenadversely affected. In a market research surveyconducted in June 2004, 274 GPs were asked about thediagnosis of the last two patients whom they treatedwith Arcoxia. The results were as follows: OA 42%;gout 25%; RA 18%; lower back pain 10%; ankylosingspondylitis 1%; joint pain 1%; dysmenorrhoea 0%; andother 3%. These results reflected the perceived actionof GPs and thus the message which they had receivedfrom promotional activity, including the claim inquestion. The vast majority of the usage was in thelicensed indications. The 10% usage in lower backpain reflected the overlap and diagnostic difficulty inthis area. There were no reported prescriptions foreither dysmenorrhoea or acute pain, the indicationswhich had been highlighted as problematic.

The phrase ‘broad range of indications’ had been usedfor the past two years without complaint that therewas a potential for misinterpretation. The marketresearch results quoted above confirmed that therehad been no misunderstanding as a consequence ofthis longstanding phrase which had been used sinceproduct launch.

PANEL RULING

The Panel noted that there was nothing in theadvertisement to suggest to the prescriber thatArcoxia was only licensed in OA, RA and acute goutyarthritis. The two claims ‘The power to move you’and ‘POWER to relieve pain and inflammation in abroad range of indications’ appeared stark against thebackground. The Panel considered that, in the contextin which it appeared, the phrase ‘broad range ofindications’ for a COX-2 selective inhibitor might beread by some as meaning that the product could beused for more than just arthritic conditions given thatother such medicines could be used for non-arthriticconditions such as acute pain of any origin andprimary dysmenorrhoea. The Panel considered thatin the advertisement in question the claim wasmisleading and inconsistent with the particulars listedin the SPC. Breaches of Clauses 3.2 and 7.2 of theCode were ruled.

Proceedings commenced 17 March 2004



A woman with HIV complained anonymously about theconduct of a representative from Bristol-Myers Squibb.

The complainant stated that she was in a clinic when awoman who she thought was a doctor started to tell herabout a new HIV medicine. The complainant then saw thatthe woman had her young daughter with her and thoughtthat she was another patient. The complainant thought themedicine would be good for her so she asked her doctorabout it. Her doctor did not want her to have it and said thatthis woman should not have told her about it. Thecomplainant gave her doctor the leaflet the woman had givenher.

The complainant found out from the clinic nurse the name ofthe woman, that she worked for Bristol-Myers Squibb andthat she was not a doctor or a patient but was selling themedicine and that it was against the Code to tell patientsabout it. The complainant was cross and upset as therepresentative had asked her lots of things about herself andher illness but was pretending to be a doctor. She would nothave told her private things if she had known. Thecomplainant was surprised that staff were allowed to taketheir children to work with them.

The complainant’s doctor had said she should write to theAuthority to make sure that the representative did not keeppretending to be someone she was not.

The Panel noted that the parties’ account of events differed; itwas thus difficult to determine exactly what had transpired.The complainant knew that the representative had beenaccompanied by her daughter. Bristol-Myers Squibb haddenied that its representative had talked to the patient asalleged.

The Panel noted that in cases concerning what arepresentative had said it usually sent the response to thecomplainant for comment before it made its ruling. This wasnot possible in this instance as the complainant wasanonymous. The Panel had no option other than to rule nobreach of the Code.

A woman with HIV complained anonymously about theconduct of a representative from Bristol-Myers SquibbPharmaceuticals Limited.

COMPLAINT

The complainant stated that she was in a clinic on 6 Augustwhen a woman who she thought was a doctor started to tellher about a new HIV medicine. The complainant then saw thatthe woman had her young daughter with her and thought thatshe was another patient. The complainant thought themedicine would be good for her so she asked her doctor aboutit. Her doctor did not want her to have it and said that thiswoman should not have told her about it. The complainantgave to her doctor the leaflet the woman had given her.

The complainant found out from the clinic nurse the name ofthe woman, that she worked for Bristol-Myers Squibb and thatshe was not a doctor or a patient but was selling the medicine

and that it was against the ABPI Code to tell patientsabout it. The complainant was cross and upset as therepresentative had asked her lots of things aboutherself and her illness but was pretending to be adoctor. The complainant would not have told herprivate things if she had known. The complainantwas surprised that staff were allowed to take theirchildren to work with them.

The complainant’s doctor had said she should write tothe Authority to make sure that the representative didnot keep pretending to be someone she was not.

When writing to Bristol-Myers Squibb, the Authorityasked it to respond in relation to Clauses 15.2 and 20.1of the Code.

RESPONSE

Bristol-Myers Squibb confirmed that therepresentative was present in the unit in question onthe day specified. She had an appointment with twodoctors detailing product information and had a briefdiscussion with two nurses who were in uniform.The representative sat in the waiting room with herdaughter and had her sales aid open while in a publicarea. She had a discussion with two nurses in acorridor but did not detail anyone in a public area.The representative denied any patient contact anddenied having a conversation with, or giving anyinformation or material to, a patient.

Two consultants at the unit and the clinic managerconfirmed that the representative was present withher daughter. There were no HIV patients scheduledinto the clinic diary on that day and no HIV patientswere seen in clinic on that day by either consultant ornursing staff. HIV clinic days were Monday, Tuesdayand Thursday. The representative did interview oneof the doctors with the door open. All the membersof staff interviewed by the representative’s managerwere surprised that a complaint had been made. Thedoctors were unclear how a patient would know howto lodge an official complaint.

Although Bristol-Myers Squibb could not confirm thatthe representative had any patient contact, it foundthis unlikely given the evidence. It also did not knowif any leavepieces were given to an inappropriateperson but also found this unlikely. Therepresentative’s level of training, experience andinterview suggested that she would have sufficientknowledge of the Code and its implications to avoidthis type of error.

Bristol-Myers Squibb noted that the complainantstated ‘…….started telling me about a new medicine…’. Although the company had recently launched anew protease inhibitor, Reyataz, the representativedid not cover this particular brand, had not beentrained on it and did not carry any Reyataz



ANONYMOUS v BRISTOL-MYERS SQUIBBConduct of representative

promotional material. The products that shepromoted were a number of years old and would notbe considered ‘new’.

Bristol-Myers Squibb therefore believed that there hadbeen no breach of the Code as alleged.

Bristol-Myers Squibb stated that it would address theissue of the representative having her child with heras this was against company policy.

PANEL RULING

The Panel noted that the parties’ account of eventsdiffered; it was thus difficult to determine exactlywhat had transpired at the clinic in question. Thecomplainant knew that the representative had been

accompanied by her daughter. Bristol-Myers Squibbhad denied that its representative had talked to thepatient as alleged.

The Panel noted that usually in cases concerning whata representative had said the response was sent to thecomplainant for comment before the Panel made itsruling. This was not possible in this instance as thecomplainant was anonymous.

The Panel had no option other than to rule no breachof the Code.




1516/9/03 Pfizer Promotion of Breaches Clauses 2 Report from Page 3v Allergan Lumigan and 18.1 Panel to

Appeal BoardAudit required byAppeal Board Report to

ABPI BoardFurther auditrequired byAppeal Board

1519/9/03 Primary Care Trust Practice Breaches Clauses 2 Report from Page 6Clinical Governance Lead Switch and 9.1 Panel tov Trinity Programme Two breaches Appeal Board

Clause 18.1

Audit required byAppeal Board Report to

ABPI BoardFurther auditrequired byAppeal Board

1559/3/04 Lilly Promotion Breach Clause 2 Report from Page 11& v Bristol-Myers Squibb of Abilify Five breaches Panel to1560/3/04 and Otsuka Clause 3.1 Appeal Board

Breaches Clauses 9.1and 15.9

Audit required byAppeal Board

Further Audit inMarch 2005 requiredby Appeal Board

1564/3/04 Pfizer Alleged disparagement No breach No appeal Page 24v Allergan of Pfizer

1570/3/04 Janssen-Cilag/Director Alleged breach of No breach Appeal by Page 25v Lilly undertaking respondent

1572/4/04 Novartis Bondronat journal Two breaches Appeal by Page 33v Roche advertisements Clauses 7.2 respondent

Two breachesClause 7.3Two breachesClause 7.4Breach Clause 7.10

1574/4/04 Pfizer Promotion of Breach Clause 4.3 Appeals by Page 42v AstraZeneca Crestor Two breaches complainant

Clause 7.2 andTwo breaches respondentClause 7.4Two breachesClause 7.10

1579/4/04 GlaxoSmithKline Symbicort Breaches Clauses No appeal Page 50v AstraZeneca leavepiece 7.2, 7.3 and 7.4


CODE OF PRACTICE REVIEW – NOVEMBER 2004Cases in which a breach of the Code was ruled are indexed in bold type.


1580/4/04 Head of Primary Avandia and Breaches Clauses No appeal Page 57Care Trust Prescribing Avandamet 3.2 and 7.2Support Unit journalv GlaxoSmithKline advertisement

1585/4/04 Novo Nordisk Lantus booklets No breach No appeal Page 60v Aventis Pharma

1587/5/04 Diabetes Specialist Nurse Alleged promotion of No breach No appeal Page 63v Aventis Pharma Lantus to diabetes

group

1588/5/04 Primary Care Trust Lead Plavix jounal Breaches Clauses Appeal by Page 65& Prescribing Support advertisement 7.2 and 7.4 respondent1589/5/04 Pharmacist/Director

v Sanofi-Synthelabo andBristol-Myers Squibb

1590/5/04 Primary Care Trust Rosiglitazone Breach No appeal Page 69Director of Clinical (Avandia and Clause 7.2Governance Avandamet) journalv GlaxoSmithKline advertisement

1591/5/04 Janssen-Cilag Promotion of Breaches Clauses No appeal Page 72v Napp Transtec 7.2, 7.4 and 8.1

1592/5/04 Gilead Sciences Epivir and Breaches Clauses No appeal Page 76v GlaxoSmithKline Ziagen leavepiece 7.2 and 7.10

1594/6/04 Roche Zometa Breach Clause 3.1 Appeals by Page 84v Novartis detail aid Four breaches complainant

Clause 7.2 andBreaches Clauses respondent7.3 and 7.4Three breachesClause 7.10

1595/6/04 Voluntary admission Abilify Breach Clause 3.1 No appeal Page 105& by Bristol-Myers Squibb mailing1596/6/04 and Otsuka

1598/6/04 GlaxoSmithKline Nicorette Patch Breaches Clauses No appeal Page 107Consumer Healthcare journal 4.7 and 7.2v Pfizer Consumer Healthcare advertisement

1599/6/04 Novartis Press articles Breach Clause 3.2 No appeal Page 110v Roche about Bondronat Six breaches

Clause 7.2

1600/6/04 Denfleet Pharma Clozaril Nine breaches No appeal Page 120v Novartis booklets Clause 7.2

Eight breachesClause 7.4

1601/7/04 Primary Care Trust Medicines Conduct of No breach No appeal Page 128Management Facilitator representativev Pfizer

1605/7/04 Consultant Pharmacist Cipralex journal No breach No appeal Page 130v Lundbeck advertisement

1611/8/04 Media/Director Promotion of Breaches Clauses No appeal Page 132v Bayer Avelox 7.2 and 7.4

1612/8/04 Schwarz Pharma Promotion of Breaches Clauses No appeal Page 134v Stiefel Duac 7.2 and 7.4

1613/8/04 Baxter Healthcare Promotion of Breach Clause No appeal Page 137v Johnson & Johnson Quixil 3.2Wound Management

1614/8/04 Scrutiny/Director Arcoxia journal Breaches Clauses No appeal Page 139v Merck Sharp & Dohme advertisement 3.2 and 7.2

1621/8/04 Anonymous Conduct of No breach No appeal Page 141v Bristol-Myers Squibb representative



The Prescription Medicines Code of PracticeAuthority was established by TheAssociation of the British PharmaceuticalIndustry (ABPI) in 1993 to operate the Codeof Practice for the Pharmaceutical Industryat arm’s length from the ABPI itself.

Compliance with the Code is obligatory forABPI member companies and, in addition,about sixty non member companies havevoluntarily agreed to comply with the Codeand to accept the jurisdiction of theAuthority.

The Code covers the advertising ofmedicines to health professionals andadministrative staff and also coversinformation about such medicines madeavailable to the general public.

It covers:

● journal and direct mail advertising

● the activities of representatives,including detail aids and other printedmaterial used by representatives

● the supply of samples

● the provision of inducements toprescribe, supply, administer,recommend or buy medicines by thegift, offer or promise of any benefit orbonus, whether in money or in kind

● the provision of hospitality

● the organisation of promotionalmeetings

● the sponsorship of scientific and othermeetings, including payment oftravelling and accommodation expenses

● the provision of information to thegeneral public either directly or indirectly,including by means of the Internet

● all other sales promotion in whateverform, such as participation inexhibitions, the use of audio-cassettes,films, records, tapes, video recordings,electronic media, interactive datasystems, the Internet and the like.

Complaints submitted under the Code areconsidered by the Code of Practice Panelwhich consists of the three members of theCode of Practice Authority acting with theassistance of independent expert adviserswhere appropriate. Both complainants andrespondents may appeal to the Code ofPractice Appeal Board against rulings madeby the Panel. The Code of Practice AppealBoard is chaired by an independent legallyqualified Chairman, Mr Nicholas BrowneQC, and includes independent membersfrom outside the industry.

In each case where a breach of the Code isruled, the company concerned must give anundertaking that the practice in questionhas ceased forthwith and that all possiblesteps have been taken to avoid a similarbreach in the future. An undertaking mustbe accompanied by details of the actiontaken to implement the ruling. Additionalsanctions are imposed in serious cases.

Complaints about the promotion ofmedicines should be sent to the Director ofthe Prescription Medicines Code of PracticeAuthority, 12 Whitehall, London SW1A 2DY(telephone 020 7930 9677facsimile 020 7930 4554).

C O D E O F P R A C T I C E R E V I E WNUMBER 46 NOVEMBER 2004

The Prescription Medicines Code of Practice Authority was established by The Association of the British Pharmaceutical Industry (ABPI) in1993 to operate the ABPI Code of Practice for the Pharmaceutical Industry independently of the Association itself.


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New publication for healthprofessionals, NHS managers, etcThe Authority and the ABPI haveissued a new publication, Guidancenotes for health professionals on theCode. The guidance is a brief summaryof key points to help health professionalsand managers understand the Codeand its operation. Copies are availableon the website (pmcpa.org.uk) and

from the ABPI (020 7930 3477 ext 1446or [email protected]). Thepublication has been sent to NHSexecutives and managers as well asorganizations such as the RoyalColleges and others. Many healthprofessionals have also been suppliedwith copies.

Health SelectCommitteeThe Health Select Committee inquiryinto the influence of the pharmaceuticalindustry on health policies, healthoutcomes and future health prioritiesand needs continues.

The inquiry covers six main areas: druginnovation; conduct of medicalresearch; provision of drug informationand promotion; professional andpatient education; regulatory review ofdrug safety and efficacy and productevaluation.

Many organizations, including thePrescription Medicines Code of PracticeAuthority, have submitted evidence tothe inquiry.

CodechangesThe European Federation ofPharmaceutical Industries andAssociations (EFPIA) has recentlyreviewed the European Code ofPractice for the Promotion ofMedicines. Member Associations arerequired to include the EFPIA Coderequirements in their national codessubject to applicable national law. TheEFPIA Code was established in 1992and revised in 1993 to comply withCouncil Directive 92/28/EEC on theadvertising of medicinal products forhuman use.

The revision of the EFPIA Code isnearly complete. The ABPI and theAuthority, as well as many companies,have been involved in the process. Therevised EFPIA Code is expected to beagreed shortly.

As part of the review of the EFPIACode, codes of conduct within theindustry across Europe are also beingreviewed. The ABPI is in the process ofa review of the Code and its operation.Part of that review will includebringing the ABPI Code into line withthe new EFPIA Code. Manyamendments to the EFPIA Code reflectthe current requirements of the ABPICode. Some will require changes to theABPI Code.

Price reductionsAs companies are aware, the revisedPharmaceutical Price RegulationScheme requires prices of medicines tobe reduced with effect from 1 January2005 so as to achieve an overallreduction for a company of 7%.

It is in the interest of advertisers toindicate the new lower prices onpromotional material as soon aspossible. In the period 1 January to 31March 2005, however, promotionalmaterial will not be considered to be inbreach of the Code if it still carries theprevious higher price.

Care should be taken, however, toensure that there is no discrepancybetween what representatives say andwhat is said on written material leftwith the doctor etc by therepresentative as this could give rise tocomplaints.

It will not be acceptable at any time togive comparative prices in promotionalmaterial where these involve the newlower price of the advertiser’s productand the superseded higher prices ofcompetitor products.

Every effort should be made to ensurethat journal advertisements are correctat the time of publication.

Goodbye LisaLisa Matthews who has been with theAuthority for six years as secretary toEtta Logan and Jane Landles will beleaving this month. Lisa has a new jobat a firm of architects, interior designersand surveyors in her home town inKent. The Authority thanks Lisa forher help and wishes her all the best forthe future.

code of practice review · 2020. 11. 20. · the prescription medicines code of practice authority,...

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