biosimilar insulins (generally) won’t need comparative clinical … · 2019-12-02 · needed for...

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Vol. 81 / No. 48 December 2, 2019

DRUG SAFETY

New Package Leaflets Needed For EU Drugs With Ethanol Excipient, p. 14

CAPITOL HILL

Real-World Evidence, Digital Health, Insurance Coverage Reforms On US Cures 2.0 Agenda, p. 6

REGULATORY UPDATE

Belgian RWE Initiative Proposes Actions To Support HTA/Payer Decisions, p. 7

CONTINUED ON PAGE 4

Biosimilar Insulins (Generally) Won’t Need Comparative Clinical Immunogenicity Data, US FDA SaysMICHAEL CIPRIANO [email protected]

C ompanies developing biosimilar and interchangeable in-sulin products for the US market will generally not need to conduct comparative clinical immunogenicity studies,

according to draft guidance issued by the to Food and Drug Ad-ministration on 25 November.

The draft guidance, which will likely be welcomed by industry, notes that, “Current analytical tools used to evaluate quality attri-butes for insulin products can support a comprehensive analytical comparison thorough enough to support a conclusion that a par-ticular proposed biosimilar insulin product that is ‘highly similar’ to its reference product generally would have little or no residual un-certainty regarding immunogenicity and would be expected, like the reference product, to have minimal or no risk of clinical impact from immunogenicity.

“In such cases, a comparative clinical immunogenicity study would generally not be necessary to support licensure of a proposed biosimilar or interchangeable product,” the draft guidance adds.

The FDA has historically advised sponsors interested in develop-ing follow-on insulin products that they will likely need a compara-tive clinical immunogenicity study to support their applications.

However, the draft guidance notes that the agency has since updated its thinking after evaluating a series of factors, such as insulin’s relatively uncomplicated structure, a literature survey confirming minimal or no clinical relevance of immunogenicity with use of insulin products, and decades of real-world experi-ence with such products.

Interestingly, the FDA also points to a 2015 revised guideline from the European Medicines Agency, which no longer recom-mends a clinical immunogenicity study to support an insulin bio-similar application.

The agency additionally cites presentations from a May 2019 public meeting on insulin biosimilars as influencing its thinking. Several speakers at the meeting argued that the FDA should be

less focused on immunogenicity concerns for insulins than for larg-er, more complex biologics. (Also see “Best Pathway To Interchange-able Insulins Is In The Eye Of The Beholder” - Pink Sheet, 15 May, 2019.)

Stakeholders also echoed this sentiment at a Drug Information Association meeting on biosimilars in September.

“The residual uncertainty is fairly minimal once we get past the structural characterization,” said Sundar Ramanan, vice president of global regulatory affairs at Biocon Ltd.

No company has publicly announced its intention to pursue an interchangeable insulin product yet. Boehringer Ingelheim Inter-national GmbH is the only company known to be pursuing in an

Sponsors are encouraged to consult with the Division of Metabolism and

Endocrinology Products regarding which data and information are needed before

submitting a 351(k) BLA.

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EMA Heeds Ombudsman’s Advice On Avoiding Perception Of Bias In Drug Evaluationshttps://pink.pharmaintelligence.informa.com/PS141272

An inquiry by the EU Ombudsman has prompted the European Medicines Agency to introduce changes to ensure that its experts, who advise companies in the premarket phase, are not appointed to evaluate marketing applications for the same drugs.

Irish Regulator Invites Feedback On Strategic Plan For 2021-2025https://pink.pharmaintelligence.informa.com/PS141276

Ireland’s drug and medical device regulator is seeking stakeholder views on what its priorities should be over the next five years, given the uncertainties of Brexit and impending regulatory changes.

Complex Generics May Need New Communications Options In GDUFA IIIhttps://pink.pharmaintelligence.informa.com/PS141227

US FDA and complex generic sponsors need a way to talk about reference product and other changes once the pre-submission meetings pathway is exhausted.

Pink Sheet Podcast: US FDA Commissioner Nominee Stephen Hahn Appears Before The Senate, Controversial Regulations In The New Unified Agendahttps://pink.pharmaintelligence.informa.com/PS141248

Pink Sheet reporters explain Stephen Hahn’s responses to Senators’ questions and discuss some of the new regulations that FDA plans to release in the coming months.

Former FDA Commissioner Frank Young Passes Away At 88https://pink.pharmaintelligence.informa.com/PS141271

From the approval of AZT to the generic drug scandal, Frank Young oversaw many seminal events at US FDA while commissioner from 1984 to 1989. After leaving the agency, he managed the approval of the NDA for Braeburn’s opioid dependence drug Probuphine. Young passed away following a short bout with cancer.

exclusive online content

CO V E R Biosimilar Insulins (Generally) Won’t Need Comparative Clinical Immunogenicity Data, US FDA Says

B I O S I M I L A R S 4 Playing It Safe? Hahn’s Biosimilar View

C A P I TO L H I L L 6 Real-World Evidence, Digital Health, Insurance Coverage

Reforms On Cures 2.0 Agenda

R E G U L ATO RY U P D AT E 7 Belgian RWE Initiative Proposes Actions To Support

HTA/Payer Decisions

8 Celgene Gets Another Myeloma CAR-T Accepted Onto EMA’s PRIME

E L E C T I O N S 9 UK Conservatives Promise ‘Innovative Medicines

Fund’ If Re-Elected

12 UK Labour Govt Would Boost Health Spending, Put Pressure On Drug Prices

D R U G S A F E T Y 14 New Package Leaflets Needed For EU Drugs

With Ethanol Excipient

M A R K E T I N G & A D V E R T I S I N G 15 Comparative Claims: CFL Guidance Gives Opening;

OPDP Research May Close It

D I S T R I B U T I O N 17 EU Parallel Trade ‘Alleviates Shortages’

Says New EAEPC President

A D V I S O RY CO M M I T T E E S 18 Recent and Upcoming FDA Advisory Committee Meetings

inside: 14 5 6

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4 | Pink Sheet | December 2, 2019 © Informa UK Ltd 2019

B I O S I M I L A R S

interchangeability designation, which the company is seeking for its biosimilar to AbbVie Inc.’s Humira (adalimumab). (Also see “Bio-similar Substitution: US State Laws Require Physician Communica-tion And, In Some Cases, Lower Prices” - Pink Sheet, 15 Jun, 2018.)

Comments on the guidance are due 25 February 2020, less than a month before 23 March 2020 date when insulins will tran-sition from being regulated as drugs to biologics.

WHEN STUDIES MAY BE NEEDED The draft guidance explains that a comparative clinical immu-nogenicity study may still be needed in certain cases to address residual uncertainty.

“For example, such a study would be needed to address un-certainty raised by, among other things, differences in certain impurities or novel excipients, but that would be a case-by-case scientific determination in the context of individual applications,” the guidance states.

Sponsors are encouraged to consult with the Division of Me-tabolism and Endocrinology Products regarding which data and information are needed before submitting a 351(k) BLA.

TYING THE GUIDANCE TO HIGH INSULIN COSTS In a statement, acting FDA commissioner Brett Giroir tied the re-lease of the guidance to the broader discussion around the high price of insulin products in addition to making the development of insulin biosimilars more efficient.

Giroir commented that, “we are aware that the high cost of in-sulin raises serious concerns about the ability of many patients to access insulin products. This is an issue the FDA takes very se-riously; therefore, today we are announcing new draft guidance that is intended to help facilitate the development of, and im-prove patient access to, life-saving insulin products.”

Giroir also tweeted out a video of himself from the @FDACom-missioner handle in which he touts the release of the guidance. Although Giroir essentially reiterated the language from his writ-ten statement, the video itself is notable, as the FDA seldom re-leases recorded statements from agency officials accompanying the release of a guidance.

Former FDA commissioner Scott Gottlieb also announced his support for the guidance. “This builds on the effort to create a more efficient path to market for lower cost, copy insulin’s that are fully interchangeable with brand counterparts through our policy last year to move these drugs to the FDA’s Biosimilars path-way,” Gottlieb tweeted on 25 November.

“We should soon see a robust market take shape for lower cost, high quality, copy insulins - many of which will be interchange-able with their brand counterparts,” he added.

Published online 25 November 2019

CONTINUED FROM PAGE 1 Playing It Safe? Hahn’s Biosimilar ViewDERRICK GINGERY [email protected]

T he US Food and Drug Administration commissioner nominee may have unintentionally got on the wrong side of some of his future colleagues with a seemingly

benign comment about biosimilars and transparency.During his 20 November confirmation hearing with the Sen-

ate Health, Education, Labor and Pensions Committee, Hahn was asked about his views on the FDA’s role in preventing pat-ent gaming. Sen. Susan Collins, R-ME, questioned whether Hahn supported adding patents to the Purple Book, which is FDA’s reference of biologics and their exclusivity expiration dates.

Hahn gave a vague answer and drew from his own experi-ence as an oncologist. He told Collins that biologics are an important treatment source for cancer patients and pricing pressure is substantial.

“The biosimilar pathway is crucial,” Hahn said. “I’m very much in favor of transparency and anti-competitive practices should be eliminated.”

Hahn also told Collins that he would work with her on the is-sue. She has introduced a bill, S. 659, the Biologic Patent Trans-parency Act, that would require public disclosure of patents, ap-proved indications, and other information about biologics.

The bill is intended to help biosimilar manufacturers navigate so-called patent thickets erected by reference product spon-sors, in part to help biosimilars come to market sooner. (Also see “AbbVie’s ‘Unjustified’ Humira Settlements Divide Market, Class Ac-tion Claims” - Pink Sheet, 19 Mar, 2019.)

FDA WORRIES ABOUT RESOURCES Unfortunately for Hahn, while it may have seemed non-con-troversial to agree with increasing transparency and ending anti-competitive practices, the proposal Collins referenced concerns FDA. The agency does not have a statutory role in the biosimilar patent process, unlike with small molecule ge-nerics, and would prefer not to get involved.

During a panel discussion at the recent Association for Accessible Medicines’ GRx Biosims conference, Eva Temkin, acting director of policy in the FDA Center for Drug Evalu-ation and Research’s Office of Therapeutic Biologics and Biosimilars, said the agency is worried about the resources that would be required to gather and publish patents in the Purple Book.

Temkin would not comment on pending legislation, but her comments did not suggest the agency is enthusiastic about the idea.

“We don’t currently have a role in the patent process for biosimilars and that means that we don’t have staff that deal with that,” she said. “We are very focused to the extent that

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B I O S I M I L A R S

we have resources to allocate on developing guidance, devel-oping regulatory certainty, reviewing applications and help-ing to create efficient and streamlined and a clear regulatory environment across applications themselves.”

“It’s a new program,” Temkin added. “We have a lot of work to do ahead of us and so we think very carefully about anything that would shift resources from that core mission.”

Temkin also said that the 2017 biosimilar user fee program reauthorization agreement with industry included Purple Book enhancements, but not inclusion of patents.

“I see that as a reflection of the conversation between FDA and stakeholders,” she said.

Brian McCormick, Teva Pharmaceutical Industries Ltd. VP and chief regulatory counsel, said during the session that add-ing patents “seems like a passive-aggressive and inefficient way of regulating those issues.”

“There’s just a whole host of issues raised by some of the leg-islation to put patents into the Purple Book and the question is: Why if you don’t have a paragraph III, paragraph IV patent

certification process here,” he said.More Purple Book changes could be made as part of the up-

coming biosimilar user fee reauthorization negotiations. Fee revenue could be devoted to additions or revisions, although that may take away from other activities.

Financing the young FDA biosimilars program remains com-plicated because of its volatile user fee revenue stream. (Also see “Biosimilar User Fee Collections Drop Well Below Estimates, But US FDA Not Worried” - Pink Sheet, 10 Jun, 2019.) Collections in FY 2018 were well below estimates after fewer applications than expected were submitted. (Also see “After Biosimilar Fee Collections Fall Short, US FDA Modifies Carryover Spend-Down Plan” - Pink Sheet, 9 Oct, 2019.)

PURPLE BOOK REVISIONS UPCOMING Temkin said during the conference that the new version of the Purple Book is in development and will include a searchable da-tabase and improved interface. She added that the agency also is considering including approved indications in it.

Among the complaints about the Purple Book’s current form is that it consists only of static pdf files. The lists include the date of licensure and reference product exclusivity expiry, as well as whether any approved follow-on products are inter-changeable or biosimilar.

During a 2018 public hearing, several stakeholders called on the FDA to include patent and exclusivity information in order to enhance biosimilar development. They said the information would help sponsors decide whether to pursue biosimilar devel-opment programs. (Also see “Make The ‘Purple Book’ More Orange, US FDA Told At Biosimilars Hearing” - Pink Sheet, 4 Sep, 2018.)

HAHN PREFERRED GENERAL ANSWERS TO MOST SENATORS’ QUESTIONS Hahn chose to give few details on his policy positions through-out the confirmation hearing. His answers to many questions were limited to a pledge to follow the science, data law when making decisions.

The strategy was intended to avoid headline-grabbing com-ments or mistakes that could endanger his confirmation. How-ever, some Senators were not pleased and one suggested Hahn revise his answers.

The biosimilar question was one of many on drug develop-ment, although much of the hearing seemed to be dominat-ed by questions and comments about vaping policy. (Also see “Drug Development Questions Dominate Hahn’s Confirmation, Despite Talk About E-Cigs” - Pink Sheet, 20 Nov, 2019.)

Senators were mostly cordial, but many interesting ques-tions about the current chief medical executive at MD Ander-son Cancer Center remain, such as why he wants the job and how he was selected for it. (Also see “US FDA Nominee Makes A Good First Impression, But This Is Still An Odd Transition” - Pink Sheet, 21 Nov, 2019.)


Phot

o cred

it: De

rrick

Ging

ery

US FDA commissioner nominee Stephen Hahn awaits the start of his Senate confirmation hearing on 20 November, where he

responded to questions about biosimilars, vaping and other issues.

Sen. Collins asked whether

Hahn supported adding patents to

the Purple Book, FDA’s reference

of biologics and their exclusivity

expiration dates.



Real-World Evidence, Digital Health, Insurance Coverage Reforms On Cures 2.0 Agenda DERRICK GINGERY [email protected]

R eal-world evidence once again will be among the themes of a congressional effort to streamline and improve access to biomedical innovation.

US Reps. Diana DeGette, D-CO, and Fred Upton, R-MI, are looking for stakeholder and patient ideas to include in another legislative package devoted to drug development and medical research in the same vein as their landmark 21st Century Cures Act. Cures 2.0 will be “an effort to modernize coverage and access to life-saving cures in the United States and across the globe,” DeGette and Up-ton wrote in a document released on 22 November that outlined their vision for the bill.

Real-world evidence is one of the issues the Cures authors said needs more work. The 2016 law mandated that the US Food and Drug Administration create a program for evaluation of RWE to help support approval of new indications and support or satisfy post-approval study requirements.

DeGette and Upton wrote in the vision document that they want to “build on our initial RWE work, both at FDA and across the fed-eral health care landscape.”

The document did not provide more detail on the RWE issues that could be addressed. Patients and stakeholders with ideas were encouraged to email them to [email protected] by 16 December.

Indeed, the proposed changes that could emerge as the bill is formulated will be interesting to watch. Many questions about RWE remain unanswered, especially with the FDA still gaining con-fidence in the usefulness of the data for regulatory purposes.

The FDA released its RWE framework in late 2018 and outlined how observational studies could be used to support new efficacy claims for drugs. Agency officials also listed several critical ques-tions that must be answered. (Also see “US FDA Is Hesitant About Using Observational Studies In Real-World Evidence Framework“ -

Pink Sheet, 6 Dec, 2018.)Robert Temple, FDA Center for Drug Evaluation and Research

deputy director for clinical science, and other FDA officials have registered their concerns about using RWE for new indications. (Also see “US FDA’s Temple On Real-World Evidence: ‘I Find The Whole Thing Very Frustrating’” - Pink Sheet, 15 Oct, 2019.)

And while the FDA has used RWE for regulatory purposes al-ready, sponsors have been skeptical about including it in their ap-plications, in part because they are not sure how the agency will react. The agency is offering internal training to help assessors un-derstand its policy. (Also see “US FDA Searches For Consistency On Assessment Of Real-World Evidence” - Pink Sheet, 29 Jul, 2019.)

Statistical and other questions also have emerged, such as how to handle missing data (Also see “Real-World Evidence: When Is Missing Data Not Really ‘Missing’?” - Pink Sheet, 29 Jul, 2019.), and where to find reliable information on deaths. (Also see “Real-World Evidence Challenges: Death Among Toughest Data Points To Mea-sure” - Pink Sheet, 14 Aug, 2018.)

The FDA is leading several efforts to determine the extent RWE could be used in drug development, including a project that at-tempts to use claims data to replicate the results of clinical trials. (Also see “RWE: Comparators, Therapeutic Area May Be Key For Trial Replication” - Pink Sheet, 14 Oct, 2019.) Agency officials also have encouraged sponsors to try various RWE projects in order to evalu-ate where it may be useful. (Also see “US FDA’s Abernethy ‘Cautious’ About Real-World Evidence“ - Pink Sheet, 6 Aug, 2019.)

MEDICARE PAYMENT, DIGITAL HEALTH ENHANCEMENTS ALSO NEEDED, DEGETTE AND UPTON SAYOther areas of interest for Cures 2.0 include digital health and Medicare coverage reform.

C A P I T O L H I L L




C A P I T O L H I L L

DeGette and Upton wrote that digital health technologies could help modernize the US health care system and “transform how Americans access medical services.”

“Digital technologies have helped to transform other sectors of the US economy in ways that improve access to products and ser-vices and decrease their costs without harming quality,” they said in the vision document. “It is time for that same transformation to occur in health care. Recognition of digital platforms as sources of medical services combined with reforms to how digital products may be covered and reimbursed for by payers such as Medicare will be critical to realizing this potential.”

The FDA’s work to streamline digital software marketed with drugs may be among the ideas considered. Agency officials said that in some cases the software outputs could be considered part of promotional labeling, meaning they would not require pre-market review as a device, an idea raised by former FDA Commis-sioner Scott Gottlieb. (Also see “Drug/Software Combos Likely Won’t Require Pre-Market Review By US FDA” - Pink Sheet, 19 Nov, 2018.)

DeGette and Upton also indicated they wanted to “modernize how cures and medical products are covered,” a process that some-times takes years.

“The financial implications of moving health care coverage from large population medical products to those developed for smaller populations is impeding our efforts,” they wrote in the vi-sion document. “As a key goal is to support access to life-savings cures, we would like to explore how reform of Medicare coding, coverage, and payment could better support patients’ access to innovative therapies.”

Coverage changes could include outcomes-based contracts (Also

see “HHS Safe Harbor For Value-Based Drug Contracts May Be On Hori-zon” - Pink Sheet, 9 Oct, 2019.), as well as long-term financing options, such as bluebird bio Inc.’s gene therapy Zynteglo (autologous CD34+ cells encoding βA-T87Q-globin gene), which following European ap-proval was offered with a price that is paid over five years and based on whether the treatment is successful. (Also see “Bluebird Pushes For Zynteglo Pricing Of Five €315K Annual Installments“ - Scrip, 14 Jun, 2019.)

UPTON WANTS EARLY 2020 BILL INTRODUCTIONDeGette and Upton said in a press release announcing the call for ideas that meetings with stakeholder groups and other experts already have started. They also envision “a similar process as their previous effort.”

A spokesperson for Upton said there is no timeline now, but the congressman would like to introduce a Cures 2.0 bill sometime early next year.

The road to the 21st Century Cures Act included several round-table discussions and public hearings with stakeholders, FDA and others offering ideas. (Also see “Congress Dives Into Biomedical In-novation: Will It Drown In A Deep Sea Of Competing Needs?” - Pink Sheet, 12 May, 2014.) The hearings and bill writing took months and from start to finish Cures required more than two years to be enacted. (Also see “Woodcock, Califf Give Thumbs Up To Certain 21st Century Cures Provisions” - Pink Sheet, 14 Dec, 2016.)

DeGette and Upton announced the beginning of work on Cures 2.0 in July. (Also see “Cures 2.0: Can Congress Recapture The Legisla-tive Magic? “ - Pink Sheet, 19 Aug, 2019.)


Belgian RWE Initiative Proposes Actions To Support HTA/Payer DecisionsVIBHA SHARMA [email protected]

A n initiative commissioned by the Belgian health care payer, INAMI/RIZIV, has resulted in a range of proposals to better use real-world evidence (RWE) to close evidentiary gaps in

health technology assessment (HTA)/payer decisions for highly in-novative technologies.

The proposals apply to a range of stakeholders – HTA bodies/payers, regulators, industry, clinicians, registry holders and patient groups. In case of national HTA bodies/payers, for example, it is rec-ommended that they should request companies to provide them with RWE generation plans with links to protocols or plans for data collection and analysis.

Feedback is now being invited on the proposals, which include specific action points for each type of stakeholder and recommen-dations to strengthen ongoing cross-country initiatives on collect-ing real-world data (RWD). The new proposals are listed in a pa-

per and stakeholder feedback is being accepted through an online survey until 6 January 2020.

In addition, there are plans to establish a new multi-stakeholder collaborative learning network to further explore using RWE to support HTA/payer decision making for highly innovative tech-nologies. Among other things, the network is expected to encour-age the uptake of these proposals in each stakeholder group and monitor their implementation.

The initiative commissioned by INAMI/RIZIV began earlier this year to focus on particular challenges HTA body and payers face when making decisions about highly innovative technologies. The aim was to explore whether RWE could be used to resolve important decision uncertainties in a manner that was “collabora-tive, overcoming issues of fragmentation and providing practical actions for implementation by each stakeholder,” the paper states.

R E G U L A T O R Y U P D A T E





As the potential use of RWD relies on many issues, the initiative involved multiple stakeholders who discussed a range of ques-tions, including whether valuable RWE can be obtained from RWD and which HTA questions can be answered with RWE, from what data, and under what conditions.

There was general consensus that by working within the principles of collaboration and transparency, each stakeholder can take respon-sibility for actions to better use RWE in HTA/payer decisions about highly innovative technologies. It is proposed, for example, that:

• EU or multi-country HTA bodies/payers should identify what questions could be answered with RWE and specify the “evi-dence bar” for each type of question.

• National HTA bodies/payers should request RWE generation plans from companies with links to protocols or plans for data collection and analysis.

• Regulators should enhance collaboration with HTA bodies on initiatives such as qualification of registries and post-autho-rization safety and efficacy studies, to agree a common core outcome set of data for HTA and regulation.

• Industry should create a RWE generation plan very early in development that addresses what outcomes will be used to determine patient benefit, how natural history and effective-ness of the comparator will be explored and plans for the evaluation of long-term effectiveness.

• Registry holders should review quality standards for registries issued by the European Medicines Agency and the EU network of HTA bodies (EUnetHTA) and apply them.

• Clinicians through European Reference Networks and other clinical networks should systematically collaborate with regulators and HTA/payers when establishing their registries or other forms of RWD collection to ensure these are fit for all purposes, including HTA.

• Patient groups should develop EU or international collabora-tions to engage in RWD initiatives and ensure that outcomes that matter to patients are collected.

The INAMI/RIZIV initiative builds on previous EU initiatives that explored the potential of RWE to close evidentiary gaps for HTA/payer decisions, specifically:

• “The use of real-world data throughout an innovative medi-cine’s lifecycle,” which outlined nine principles for good RWD practice in Europe.

• “Outcomes based pricing and reimbursement of innovative medicines with budgetary limitations,” which defined 10 principles to assess value for money of a medicine, with a key focus on outcomes-based agreements.

• TRUST4RD, which is a tool to reduce uncertainties in evidence generation for specialized treatments for rare diseases.

The Belgian initiative was financially supported by Amgen, As-traZeneca, Gilead Sciences, Roche and the European Confedera-tion of Pharmaceutical Entrepreneurs (EUCOPE), which represents small to medium-sized innovative drug companies.


Celgene Gets Another Myeloma CAR-T Accepted Onto EMA’s PRIMENEENA BRIZMOHUN [email protected]

Y et another CAR-T therapy for multiple myeloma and a treat-ment for paroxysmal nocturnal hemoglobinuria (PNH) are the latest investigational products to make it onto the Eu-

ropean Medicines Agency’s PRIME (priority medicines) scheme for getting drugs for unmet medical needs to patients faster.

JCARH125, the B-cell maturation antigen (BCMA)-targeting CAR T-cell therapy that Bristol-Myers Squibb company Celgene is de-veloping, and Achillion Pharmaceuticals’ danicopan (ACH-4471) for treating PNH were accepted onto the scheme this month. They were among eight applications for PRIME designation that the EMA assessed in November. The other six were denied.

PRIME offers developers enhanced scientific and regulatory support from the EMA to help optimize their development plans, and the likelihood of having their product reviewed under the EU’s accelerated assessment procedure when it is eventually filed for regulatory review.

The acceptance of the Celgene and Achillion products onto the scheme means the companies met PRIME’s tough entry criteria and managed to convince the EMA that their products have the potential to benefit patients with an unmet medical need based on early clinical data.

JCARH125 is for the treatment of relapsed/refractory (r/r) mul-tiple myeloma in patients whose prior therapies included autolo-gous stem cell transplant if they were eligible, a proteasome inhibi-tor, an immunomodulatory agent and an anti-CD38 antibody.

It is one of four investigational BCMA-targeted CAR-T thera-pies for r/r multiple myeloma currently in PRIME, and the sec-ond one for the disease that Celgene has managed to get onto the scheme. Idecabtagene vicleucel (ide-cel, formerly bb2121), which the company is developing with bluebird bio, received PRIME designation in November 2017. The remaining BCMA-tar-geted CAR-T therapies in PRIME for multiple myeloma are CARs-gen Therapeutics’ CT053, which was accepted onto the scheme in September, and Janssen Pharmaceutical’s JNJ-68284528, which received PRIME designation in March.

There is also another investigational treatment for the disease in the scheme: GlaxoSmithKline’s GSK2857916 (belantamab ma-fodotin), which is a BCMA-targeting antibody-drug conjugate

Since March 2016, 62 products have

been accepted onto the PRIME

scheme and 196 have been rejected.




that made it onto PRIME in October 2017. BCMA has be-come an exciting novel drug target in multiple myeloma, and GSK is ahead of its rivals here. (Also see “Myeloma BCMA Therapy In Spotlight: EMA Considers Fast Tracking GSK Filing “ - Pink Sheet, 13 Nov, 2019.)

Celgene was acquired by BMS this week. (Also see “With Celgene Acquisition Closed, Bristol Faces Major Milestones” - Scrip, 21 Nov, 2019.)

DANICOPANAs for danicopan, the product received PRIME designation for the treatment of PNH in patients who are not adequately responding to a C5 inhibitor, the current standard of care.

The decision by the EMA was based on safety and efficacy data for danicopan from the Phase II PNH combination trial, said Achil-lion, which is being acquired by Alexion Pharmaceuticals. Alexion is the current market leader in the PNH space with its C5 inhibitor Soliris (eculizumab) and second-generation drug Ultomiris (ravu-lizumab). (Also see “Alexion Buys A Complementary Business With Achillion” - Scrip, 16 Oct, 2019.)

Achillion said it was planning to advance the develop-ment of danicopan into a global Phase III trial in early 2020.

APPLICATIONS THAT MISSED THE MARKCelgene and Achillion’s applications for PRIME were ac-cepted during the latest monthly meeting of the EMA’s drug evaluation committee, the CHMP, which took place on 11-14 November.

The six applications that were turned down this month covered investigational treatments for postbariatric hy-

poglycemia, inherited disorders of oxidative phosphorylation, chronic hepatitis D virus infection, amyotrophic lateral sclerosis, children with Rett syndrome, and early Alzheimer’s disease.

PRIME was launched in March 2016. To date, 62 products have been accepted onto the scheme and 196 have been rejected. In addition, applications for a further nine products have been turned down because they were outside the scope of the scheme or had a format and content inadequate to support their review.


E L E C T I O N S

UK Conservatives Promise ‘Innovative Medicines Fund’ If Re-ElectedIAN SCHOFIELD [email protected]

T he UK Conservative Party unveiled its general election manifesto on 24 November, promising a range of mea-sures to improve access to medicines and boost innova-

tive drug research, alongside commitments on higher day-to-day health care spending.

Entitled “Get Brexit Done – Unleash Britain’s Potential,” the mani-festo promises that if the Conservatives win the 12 December elec-tion and form a government, they will make the UK “the leading global hub for life sciences after Brexit.” It also reiterates assurances that the National Health Service will not be “on the table” in nego-tiations on future trade deals.

There are a few eye-catching pledges in what is otherwise a rath-er cautious policy platform, such as extending the Cancer Drugs Fund into an “Innovative Drugs Fund” covering all medicines, creat-ing a new arm’s-length agency for “high-risk, high-payoff” research, and increasing public R&D spending to 2.4% of GDP.

The manifesto offers a relatively modest rise in spending on the NHS on top of the £33.9bn increase over five years that was out-lined in June 2018 last year in the NHS long-term plan. The Insti-tute for Fiscal Studies said the proposals would increase day-to-day spending on the NHS in England by an average of 3.3% per year between 2019/20 and 2023/24, compared with the 3.8% and 3.7% offered by the Labour and Liberal Democrat parties.

“ We’ve been calling for such a fund

for years, and so the announcement

today is good news.”

– Leslie Galloway,

Ethical Medicines Industry Group

Boris Johnson is promising support for innovation after Brexit.

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E L E C T I O N S

It is quite a different beast from the Labour manifesto launched last week, which also offered health spending rises but proposed to put pressure on drug prices through wider use of compulsory li-censing and the creation of a state-run generics company, to phase out the R&D tax credit for large corporations, and to abolish the Patent Box. (Also see “UK Labour Govt Would Boost Health Spend-ing, Put Pressure On Drug Prices” - Pink Sheet, 22 Nov, 2019.)

£500M INNOVATIVE MEDICINES FUND The plan to expand the Cancer Drugs Fund into a new Innovative Drugs Fund, with an extra £160m in government funding, has re-ceived wide support from the life science industry. This would be a ring-fenced fund within the medicines budget to support access to more innovative medicines in areas like cancer or autoimmune dis-ease, or for children with rare diseases. The total in the fund would be £500m compared with £340m for the current CDF.

“Our Innovative Medicines Fund will give patients faster access to the newest and most cutting-edge treatments, said Prime Min-ister Boris Johnson. “This means that the new drugs our brilliant life sciences industry is currently developing – for Alzheimer’s, motor neurone and Parkinson’s disease and cancer – will be made avail-able to patients across the country faster.”

Mike Thompson, chief executive of the Association of the Brit-ish Pharmaceutical Industry, commented: “We are delighted to see this proposal, which is excellent news for patients. If this fund is brought in, it would help people get the breakthrough medicines they need faster and make a real difference to people’s lives.”

The BioIndustry Association said the fund would “go a long way towards ensuring that patients – and in particular those with rare diseases – are able to access the latest lifesaving medicines, as the Cancer Drugs Fund is already doing for oncology.” It would also “help to support data collection on clinical effectiveness that builds the case for these new medicines while giving patients access.”

“This will allow commercial negotiations to continue without delaying access to much-needed medication,” a BIA spokesperson said. “We hope that this new fund will send a clear signal that, de-spite Brexit, the UK can be the world leader in patient access to innovative medicines and generating real-world evidence.”

Leslie Galloway, who chairs the Ethical Medicines Industry Group, also welcomed the move, saying: “We’ve been calling for such a fund for years, and so the announcement today is good news. The commitment stands to benefit patients, the NHS and the economy.”

Details are thin on the ground at this point, though, and is not clear exactly what criteria might be used to determine which medi-cines should benefit from the new fund.

“Like virtually all manifesto commitments, the headline an-nouncement needs to be fleshed out with further detail,” Galloway said. “We look forward to working with Conservative ministers, if elected, and the NHS to translate the Prime Minister’s clear com-mitment to better access to innovative medicines into a reality. We hope other parties will make similar commitments too.”

POST-BREXIT REASSURANCESThe manifesto is liberally sprinkled with the “Get Brexit Done” slogan, together with illustrations of how a new Conservative government would “unleash Britain’s potential” once it leaves the EU. This includes commitments in the area of scientific re-search, where it promises that “we will make the UK the leading global hub for life sciences after Brexit.”

It commits to “the fastest ever increase in domestic public R&D spending, including in basic science research to meet our target of 2.4 per cent of GDP being spent on R&D across the economy,” and says the government will focus its efforts on ar-eas where the UK can “generate a commanding lead in the in-dustries of the future – life sciences, clean energy, space, design, computing, robotics and artificial intelligence.”

The BIA spokesperson said that the UK was “the third global cluster behind Boston and San Francisco, and we have the sci-ence, the people and the ambition to be the leading hub, so it is great to hear the Conservatives are ready to back our vision and work with us to achieve it.”

Some of the new spending will go into setting up a new “agency for high-risk, high-payoff research, at arm’s length from government,” although no details are given as to what this agency might actually do and how it would operate. The BIA said it would welcome any new funding to allow UK bio-tech firms to take risks and innovate, adding that “we look forward look forward to discussing the shape and function of a new funding agency with the Conservatives if they form the next Government.”

The manifesto also commits a future Conservative govern-ment to invest in “world-class computing and health data sys-tems that can aid research, such as the ground-breaking genet-ic sequencing carried out at the UK Biobank, Genomics England and the new Accelerating the Detection of Disease project, which has the potential to transform diagnosis and treatment.”

“We will use our increased R&D funding from government to attract and kickstart private investment,” it declares. “We will support international collaboration and exchange and en-sure UK teams can recruit the skills and talent they need from abroad.” The UK would also continue to collaborate with the EU on scientific research, including through the Horizon program.

On the skills front – where the life sciences industry has ex-pressed concern about the UK’s post-Brexit ability to attract the best scientists and researchers – the manifesto says there will be “special immigration routes for those who will make

“ The pledges made on education,

skills and migration will be critical for

securing the talent we need for the

future of life sciences.”

– Mike Thompson, ABPI


E L E C T I O N S

the biggest contribution. We will create bespoke visa schemes for new migrants who will fill shortages in our public services, build the companies and innovations of the future and benefit Britain for years to come.”

It promises a new National Skills Fund worth £3bn over the next parliament. “This fund will provide matching funding for individuals and SMEs for high-quality education and training.”

The ABPI said that the UK was “a world-leader in R&D for new medicines and vaccines. This manifesto puts forward an ambi-

tious agenda to strengthen our position and make sure NHS pa-tients can get breakthrough medicines faster.”

“Developing new treatments relies on having the right skills and the right experts. The pledges made on education, skills and mi-gration will be critical for securing the talent we need for the future of life sciences. “We look forward to working with any new Govern-ment to achieve our goal of making the UK the best place in the world to research, develop and use new medicines.”

OUT AND ABOUTIf the Conservatives win the election with a clear majority, Johnson will aim to get his withdrawal deal through parliament in short or-der and take the UK out of the EU by the new Brexit deadline of 31 January 2020. After “three and a half years of procrastination, we have a great new deal that is ready to go – so that we will finally be out of the EU by January 31,” the manifesto states.

If this happens, it will trigger a transition period during which time things would pretty much stay as they are while the UK began negotiations on a new trading relationship with the EU. However, as presently configured, the transition period would expire at the end of 2020, leaving just 11 months in which to complete the negotiations.

Critics have questioned the feasibility of agreeing such a

wide-ranging relationship in such a short time, saying it is likely to take many years, but the Prime Minister insists there is “bags of time” to do so.

The UK does have the option of seeking an extension to the tran-sition period beyond the end of next year, although any decision to do so would have to be taken by 1 July 2020. But the government insists this will not happen: “We will not extend the implementa-tion period beyond December 2020,” the manifesto states.

After Brexit, it says, the UK will be “able to deliver all the advan-tages of leaving the EU: making our own laws, controlling our own borders, taking back our money, and exercising all kinds of new freedoms.” It adds: “We want to move on, with our programme of investment in education, infrastructure and technology, to create a high-wage, high-skill, low-tax economy.”

The UK “will be able to remain close to our European friends and partners; but where we choose, we will be able to do things dif-ferently and better,” it declares. Industry will be hoping that doing things “differently” will not apply to the current alignment of drug regulatory standards between the UK and the EU.

The government will also need to negotiate a free trade deal with the US as well as with countries whose UK trade relation-ships are currently governed by EU deals. Some have expressed concern over suggestions that US pharmaceutical companies will be seeking higher drug prices in the UK and that US health care corporations might ask for a bigger role in the NHS as a condition for agreeing a deal favorable to the UK. (Also see “UK Gov’t Dis-owns ‘Secret’ Meetings With US On Post-Brexit Drug Pricing” - Pink Sheet, 30 Oct, 2019.)

But the Conservative manifesto says: “The NHS is not on the table. The price the NHS pays for drugs is not on the table. The ser-vices the NHS provides are not on the table.”

It says the UK will “drive a hard bargain with all of our trading partners – and, as with all negotiations, we will be prepared to walk away if that is in the national interest. We will seek to gain market access for British businesses and lower the cost of trade for them.”

Moreover, the government will “aim to have 80 percent of UK trade covered by free trade agreements within the next three years,” starting with the US, Australia, New Zealand and Japan.


“ We will not extend the

implementation period beyond

December 2020”

– Conservative Party manifesto

Intelligence with a Global Perspective

www.pharmaintelligence.informa.com



E L E C T I O N S

UK Labour Govt Would Boost Health Spending, Put Pressure On Drug PricesIAN SCHOFIELD [email protected]

T he UK opposition Labour Party has promised that if it wins the 12 December general election it will

boost health spending, abolish prescrip-tion charges, support the development of genomics and cell therapies, and ensure continued post-Brexit UK participation in EU agencies and funding programs.

But it also plans to set up a state-run generics company, use compulsory licens-ing provisions to secure access to cheaper medicines, and phase out R&D tax credits as well as the “Patent Box,” which lowers the tax companies pay on patent-derived profits. And after Brexit, it says it will seek continued close regulatory, scientific and trade ties with the EU.

The promises are contained in Labour’s election manifesto, “It’s Time for Real Change,” a sweeping set of commitments that would, if implemented, lead to a mas-sive upheaval in the political, social and fi-nancial landscape of the UK.

Party leader Jeremy Corbyn says: “La-bour will rewrite the rules of the economy, so that it works for everyone. We will re-build our public services, by taxing those at the top to properly fund the services we all rely on.” A Labour government, he claims, “will give the NHS [National Health Service] the funding it needs, end privati-sation, and never let our health service be up for grabs in any trade negotiation.”

Industry bodies gave the manifesto a mixed reception, welcoming plans to sup-port innovation in areas like cancer and dementia and to increase access to medi-cines, but warning that abolishing incen-tives like the R&D tax credit and the Patent Box, and widening the use of compulsory licensing, would remove a “powerful in-centive” to R&D investment in the UK.

HEALTH SPENDING TO RISEAmong Labour’s key promises is to increase expenditure across the health sector by an average of 4.3% a year. “This investment

enables us to end patient charges, guaran-tee the standards of healthcare patients are entitled to receive from NHS England, invest in education for the health workforce and re-store public health grants,” it declares.

The manifesto says that the experience in Scotland, which dropped prescription charges in 2011, shows that such a move would not lead to a huge upsurge in pre-scriptions. The volume of prescribed items dispensed rose in Scotland by only 3.8% from 2010/11 to 2011/12.

Scottish Government Ministers conclud-ed that it was “simply not the case that free prescriptions have led to a free-for-all, or caused a hike in prescribing,” the manifesto says. However, Labour is giving itself some room for manoeuvre on prescribing levels: “Erring on the side of caution we have bud-geted for a 5% increase.”

GIVING WITH ONE HAND, TAKING WITH ANOTHERLabour says that in its hands the NHS “will be at the forefront of the development of genomics and cell therapies so that pa-tients can benefit from new treatments for cancer and dementia, whilst ensuring the UK continues to lead in medical develop-ments.” It has also promised to raise R&D investment to 3% of GDP and to “increase jobs in the pharmaceutical industry.”

But the sector is not convinced that La-bour has its back. The Association of the British Pharmaceutical Industry welcomed the party’s “manifesto aspirations” to im-prove patient access to medicines, to be at the forefront of scientific innovation, to raise R&D investment and to increase jobs in the pharmaceutical industry.

However, it said, “we do not believe that Labour’s aspirations can be realised if mea-sures that damage the UK’s R&D ecosystem are carried out.” ABPI CEO Mike Thompson declared: “Whilst ambitions to improve patient access to medicines, increase jobs and raise R&D investment to 3% of GDP are welcome, these proposals will actively un-dermine achieving them.”

Among those proposals are phasing out the R&D tax credit for large corporations and abolishing the Patent Box during the next parliamentary term.

Labour’s reasoning – as explained in an accompanying document entitled “Fund-ing Real Change” – is that such tools do not really serve to incentivize R&D in the real world. It bases its conclusions on reports by the Institute for Innovation and Public Purpose and the Institute for Public Policy Research which, it says, “have been critical of the effectiveness of blanket tax reliefs for research and development.”

According to the Labour document, a



E L E C T I O N S

report from the IIPP said there was “little evidence” that the R&D tax credit “played a part in the decision to engage in R&D.”

But the UK BioIndustry Association criti-cized the move, saying that abolishing the tax credit scheme for large companies would “remove a powerful incentive for them to invest in R&D in the UK, which will have a knock-on effect on SMEs, universi-ties and NHS hospitals that benefit from the co-location of international companies’ R&D activity in the UK.”

It added that the Patent Box was “highly effective” in supporting R&D-intensive companies and encouraging them to “lo-cate the high-value jobs and activities as-sociated with the development, manufac-ture and exploitation of patents in the UK.”

COMPULSORY LICENSING, STATE GENERICS COMPANYLabour’s plans also include wider use of compulsory licensing and the establish-ment of a state-run generics company, an idea that was first floated at the Labour Party conference in September.

Citing the case of Orkambi as “just the lat-est example of patients held to ransom by corporations charging extortionate prices for life-saving drugs, the manifesto says: “We will establish a generic drug company. If fair prices are rejected for patented drugs we will use the Patents Act provisions, com-pulsory licences and research exemptions to secure access to generic versions, and we will aim to increase the number of pharma-ceutical jobs in the UK.”

The manifesto does not go into any detail on the proposed generics firm or what it might produce, but the idea was discussed more widely in a policy document pub-lished earlier this year.

Instead of “handing over the research to the private sector, the state should take on a more active role and produce priority drugs to sell to the NHS at affordable and acces-sible prices,” that document says. This could include manufacturing generic medicines that are facing supply or pricing issues and facilitating a straightforward enactment of Crown use licences on patented medicines where necessary.

The document cites “successful examples of publicly owned pharmaceutical compa-

nies that produce both originator and ge-neric medicines, in many countries, particu-larly middle-income countries.”

In the US, for example, it says, “Civica Rx is a new non-profit generic drug company that was launched in January 2018 to pro-duce drugs in response to the problems of shortages and high drug prices.”

In Brazil, state-owned pharmaceutical companies compete with private compa-nies, while China has a “long-standing and strong local pharmaceutical manufacturing capacity, including three major state-owned pharmaceutical companies.”

The BIA said that NHS patients and the UK economy “would both lose the chance of new life saving treatments if the UK be-comes a hostile environment for intellec-tual property.” New life-saving medicines are not just being developed by a few large pharmaceutical companies but also hundreds of innovative SMEs across the UK, the association noted.

“Labour’s proposal to use compulsory licenses risks cutting off investment in the small companies up and down the UK that are working hard to develop new treat-ments for patients that have few options.”

The ABPI agreed that “overturning pat-ents for breakthrough medicines and

phasing out R&D tax credits and the patent box would damage the UK’s research base. This underpins thousands of highly skilled jobs and helps the UK to compete on the global stage.”

It said it looked forward to “working constructively with Labour to help them develop proposals that will meet their am-bitions and help patients get access to new medicines.”

BREXITOn the UK’s departure from the EU, La-bour says it will “give the people the final say on Brexit” by securing a “sensible” deal within three months of coming to power and then putting this deal to a public vote three months after that, with a “remain” op-tion on the ballot paper.

“Labour rules out a no-deal Brexit, and we will end the scandal of billions of pounds of taxpayers’ money being wasted on no-deal preparations,” the party says. “No deal has never been a viable option. It would do enormous harm to jobs, rights, security and to our NHS.”

It says the deal would be based on prin-ciples that the Labour Party has set out over the past two years:

• A permanent and comprehensive UK-wide customs union, which is vital to protect our manufacturing industry and allows the UK to benefit from joint UK-EU trade deals, and is backed by businesses and trade unions.

• Close alignment with the Single Mar-ket – ensuring we have a strong future economic relationship with the EU that can support UK businesses.

• Continued participation in EU agen-cies and funding programs, including in such vital areas of co- operation as the environment, scientific research and culture.


According to Labour,

a report from the IIPP

found “little evidence”

that the R&D tax credit

“played a part in the

decision to engage

in R&D.”

LET’S GET SOCIAL@PharmaPinksheet



D R U G S A F E T Y

New Package Leaflets Needed For EU Drugs With Ethanol ExcipientVIBHA SHARMA [email protected]

T he European Medicines Agency has issued guidance on the information that companies should include in

the package leaflet of medicines that use ethanol as an excipient to explain the po-tential effects of the substance in children. Sponsors of affected medicines have three years to update their product information.

Ethanol may be used as a solvent, pre-servative or a cutaneous penetration en-hancer in medicines. Although human exposure to ethanol through medicines is usually low, the EMA points out that there has been no evaluation of the effect of long-term exposure to even low levels of ethanol in medicines on the health and de-velopment of children.

As excessive consumption of alcoholic beverage during pregnancy can result in fetal alcohol syndrome, this raises the con-cern “that there is at least, in theory, a risk to development from chronic exposure to ethanol during childhood,” the agency said.

In neonates especially, elevated levels of the metabolite acetaldehyde have been observed after exposure to ethanol from medicines. Moreover, in neonates, cuta-neous absorption of ethanol is significant, which may lead to significant local reac-tions (such as hemorrhagic skin necrosis) and systemic toxicity.

The new guidance contains recommen-dations on how sponsors should present information about the risks of ethanol, es-pecially in children, on the drug’s package leaflet. It requires that the warnings should be based on each dose rather than daily ex-posure, and suggests three levels of warn-ing depending on the exposure – below 15mg/kg/dose, 15mg to less than 75mg/kg/dose, and 75mg/kg/dose and above.

As the skin of neonates is more perme-able to ethanol than adult skin, sponsors are required to include information on sig-nificant local reactions and systemic toxic-ity where neonates are exposed to cutane-ous ethanol.

THREE YEARS TO UPDATE PACKAGE INFOThe EMA guidance was drawn up in the context of the revised annex to the Eu-ropean Commission’s guideline on “Ex-cipients in the label and package leaflet of medicinal products for human use.” The an-nex contains a list of all excipients known to have a recognized action or effect that needs to be displayed on the label of any medicine authorized in the EU.

The EMA published the updated an-nex on 22 November to include informa-tion on ethanol. The updated annex came into effect immediately and requires spon-

sors of affected medicines to update their product’s package information.

For medicines already authorized, the EMA suggests that sponsors should use the first available opportunity to imple-ment the wording in compliance with the revised annex. For medicines with no fore-seeable regulatory submissions, compa-nies should submit a Type IB variation ap-plication within three years of the revised annex being published.

MORE GUIDELINES ON OTHER EXCIPIENTSThe EMA is also drawing up similar guidelines for the labeling of medicines that have dextrans, proline, lactose or polysorbates as excipients. The draft ver-sions of these guidelines have already been prepared and were adopted by the EMA’s drug evaluation committee, the CHMP, for a six-month consultation, as per the minutes of the CHMP’s Septem-ber meeting.


Due in three years, the

updated leaflets should

include information on

the potential effects of

ethanol in children.



M A R K E T I N G & A D V E R T I S I N G

COMPARATIVE CLAIMS: CFL Guidance Gives Opening; OPDP Research May Close ItSUE SUTTER [email protected]

T he US Food and Drug Administra-tion’s “consistent with labeling” fi-nal guidance has opened the door

wider for biopharma manufacturers inter-ested in making comparative promotional claims, but companies nevertheless are moving cautiously across the threshold.

That was the consensus of legal experts during a panel on the FDA’s evolving ap-proach to comparative claims at the Food and Drug Law Institute’s recent meeting on medical product advertising and promotion.

The experts generally agreed that com-parative safety claims pose a greater en-forcement risk than efficacy claims, and they highlighted some presentation formats like-ly to draw attention from regulators.

They also suggested the FDA Office of Prescription Drug Promotion’s current re-search agenda eventually could lead to restrictions on companies’ ability to make comparative promotional claims as more data are developed on consumers’ ability to understand such claims.

CFL GUIDANCE ‘OPENS THE DOOR’ TO DISCUSSIONThe agency’s June 2018 final guidance on medical product communications that are consistent with FDA labeling (known by the acronym CFL) spelled out a three-fac-tor test to determine if a communication presents information that is not specifi-cally contained in, but is consistent with, the FDA-required labeling. (Also see “’Off-Label’ Communications That Are Still ‘Con-sistent’ With Labeling Get Better Defined” - Pink Sheet, 12 Jun, 2018.)

The final CFL guidance retained the “scientifically appropriate and statistical-ly sound” evidentiary standard for data and studies to support representations made in communications, as spelled out in an earlier draft guidance, but included more examples of the kinds of informa-tion that could be consistent with FDA-required labeling.

The guidance was viewed as an effort by the agency to navigate unfavorable First Amendment case law without opening the door entirely to off-label promotion. (Also see “Learning To Love The “CFL”: US FDA’s New Communication Policy” - Pink Sheet, 5 Aug, 2018.)

FDLI panel moderator Coleen Klasmei-er, a partner in the Washington, DC office of Sidley Austin, said the FDA’s issuance of the CFL guidance was “truly a revolution-ary moment” and questioned whether sponsors’ promotional review commit-tees are now giving the go-ahead for comparative claims that previously might have been regarded as too risky.

Justin Drinkwine, corporate counsel at Jazz Pharmaceuticals PLC, said the guid-ance does not give companies “carte blanche” to do whatever they want with comparative claims or with data outside the label.

“I think it opens the door just enough for where now we can have the discus-sion” about a comparative claim, he said.

However, “I don’t think we’ve gotten quite comfortable” making such claims in

the absence of a well-controlled, head-to-head trial that was powered to measure either noninferiority or superiority against a competing product, Drinkwine said.

Companies may want to seek recon-sideration of OPDP advisory opinions on particular comparative claims when those opinions were issued prior to the final CFL guidance’s release, the panelists said.

“I would imagine there are plenty of companies that have reached back out to the agency to re-evaluate advisory com-ment,” Drinkwine said. “I would have to imagine there might also be companies who are doing their own analysis and say-ing that the advisory comment was issued under a prior framework, and now that CFL has been issued we’re free to move forward and we’ll sort of take our chances that the agency agrees that their advisory comments no longer apply.”

The CFL guidance’s “scientifically ap-propriate and statistically sound” standard also has necessitated getting biostatisti-cians more involved in the promotional review process, panelists said.

MINIMIZING SAFETY IS RISKING ENFORCEMENTDespite the opening provided by the CFL guidance, some comparative claims are just never going to pass muster with the agency, panelists said.

Promotions that assert comparative safety claims present the highest risk of enforcement, said Dara Katcher Levy, a di-rector at Hyman, Phelps and McNamara in Washington, DC.

She pointed to the agency’s September warning letter citing a violative promotion-al email for Galt Pharmaceuticals’ insomnia drug Doral (quazepam). (Also see “Warning Letter: New Sponsor, Same Violative Promo-tional Practices For Insomnia Drug Doral” - Pink Sheet, 26 Sep, 2019.)

The agency said the promotion mini-mized risk, including by omitting the

The CFL guidance’s

“scientifically appropriate

and statistically sound”

standard has necessitated

getting biostatisticians

more involved in the

promotional review

process.




warning and precaution regarding ben-zodiazepine withdrawal syndrome. OPDP also took issue with a bar chart showing the “relative likelihood of abuse” of various products, and statements asserting that quazepam is less likely to be abused than other prescription sleep aids and even over-the-counter drug diphenhydramine.

“When you think about comparative claims and you think about relative risk of making the comparative claim, I would say that if you are minimizing your safety infor-mation in any way, if you are suggesting that you are safer to an OTC product that otherwise is generally recognized as safe and effective … that inherently may mini-mize risk,” Levy said. “I think the overall con-text needs to be taken into consideration.”

Drinkwine noted that while the CFL guidance provides a framework for ana-lyzing claims consistent with labeling, it also reiterates that claims cannot be misleading.

The Galt letter is “one of those sort of easy bar graph, pie chart claims that puts a bunch of products in line and ei-ther selects attributes or selects relative risk,” Drinkwine said. “I think even with disclaimers those are just something FDA disfavors.”

When it comes to comparing product characteristics, simpler is not always bet-ter from an enforcement perspective.

“The simpler the graphical represen-tation, the riskier it is,” Drinkwine said. “That’s maybe the reason why the mar-keting or the commercial folks like it, because it distills down three or four at-tributes that your product has that two others don’t.”

However, “the simpler you make it in terms of cherry-picking, the more risk you are at leaving something out which might be considered a negative for your product,” Levy said.

Nevertheless, Levy said there are some types of comparative claims that are de-fensible, such as differences in dosing convenience, route of administration, storage requirements, indicated popula-tion and drug-drug interactions.

“I think it’s fair to point out different fea-tures,” Levy said. “Marketing oftentimes doesn’t want to lead the horse to water, it

wants to just make it drink, it wants to get you right there. And I think when you start getting into clinical outcomes as a result of those differentiated features, that’s when you start getting into a different territory.”

FDA’S STEP BACK MEANS A STEP UP IN PRIVATE LITIGATIONIn the wake of several high-profile losses in First Amendment cases, the agency has said it is focusing its promotional enforce-ment efforts on violations involving public health and safety, and it is willing to let competitors “duke it out” in disputes over marketing and comparative claims. (Also see “Advertising Enforcement: US FDA Con-tent To Let Competitors ‘Duke It Out,’ Wood-cock Says” - Pink Sheet, 23 Sep, 2018.)

With the FDA taking itself out of the picture except for in the most egregious cases, companies increasingly are bring-

ing private actions under the Lanham Act and unfair competition laws.

Two such cases have been filed by, and against, big pharma companies in 2019.

In a March lawsuit, Novartis AG as-serted Janssen Pharmaceutical Cos.’ mar-keting material describing the results of a head-to-head study of its Tremfya (guselkumab) versus Novartis’ Cosentyx (secukinumab) omitted adverse events, suggesting Tremfya is safer for treating psoriasis. (Also see “Novartis Can’t Halt Janssen’s Promo Comparing Their Psoriasis Drugs“ - Pink Sheet, 5 Mar, 2019.)

A federal judge rejected Novartis’ re-quest for a temporary restraining order blocking Janssen’s distribution of the material at a medical meeting, and the two companies subsequently settled. (Also see “Novartis Settles Short-Lived Suit Over Janssen’s Psoriasis Drug Promo” - Pink Sheet, 28 Apr, 2019.)

On 12 November, GlaxoSmithKline PLC sued Boehringer Ingelheim International GmbH over its marketing campaign for the Respimat inhaler. The lawsuit alleged the promotions convey false and mislead-ing claims that GSK’s Ellipta and Diskus dry powder inhalers are not effective for patients with more severe breathing dif-ficulties and are more difficult for such pa-tients to use than other inhalers. (Also see “GSK Seeks To Halt Boehringer Promos That ‘Denigrate’ Effectiveness Of Ellipta, Diskus Inhalers” - Pink Sheet, 14 Nov, 2019.)

Drinkwine said he can appreciate the agency does not want to get involved in the petty back-and-forth between two companies over market share and rev-enue. Nevertheless, “if there are compara-tive claims that are in any way minimizing the safety or potentially putting public health or patients at harm, I think that’s a definite role for the FDA, and I don’t think they’re ever going to back down on their responsibility to ... make sure that compa-nies are updating doctors and patients on the safe use of medicines.”

“I think any time you overall may be seen as minimizing risk, you are inviting enforcement,” Levy said. “Those are con-versations that we have had and being judicious about where we would want to push the envelope.”


“If you are a deeply

paranoid human being

looking at the OPDP

research agenda, you

might think … what

could these data do

in terms of informing

a policy initiative at

FDA that could result

in reviving that stayed

regulation, which would

drive all comparative

claims through an

sNDA process?”

– Sidley Austin’s

Coleen Klasmeier


OPDP RESEARCH AGENDABoth the FDA and industry are doing a lot of cognitive research to better understand how consumers digest information about prescription drugs, and the results of this research could inform enforcement and fu-ture agency guidance, panelists said.

OPDP’s website lists 33 completed re-search projects investigating direct-to-consumer and professional Rx drug ad-vertisements, with another five studies pending peer review and publication and 12 in progress. (Also see “Do Consumers Understand TV Ads For Oncology Drugs?” - Pink Sheet, 25 Jun, 2019.)

OPDP has a “very ambitious research agenda” that “touches on issues that are highly relevant to comparative claims, in-

cluding the standard for consumer take-away, the ways in which risk and benefit information are presented in drug com-munications,” Klasmeier said. “There is the potential for that research agenda to gen-erate a whole host of data that could sup-port restrictive regulation aimed directly at comparative claims.”

Klasmeier suggested OPDP’s research could lead to a revival of 1979 regulatory provision, which was indefinitely stayed and subsequently amended, that would have prohibited comparative claims in Rx drug advertising unless they were set forth in labeling.

“If you are a deeply paranoid human be-ing looking at the OPDP research agenda, you might think … what could these data

do in terms of informing a policy initiative at FDA that could result in reviving that stayed regulation, which would drive all comparative claims through an sNDA pro-cess?” Klasmeier said.

Drinkwine said that if OPDP’s research produces “a lot of data that consumers or even doctors cannot digest comparative claims, it always implies that one is better than the other, then that might put an end” to such promotional claims.

“The more data that’s out there it could help, but it also could become really re-strictive where FDA says look no one’s un-derstanding what you’re doing and here’s the data to back it up,” Drinkwine said.



EU Parallel Trade ‘Alleviates Shortages’ Says New EAEPC President IAN SCHOFIELD [email protected]

A s the debate over high prices and medicines shortages continues to rage, Jörg Geller, CEO of Kohlphar-

ma, has said that parallel trade is “the key” to driving down prices and can also serve to mitigate drug supply problems.

Speaking after his election as president of the European parallel traders’ association, the EAEPC, Geller said that in the past four decades parallel distribution had become “more and more a significant player in the fight for better affordability of and thereby access to medicines all over Europe.”

Geller claimed parallel trade activ-ity helped to inject competition into the EU market, thereby driving down prices and saving health care systems money, and that it also helped to prevent drug shortages in EU countries.

“Recent studies indicate that parallel dis-tribution in the Single Market, as the only price competition in the field of patent pro-tected and prescription pharmaceuticals, is the key to save patients and healthcare sys-tems money. By working in parallel we sim-

ply offer the better deal,” he declared.Europe, he said, was “facing both access

and affordability problems like never be-fore.” In the coming years his sector would “continuously show its value by importing into all member states,” bringing savings and “alleviating shortages for all Europeans.”

The EAEPC’s argument is that parallel trade can “provide alternative supply sourc-es in case of shortages” – an assertion that has been disputed by the European phar-maceutical industry, which claims that par-allel exporting actually creates shortages in some markets.

The EAEPC, though, insists that the blame for shortages lies at the door of pharma firms who fail to meet their supply obligations. The association also recently criticized what it called a lack of transpar-ency on the part of the UK government, which has drawn up a list of medicines that cannot be parallel exported in an effort to prevent shortage problems. (Also see “UK Adds MMR Vaccine To Export Ban List” - Pink Sheet, 6 Nov, 2019.)

As well as heading up Kohlpharma, one of the EU’s largest parallel importing com-panies, Geller is a member of the board of one of the EAEPC’s German national bod-ies, VAD, and has taken “an active role in the development and promotion of the sector both in Germany and in the EU,” the association said.

He succeeds Richard Freudenberg, who has held the post of EAEPC president since 2013. Freudenberg played a key role in getting parallel distribution included in the scope of the EU’s Falsified Medicines Directive and giving the sector a role in creating the European Medicines Verifica-tion System, which came into operation in February this year.

The EAEPC has member associations in 23 European Economic Area countries, and more than 120 companies covering 85% of the EU parallel import market. It says paral-lel distribution has a 2.5% share of the total European medicines market.


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