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Conference Insights

Reporting Adverse Events

in-depth report from an SMi Conference

held in London, 24–25 April 2006

by Dr Richard KH Wyse

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Reporting Adverse Events:in-depth report from an SMi conferenceDr Richard KH Wyse

Executive summaryThese are challenging times for drug safety professionals. Much is to be done within the profession to gain and maintain public trust by improving drug safety, pharmacovigilance and risk management practices. In the USA, drug-related adverse reactions (ADRs) result in an estimated 100,000 deaths per year, and up to 5% of all hospitalisations involve some of the most widely prescribed drugs. Less than 10% of ADRs are currently reported back to the manufacturer or the regulatory authorities.

Mandatory legislation changes have altered the landscape on both sides of the Atlantic. Product safety is a key element, and the clinical trial process is now more highly regulated. These changes cover applications to ethics committees, clinical trial study monitoring, adverse event reporting during trials, clinical practice audits and inspections, and preparing for marketing authorisation of products. The European Union (EU) Clinical Trials Directive has had a great impact on post-marketing surveillance. It introduced two new terms to the pharmacovigilance vocabulary: SUSAR (a suspected unexpected serious adverse reaction) and SAR (a serious adverse reaction). The pharmacovigilance requirements of the Food and Drug Administration are also evolving, especially in the areas of electronic submissions, pre-marketing safety assessment plans and risk management.

The SMi Reporting Adverse Events conference discussed various tactical and transactional aspects of safety, providing an overview of strategic aspects of risk assessment and risk management. This Conference Insights review provides analysis of the most salient issues raised in selected presentations at the event. These included electronic reporting, signal detection, high-profi le drug withdrawals, drug risk–benefi t assessments, the implementation of risk management and a glimpse into future developments.

Industry professionals are currently being forced to react to changing regulatory requirements, internal company integration and public/political pressures. This report highlights how the industry is addressing these evolving needs. It concludes that drug safety groups should play a more prominent role not only in the procedures mentioned above but also in strategic aspects of risk–benefi t optimisation.

Contents

Reporting Adverse Events – Programme 4Introduction 6About the author 6Background 7Current legislative environment – EU 7 – USA 11Safety risk management and clinical development 14Prominent drug safety issues change FDA and industry practices 17

Global aspects of adverse event reporting 20Role of Eudravigilancein drug development 21RxWise: effective ADR avoidance by complete medication safety checking 22The future of pharmacovigilance in Europe 23Conclusions 25References 25

4 Wyse RKH. Reporting Adverse Events. September 2006. www.KeywordPharma.com

Day oneChairperson:Dr Sean Zhao, Director, Global Safety, Pharmacoviligance, Amgen, USA

IMPACT OF THE CLINICAL TRIALS DIRECTIVE: Post May 2004Dr Dipti Amin, Senior Vice President, Clincial & Scientifi c Operations, Medical Affairs, QuintilesCHANGES IN REGULATORY THINKING AND ACTIONS: Lessons from the front linesDr Kenneth Hintze, Director, Global Safety & Pharmacoviligance, KendleROLE OF EUDRAVIGILANCE IN DRUG DEVELOPMENTGurdyal Kalsi, Director, Medical Affairs, MDS Pharma ServicesTHE FDA’S ADVERSE REPORTING SYSTEM: An adequate surveillance system for approved drugs?Dr Sven Knudsen, Life Sciences Statistical Consultant, Insightful LtdA COMPREHENSIVE NEW MEDICATION SAFETY CHECKING TOOL THAT UNIQUELY EMPOWERS CONSUMERS, PHYSICIANS AND PHARMACISTS ACROSS THE ENTIRE PRESCRIPTION, OTC & HERBAL SPECTRUMDr Richard Wyse, Chairman, Economic Healthcare Associates, UKREPORTING ADVERSE EXPERIENCES FOR COMBINATION PRODUCTS: Work in progressMason W Diamond, DDS, Vice President, Clinical & Regulatory Affairs, Tyrx Pharma

AGGREGATE ADVERSE EVENT REPORTING AND DRUG SAFETY RISK MANAGEMENT TOOLSJennifer Markey, Vice President, Practice Management, Intrasphere Technologies

John Whitebrook, Vice President, Pharmaceuticals, Intrasphere Technologies

COLLECTION, MANAGEMENT, DISTRIBUTION AND ANALYSIS OF SUSPECTED ADVERSE DRUG REACTION INFORMATION: What are the reporting requirements for adverse drug reactions for all products reported in the EU?Simon Sparkes, Vice President, Global Sales & Marketing, ArisGlobal

GLOBAL ADVERSE EVENT REPORTING: How reporting and regulatory requirements vary country to countryDr Livia Stankovics, Affi liate Pharmacovigilance Head, Sanofi -Aventis

Day twoChairperson: Dr John Ferguson, Vice President, Pharmacovigilance, Millennium Pharmaceuticals

SAFETY DATA REPORTING IN ELECTRONIC SUBMISSIONSGuy Pawson, Manager, Electronic Submissions, Genentech

SIGNAL DETECTION: The most important objective of pharmacovigilanceDr Tjeerd-Pieter Van Staa, Head, Research, General Practice Research Database, Medicines & Healthcare Products Regulatory Agency (MHRA)

GLOBAL PRODUCTS SAFETY: Shielding products from riskDr Sean Zhao, Director, Global Safety, Pharmacovigilance, Amgen, USA

SAFETY RISK MANAGEMENT AND CLINICAL DEVELOPMENT: A product life cycle perspectiveDr Joanna Haas, Vice President, Pharmacovigilance, Genzyme

RISK MANAGEMENT PRINCIPLES TO PHARMACOVIGILANCE: Securing the safety of productsDr John Ferguson, Vice President, Pharmacovigilance, Millennium Pharmaceuticals

PV QUALITY ASSURANCE: Case study – PV QA tools and techniques implemented by large pharmaceuticalsBrian Dinardo, Partner, Drug Safety Group, LLC

TOOLS TO HELP MINIMISE RISK IN PHARMACOVIGILANCE: Developing a risk conscious environmentProfessor Ragnar Lofstedt, Director, King’s Centre for Risk Management

FUTURE OF PHARMACOVIGILANCE IN EUROPE: What will happen next?Dr Birgitt Gellert, Drug Safety Manager, Bayer Vital

Reporting Adverse Events – ProgrammeOrganised by SMi, London, 24–25 April 2006


Introduction

The pharmaceutical congress on Reporting Adverse Events, held in London 24–25 April 2006, and organised by SMi, brought together speakers and delegates from a wide range of pharmaceutical companies and Contract Research Organisations (CROs). Many of these speakers have direct responsibilities for safety and pharmacovigilance within their companies. This conference update proved an excellent and timely review of how companies are now dealing with new US and EU drug safety legislation, and the changing commercial demands, in the face of a progressively more diffi cult regulatory, public and political environment.

How companies now try to assess the risk–benefi t of their drugs, and the development of risk management systems, were topics that recurred throughout the conference. It was clear that the search for industry best practices was still ongoing. Achieving adequate adverse-event signal detection emerged as a major public health issue, especially in the light of recent expensive, high-profi le drug withdrawals, and one that can have massive leverage on company profi tability. There was therefore an underlying theme that drug safety groups within companies should enjoy a much higher profi le and a more prominent role in the strategic aspects of risk–benefi t optimisation of products.

Advances in technology and data harmonisation were also recurring themes. The conference highlighted recent improvements in the use and availability of safety data for both physicians and consumers, which will mean that avoidable adverse drug reactions can be greatly reduced by providing the right drug safety information to doctors and patients, in the right context, at the right time.

Dr Richard WyseSeptember 2006

About the author

Formerly senior lecturer in paediatric cardiology at Great Ormond Street Hospital in London, he now has joint commercial and academic careers. He is the author of over 100 medical and scientifi c papers, and pharmaceutical industry articles in journals. He has also written four industry books, and several independent evidence-based medicine reports in various therapeutic areas. Commercially, he has worked for a CRO as Director of European Health Economics, and as Medical Director for a US pharmaceutical IT company and a medical device company. He has been involved in a wide variety of industry clinical trials and several other areas of drug development for many years. Academically, he is currently a visiting professor in Saudi Arabia, an active member of the Association for Research in Vision and Ophthalmology and President-Elect of the Division of Genetics at the Royal Society of Medicine. He is on the editorial board of several journals. He has spoken at many academic and international pharmaceutical and medical device conferences, and has chaired 25 of them. Notably, he was global chairman of a major cardiac patient database initiative that involved 2700 hospitals worldwide, speaking at national conferences in a large number of fi rst- and third-world countries. In this capacity he reported a landmark paper on risk prediction and outcomes in >600,000 US patients.

Richard can be contacted at [email protected]


Background

These are extremely challenging times for drug safety professionals. Both in Europe and the USA, politicians are regularly raising issues fed by public concerns regarding safety that are aired in the media on an almost daily basis. Much is to be done internally within the profession to gain, then maintain, public trust by improving drug safety, pharmacovigilance and risk management practices. In addition, mandatory legislation changes have recently altered the landscape on both sides of the Atlantic. With the EU Clinical Trials Directive having been implemented on 1 May 2004 there have been a variety of changes in the way clinical trials are conducted and monitored throughout Europe. Product safety is a key element in this, and the clinical trial process is now much more regulated from this perspective. These changes cover applications to ethics committees, clinical trial study monitoring, data management in clinical trials, adverse event reporting during clinical trials, good clinical practice (GCP) audits and inspections, and preparing for authorisation of the product.

The EU Clinical Trials Directive also has a great impact on post-marketing surveillance. This is essential to ensure the continued patient safety of a product since, without adequate surveillance in place, the product risk–benefi t profi le cannot be properly assessed and/or managed.

In the USA, Food and Drug Administration (FDA) requirements are also evolving, especially in the area of electronic submissions, pre-marketing safety assessment plans and risk management. In the USA, drug-related ADRs result in an estimated 100,000 deaths per year. Up to 5% of all hospitalisations worldwide are due to ADRs, with some of the most common, widely prescribed drugs involved (warfarin, alpha- and beta-blockers, angiotensin-converting enzyme inhibitors and non-steroidal anti-infl ammatory drugs [NSAIDs], as well as polypharmacy). Despite this, however, less than 10% of ADRs are actually reported back to the manufacturer or the regulatory authorities because most of the reporting systems used globally are voluntary. Therefore, because ADRs represent a signifi cant cause of iatrogenic disease, extensive resources are currently being devoted by industry to improve pharmacovigilance. From the perspective of the understanding and delivery of healthcare, there is currently still a serious disconnection, both at the physician and consumer levels, between the availability of safety information and the integration of its effective use. But times are now changing.

In the USA, drug-related adverse reactions (ADRs) result in an

estimated 100,000 deaths per year

All these issues were discussed at the SMi conference Reporting Adverse Events. Day one concentrated on various tactical and transactional aspects of safety, whereas Day two gave a comprehensive overview of strategic aspects of risk assessment and risk management. These included electronic reporting, signal detection, the context of safety in the global environment, the implementation of risk management and the ever-changing risk minimisation toolbox, followed by an interesting glimpse into future developments.

Current legislative environment

EU

Dr Dipti Amin (Quintiles) described the impact of the EU Clinical Trials Directive on adverse event reporting. Now 2 years post-implementation, Amin reported that the Directive was fairly well understood by most industry professionals, and therefore opted to outline only its basics, while also describing how pharmacovigilance is incorporated within the Directive. She focused more comprehensively on some of the important issues that have emerged in the 2 years since the implementation of the Directive. The salient points of her presentation are outlined below.

Legislative framework for pharmacovigilance in EuropeThe EU defi nition of pharmacovigilance is “the collection and scientifi c evaluation of ADRs under normal conditions of use for regulatory purposes. It includes the collection of data on drug consumption as well as use, misuse and abuse.” Within Europe there are a number of regulations and directives that govern pharmacovigilance. Amin chose to concentrate on the EU Clinical Trials Directive 2001/20/EC,1 which came into force on 1 May 2004. This Directive describes the legal basis for pharmacovigilance and GCP obligations within clinical trials (Table 1). Although industry professionals often struggle with the bureaucracy that accompanies this Directive, Amin urged critics to realise that it is fundamentally designed to try to protect the rights, safety

Reporting Adverse Events:in-depth report from an SMi conference


and well-being of patients and study participants, as well as to try to get good clinical data from trials.

The EU Clinical Trials Directive 2001/20/EC is designed to

try to protect the rights, safety and well-being of patients

and study participants

It is important to understand that this is an EU directive, which is quite different from an EU regulation. All countries within the EU have the autonomy to interpret a directive in a country-specifi c way, whereas regulations need to be enforced exactly as written. As a result, there are variations in the actual requirements that each of the countries has adopted for their own pharmacovigilance reporting.

In April 2004, the EU Commission published detailed guidance (ENTR/CT52) on how to collect, verify and present adverse events in clinical trials concerning the investigation of medicinal products for human use. Responsibilities are loaded towards the sponsor; Section 5 of this publication comprises three paragraphs on the responsibilities of the investigator, whereas Section 6 has nine pages on the responsibilities of the sponsor. The investigator needs to make sure all adverse events are reported to the sponsor promptly and fully, and provide all information that the sponsor requests. All other responsibilities reside with the sponsor.

The principles of clinical safety in Europe are that public health and public safety are addressed as thoroughly as possible. In an environment where drugs are widely prescribed, the only system currently available in the USA, Europe and Japan is pharmacovigilance. These principles also serve to inform healthcare professionals and thus improve their knowledge of prescribing, and where safety and risk profi les are changing. Whereas these principles represent a requirement for regulatory compliance, a good pharmacovigilance system that sets high standards also enhances a company’s reputation.

The EU Clinical Trials Directive introduced two new terms:

SUSAR – a suspected unexpected serious adverse reaction, which occurs when the ADR itself is not consistent with information already available in the relevant company product information. Information

•

‘already available’ is defi ned as either what is already available in the investigator’s brochure or, for a marketed product, in the summary of product characteristics. A known adverse reaction that is reported at a different severity is considered to be an unexpected adverse reaction.

SAR – a serious adverse reaction, defi ned as an adverse reaction that:

results in deathis life threateningrequires inpatient hospitalisation or the prolongation of existing hospitalisationresults in persistent or signifi cant disability or incapacityis a congenital anomaly or birth defect.

Any one of these events independently qualifi es as an SAR.

The Directive now newly includes phase I studies, and also pivotal studies such as bioavailability and bioequivalence. Because the Directive is independent of marketing status it also includes phase IV studies if they are interventional (i.e. if any part of patient treatment or normal care is altered in order to conduct the trial then any associated adverse events must be reported to the regulatory authorities).

All SUSARs occurring during a trial have to be submitted as an expedited report within 7–15 days (within 7 days for any death). Annual reports must be sent to competent authorities in all countries involved in the trial, and ethics committees now also receive unblinded expedited reports. The sponsor must, by law, keep detailed records of adverse events, and has to evaluate seriousness, causality and how expected were these adverse events. A safety summary must also be included, representing a critique of the observed adverse events and what this means to the safety of patients who still remain on the trial, as well the relevance to later prescribing.

All SUSARs occurring during a trial have to be submitted as an

expedited report within 7–15 days (within 7 days for any death)

The European Agency for the Evaluation of Medicinal Products (EMEA) prefers to receive all reports electronically through specifi ed partners. Expedited reports must include any SAR or SUSAR that occurs within the trial, or in any other trial conducted elsewhere by the same sponsor on the same compound. They must also include any reports of adverse events that occur spontaneously from any source and that have just come to the attention of the sponsor, even in recently published animal studies. It is also a requirement to report any signifi cant adverse report that the sponsor discerns from

•

•••

•

•

Article 2 Refers to defi nitionsArticle 16 Refers to notifi cation of adverse eventsArticle 17 Refers to notifi cation of serious adverse reactionsArticle 18 Gives guidance concerning adverse event

reporting

Table 1. Key sections of the EU Clinical Trials Directive 2001/20/EC that particularly pertain to pharmacovigilance.


the literature; this might typically be an adverse event that has just been reported within a recently published study on a marketed drug by an independent investigator. Also to be included in an expedited report are any issues that might materially alter the current known risk–benefi t of the compound, the way it might be administered and anything that may suggest a change in the overall way the trial is being conducted. Latent events must also be reported: even if a patient has completed a study any subsequent SUSARs must still be reported. Lack of effi cacy would also be regarded as a signifi cant, reportable hazard if patients in the trial had a life-threatening disease under treatment. Additional adverse event reports must be sent (with no mandatory timescale, except in Germany) to all investigators; these reports must remain blinded. In practice it is encouraged that they should be sent out to investigators as soon as possible since such reports may affect their own management of the patients.

Different levels of implementation of the EU Directive across the 28

EU countries have caused practical diffi culties in the way reporting is handled by sponsors and CROs

EU country differences in reporting adverse eventsMost of the EU member states – Austria, Belgium, Denmark, Finland, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden and the UK – have now implemented the Directive. Currently, of the members, only France still has not. There was also fairly rapid implementation in most of the accession countries that were accepted into the EU in 2004 (Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Slovakia and Slovenia). The three additional European Economic Countries – Liechtenstein, Iceland and Norway – have also signed up to the Directive. However, there have been different levels of implementation of the Directive across the 28 countries, and this has caused practical diffi culties in the way that reporting has been handled by sponsors and their CROs. Some countries have continued to follow the old processes, whereas others have asked for more than just SUSARs to be reported. Likewise some countries do not want reports to go to their ethics committees, whereas others have asked for blinded reporting to the ethics committees to continue.

The EU country differences in reporting adverse drug events cause logistic diffi culties, and sometimes a great deal of additional work for sponsors and CROs. Italy wants all adverse events reported to all ethics committees in Italy; Amin said this can be a diffi cult task if a sponsor has numerous investigator sites across a country. Denmark does not require any adverse events to

be reported back to ethics committees. Greece requires only SARs that occur in Greece to be reported, and Finland will take a similar stance to Greece once the Eudravigilance Database is implemented (see page 10).

Issues surrounding the appropriate blinding and unblinding of studiesThe potential unblinding of data surrounding an adverse event has wide implications if not carried out appropriately. The implementation of the new EU Directive has required industry to rethink how the practicalities of this issue should be addressed. The goal of a clinical trial is to provide data on the safety and effi cacy of an experimental drug. A good clinical trial must therefore minimise bias, which is why much effort is put into patient randomisation and the appropriate blinding of studies. The earlier GCP regulations state that, if it is necessary to unblind, the investigator should document and explain to the sponsor any premature unblinding, whether accidental or due to an SAR. They also state that appropriate personnel should be unblinded only when data are clean to an acceptable level of quality, and ask for adequate standard operation procedures (SOPs) to guard against the inappropriate dissemination of treatment codes. Thus, for many years the regulatory authorities have taken a very serious view about keeping data blinded appropriately. The new EU Directive is completely in line with these earlier GCP regulations, stating that, where possible and appropriate, investigators must be kept blinded and, although they need to be told about any SUSARs, they should be informed in a blinded manner. The implication is that if there is any inappropriate unblinding then the regulators may not accept the data at the end of the study. This may have a consequential impact on whether the marketing authorisation application is accepted.

Although investigators need to be told about any SUSARs,

ideally, they should be informed in a blinded manner so as not to invalidate the trial

In practice, whilst reporting SUSARs blind to the ethics committees is a requirement, the risk is that some companies are sending these through the investigator – thus unblinding the investigator. Furthermore, when clinical teams are handling adverse events there is a risk of people involved in analysing the data becoming unblinded. According to Amin, one of the ways to get around this is simply to keep the central ethics committee informed. If local ethics committees need to be informed (as is the case in the UK) then send them only blinded data while sending unblinded data to the central ethics committee. However, some countries (e.g. Germany and Hungary) require SUSARs


to be sent rapidly, and there have been cases when pharmaceutical sponsors have sent unblinded data to the investigators in order to meet these expedited timelines. Their rationale is that the safety aspect is important, so some sponsors feel they should let the investigators know quickly in order to comply with the regulations. The wider risk, however, is that the entire trial may be invalidated. To prevent investigators, and various teams within the company, becoming inappropriately unblinded in such circumstances, it is clear that the entire adverse event fl ow process, including how the data are actually unblinded quickly yet appropriately to meet the timelines, needs to be thought through carefully and revised. Consequently, many companies have now chosen to organise the information fl ow so that blinded and unblinded data are handled completely separately. Safety personnel unblind the data and enter them into a safety database. Only safety personnel handle unblinded data. Access to the safety database is limited to very few personnel. The safety database is confi gured to be able to produce both blinded and unblinded listings. When SUSARs need to be sent to an investigator, this task is undertaken by the safety personnel unless these are blinded SUSARs, in which case the clinical team may be involved. Where possible, even blinded SUSARs are handled just by the safety team as this decreases the risk of any unblinded data going out to an investigator in error.

Eudravigilance DatabaseThe Eudravigilance Database is the European data processing network and database management system. Amin explained how the Database represents a process for exchanging adverse reactions between the sponsor and the regulatory authorities, enabling the EMEA to make these available to all competent authorities that are

members of the EU and the EU Commission. Belgium, Denmark, Cyprus, Czech Republic, Finland, Lithuania, Norway and Poland are now accepting electronic reports, whereas the remainder of EU countries still use a paper-based format.

The Eudravigilance Database represents a process for

exchanging adverse reaction information between the sponsor

and the regulatory authorities

Pharmacovigilance inspections in EuropePharmacovigilance inspections have been common for many years but are now defi ned within the EU Directive. It is now a legal requirement for the regulatory authorities to have inspection programmes specifi cally relating to adverse events and the reporting process surrounding them. In the UK these inspections started in mid 2004 and are carried out by the Medicines & Healthcare products Regulatory Agency (MHRA) (Table 2).

The MHRA is very focused during its inspections, especially in the post-Vioxx era (more information on Vioxx is given on page 18), in the emerging areas of trend analysis and signal generation. Also important are the product complaint and recall procedures, how pharmacovigilance staff are trained, and how clinical staff are trained in adverse event issues and how to deal appropriately with investigators. Contractual agreements with any co-marketing partners, and with any contractors (such as CROs) who might be handling adverse event information on behalf of the company, are also inspected. In addition, the MHRA:

looks at the validation of pharmacovigilance systems, IT support systems, and the requirements of being compliant with audit trails

investigates whether the company has a process of quality assurance that ensures that the company’s practices will remain up to date with local and global requirements

assesses whether there is an adequate process for archiving safety data.

Impact of the EU DirectiveDespite the diffi culties of practical implementation that have been generated since implementation of the EU Directive, the overall feeling is that it is a major advance in patient care. This, believes Amin, is due to a range of factors. Primarily, giving ethics committees unblinded reports and a safety summary allows them to make more informed judgements on the relevance of a particular adverse event to their local population, which leads to better safety judgements. Equally, says Amin, the Eudravigilance Database promises to be a major data

•

•

•

The MHRA:

Looks at the role of the EU Qualifi ed Person (defi ned as an individual, mandatorily nominated by the company, who is required to have all knowledge regarding the compound in a trial, and of reporting requirements in all EU countries) – the MHRA wants to know who has been appointed to this role, their qualifi cations, location and relevant knowledge

Examines the procedures used by the company in handling adverse events, and individual case safety reporting

Looks at how the company compiled and submitted the periodic safety update reports, the process for responding to safety queries from competent authorities and how foolproof they were (what are the contingencies for anything that might go wrong, and how promptly can the company respond?)

Explores processes for conducting proactive literature searches looking for adverse events that may be reported on the same compound by independent investigators (there is a legal obligation for a drug company to monitor the worldwide literature on their compounds)

•

•

•

•

Table 2. The scope of the Medicines & Healthcare products Regulatory Agency (MHRA).


repository. When all member countries are able to submit data electronically then it will be an extremely powerful source of information about ongoing clinical trials and safety data, and will lead to better signal detection.

Giving ethics committees unblinded reports and a safety summary allows them to make

more informed judgements

Likewise, the annual safety summary embraces a number of positive elements. It provides regulatory authorities with an annual review of what is going on in any particular clinical trial and, more importantly, forces the company on an annual basis to look at its data far more closely. In particular, the evaluation of drug safety must be actively compiled and critiqued in a structured way hitherto unrequired to assess its relevance and impact on patient benefi t and risk.

Since the implementation of the EU Directive, Amin noted there is now a far more consistent process for collating and reporting SAEs across the EU member states. This improves the sharing of information across all regulatory agencies and ethics committees. Moreover, the move towards a fully electronic reporting system will facilitate access to key data, and allow an audit trail to be maintained. This centralised system will permit better signal detection and sharing of information, and thus more transparency. In time, the EMEA and the FDA will be technically capable of sharing safety information on a global basis.

Useful internet sources of information on EU reporting of adverse events can be found in Table 3.

Since the implementation of the EU Directive, there is now a far more consistent process for collating and reporting serious adverse events across the EU

USA

Guy Pawson (Genentech, USA) and Dr Sven Knudsen (Insightful Ltd, USA) both gave detailed presentations on various aspects of collecting and reporting adverse event information to ensure effective interaction with the FDA, with Pawson mainly concentrating on electronic submissions. Pawson said that, compared with Europe, when submitting clinical trial information in the USA, there is an enormous emphasis on the data themselves. The focus of the FDA is not to read a clinical study report, nor to confi rm a sponsor’s analysis, but to replicate it. They use their own tools to see if they arrive at the same answers concerning the safety and effi cacy of the drug in the trial, often using the raw data in preference to the collated data summaries, or to the written summaries of results and analyses. He said there are many new initiatives at the FDA to avoid replication of the 2005 Vioxx case (see page 18), and to perform safety data analysis across multiple fi lings.

Dr Knudsen added that in the current US environment there are an increasing number of product withdrawals and litigations. This has led to share price erosion, damaged relations with pharmaceutical companies and regulatory action. As a result, the FDA has proposed rules on safety reporting and issued guidelines for safety data analysis. Following the withdrawal of Vioxx, US$27 billion in market capitalisation was lost overnight. In terms of litigation, one major product withdrawal resulted in a US$1 billion jury award for a single product-related death, a US$5 billion class action settlement and US$17 billion to be set aside as litigation reserves.

EU resources

www.pharmacos.eudra.org/F2/eudralex/index.htm Outlines the rules governing medicinal products in the EU

www.www.emea.eu.int/ Website of the EMEA

USA resources

www.fda.gov/cber/rules/safereport.pdf FDA Safety Reporting Requirements for Human Drug and Biological Products

www.fda.gov/cder/guidance/6357fnl.htm FDA 2005 Risk Assessment and Minimization Guidances Pre-marketing Risk Assessment

www.fda.gov/cder/guidance/6358fnl.htm FDA Development and Use of Risk Minimization Action Plans

www.fda.gov/cder/guidance/6359OCC.htm FDA Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

Table 3. Useful internet sources of information on EU and USA reporting of adverse events.


Useful internet sources of information on USA reporting of adverse events can be found in Table 3.

Requirements for data and source documentsAn FDA review has clinical and statistical components. Pawson said that the PDF format is the written standard document for submitting case record forms (CRFs) and reports, whereas SAS represents the statistical standard (though this may change in the future). Increasingly, medical imaging,3–5 typically using radiologist-blinded computed tomography scans, now forms an integral part of FDA submissions in some therapeutic areas. There is a requirement to submit raw, largely unmodifi ed clinical datasets drawn directly from the information contained on the CRF. The analysis datasets, known as derived datasets, contain information that requires calculation, such as the body mass index and the duration of an adverse event.

From the FDA’s perspective, CRFs are fundamentally important. For a clinical trial that has closed there will be a signature page within the patient casebook that will verify the authenticity of the clinical data in that document. This ‘chain of command’ structure represents a core value for the FDA. CRFs also give a window on the study conduct for the FDA reviewer. All forms, annotations and changes must be dated and signed, and there is a legal requirement to have an audit trail available to the FDA. CRFs represent legal authentication for the clinical data that the company supplies in the SAS datasets, and the FDA checks them thoroughly since they typically receive 4–5 fraudulent submissions each year. Constructed CRFs represent an excellent way for them to pick this up. There are, however, many non-standard CRFs from a variety of sources worldwide. Genentech uses a low-cost tool called CRF-Publisher,6 which consolidates all received CRF structures into a unifi ed format for FDA submissions.

CRFs represent legal authentication for the clinical data that the

company supplies, and the FDA checks them thoroughly since they

typically receive 4–5 fraudulent submissions each year

Dataset notes, written by those closest in the company to the data, help the reviewer with orientation of their understanding of the datasets. They are not mandatory but the FDA reviewers state they fi nd them particularly helpful. Genentech uses a tool called Defi nePDF7 to create these dataset notes. It is simple and inexpensive software that inhabits the territory between SAS and Microsoft Word. Similarly, an annotated CRF to map fi elds on the source document to fi elds on the SAS

dataset is extremely valuable. This allows the FDA reviewers to orientate quickly when they go back and forth between the two types of document as is frequently required. The tool also summarises the key variables used to identify effi cacy, and the key variables used to identify safety.

Elements of the FDA reviewThe FDA clinical review focuses on the results of safety analyses, narratives and CRFs. The FDA statistical reviewer will try to replicate the sponsor’s analysis using a different set of statistical tools to those in the company’s report. The review will focus on analysis outcomes, particularly subset analysis, sometimes relentlessly slicing and dicing the data to try to tease out effi cacy and safety signals. The main focus is on the results of the safety analysis. Companies are required to write a narrative for every major adverse event. This is a short summary of the patient’s background that links to the patient’s CRF, enabling the medical reviewer to gain a full perspective of the background clinical and demographic environment of the adverse event and its nature. Genentech fi nds a computer-linked dataset table of contents is crucial to the FDA submission, fi nding that, by following this approach (Fig. 1), they make their own work, and that of the FDA reviewers, a great deal easier. These hyperlinks connect directly either to data dictionaries, other reports in the submission (including those of serious adverse events) or into the datasets themselves using the SAS data viewer or another product called SAS-JUMP, both of which are used by the FDA reviewers.

Genentech invented a ‘two-click’ rule, in which a reviewer can get anywhere in the entire record system with just two clicks of the mouse. Pawson said that FDA reviewers like this ease of navigation and it makes for a far more effi cient and speedy review. Reviewers like to make the connection between the data dictionaries, the dataset, the metadata, spreadsheets and the actual relevant source document. So, by providing them with a simple, bidirectional link between CRFs and all analyses and documents, reviewers can easily go back to fi nd the context, and the dataset, in which any and every data fi eld is connected. Genentech fi nds it receives strong positive feedback from FDA reviewers when it provides these intuitive links between reports and source documents in this way.

Clinical Data Interchange Standards Consortium The Clinical Data Interchange Standards Consortium (CDISC)9 is an important joint initiative by the FDA and industry that allows the submission of harmonised data across different trials and thus enables the earlier detection of safety signals that may prevent another Vioxx from happening. CDISC is essentially a way of bringing a level of standardisation to how metadata from a large number of separate trials are defi ned so that they can be used for large-scale comparisons of disparate safety data. Using a Standard Data Tabulation


Fig. 1. In the ‘Dataset Table of Contents’, items in blue lead to another table or diagram or report. FDA reviewers never need to have to fi nd a CRF since there is always a link that will take them there. The (low-cost) software utilities used to compile these PDF links and bookmarks for FDA submissions is from a company called Image Solutions.8 Reproduced with permission of Pawson (Genentech).

Dataset Table of Contents

Dataset Table of Contents

Dataset Tipsheet

Annotated CRF

Dataset Metadata (defi ne document)

CRF Table of Contents

Patient CRF and Audit Trail


Model, CDISC aims to capture all submitted data as a series of observations in domains based on standard structures, and enforces specifi c rules on domain and variable names, structures and data consistency. It is an important initiative for any company that might submit trials comprising a large quantity of safety data. It promises to make their reviews much easier and ultimately will benefi t the patient by picking up safety signals a lot earlier. CDISC V3.1 specifi cations are available for download.9

CDISC is an important joint initiative by the FDA and industry

that allows the submission of harmonised data across different trials and thus enables the earlier

detection of safety signals

Strategies for a successful FDA fi lingIn an analysis of those factors that predispose to early approval of a particular fi ling, the only two variables that correlated were the time at which the company started discussing the fi ling with the FDA, and the number of times they subsequently discussed it with them. This is not surprising to those who view the relationship between sponsor and FDA as one of cooperation, and not of confl ict. For this reason, Genentech communicates with the FDA early in the process. It considers it important to orientate the FDA reviewers towards a quick start by giving them the dataset notes early on. Genentech feels its two-click system of straightforward data and document navigation is key in receiving a successful and rapid review. Genentech also ensures that all key published references are hot-linked to the fi ling, so that reviewers do not have to go off to a library to check relevant information: this keeps them working on the fi ling and not returning to it possibly hours later after visiting their library.

Pawson suggested making sure that datasets are easy to work with. He cited an instance some time ago when the FDA was unable to link separate datasets in a joint submission because there were no common keys amongst them, causing the FDA to issue a ‘refusal to fi le’ because it was technically unable to do the analyses it wished. Another thing to avoid is printing the CRFs from

the datasets. This really upsets the FDA, who will quickly refuse to fi le on authentication grounds. The FDA does not like to hear that this is ‘not the way we do that in our company’ or that we ‘don’t need to do that much quality assurance’. According to Pawson, you can never do too much quality assurance and, if you have bodies buried in your submission, it is best you fi nd out where they are buried before the FDA does.

Safety risk management and clinical development

Dr Joanna Haas (Genzyme, USA) pointed out that most of the issues safety professionals deal with now are unlike the thalidomide paradigm (which generated most of the regulation safety legislation). This paradigm embraced the notion that if you see it, you know it; that the safety events encountered would be exceptional; that they are set against a background of infrequent but highly notable events; and that there is going to be something special about them. Once three or four of such events had occurred then it was clear there was a problem.

However, these days, the types of safety problems encountered are much more subtle and cannot be addressed by the same technique. For example, antidepressants may be prescribed for conditions that are so serious, such as adolescent suicide, that there inevitably will be some reportable adverse events. However, it is clear that no physician would prescribe an antidepressant for an adolescent unless they were already viewed as high risk within the natural history of their disease. Thus, safety has mainly become a ‘numbers game’, and far less about recognising a unique event such as that surrounding thalidomide.

Another example would be the Vioxx case, in which a fairly subtle increase in a very common background event was involved (see page 18). This is not something that can be addressed with case reports. Whereas such reports may be valuable for identifying unusual distinctive events (and the top 20 pharmaceutical companies spend >US$800 million per annum on detecting these) this approach is nevertheless greatly limited in its ability to address the kind of problem that safety professionals now commonly face. The alternative approach is safety risk management that starts from day one. Haas recommended the proactive management of safety issues and concerns while being aware that safety is

Patient risk Patients need to be protected from any potential harm and fi nancial loss when a drug is taken. It is important to maximise the risk–benefi t ratio and improve patients’ lives through continuous assessment, timely communication and the management of medical product safety

Product risk Centres on issues surrounding the suspension or delay of either a development programme, approval or formulary inclusion, or a product being withdrawn from the market

Corporate risk Centres on legal or fi nancial issues or those that involve the credibility of the company

Table 4. Elements of drug safety-related risk, which need to be managed by pharmaceutical companies.


an iterative process in that it does not stay static, with ongoing issues constantly changing.

In another presentation, Dr Sean Zhao (Amgen, USA) described three elements of drug safety-related risk, all of which need to be managed by pharmaceutical companies: patient risk, product risk and corporate risk (Table 4). Zhao presented a graphic (Fig. 2) that

demonstrated Amgen’s approach to the design of an end-to-end risk management process that they consider critical toward optimising the safe use of their products. He also showed a slide (Fig. 3) that demonstrated how pharmacovigilance must evolve and refocus in the face of changing requirements to meet a new challenge where safety risk management has become a factor of primary importance.

Fig. 2. Amgen’s approach to the design of an end-to-end risk management process. Reproduced with permission from Zhao (Amgen, USA).

Fig. 3. How pharmacovigilance must evolve and refocus in the face of changing requirements to meet a new challenge where safety risk management has become a factor of primary importance. Reproduced with permission from Zhao (Amgen, USA).


Life-cycle management of safety issuesRisks are in-built and have to be managed, said Haas. If you try to avoid them you will discard enormous numbers of valuable approaches. Professionals have to fi nd a way to evaluate the risks, and to be able to handle them. Planning ahead is now a crucial factor for success. From a clinical development point of view, the key is to try to anticipate safety issues that might be confronted during trials, and to fi nd methods of dealing with them. Anticipation may come from the literature, from product characteristics such as structure or mode of action, or from toxicological fi ndings, or pharmacokinetics or pharmacodynamics.

From a clinical development point of view, the key is to try to

anticipate safety issues that might be confronted during trials, and to fi nd methods of dealing with them

As an example, Haas discussed the recent Northwick Park incident in which an exceptional and unique catastrophic effect occurred in a series of healthy human volunteers. The mechanism of action of the agent being investigated was to stimulate (agonise rather than antagonise) a co-stimulatory molecule that is involved in immunological T-cell activation. Reading through the investigator’s brochure and the informed consent document, Haas said that it seemed as though the agonist aspect was being played down. It seems probable that a lot of people were worried ahead of time about the agent’s potential (from a mechanistic point of view) in terms of generating a major stimulatory effect with a possible resulting cytokine storm, even though this was not seen in earlier studies in monkeys. Haas felt this was an excellent demonstration of a situation in which the known mechanism of action of a drug could have predicted the possibility of a certain kind of adverse event, and could have suggested some anticipatory contingency preparation.

Another way of anticipating possible safety issues is to look at comparator products to the new agent under development. Haas quoted the example of the use of different immune modulators in multiple sclerosis, in which the development of a rare viral disease, progressive multifocal leukoencephalopathy, may occur during treatment. Whether or not this will be an issue with any new immune modulator therapy under investigation, possible adverse events such as this must nevertheless be proactively addressed because they come under the background of previous experience with its range of earlier public health and regulatory implications.

Another example is the development of new cyclo-oxygenase (COX)-2 inhibitors. The issues in this fi eld following the withdrawal of Vioxx (a COX-2 inhibitor;

see page 18 for more details) will shape any additional drug development efforts and forward-thinking safety protocols of this drug type. Other things to think about in anticipating safety issues are the clinical setting and drug interactions: is this a disease for which other drugs might be given simultaneously, such as coronary heart disease? Does the population under study include women who might get pregnant? Answers and advice need to be prepared by the safety team well ahead of time. In patients with renal disease or insuffi ciency, the background rate of adverse vascular events is very high so the safety team must proactively consider ahead of time not only the pharmacokinetics, but the clinical setting also. Risk has a number of elements, such as severity, the relative and absolute frequencies of events, and the impact on public health, but even with a disease such as multiple sclerosis, in which the risk of progressive multifocal leukoencephalopathy with a particular drug might be considered extremely low, it is important to document the possibility of such an event and to demonstrate clearly that it has been actively looked for during studies.

If a series of possible adverse events is predefi ned, then processes to monitor them can be proactively implemented from the outset. For example, a transient ischaemic attack might be regarded as minor since it would probably be treated in an outpatient setting. However, if this is thought to be an issue of particular interest then plans can be implemented upfront to capture all this information. It is sometimes important to control the information that comes back from the Clinical Research Associates (CRAs). Terminology is vital and must be taught to CRAs accurately and in a standard way. For example, the presence of ‘fl u-like symptoms’ has a different meaning to everyone. It can represent a wide variety of symptoms and include a great deal of variability that can confound safety assessments. It may therefore be important to train CRAs to record data for specifi c symptoms, as well as noting the precise timing of symptom onset and recovery, and thus only use the term ‘fl u-like symptoms’ in clearly defi ned circumstances.

If a series of possible adverse events is predefi ned, then processes to monitor them can be proactively

implemented from the outset

The pre-marketing risk assessment guidance that has been published by the FDA10 contains a lot of guidance on exploratory safety analysis. This is now regarded as both legitimate and critical.

Creating a global integrated approachIt is critical that safety is understood within the company to have no borders (i.e. it is not just geographical, but also covers development time borders). The old terminology, that clinical safety is pre-marketing and


pharmacovigilance is post-marketing, is now obsolete. These systems should be integrated across all global activities of the company. FDA regulations state that safety data must be reviewed by the company every 3 months; the introduction of electronic CRFs (e-CRFs) makes this requirement far easier. Pre-marketing risk assessments can improve the later assessment and reporting of safety during drug development trials. They also improve the assessment of important safety issues during registration trials, create best practices for analysing and reporting data developed as a result of a careful pre-approval safety evaluation and build on existing FDA and International Conference on Harmonisation (ICH) guidance related to pre-approval safety assessments.

When a population group in clinical trials is excluded, whether through inclusion or exclusion criteria, then a question to ask is whether this should be converted into a later contraindication. Elements of a structured approach to the development of a risk management plan are summarized in Fig. 4.

Lack of effi cacy also has safety implications. For example, if a potential new angiogenesis drug is given to patients who require increased perfusion in their extremities, although amputation could be defi ned as an adverse event, given the nature of the patient it may be coded as unrelated. However, it could simply refl ect a lack of effi cacy of the new compound. For this reason, Haas says, she often has a greater insight about a drug, even in blinded studies, from the positive or negative effi cacy data that come in as the trial progresses.

MedDRA (Medical Dictionary for Regulatory Activities) is increasingly being used worldwide as a standardised terminology for adverse events, although it does not provide formal or complete defi nitions of terms. Haas

recommended the use of problem-oriented safety analysis. MedDRA standardised queries can often be used for this and, she said, she tries to do this, although this is sometimes controversial. It is also possible for a company to develop its own terminology, which more accurately describes the adverse events that the safety team is looking for. The danger in doing this is that the information can be forced, but the benefi t is that the data collected are more focused on precisely the safety information that is needed.

Prominent drug safety issues change FDA and industry practices

Dr Kenneth Hintze (Kendle, USA) gave a presentation on a series of drug safety-related problems that have hit the headlines in recent years. His main brief was to cover the issues surrounding the withdrawal of Vioxx and its repercussions throughout industry, but he also discussed some other prominent adverse events that have been widely aired in the public domain and how these have changed industry practices and the safety environment. These recent safety ‘headlines’ include:

Vioxx, an arthritis treatment, voluntarily withdrawn from the market

Bextra (another anti-infl ammatory drug), withdrawn at the request of the FDA

The relation between use of antidepressant and suicides in teenagers

Accutane (treatment for acne) and concerns about birth defects

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Fig 4. The periodic safety update report (PSUR) for marketed drugs is confi gured to be a stand-alone document that permits a periodic, comprehensive assessment of marketed drugs. The Risk Minimization (Action) Plan (Risk MaPP) is safety concern-oriented and is developed only if needed. Reproduced with permission from Haas (Genzyme, USA).


Crestor, a relatively new statin, associated (primarily in people of Asian descent) with muscle damage and kidney failure

TeGenero antibody and organ infl ammation (the Northwick Park Hospital tragedy).

All the safety-related adverse events behind these ‘headlines’ were, for the most part, undetected at the time the products were approved for testing and/or marketing, and were only subsequently found to be an issue.

Vioxx

The chronology of the major issues surrounding the withdrawal of Vioxx, and subsequently that of Bextra, is outlined in Fig. 5.

The FDA Arthritis Advisory Committee recommended approval of Vioxx (a COX-2 inhibitor designed and marketed by Merck for the treatment of pain and infl ammation in osteoarthritis) in 1999, and over the next 4–5 years the use of this product was expanded on a global basis. During this time concerns started to grow about the incidence of cardiovascular events with the drug, particularly strokes and myocardial infarctions. This led to some labelling changes in 2002. New clinical data became available in 2004 and Merck requested a meeting with the FDA. On the following day, Vioxx was voluntarily removed from the market by Merck. Soon after, the FDA set up a Joint Advisory Committee to review all COX-2 inhibitors, including Vioxx. As a result, the FDA asked Pfi zer to remove Bextra from the market (citing some potentially fatal skin reaction concerns as well as the increased cardiovascular risk it shared with Vioxx).

Being, by defi nition, pharmacologically active, no drug is entirely safe. Regulators are interested in balancing risks versus benefi ts. In the cases of Vioxx and Bextra, the FDA considered the potential risks to be greater than the

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potential benefi ts. The FDA was less concerned about another Pfi zer COX-2 inhibitor, Celebrex, feeling that the benefi ts of this drug outweighed the risks, simply asking for warning labels to be placed on the product. Celebrex continues to be marketed today. During the course of this FDA advisory group investigation they found that some NSAIDs, many of which are sold over the counter (OTC), also showed some level of increased cardiovascular risk and, as a result, they now carry appropriate label warnings.

It is informative to look at the clinical data for Vioxx. At approval, 5000 patients with osteoarthritis had been evaluated. Much of the work by Merck was focused on showing that the gastrointestinal side effects were fewer with Vioxx than with standard NSAIDs such as ibuprofen. By the time of market approval, Merck had found that Vioxx ameliorated gastric ulcers, but there was no evidence of stroke or cardiovascular issues. After approval, Merck studied gastrointestinal outcome in 8000 patients with rheumatoid arthritis (rather than the osteoarthritis patients studied earlier), and compared Vioxx with naproxen (a non-COX-2 NSAID). Merck found that double the dose of Vioxx used to treat osteoarthritis (25 mg/day) was required to treat the symptoms of patients with rheumatoid arthritis adequately (i.e. 50 mg/day). As part of the criteria for the rheumatoid arthritis study, Merck also asked patients who were already on low-dose aspirin (as a prophylactic to protect against cardiovascular risk) to stop taking it for the entire duration of the trial.

It was the combination of the cessation of aspirin plus the higher dose of Vioxx that revealed an increase in the risk of cardiovascular events with this agent. As a result of this fi nding, some label changes were made describing the cardiovascular risk, and the 50 mg dose was not recommended for chronic use. Concurrently, a Vioxx trial in patients with Alzheimer’s disease showed no increased cardiovascular risk at the 25 mg dose level.

Fig. 5. The chronology of the major issues surrounding the withdrawal of Vioxx, and subsequently that of Bextra. Reproduced with permission from Hintze (Kendle, USA).


Therefore, at this point Merck had mixed data. The clinical trial that led to the withdrawal of the drug was the APPROVe (Adenomatous Polyp Prevention on VIOXX) study. At 18 months, but also prior to this, the results indicated a clear increase in cardiovascular risk relative to placebo. This was the fi rst major long-term study of Vioxx in which there was a placebo control. The drug safety management board of APPROVe recommended discontinuation of the study and, when it looked at all of its Vioxx data, decided to call the meeting with the FDA that led to the discontinuation of the product.

It was reported during the conference that the fi nancial impact to Merck was loss of annual sales of US$2.5 billion. The estimated losses through damages and litigation by July 2005 were thought to be US$8–25 billion. Echoing Zhao’s point on drug safety and corporate risk, it is clear that Merck also suffered a major impact on its image, and therefore its market competitiveness in other areas. Its share price refl ected this negativity.

It can take 4–5 years to accumulate the right data to reveal safety issues

The message from this is that it can take 4–5 years to accumulate the right data to reveal safety issues of this nature. Now, two of the three approved COX-2 inhibitors have been removed from the market, and there are substantial label changes on the one remaining. Safety inhabits a world of grey, not black and white, and if information that will make a decision swing one way or the other comes in periodically, gaining suffi cient information can take years. Lessons that can be learned are that when one changes from one population to another then the risk profi le changes. In retrospect, there was clearly a shift in risk profi le when moving from an osteoarthritis population to one with rheumatoid arthritis. Also, there is a shift in risk profi le when moving from a clinical trial situation to the real world. This is especially true in situations where subpopulations may not have been adequately represented in clinical trials, thus rendering safety signals undetectable.

Clinical trials explain little about reality, whereas post-marketing studies explain little about causality. In addition, after market approval some patients use drugs in an off-label way; for example, Vioxx may have been used by many to relieve headaches rather than for arthritic pain, and this might have put people at increased risk.

Dr John Ferguson (Millennium Pharmaceuticals) said that although many companies may have a ‘Corporate Crisis Management Plan’, this plan probably has very little to do with product safety and adverse events, yet no one may realize it. Crisis prevention, he said, will not work if you do not have a risk management framework in place. When you have both in place, the one informs the other. Defi ning crisis, and thinking about what constitutes a

crisis, makes it clear what you have to do with regard to pharmacovigilance and risk management to prevent it.

FDA and EU regulatory authorities’ response to the Vioxx issue

Hintze said that the FDA came in for considerable public and Senate criticism over the Vioxx issue amid accusations of not properly protecting public health. As a result of this, it developed a fi ve-point programme:

It commissioned the Institute of Medicine to review the FDA’s safety practices and to ensure they were state-of-the-art and had no gaps. The emphasis was on post-marketed products.

It appointed a permanent director for the Offi ce of Drug Safety.

It began a series of joint academic and industry workshops and meetings on drug safety and risk management to explore where there were gaps in understanding and what was the best management structure for them to adopt.

It introduced a peer-review system to incorporate differences of opinion into the FDA decision-making process. On the basis of the early 2002 data (see above), some in the FDA felt Vioxx should not have been on the market but their views were not made public. The FDA now intends to be far more transparent on such matters and will proactively make publicly available any such dissenting views, and how any decision was reached.

The FDA published three Risk Management Guidelines related to this issue. They were intended to cover both pre- and post-approval of all drugs. These guidelines defi ne a specifi c process requiring a company to publish a plan to describe how the company will deal with any safety signals that develop as a result of marketing their product, and how they are going to minimize that risk. The plan requires FDA buy-in so, in essence, there is an approval process involved.

A month before the FDA published these plans (March 2005), three ‘Risk Management Guidelines’ were also published in Europe and covered similar areas:

Safety specifi cations – what do you know about the drug? How is it positioned?

A pharmacovigilance plan – how will you deal with any safety signals that are picked up?

Risk management – how will you minimize the risk?

As with the FDA, all these plans must be submitted as a fundamental part of the marketing authorisation.

Finally, Hintze discussed some issues relating to future FDA activities. Data mining is set to become far more important. Using the FDA and Eudravigilance systems there will be a greater use of data mining to identify multiple uses of a drug. MedDRA has now been

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mandated as part of the ICH guidelines in both the EU and the USA. This will permit far easier comparisons between drug safety experiences across the two geographies. US Congress has a number of pending legislative initiatives. One of these will involve fair access to clinical trials, an FDA-controlled web-based system that will allow the posting and public viewing of clinical trials that are in progress, and their major fi ndings. Knudsen emphasized that data mining is key in signal detection, and new Baysian methods can assist in reducing false-positive safety signals. These methods are being driven by the FDA and opinion leaders. Further, interactive graphical displays make it easy to detect fl awed data and outliers, while they also are excellent in presenting analytical results.

In the future there will be ever greater emphasis on early and more extensive toxicology studies to try to fi nd safety signals. There will be greater regulatory scrutiny as a result of the risk management systems, both in the USA and in the EU. Safety issues will mean larger and more costly clinical trials, both pre- and post-marketing, and will probably slow down approvals. Life is becoming tougher for the safety and pharmacovigilance professional, with a tug-of-war between society, which wants risk-free drugs, and industry’s need to provide effective medicines.

In the future there will be greater regulatory scrutiny as a result of the risk management systems, both in the USA and in the EU

Global aspects of adverse event reporting

Dr Livia Stankovics (Sanofi -Aventis) said that she views pharmacovigilance as representing a written contract between the marketing authorisation authorities, the healthcare professional and the patient. Using data provided by the manufacturer, the marketing authorisation authorities agree to inform the healthcare professional of all relevant information that affects the effi cacy and safety of the product. The healthcare professional, by signing a prescription, agrees to treat the patient in line with the summary of the product characteristics, and to inform the marketing authorities of any new experience they observe concerning the effi cacy and safety of this product. The patient agrees that they will use the medicine according to the instructions of the healthcare professional and the marketing authorities, and to report any adverse experience with that medicine. Thus, in pharmacovigilance, all three parties should work towards the same objective.

From a regulatory point of view, the conduct of pharmacovigilance is becoming more globalised

and standardised. The main global drive of pharmacovigilance is just starting now, said Stankovics, with the implementation of the ICH E2E guideline on pharmacovigilance planning,11 which will open a new horizon in pharmacovigilance. The objective of the ICH E2E guideline is to aid industry regulators in planning pharmacovigilance activities, especially for new drugs. Planning is a new word here, and replaces the former ‘reactive’ approach. This concept has a safety specifi cation, a pharmacovigilance plan itself and an annex that specifi es how the goal may be achieved. The aim of the safety specifi cation is to help the sponsor and the regulators identify any need for specifi c data collection in the post-approval period, and also to facilitate the production of the pharmacovigilance plan. This pharmacovigilance plan provides guidance on the structure for documenting actions, as well as action plans for the issues identifi ed. For products with no special concerns, routine pharmacovigilance might be considered suffi cient for post-approval safety monitoring without the need for specifi c action.

After product registration, routine pharmacovigilance starts. The safety specifi cation of the product is developed, and is logically divided into two main sections, non-clinical and clinical. The non-clinical section covers toxicity, general pharmacovigilance, and central nervous system and cardiovascular interactions. The clinical section covers the limitations of the human safety database, populations not studied, adverse events and adverse drug reactions identifi ed, interactions identifi ed and epidemiological data surrounding the disease. From these two sources clearly identifi ed risks and potential risks (i.e. those that are not verifi ed during preclinical and clinical development but are likely to be potential risks in the near future) can emerge. In addition, what is not known can be identifi ed from the safety specifi cation. Thus, a summary of ongoing safety issues can be derived and, from this, an action plan can be developed together with an objective for the proposed actions or, if the risks are not alarming, standard routine pharmacovigilance can instead be recommended.

Pharmacovigilance methods that may be used (combined with drug utilisation studies and natural history of the disease) include:

passive surveillance of spontaneous reporting (but this is still currently only effective and reliable in a very limited number of countries)

stimulated reporting

active surveillance

cooperative observational studies

targeted clinical investigations.

When combined, these approaches fulfi ll the requirements of the E2E guidelines.

Stankovics concluded with the thought that there are no safe and no dangerous drugs. It is all about context. Instead, it is better to consider that there are well-known

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and well-applied drugs and, conversely, unknown and/or inadequately applied drugs. When the dangers of certain drugs are fully known then they should be applied only where appropriate. Pharmacovigilance seeks to improve understanding, translating into practical use, in all these areas.

There are no safe and no dangerous drugs; rather there are well-known

and well-applied drugs and, conversely, unknown and/or inadequately applied drugs

Role of Eudravigilance in drug development

Dr Gurdyal Kalsi (MDS Pharma Services) discussed the role of Eudravigilance in drug development, starting by reviewing aspects of and changes in EU safety legislation. Patients are now being encouraged to report (as consumers) safety issues through the Yellow Card system (this was formerly carried out only by medical professionals). Periodic safety update report (PSUR) submission periodicity has changed to three per year. There is now a requirement for submission of a risk management plan together with any Marketing Authorisation Application, or if there is a signifi cant change to an existing product. There is also a move towards creating improved visibility and transparency of information available to the public via the EMEA website, although some feel this is in confl ict with requirements for confi dentiality, and commercial risks involved. The scope

of the EMEA has widened: it now has a larger array of centralised procedures, and there is a strong move towards harmonisation in many areas (such as drug label leafl ets), which is also likely to improve transparency. There is now in place a centralised procedure mandate for late-stage drug development that, in addition to the biotechnology sector, from November 2005, key therapeutic areas for new chemical entities are defi ned, as AIDS, cancer and neurodegenerative disorders. As of May 2008, there will be further inclusion of autoimmune disorders and products used for immune disease control.

The scope of the EMEA has widened: it now has a larger array

of centralised procedures, and there is a strong move towards harmonisation, which is also

likely to improve transparency

The role of Eudravigilance

This drug safety data warehouse initiative aims to link safety information from a wide variety of data sources, both pre- and post-marketing. Its primary focus is on data collection, data analysis and its communication capabilities. Currently in development, the Eudravigilance database now has 360,000 reports covering 229,000 cases; 86.5% of these are post-marketing reports. The Eudravigilance system is likely to take care of source errors, creating better systems for managing the analysis of data, and linking exposures across not just one product, but also all its comparators without any breach

Fig. 6. The scope of MedDRA. Reproduced with permission from Kalsi (MDS Pharma Services).


of confi dentiality. It will eventually, said Kalsi, evolve into a highly sophisticated analytical tool. There is also far less risk of missing data because of its electronic data conventions. The MedDRA system, which is integrated within Eudravigilance, allows the meaningful comparison of data elements with a sophistication not previously available. It also provides the ability to analyse data sequentially rather than just at one time point, and will almost certainly lead to eventual resource savings. Fig. 6 shows what is included in MedDRA, and what is not.

Kalsi said that the future for drug development in the context of increasing drug safety demands is to develop more robust trial designs that are cost effective with comparators in the same class. He expects more partnerships between industry, prescribers and health authorities, and above all, with patient interests in mind. Evolving risk management plans will be drawn in parallel with clinical development plans, and the use of signal evaluation at different levels of detail and interpretation based on comparative data in the drug class will be greatly facilitated through the Eudravigilance initiative. Also facilitated will be harmonised risk management strategies within each drug class. Equally, centralised monitoring using evolving evidence-based database management systems will assist the greater accountability of drug developers towards public safety. There will be greater transparency of research objectives, particularly focused on healthcare outcomes, with the involvement of patient groups directly in the clinical development strategy of companies. In this context, patient-reported outcomes (PROs) will play a key role in the future of drug development and safety evaluation.

Patient-reported outcomes will play a key role in the future of drug development and safety evaluation

RxWise: effective ADR avoidance by complete medication safety checking

Dr Richard Wyse (Economic Healthcare Associates) picked up on Kalsi’s theme of patient involvement by describing a new drug safety initiative that for the fi rst time places far more control in the hands of the consumer. Up to now, the reporting of adverse events would typically be initially by investigators and/or companies within prospective clinical trials, or in the post-marketing phase, to their respective national regulatory authorities. A third form of reporting is emerging: ADR checking and reporting by individuals themselves. As Kalsi discussed, this can be through the newly and rapidly developing area of PROs. This is also expanding rapidly in a very large area of previously unmet need, that of consumer electronic checking of

their own medications. An evidence-based electronic system, regularly updated over the Internet, now permits highly effective consumer avoidance of adverse events across the entire prescription, OTC and herbal medicine spectrum.

The factors driving these changes are astonishing. There are over 2 million serious ADRs per year in the USA. With the annual US death rate currently at approximately 100,000, ADRs represent the fourth leading cause of death, ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths. Between 7% and 30% of all hospital admissions in the USA are caused by the side effects of drugs, and the nursing-home patient ADR rate is also very high (~350,000 per year). In the UK, over 250,000 serious ADRs are reported annually, with around 20,000 deaths per year. Bandolier. reported that adverse drug events in the UK constantly fi ll the equivalent of 15–20, 400-bed hospitals.12 This is equivalent to the occupation of some 6000–8000 UK hospital beds on a daily basis.

There are over 2 million serious ADRs per year in the USA, and the

associated costs are extremely high and estimated to exceed US$4 billion

The costs associated with ADRs are also extremely high. Severe ADRs result in excess of US$4 billion in annual US healthcare costs,13 which is greater than the total costs of cardiovascular or diabetic care. ADRs cause one of every fi ve injuries or deaths per year to hospitalised patients. The mean lengths of hospital stay, cost and mortality in ADR patients are double those for non-ADR patients. Annually, ADRs cost approximately £400–500 million in the UK.

One reason there are so many ADRs in the USA is because two-thirds of all patient visits result in a prescription. There were 2.8 billion outpatient prescriptions (10 per person in the USA) fi led in 2000, and the incidence of ADRs increases exponentially with four or more medications. Furthermore, OTC and herbal medicines are signifi cant contributors to the risk of experiencing a serious ADR and their usage has increased from >5% to 20% in the past decade. Physicians have little control over what OTC and herbal medicines their patients take. Even self-treating a fl u-like illness with an OTC may jeopardise patients on prescription drugs.

The high level of unmet need for medication checking has been behind the development of a new ADR avoidance device. RxWise14 is a USB stick containing a comprehensive database of 60,000 prescription drugs, OTC drugs and herbal medicines that an individual can use to check their own prescribed, and self-purchased, medications. It places a level of control and healthcare safety checking back into the hands of the individual


consumer. As such, it is in line with the growing concepts of personalised medicine, and even contains personalised genetics reporting capabilities for DNA alleles associated with serious ADRs.

Recently launched in the USA, RxWise is a drug–drug interaction ADR avoidance device and, uniquely, also covers the very much larger category of drug–disease interactions that represent up to 85% of all ADRs. Although aimed at consumers, physicians and pharmacists, it is the consumer part of RxWise that is sociologically revolutionary. It allows very large numbers of individuals in the population to cross-check the appropriateness of their own prescribed therapies in the context of their disease(s), their other prescribed medications, plus any individually chosen OTC and/or herbal supplements they may be taking or considering. Furthermore, physicians are generally unaware of the OTC drugs and herbals their patients take. This device allows consumers to combine all their prescription, OTC and herbal intake in a central analysis. They can also prospectively carry out potentially protective ‘what-ifs’ on any new OTC drug or herbal they are considering, and completely in the context of any diseases they may have, and what drugs they are already taking. In time, consumers should be able to access their own personal RxWise database over their mobile phone when they fi nd themselves in a chemist or herbal shop and, given the medications they are already taking, even decide what not to buy while at the counter.

Individuals input their own demographics, diseases, allergies and list of prescription, OTC and herbal medicines they are taking (Fig. 7). All potential interactions are immediately reported as a series of alerts, warnings and cautions that are context-sensitive to the particular diseases they carry (Fig. 8). If concerned, the individual can then opt to send a separate, fully

referenced, scientifi c version of this report to their physician or pharmacist to check that no mistake in medicines prescribed has been made. If an ADR alert is received, unilateral action by the individual is strongly discouraged in favour of direct physician contact.

Also unique about this device is its genetics capability. It contains software that handles and incorporates potentially relevant cytochrome P450 allele results from an outsourced Roche Amplichip analysis of a DNA buccal swab. When incorporated into a person’s ADR safety report, this represents the fi rst example of genetic results ever being processed by individuals themselves.

Although RxWise also runs from a central local server in a patient registry format in pharmacy practices, physician practices and large employer healthcare benefi t schemes, it is the power given to the individual consumer that represents the major dynamic change in national healthcare safety checking. Indeed, hundreds of thousands of these individual USB devices have been sold to individuals in the USA since the launch in mid-2005. Evidence-based studies over the next few years are needed to determine the impact RxWise will make on national ADR rates.

The future of pharmacovigilance in Europe

Dr Birgitt Gellert (Bayer Vital, Germany) closed the meeting with a look at the future of pharmacovigilance in Europe. She echoed Wyse’s earlier statement by saying that potentially preventable ADRs cause signifi cant harm to patients. One reason for this is that the known risk profi le of drugs is not considered adequately in the act

Fig. 7. RxWise is a drug–drug interaction ADR avoidance device. Individuals input their own demographics, diseases, allergies and list of prescription, OTC and herbal medicines they are taking. Reproduced with permission from Lee Morse (Iatrogen).


of prescription. In looking for areas of improvement it is important fi rst to ask what cannot be changed:

Treatment with drugs will always be associated with the risks that are innate to the product. They can be handled, but not always prevented.

Risk management tools are well established, so that no signifi cant innovations might be expected.

Risk-minimising strategies will remain challenging. It is a sensitive area and changes and effects are rarely foreseeable.

Rare and serious ADRs will always be detected eventually, and may lead to market withdrawals even in the best pharmacovigilance system.

Where are we now?

The current situation is illustrated in Fig. 9.

What might happen next?

Signal detection tools may create a fl ood of signals requiring validation.

Increased transparency might lead to a fl ood of queries from different sites.

Increased availability of raw data may lead to increasing litigation.

What is fi rst needed is all clinical data (including safety data, and even medical images and ECGs) to be contained within a single prospective, integrated, problem-oriented central database repository. This will allow immediate availability for appropriate and timely assessment. The next level is to establish a process which analyses and aggregates all data from all sources in an ongoing day-by-day assessment of the safety profi le of the product, but also its risk–benefi t profi le. Immediate access to the complete dataset related to a problem would permit an immediate real-time action if required, and an immediate and accurate response

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to queries. Focusing on the risk–benefi t profi le is far preferable to focusing just on the risks.

Focusing on the risk–benefi t profi le is far preferable to focusing just on the risks

The development of a sophisticated system as described above, although a critical factor in improving pharmacovigilance, mainly demonstrates its benefi ts over long time periods. There is, however, an important area where results can be delivered on a short-term basis. Again echoing Wyse’s remarks, Gellert said that, in the USA, prescription errors cause about 7000 deaths per year, generating US$2 billion in extra costs. The current focus of pharmacovigilance is on identifying the very rare unknown risks. However, the future focus of patient protection should be about preventing prescription errors, assuring adherence to drug safety labels and averting preventable ADRs.

The future focus of patient protection should be about preventing prescription errors, assuring

adherence to drug safety labels and averting preventable ADRs

A Dutch study of 3540 prescriptions found 9.9% prescription errors, 1.8% of which were potentially dangerous.15 Although unacceptable, this is not perhaps entirely surprising given that there are approximately 34,000 drug products on the market, and 6600 labelled drug interactions, that have to be understood and considered when writing a prescription. A study of the availability and usefulness of drug information among

Fig. 8. All potential interactions are immediately reported as a series of alerts, warnings and cautions that are context-sensitive to the particular diseases that the patients carry. Reproduced with permission from Lee Morse (Iatrogen).


16,000 German physicians16 found that 88% of the available information is not adequate for use in their daily clinical work and that the information that is available is not structured according to clinical relevance. Eighty per cent of physicians needed information that was not available, either at the right place or at the right time, and 78% said it took too long to obtain adequate information.

There is thus a gap in the pharmacovigilance cycle in bringing safety information to the physician in an effective way that would help prevent common ADRs. The solution is software for the electronic support of prescriptions, either via a centralised system or via initiatives such as the project of the University Hospital of Saarbrücken, which integrates individual patient data with drug information. By checking physician’s prescriptions with regard to clinical relevant interactions, dosage according to indication, and patient demographics, special medical conditions, and frequency of drug application, and providing background information such as literature citations and relevant underlying mechanisms, it reliably matches patient information with drug information to prevent ADRs.

In conclusion, challenges for the pharmaceutical industry so that they are prepared for future demands include:

to structure and focus safety data into one continuous, problem-oriented, prospective information and knowledge management process

to put a new focus on the prevention of known, common risks with public health relevance.

Conclusions

The SMi conference on Reporting Adverse Events was an excellent review and timely update on how companies are fi nding their way through new legislation on drug

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safety, and on changing demands in a progressively more diffi cult regulatory and public image environment.

Assessing the risk–benefi t profi les of drugs and the development of risk management systems were themes that recurred throughout the conference, and it is clear that industry best practices are still emerging. In the light of recent, exceptionally expensive and high-profi le drug withdrawals, a major defi ciency that is being urgently addressed by companies is to achieve adequate adverse event signal detection for their products. It was felt that drug safety groups within companies should have a much higher profi le and a more prominent role in the strategic aspects of risk–benefi t optimisation.

Major recent improvements in the use and availability of safety data for physicians and consumers will mean that avoidable drug adverse reactions can be greatly reduced by providing the right drug safety information, in the right context, at the right time.

References

Directive 2001/20/EC of the European parliament and of the council of 4 April 2001. L 121/34. Offi cial Journal of the European Communities. Available at www.eudract.emea.eu.int/docs/Dir2001-20_en.pdf

Detailed guidance on the European clinical trials database (EUDRACT Database). ENTR/CT 5. April 2003. Available at www.eudract.emea.eu.int/document.html#guidance

Details available at www.bioimaging.com

Details available at www.radpharm.com

Details available at www.worldcare.com

Details available at www.dtgsw.com

Details available at www.meta-x.com/defi nedoc

Details available at www.imagesolutions.com

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Fig. 9. Where are we now? Reproduced with permission from Gellert (Bayer Vital).


www.cdisc.org CDISC V3.1 specifi cations are available for download at www.cdisc.org/models/sds/v3.1/index.html

FDA Guidance on Risk Management Systems for Medicinal Products for Human Use. Published on 20th November 2005. Available at www.ashp.org/emplibrary/RiskManagementPlans.pdf

ICH E2E Pharmacovigilance planning (PVP). Note for guidance on planning pharmacovigilance activities (CPMP/ICH/5716/03). 1 December 2004. Available at www.emea.eu.int/pdfs/human/ich/571603en.pdf

Adverse drug reactions. Available at www.jr2.ox.ac.uk/bandolier/band52/b52-3.html

Steimer W, Potter JM. Pharmacogenetic screening and therapeutic drugs. Clin Chim Acta 2002;315:137–55.

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Full details and online demonstrations are available at www.rxwise.com

van den Bemt PMLA, van Roon EN, Cjow M-CC et al. Cost-benefi t analysis of the detection of prescribing errors by hospital pharmacy staff. Drug Saf 2002;25(2):135–43. Available at www.ingentaconnect.com/content/adis/dsf/2002/00000025/00000002;jsessionid=11ovgibkq5ft3.victoria

Reng CM, Friedrich HJ, Timmer A et al. German physicians’ access to professional knowledge. Acceptance, quality and availability of professional information with special reference to electronic information media [in German]. Med Klin (Munich) 2003;98:648–55.

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