Regulatory benefit - risk assessment Different perspectives Paranimfen: Baldur Örn Arnarson Kolbrún Arnardóttir The studies presented in this thesis were performed in the context of the Escher project (T6- 202), a project of the Dutch Top Institute Pharma. Printing of this thesis was partially supported by the University of Groningen, the Graduate School for Health Services Research (SHARE) and the University Medical Centre Groningen. Additional financial support from the Nederlandse Bijwerkingen Fonds and the Dutch Medicines Evaluation Board for the publication of this thesis is gratefully acknowledged. ISBN: 978-90-367-6033-1 © 2012, Arna Hrund Arnardóttir No parts of this thesis may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission of the author Cover design: Jón Ingiberg Jónsteinsson (www.joningiberg.is) Printed by: GVO drukkers & vormgevers B.V. RIJKSUNIVERSITEIT GRONINGEN Regulatory benefit - risk assessment Different perspectives Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op woensdag 13 maart 2013 om 12:45 uur door Arna Hrund Arnardóttir geboren op 3 januari 1979 te Reykjavík, IJsland Promotores: Prof.dr. F.M. Haaijer-Ruskamp Prof.dr. P.A. de Graeff Copromotores: Dr. P.G.M. Mol Dr. S.M.J.M. Straus Beoordelingscommissie: Prof.dr. H.G. Leufkens Prof.dr. A.C. van Grootheest Prof.dr. N. Moore TABLE OF CONTENTS Chapter 1: General introduction 7 Part I Uptake of safety knowledge in regulatory practice 15 Chapter 2: Does safety information on newer HIV drugs benefit from 17 experience with older HIV drugs? A regulatory perspective Chapter 3: Additional safety risk to exceptionally approved drugs in Europe? 41 Chapter 4: Are more safety issues identified post approval for innovative drugs? 59 Part II Importance of drug effects as perceived by regulators, doctors and 79 patients Chapter 5: Selecting drug effects for a discrete choice study 81 Chapter 6: Benefit and risk preferences of patients for oral anti-diabetes drugs 107 Chapter 7: Do regulators value benefits and risks of oral anti-diabetes drugs in 123 the same way as doctors and patients? Chapter 8: General discussion and summary 141 Nederlandse samenvatting 159 Samantekt á íslensku 169 List of co-authors 177 Acknowledgements 179 About the author 183 Curriculum Vitae and list of publications 184 SHARE publications 187 General introduction Chapter 1: General introduction 7 Chapter 1 The strict regulations of the pharmaceutical industry are aimed at ensuring that only safe, effective and high quality drugs reach the market. Regulators are under increasing pressure to balance the desire for rapid market access to new drugs with the need for having an acceptable knowledge of the benefits and risks of new drugs at time of approval. (1) A productivity decline in the pharmaceutical industry has been observed where increased investment in pharmaceutical research and development did not result in an increased number of new active substances approved each year. (2) This development is in part caused by what has been called “the cautious regulator problem”; where regulators continue to lower their risk tolerance in response to safety issues or scandals, raising the bar for introduction of new drugs which increases development costs. (3) This development is of concern as new drugs might become too expensive to develop or unaffordable to pay for by consumers or insurers. (4) While there are still diseases for which no pharmaceutical treatments are available, or considered inadequate, the new drugs coming to the market usually do not target these unmet medical needs. (5,6) In fact, many of the new drugs have only limited added value to what is already available. Pharmaceutical companies might prefer to avoid risks and focus on areas they are familiar with and that have higher probability of success. The industries view may be understandable, as the success rate for drugs entering phase III clinical trials is estimated at 64%. (7) In 2009, only 60% of new drug applications received a positive opinion by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). (8) Drugs for which industry sought scientific advice from the EMA were more successful than those for which this was not the case. Some of these failures might have been prevented by improving the dialogue during drug development and by better adherence of the industry to the scientific advice given by regulators. (9) In this context TI-Pharma initiated the Escher project. It aims at improving science-driven drug regulation and innovative research throughout phased drug development. Top Institute Pharma is a public private partnership where universities and partners from the pharmaceutical industry work together on multidisciplinary research. The Escher project also involves co-operation from the Dutch Medicines Evaluation Board with the aim “to evaluate and remove regulatory bottlenecks hampering the efficiency in pharmaceutical innovation and stimulate factors helping innovation ”. (10) The research presented in this thesis was performed within this project. 8 General introduction Regulatory procedures to help meet unmet medical need For many diseases with unmet medical need, new therapeutic options are essential. For those cases, the regulators have established special registration procedures that either accelerate the approval procedure (e.g. Accelerated Approval procedure in the USA) or reduce the requirements for the amount of data to be presented at registration (e.g. the Exceptional Circumstances (EC) or Conditional Approval (CA) procedures in Europe). (11-13) Regulatory mechanisms for continuous safety ascertainment When a drug is approved, a new phase of its life cycle begins. The population using the drug is no longer the limited trial population from the clinical development, but includes also patients that might not have been included in the trials. (1,14) To meet the challenges of continuous safety ascertainment, regulatory agencies have moved from a reactive system monitoring, mostly spontaneous ADRs, to a proactive system of Risk Management Plans which is a mandatory part of the marketing application since 2005. (15) An important part of risk management and risk minimization is timely and accurate risk communication of serious safety concerns identified post marketing. (16) In Europe the risk communication can have the form of a Direct Healthcare Professional Communication (DHPC), a letter sent out by the marketing authorisation holder, in collaboration with the regulators, to physicians, pharmacists and other healthcare professionals involved in the use of the particular drug. Safety related market withdrawal and DHPCs are regarded as safety related regulatory actions. (17) Regulatory learning and drug class effects Adverse drug reactions that were discovered post-marketing have sometimes triggered recalling drugs from the market. (18,19) Review of registration dossiers showed that some adverse events could have been predicted at time of approval. (20) Adverse drug reactions (ADRs) related to the drug’s mechanism of action can potentially be identified pre-approval while ADRs that are due to off-target (unexpected) pharmacological effects are often unpredictable and are likely only identified post-approval. Thus, for certain drug classes safety issues may be relevant for subsequent new drugs in the same class. These should be monitored in the clinical development program and, where necessary, long term, using appropriate methods. (21) Determining ADRs for novel drugs as compared to next-in-class (or ‘me-too’) drugs seems more difficult as there is no class experience. This is acknowledged 9 Chapter 1 in the new European pharmacovigilance legislation which stipulates that first-in-class or novel drugs could be subject to additional monitoring post-marketing or will be subject to restricted medical prescription. (22) This raises the question whether more DHPCs are being issued for drugs that lack safety knowledge at time of approval and should be subject to additional monitoring post marketing. Patient involvement in regulatory decision making Today, the importance to take the patients’ perspective into account in health care is acknowledged as the most important next step in developing quality of health care. In management of chronic diseases, patient self-management and participation in treatment decisions is an integral part. (23) Active patient involvement in monitoring and reporting of side effects is also increasing and is becoming an important source for detection of ADRs. (24,25) Also regulating agencies also recognize this development as illustrated by the increasing interest in patient reported outcomes. (26) Regulators have accepted that patients are not only important in reporting of ADRs, but can also contribute to work within the regulatory agencies. As a platform for patient co-operation the European Medicines Agency has set up a framework for collaboration with qualified patient organisations with the Patients’ and Consumers’ Working Party (PCWP) and the US Food and Drug Administration has established the Patient Representative Program. (27,28) Throughout the years, patient involvement in the European Medicines Agency has been of an advisory nature. Patient organisations do have representatives