1. REFORMING THE CLINICAL TRIALS DIRECTIVE Opportunities and Challenges Hubert E. Blum Federation of the European Academies of Medicine (FEAM )

2. VIEW FROM FEAM Value of medical research Transparency and consistency in regulation of clinical research in EU: objectives, advantages and concerns Analysis of problems in current Directive Options for reform of policy and legislation Other issues for building clinical research

3. ACHIEVEMENTS IN EUROPEAN MEDICAL RESEARCH Nobel Prize Winners Legacy of success in combining curiosity- driven/clinical/ translational research 2008 zur Hausen (Germany) - HPV 2008 Barre-Sinoussi, Montagnier (France) - HIV 2001 Nurse, Hunt (UK) - cell cycle control 2000 Carlsson (Sweden) - nervous system signal transduction 1995 Nuesslein-Volhard (Germany) - embryonic development

4. VALUE OF MEDICAL RESEARCH Academic clinical research is vital for: –better patient care –professional education –industry innovation –informing public policy Major socio-economic benefits: –UK academy study finds up to 40% annual rate of return on public investment in cardiovascular and mental health research

5. CORE ROLE OF CLINICAL TRIALS Health delivery and research depend on each other CTs test the efficacy and safety of medicines CTs are essential in new drug development and in improving medical care Many CTs involve multiple countries but, historically, different Member States had different approaches to regulation

6. THE EU CLINICAL TRIALS DIRECTIVE (CTD) 2001/20/EC CTD implemented in 2004 –to harmonise authorisation procedures for trials on medicinal products –to improve collection of reliable patient data –to increase protection of health and safety of participants and ensure ethical soundness of trials In 2004, FEAM welcomed potential benefits for multi-national collaboration but predicted problems to academic research in case of inflexible application

7. PROBLEMS AFTER IMPLEMENTATION Continuing inconsistencies in regulatory standards and uncertainties in practice Increased administrative burden and costs for academia (and other researchers) EU becomes less attractive location - deterrent effect on new clinical research No good evidence to show improved patient protection or ethical soundness

8. CONCERNS ABOUT NEGATIVE IMPACT OF CTD “UK research trials are on verge of extinction” Letter signed by >100 leading medical academics The Times, January 2009

9. NEGATIVE IMPACT - FACTS (1) Reduction of planned number of participants in EU trial applications (DG Sanco statistics) –2007: 535,000 –2009: 358,000 Reduction of proportion of world’s pharmaceutical CT in UK (BMJ 2009) –2000: 6% –2009: 2% EU trials (ICREL statistics) –More costly –More difficult to plan, start and conduct

10. NEGATIVE IMPACT - FACTS (2) Particular problems in multi-national, non- commercial trials in cancer, paediatrics, transplantation (PLoS Medicine 2009) Striking decrease in number of drug development companies formed in Europe (EuropaBio 2010)

11. CTD - WHERE ARE WE NOW? 2008 Collection of evidence on impact 2009 EC consultation on issues; pharma- ceutical policy moves from DG Enterprise to DG Sanco 2010 Consultation responses published with Commission Roadmap 2011 Proposed options for legislative reform, involvement of European Parliament and Council of Ministers

12. FEAM ACTIVITIES FEAM Initiative Clinical Trials Directive analysis and advice at EU and country level 2009 Working Group Discussion Response to Consultation 2010 Further Academies Discussion FEAM Statement Published 2011 Key Issues Role of National Competent Authority (NCA ) Multiple/ Inconsistent Procedures Ethics Review Risk-based Assessment

13. FEAM GUIDING PRINCIPLES FOR REGULATING CLINICAL RESEARCH (1) Research must be recognised as part of the mission of health care systems Patient safety is highly important, but regulation of a trial should be proport- ionate to risk to patient Roles of researchers, sponsors, national competent authorities (NCAs), ethics reviewers must be clarified

14. FEAM GUIDING PRINCIPLES FOR REGULATING CLINICAL RESEARCH (2) CTD reform should reduce administrative burden, streamline review procedures and avoid duplication Change should be evidence-based, piloted and rigorously evaluated before widespread adoption

15. REFORMING NCA ROLES IN MULTINATIONAL STUDIES (2) Burden on trials based within single Member State (70% of total) must not further increase Multinational trial assessment can be streamlined: –Further potential for NCA voluntary cooperation –Explore option “common agreement” where lead NCA reviews/ approves with expedited approval from other NCAs –Avoid creating new centralised body

16. RESOLVING PROBLEMS IN TRIAL SUPPORT AND REPORTING - OBJECTIVES - Insurance –need consistent, but flexible, risk-based, EU-wide insurance system Substantial Amendments to Research –need clarity in definition and interpretation between countries and focus on what is truly substantial Suspected Unexpected Serious Adverse Reactions (SUSARS) –need clarity in definition, simplification of reporting procedures plus improved safety signal detection

17. REFORMING ETHICS COMMITTEE ROLES Clarify responsibilities and train committees Improve efficiency and create centralised ethics opinion at country level Increase consistency across EU, e.g.: –Common template for consent –Mutual recognition Doubt if possible to create single ethics review for all multi-national trials – national differences in ethical views (e.g., embryonic and stem cell research)

18. ADOPTING A RISK-BASED APPROACH (1) Current central CTD weakness: regulation is not proportionate to expected risks Need to develop regulatory flexibility to: –Handle different types of current and future trials –Focus on benefit-risk, not safety alone Consider implications for: –Ethics –Safety reviews –Monitoring –Insurance –Quality assurance

19. ADOPTING A RISK-BASED APPROACH (2) Decreased regulatory burden on low-risk trials (e.g., those equivalent to “usual care”) New approach must be implemented before CTD extension of scope can be considered

20. BUILDING EU CLINICAL RESEARCH ENVIRONMENT - OPPORTUNITIES (1) New funding models for –research –infrastructure in translational medicine New support for training and career pathways Building partnership across disciplines and between academia and industry - without compromising academic indep- endence

21. BUILDING EU CLINICAL RESEARCH ENVIRONMENT - OPPORTUNITIES (2) Making best use of research already done - usable databases of protocols and results Ensuring research community has early awareness of EU policy developments

22. FEAM - CONCLUSIONS AND MAIN MESSAGES - Clinical research is vital for Europe - administrative burden can be lessened CTD must be urgently reformed - key issues: –Clarifying –Simplifying –Streamlining roles and procedures Discussion of options for regulatory reform and building supportive infra-structure must include all research interests - patients, academia, industry, other funders