06.04.2011 Ingrid Klingmann, MD, PhD, FFPM, FBCPM European Forum for Good Clinical Practice

1. Bratislava University Workshop on GCP Changing the Clinical Trials Directive – Needs and Opportunities for Academic Research 06.04.2011 Ingrid Klingmann, MD, PhD, FFPM, FBCPM European Forum for Good Clinical Practice Brussels, Belgium

2. The Current Situation in Europe • Numerous articles and case studies have postulated that Directive 2001/20/EC, the „Clinical Trials Directive“ (CTD) has failed to promote efficient clinical research in Europe and to better protect the study participants • However, there are more causes for the decreasing clinical research activity in Europe than the legal framework • The European Medical Research Council of the European Science Foundation has analysed in a series of workshops the current problems faced in IITs. They developed 26 high-level recommendations to improve patient-oriented research in Europe, presented in „Forward Look: Investigator-Driven Clinical Trials“ (2009)

3. European Science Foundation Report • ESF‘s EMRC identified 5 main issues: • Categories and design of patient-oriented research needed for promoting health research • Regulatory and legal issues, intellectual property rights and data sharing between stakeholders such as academia, industry and patient groups • Management of investigator-driven clinical trials • Education, training, careers and authorship • Funding and models of partnership

4. European Science Foundation Report • ESF‘s EMRC developed 26 recommendations. The top 5 were: • Better conditions for education, training and career for clinical researchers • Level of funding for clinical research in Europe • Risk-based approach to regulating clinical trials • Improved clinical trial authorisation process, ideally with a single CTA • Adequate scale for IITs: funding infrastructure for correctly powered trials

5. The ICREL Study • Focusing on the legislative environment as a potential source of hurdles for clinical research, DG Research funded within FP7 the „ICREL Study“ with the aim to generate objective information on the current situation • ICREL was performed in 2008 and provided evidence that important steps towards more sophisticated study review and harmonisation of clinical trial procedures in all EU Member States (MSs) have been made BUT so far the new legislation has made the preparation and performance of clinical trials more complicated and most probably hindered the performance of important research

6. Index of Total Number of CTAs

7. Number of CTAs Submitted by Commercial Sponsors

8. Number of CTAs Submitted by Non-commercial Sponsors

9. 20%

10. 36%

11. Number of Protocol Amendments Submitted to NCAs For Approval

12. Index of the Number of FTEs in Competent Authorities for Scientific Evaluation

13. Increases in Work Forces for CT-Related Tasks in Pharmaceutical Companies

14. Increases in Work Forces for CT-related Tasks in NCS

15. Mean Time To Obtain Authorisation Mean time to obtain authorisation per NCA Time lines from CS protocol finalisation to inclusion of first patient and from (substantial) amendment release to first implementation in 2003 and 2007

16. Number of Involved Countries, Centres and Participants in Commercial Trials

17. Number of SAEs or SUSARs Reported to NCAs

18. Impact of Implementation of the EudraVigilance Database on the Safety of Participants per Stratum

19. Room for Improvement! So, what can be done to improve the future of clinical trials in Europe?

20. Road Map Initiative for Clinical Research in Europe • Formed by academic organisations and institutions like ECRIN, EORTC, EFGCP, EBMT, ICREL, CLINT, LeukemiaNet • Organised multi-stakeholder one-day workshops to identify problems and discuss solutions on • Single CTA • Co-sponsorship • Risk-based approach • Harmonised ethical review • Safety reporting in clinical trials • Final workshop

21. Single CTA Workshop • Reducing the complexitiy of the study approval process: • ONE CTA application dossier, centrally placed, accessible to all CAs and ECs involved • Single CTA for multi-national trials • Single ethical approval with national input in multi-national trials • Clear definition of terms like „Investigational Medicinal Product“, „Non-interventional trial“, „Substantial Amendment“, etc. • Clear assignment of responsibilities in the process to NCAs and ECs • No additional review hurdles on national levels

22. Other Workshop Results • Facilitating sponsor definition and obligations: • Possibility of co-sponsorship based on a detailed contractual agreement between the parties • Identical application range of the legislation in all countries (e.g. Surgery trials? Medical devices? Radiotherapy?...) • Simplification of the administrative requirements according to a „risk-based approach to clinical trial regulation “

23. Other Workshop Results • Facilitating sponsor definition and obligations: • Coverage of the clinical trial liability insurance by government or healthcare system • Facilitating SUSAR-reporting through single entry into EudraVigilance and only periodic safety information to ethics committees and investigators • Harmonisation of safety reporting requirements between EMA and FDA • Harmonisation of inspection requirements between EMA and FDA

24. Other Workshop Results • Improving the infrastructure for clinical trials: • Adaptation of the funding level per study to the increased professionalism of the trial administration • Public funding of the creation of more dedicated, highly trained and efficiently managed clinical trial centres

25. Participants to the Survey & Countries Represented

26. Instead of parallel reviews and approvals by all NCAs involved there should be a “Single CTA” for multi-national clinical trials

27. For single-centre and national multi-centre CTs, the CTA should be submitted to the competent NCA

28. There should be a single application dossier, submitted at a central location (e.g. EudraCT) with access for the reviewing NCA(s). No additional national documents would be requested STANDARD OPERATING PROCEDURES

29. There should be a more harmonised Ethical Review Process in the EU

30. Improvement of Ethical Review The quality of the ethical review should be improved and harmonised through accreditation of ethics committees There should be substantial funding for training of EC members

31. Common Ethical Review Dossier EC Common EC/NCA Dossier

32. SUSAR Reporting Single entry in EVCTM -e-copy to CA No expedited SUSAR reporting to EC and PI

33. The Risk-based Approach Replacement of „one-fits-all“ by risk-based approach Implementation of risk categories

34. Initiatives for Improvement • DG Enterprise launched a public consultation that closed in January 8, 2010. Key issues to be commented: • Multiple and divergent assessments of clinical trials • Inconsistent implementation of the CTD • Regulatory framework not always adapted to the practical requirements • Adaptation to pecularities in trial participants and trial design • Ensuring compliance with GCP in CTs performed in third countries

35. Initiatives for Improvement • DG SANCO released on 30.03.2010 a revision of the CTA guideline which will require legal changes in most Member States • Major revision with different structure • Including the new developments for paediatric and first-in-man trials • Possibility to submit additional information during an ongoing review procedure • CTA Submission electronically, only cover letter in paper • Information that specified EUDRACT entries will be made public

36. Initiative for Improvement • DG SANCO released on 30.03.2010 a revision of the CTA guideline which will require legal changes in most Member States • National Competent Authorities are requested to accept all documents in English with exception of PIS and EC • Definition of the content of the CTA dossier – not foreseeing national additional documentation requests anymore • Voluntary Harmonisation Procedure or any other CTA harmonising procedure is not mentioned

37. Initiatives for Improvement • DG SANCO released on 17 July 2010 a revision of the AE Guideline for consultation until 10.09.2010 • SUSAR reporting by sponsor to EVCTM or Competent Authorities of all countries where the trial is performed • SUSAR reporting only to lead EC in which the SUSAR occurred • Annual Safety Report to other ECs and investigators • Definition of responsibilities for assessment of causality and expectedness between PI and sponsor

38. Initiatives for Improvement • DG SANCO released on 09 February 2011 the public consultation of a Reflection Paper on „Revision of the Clinical Trials Directive 2001/20/EC“ • Proposal to have a single dossier submission to all Member States through a single portal, the EudraCT database • Proposal for different central CTA assessment procedures • Discussion of new scope of the CTD, especially concerning non-interventional study definition • Risk-adapted rules for the content of the application dossier and safety reporting • New definition of „IMP“ • Proposal for insurance coverage by national healthcare systems

39. Initiatives for Improvement • DG SANCO released on 09 February 2011 the public consultation of a Reflection Paper on „Revision of the Clinical Trials Directive 2001/20/EC“ • Proposal for sharing of sponsorship • Proposal for emergency clinical trials • Proposals for clinical trials in third countries

40. Conclusions • There is much clearer and more common understanding of what is going wrong at the moment • There is much common understanding between academic and commercial sponsors on how the situation should be improved • DG Research strongly supports the interests of the academic researchers • DG SANCO is in the process of achieving as much improvement as possible through guidelines and makes first attempts towards new legislation • The Heads of Agencies make strong efforts to improve the situation of CTAs within the current legal framework • However, new legislation will be required to force the Member States to apply strictly the same rules for clinical trial authorisation and safety reporting to enhance the performance of multi-national clinical trials in in the interest of patients‘ rapid access to n new treatments

41. Thank you for your attention