International Research and Subjects Protections

1. International Research and Subjects Protections Richard Carpentier, National Council on Ethics in Human Research and FOCUS Secretariat, CANADA

2. Agenda

3. Why is Research Subjects Protections in International Research So Important Now?

4. Increase in International Research Activities

7. Growth of International Federal Wide Assurance

8. Number of Overseas Human Clinical Trials for New Drugs

9. Human Subjects in Clinical Trials

10. Foreign Clinical Trials Percentage of NDA submissions using foreign data 1995 --- 9% 1999 --- 27% Numbers of foreign human subjects participating in NDA clinical trials 1995 --- 4,000 1999 --- 400,000

11. U.S. Department of Health and Human ServicesThe Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects Janet Rehnquist Inspector General, September 2001

12. The Globalization of Clinical Trials Purpose of the Report To document the growth of non-U.S. clinical drug trials contributing data to New Drug Applications for Food and Drug Administration (FDA) approval, and to assess FDA�s capacity to assure human subject protections in these trials.

13. The Globalization of Clinical Trials Background In our June 2000 report, Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research (OEI-01-97-00195), we drew attention to the fact that clinical drug trials conducted outside the U.S. can be an important source of data in FDA�s determination of the safety and efficacy of new drugs.

14. The Globalization of Clinical Trials We recommend that FDA: Obtain more information about the performance of foreign institutional review boards Help foreign review boards build capacity to conduct effective human subject reviews

15. The Globalization of Clinical Trials Encourage sponsors to obtain attestations from foreign investigators that they will adhere to ethically sound principles of research Encourage greater sponsor monitoring Develop a database to track the growth and location of foreign research

16. The Globalization of Clinical Trials We recommend that the Office for Human Research Protections Exert leadership by developing strategies to ensure that adequate human subject protections are afforded for non-U.S. clinical trials that are funded by the Federal government and/or that contribute data in support of a New Drug Application

17. The Globalization of Clinical Trials Encourage accreditation of institutional review boards in a voluntary accreditation system as one way to improve the capacity to conduct appropriate reviews of human subject protections in proposed research. The Office for Human Research Protections, working with FDA, NIH, and others, can help develop such a system internationally

18. Department of Health & Human Services Office of Inspector General The Orange Book 2005 Daniel R. Levinson, Inspector General

19. The Orange Book 2005: Obtain Data on IRBs We recommended that FDA examine ways to obtain more information about the performance of non-US IRBs and help those inexperienced IRBs build their capacities; encourage all non-US investigators participating in research to sign attestations upholding human subject protections; and develop a database to track the growth and location of foreign research.

20. The Orange Book 2005 We recommended that OHRP exert leadership in developing strategies to ensure adequate human subject protections for non-US clinical trials funded by the Federal Government and those that contribute data to new drug applications.

21. Ethical Breaches

22. Illegal Trials in India

23. Improper Research by Johns Hopkins Researcher in India A Johns Hopkins University scientist, Dr Ru Chih C. Huang, tested experimental cancer drugs on patients in India without required federal approval, nor university research ethics approvals and without adequate preliminary tests in animals.

24. Use of placebos in AIDS vaccine research in Bankok

25. VanTx Research, Basel, Switzerland In 1998-1999, VanTx, a CRO, was recruiting Estonian and Polish students, proposing �vacations in Switzerland�, with high salary. It was working for major pharmas. Reports say subjects were sequestrated with passports confiscated

26. VanTx Research, Basel, Switzerland Use of non-recognized ethics committee Consent form signed after minimal information, in a foreign language (German) Participants coerced to remain enrolled in trials The firm falsified test results Absence of medical follow-up after study

27. Has Canada Let Her Down?

28. Lack of Ethics Review A survey of more than 200 developing-country health researchers has found that a quarter of clinical trials carried out in developing countries do not undergo any kind of ethical review in the host nation. Re Journal of Medical Ethics, February 2004

29. Sustaining Trust

30. Erosion of Public Trust There is a public perception that subjects of clinical trials are equivalent to guinea pigs Trust is an essential ingredient in the success of clinical trials � as necessary to recruit subjects Need to be very honest with subjects about the nature of research (this is not treatment) the risks and benefits, and avoid conflicts of interest

32. 2004 International Will & Why Survey "Of the Polish respondents who would not participate in a clinical trial, 45 percent responded because of the health risks in clinical trials and 28 percent responded because of the "guinea pig" perception associated with clinical trials. "

33. Erosion of Public Trust People are not aware that over and above the confidence they have in their doctors, there are protections in place International research should not create double standards in terms of experimental treatment Need to publicize ethical protections, make policies available

34. Erosion of Public Trust There is a fear that only lip service paid to ethics

35. Ethics Committees are instruments which should help maintaining trust Need for capacity-building

36. Capacity-building for Ethics Committees Local research ethics committees are essential as they provide the knowledge of the local research context Vulnerability of research participants Specific conditions of research and of health system Cultural variability in the application of norms and policies Assessing risks and benefits, appropriate language

37. Capacity-building for Ethics Committees National education strategy aimed at researchers, institutions and Research Ethics Committees Applicable law, regulations and policies How to review a protocol Rules for informed consent Inventory of RECs

38. Capacity-building for Ethics Committees Development of national criteria and standards based on cultural background and needs Friendly educational visits to help at the application of criteria and standards � to develop eventually into accreditation

39. About International Standards

40. International Standards Most standards are principle-based Most standards are voluntary, for example Helsinki and CIOMS; International declarations agreed upon by states need to be embedded in enforceable instruments However there is little verification in terms of quality of implementation

41. International Standards The implementation of other standards subject to better monitoring: Good clinical practice US Regulations (FDA, OHRP)

42. US FWA One of the most powerful instrument is perhaps the FWA required from all institutions receiving funds from HHS Many institutions seem to adopt a na�ve attitude and not to read the fine prints: but signatory institutions commit themselves to doing many things

43. US FWA All research in the institution must be guided by a statement of ethical principle Need written procedures for: Reporting to the EC and appropriate officials Unanticipated problems creating risks to subjects Serious or continuous non-compliance Suspension or termination of research Conducting initial and continuing review Determining which projects need more than annual review

44. US FWA Ensuring prompt reporting to EC of proposed changes to research activities and ensuring they are not implemented without EC approval, unless I would eliminate risks to subjects AND THERE IS MORE TO READ � Inspections may be conducted on the basis of FWA and use of research funds suspended if not satisfactory

45. FOCUS : the Canada-US Forum

46. About FOCUS FOCUS strives to achieve its objective through the following activities: Providing a forum for regular meeting and discussion of research ethics issues common to Canada and the United States and to facilitate dialogue, co-operation and exchange of experience between individuals and organization in order to enhance the protection of human participants in research; Fostering communication and partnerships between Canada and the United States, between governments and other organizations that share common values and goals;

47. About FOCUS Improving communication among IRBs/REBs; Promoting the development and implementation of actions designed to improve the quality of ethics review (e.g., accreditation); Promoting education about the ethics of research in humans across all disciplines.

48. Annual Conferences and Publications 2003 Canadian and American Perspectives on Quality Improvement and Performance Evaluation in Systems of Human Research Protection 2004 International Conference on Conflicts of Interest 2005 Ethical Issues in Behavioral and Social Sciences Research 2006 Research Ethics Education for Investigators 2007 Maintaining Public Trust in Clinical Research