1. Overview of Research Oversight: U.S. Perspective Leslie K. Ball, M.D., F.A.A.P. Office for Human Research Protections Department of Health and Human Services Email: LBall@osophs.dhhs.govLBall@osophs.dhhs.gov FDA Pediatric Oncology Subcommittee July 15, 2003

2. 2 Regulatory Oversight of Clinical Research in International Settings: U.S. Perspective Increasing pace and scope of international biomedical research Framework of U.S. regulatory oversight Role of OHRP in relation to FDA Research involving children International Research Issues and Obstacles

3. International Clinical Trials for New Drugs Sources: FDA Biomonitoring Research database; Parexel’s Pharmaceutical R&D Statistical Sourcebook 1999; Aculaunch; Washington Post Research Courtesy of Dr. Melody Lin, Deputy Director, OHRP

4. NIH International Research Expenditures Dollars Fiscal Years 1994 to 2000 Training = $103 million (34%) Research = $203 million (66%) Fiscal Year 2000 Courtesy of Dr. Melody Lin, Deputy Director, OHRP

5. 5 Clinical Research Balance Scientific advancement Product development Regulatory oversight Human subject protections

6. 6 Regulatory Oversight of Clinical Research in International Settings: U.S. Perspective Increasing pace and scope of international biomedical research Framework of U.S. regulatory oversight Role of OHRP in relation to FDA Research involving children International Research Issues and Obstacles

7. 7

8. Regulatory Framework: Drug Development HHS conducted or supported research Domestic* International 45 CFR 46 Subpart A (“Common Rule”) Subpart B (Fetus, Pregnant Women) Subpart C (Prisoners) Subpart D (Children) Research that involves products regulated by FDA 21 CFR 50, 56 Part 50: Protection of Human Subjects Subpart D (Children) Interim Rule Part 56: IRBs 21 CFR 312 – INDs 21 CFR 361 – Drugs used in research Regulatory Protection of Human Subjects: OHRPFDA Applies to: *Domestic institutions may elect to apply 45 CFR 46 to all of its research regardless of source of support

9. Secretary of HHS Commissioner FDA Assistant Secretary of Health Office of Public Health and Science Director OHRP Department of Health and Human Services

10. U.S. Regulatory Oversight for Clinical Research HHS conducted or supported (OHRP) HHS conducted or supported and FDA regulated (FDA) Studies that are neither HHS conducted or funded nor FDA regulated

11. 11 Office for Human Research Protections (OHRP) Mission Develop and implement regulations, policies and programs for protecting the rights and welfare of human subjects participating in research that is conducted or supported by the U.S. Department of Health and Human Services

12. 12 Regulatory Oversight of Clinical Research in International Settings: U.S. Perspective Increasing pace and scope of international biomedical research Framework of U.S. regulatory oversight Role of OHRP in relation to FDA Research involving children International research Issues and obstacles

13. 13 Research Involving Children: Historical Context Ethical lapses in the conduct of clinical research Beecher HK. NEJM 1966; 274:1354-60 1974: National Research Act Creation of the National Commission Charge included recommendations on research involving children 1979: Belmont Report 1981: Final Rule – 45 CFR 46 1983: Final Rule – 45 CFR 46 Subpart D Additional DHHS Protections for Children Involved as Research Subjects 1997: FDAMA 1997 Economic incentives to conduct pediatric drug studies (marketing exclusivity)

14. 14 Research Involving Children: Historical Context (cont.) 1998: FDA’s Pediatric Rule Requirement for assessing the safety and effectiveness of certain drugs in pediatric subjects 10/02 Court ruling: FDA did not have authority to issue Pediatric Rule and barred FDA from enforcement 2000: Children’s Health Act Directed Secretary of HHS to require all research involving children conducted, supported or regulated by HHS (incl. FDA) to be in compliance with Subpart D 2001: FDA’s Subpart D (Interim Final Rule) 2002: Best Pharmaceuticals For Children Act Reauthorized pediatric exclusivity incentives for drug products IOM review of research involving children

15. 15 Belmont Report Ethical Principles Respect for persons Individuals should be treated as autonomous agents Persons with diminished autonomy are entitled to protection Beneficence: Maximize benefits and minimize possible harms Justice: Relevant on individual and societal levels. Selection of subjects deserves scrutiny to determine whether some classes of subjects are unduly targeted for research

16. 16 Belmont Report (cont.) Application of Ethical Principles Informed consent – special provisions should be made when comprehension is limited Assessment of benefits and risks – when vulnerable populations are involved in research, the appropriateness of involving them should be demonstrated Selection of subjects –order of preference in selection of classes of subjects (e.g., adult before children); some classes of potential subjects may be involved as research subjects, if at all, only under certain conditions

17. 17 Basic Protections of U.S Federal Regulations 45 CFR 46 Informed consent of research subject Independent review of research Institutional assurances of compliance

18. 18 Assurances: Research conducted or supported by HHS “Each institution engaged in research which is covered by this policy and which is supported by a Federal Department or Agency shall provide written assurance…that it will comply with the requirements set forth in this policy.” [45 CFR 46.103(a)] Negotiated and approved by OHRP

19. 19 Assurances: Research conducted or supported by HHS (cont.) Formalizes institution’s commitment to protect human subjects Requires filing of an Assurance by both "awardee“ receiving HHS funds and collaborating institutions Requires designation of IRB or Independent Ethics Committees

20. 20 Institutional Assurances Institution Investigator Sponsor Assurance of Compliance with OHRP

21. 21 45 CFR 46 Subpart A: Selected provisions relevant to children IRB membership If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children consideration shall be given to inclusion of individuals who are knowledgeable about and experienced in working with these subject [45 CFR 46.107(a)] Criteria for IRB approval Selection of subjects is equitable – IRB should be particularly cognizant of the special problems of research involving vulnerable subjects, including children [45 CFR46.111(a)(3)]

22. 22 45 CFR 46 Subpart D: Additional Protections for Children IRBs review research and approve only research which satisfies the conditions specified by Subpart D regulations (e.g., minimal risk; more than minimal risk but prospect of direct benefit, etc.) Generally, as risk increases in relation to the presence or absence of direct subject benefit, criteria for IRB approval under Subpart D categories become more stringent

23. 23 45 CFR 46 Subpart D: Additional Protections for Children 46.404: Research not involving more than minimal risk 46.405: Research involving more than minimal risk but presenting prospect of direct benefit to individual subjects Risk justified by anticipated benefit The relation of anticipated benefit is at least as favorable to subjects as that presented by available alternatives Adequate provisions for assent and permission 46.406: Research involving minor increase over minimal risk and no prospect of direct benefit but likely to yield generalizable knowledge about subject’s disorder or condition 46.407: Research not otherwise approvable which presents opportunity to understand, prevent or alleviate a serious problem affecting health or welfare of children Review by panel of experts in relevant disciplines

24. 24 Regulatory Oversight of Clinical Research in International Settings: U.S. Perspective Increasing pace and scope of international Biomedical Research Framework of U.S. regulatory oversight Role of OHRP in relation to FDA Research involving children International research Issues and obstacles

25. 25 International Research Regulatory requirements for HHS conducted or supported research are the same, wherever research takes place 45 CFR 46.101(h): Procedures normally followed in foreign countries to protect human subjects may differ from those set forth in this policy… If foreign institution’s protections are at least as equivalent, the U.S. Department or Agency Head may approve the substitution of foreign procedures

26. 26 International Assurances Institution assures that its activities: Will be guided by ethical principles (one of the following) Declaration of Helsinki Belmont Report Other appropriate international ethical standards

27. 27 International Assurances (cont.) 45 CFR 46 Subparts A, B, C, D 45 CFR 46 Subpart A 21 CFR 50, 56 ICH-GCP-E-6 CIOMS Int’l Ethical Guidelines Canadian Tri-council Policy Indian Council of Medical Research Guidelines Other standards recognized by U.S. Federal Departments Institution assures that its activities Will comply with procedural standards (one or more)* *Under FWA “Terms of Assurance”, all U.S. federally- supported research must comply with requirements of any applicable U.S. federal regulatory agency.

28. 28 Issues and Obstacles in Regulatory Oversight of International Research Regulatory harmonization Different requirements of each regulatory agency Development of consistent approaches for Study monitoring Reporting requirements Ensuring review by IRB/Ethics Review Committees having knowledge of local research context For developing countries: building of host country capacity to conduct and review research

29. 29 For more information… OHRP website: http://ohrp.osophs.dhhs.gov/pdjay/pdjayin dex.htm http://ohrp.osophs.dhhs.gov/pdjay/pdjayin dex.htm Assurances Assurance information: http://ohrp.osophs.dhhs.gov/humansubject s/assurance/fwas.htm http://ohrp.osophs.dhhs.gov/humansubject s/assurance/fwas.htm Search for international assurances: http://ohrp.cit.nih.gov/search/asearch.asp