1. DHHS/NIH/NIAID/DAIDS 5 October 2006 HIV Vaccine Research: Ethical and Regulatory Issues NIH (DAIDS) Experience Alan Fix, MD, MS Chief, Vaccine Clinical Research Branch (VCRB) Vaccine Research Program (VRP) Division of AIDS (DAIDS) National Institute of Allergy & Infectious Diseases (NIAID) US National Institutes of Health (NIH)

2. DHHS/NIH/NIAID/DAIDS 5 October 2006 Division of AIDS (DAIDS) Mission To help end the HIV/AIDS epidemic by: increasing basic knowledge of the pathogenesis and transmission of HIV, the development of therapies for HIV infection and its complications, and the development of vaccines and other prevention strategies.

3. DHHS/NIH/NIAID/DAIDS 5 October 2006 NIAID Supported HIV Vaccine Trials >24,000 volunteers 14 countries 17 international trials 97 preventive HIV vaccine trials 83 phase I 12 phase II 1 phase IIB 1 phase III 36 products, 14 adjuvants 10 different routes/methods of administration Excellent safety experience

4. DHHS/NIH/NIAID/DAIDS 5 October 2006 Vaccine Safety Safety data published for Phase I/II trials (1988 – 2001)* 3,189 volunteers followed for 12,340 person years: 2,458 in 49 phase I trials 731 in 2 phase II trials Similar safety patterns in over 2,000 additional volunteers enrolled in the last 5 years No increased incidence in grade 3 or 4 adverse events between vaccine and placebo for any local or systemic toxicity except for one study using IFA No evidence of autoimmunity, cancer, vaccine allergy, death or disability *Gilbert, et al. (2003). Vaccine 21: 2933-47.

5. DHHS/NIH/NIAID/DAIDS 5 October 2006 DAIDS Global HIV Vaccine Trial Activity Americas Caribbean Dominican Republic, Haiti, Jamaica, Puerto Rico North America United States (continental) South America Brazil, Peru Africa Southern Africa Botswana, Malawi, South Africa Eastern Africa Kenya, Rwanda, Tanzania, Uganda Asia Thailand

6. DHHS/NIH/NIAID/DAIDS 5 October 2006 Trials Supported by DAIDS (2006/07)

7. DHHS/NIH/NIAID/DAIDS 5 October 2006 HVTN: A Global Network

8. DHHS/NIH/NIAID/DAIDS 5 October 2006 DAIDS Protocol Review (general steps) DAIDS Prevention Sciences Review Committee (PSRC) DAIDS regulatory review FDA Host country regulatory reviews EC/IRBs IBCs

9. DHHS/NIH/NIAID/DAIDS 5 October 2006 Regulatory Compliance DAIDS’ Requirements Compliance with host country regulations Compliance with U.S. regulations Approval by local IRB/EC & IBC Approval by local required bodies (government, scientists, ethical) Site initiation by DAIDS, Network Rigorous adherence to protocol Timely reporting of Adverse Events Security of files, product Availability for audits

10. DHHS/NIH/NIAID/DAIDS 5 October 2006 US Requirements Regulation/Law FDA - 1572 OHRP (Office of Human Research Protections) – FWA & IRB registration State Required review per US regulation FDA Local IRB/EC NIH requirements OBA (Office of Biotechnology Activities) “NIH Guidelines for Research Involving Recombinant DNA Molecules” RAC (Recombinant DNA Advisory Committee) Local IBC (Institutional Biosafety Committee) Equivalence

11. DHHS/NIH/NIAID/DAIDS 5 October 2006 Non-US Host Country Requirements National ethical and/or scientific review(s) Pharmacy Boards (or equivalent) Biosafety review Local review

12. DHHS/NIH/NIAID/DAIDS 5 October 2006 Sources of Delay Lack of understanding of requirements (including initial failure to identify all review requirements) Incomplete submissions and responses to review Infrequent/missed meetings of regulatory bodies Reorganization of review bodies Relatively new agencies

13. DHHS/NIH/NIAID/DAIDS 5 October 2006 Multi-Network Phase I/II Trials of VRC HIV Vaccine Birmingham, AL Nashville, TN Rochester, NY Baltimore, MD Kingston, Jamaica Rio de Janeiro, Brazil KOSH*, South Africa Soweto, South Africa Sao Paulo, Brazil Boston, MA Port-au-Prince, Haiti * Klerksdorp, Orkney, Stiflontein, Hartbeesfontein Capetown, South Africa Kigali, Rwanda Kericho, Kenya Kampala, Uganda Mbeya, Tanzania Nairobi, Kenya Providence, RI HIV Vaccine Trials Network (HVTN) US Military HIV Research Program (USMHRP) International AIDS Vaccine Initiative (IAVI)

14. DHHS/NIH/NIAID/DAIDS 5 October 2006 Partnership for AIDS Vaccine Evaluation (PAVE) A voluntary consortium of USG agencies and key USG-funded organizations involved in the conduct of HIV vaccine clinical trials NIH/NIAID, including DAIDS Dale and Betty Bumpers Vaccine Research Center (VRC) HIV Vaccine Trials Network (HVTN) AIDS Vaccine Research Working Group (AVRWG) Centers for Disease Control and Prevention (CDC) U.S. Military Program for HIV Research Program (USMHRP) U.S. Agency for International Development (USAID) International AIDS Vaccine Initiative (IAVI) Initiated January 2003

15. DHHS/NIH/NIAID/DAIDS 5 October 2006 PAVE 100 DAIDS-sponsored, multi-network Phase IIB trial of VRC DNA/rAd5 (if supported by results of current Phase II Triad) CDC HVTN IAVI USMHRP Three regions Americas – HVTN East Africa – CDC, IAVI, & USMHRP South Africa – HVTN, IAVI

16. DHHS/NIH/NIAID/DAIDS 5 October 2006 Global HIV/AIDS Vaccine Enterprise Meeting in Airlie, Virginia – August 19, 2003 “The Airlie group agreed that the Global HIV/AIDS Vaccine Enterprise should be developed as an alliance of independent organizations committed to: accelerating the development of a preventive vaccine for HIV/AIDS through implementation of a shared scientific strategic plan, mobilization of additional resources, and greater collaboration among HIV vaccine researchers worldwide.” The Global HIV/AIDS Vaccine Enterprise: Scientic strategic plan. 2005. PLoS Med 2(2): e25.

17. DHHS/NIH/NIAID/DAIDS 5 October 2006 A Global Vaccine Enterprise Potential Benefits Accelerated rate of vaccine candidate development Expanded clinical trials capacity Assured availability of manufacturing capacity Harmonized regulatory approaches Provision of a forum and mechanisms for multiple stakeholders to collaborate more closely

18. DHHS/NIH/NIAID/DAIDS 5 October 2006 Enterprise Regulatory Action Priorities 1.Harmonize and exchange information needed by regulatory bodies within the differing legal frameworks of different countries 2.Facilitate regulatory decision making, possibly using regional approaches for reviews & recommendations 3.Build regulatory capacity 4.Perform risk/benefit evaluations in the context of differing epidemic dynamics and country needs and resources 5.Identify and remove potential scientific impediments to rapid regulatory decision making 6.Address ethical issues that interface with regulatory decision making The Global HIV/AIDS Vaccine Enterprise: Scientic strategic plan. 2005. PLoS Med 2(2): e25.

19. DHHS/NIH/NIAID/DAIDS 5 October 2006 Challenges Multiple EC/IRB & national agency review and potential for multiple directives for modification Communication among agencies Insurance and other mechanisms to cover expense of care of study related injury Maturing agencies (fledgling) – “learning curve” Mutual understanding of regulations, requirements, and areas of harmony, e.g., Recommended vs. required Terminology: e.g., Compensation, Indemnification