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HIV Vaccine Research: Ethical and Regulatory Issues NIH (DAIDS) Experience

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)

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HIV Vaccine Research: Ethical and Regulatory Issues NIH (DAIDS) Experience

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  1. 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. 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. 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. 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. 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. Trials Supported by DAIDS (2006/07)

  7. HVTN: A Global Network

  8. DAIDS Protocol Review(general steps) • DAIDS Prevention Sciences Review Committee (PSRC) • DAIDS regulatory review • FDA • Host country regulatory reviews • EC/IRBs • IBCs

  9. Regulatory ComplianceDAIDS’ 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. 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. Non-US Host Country Requirements • National ethical and/or scientific review(s) • Pharmacy Boards (or equivalent) • Biosafety review • Local review

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

  14. 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. 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. 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. A Global Vaccine EnterprisePotential 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. Enterprise Regulatory Action Priorities • Harmonize and exchange information needed by regulatory bodies within the differing legal frameworks of different countries • Facilitate regulatory decision making, possibly using regional approaches for reviews & recommendations • Build regulatory capacity • Perform risk/benefit evaluations in the context of differing epidemic dynamics and country needs and resources • Identify and remove potential scientific impediments to rapid regulatory decision making • 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. 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

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