dhhs/nih/niaid/daids 5 october 2006 hiv vaccine research: ethical and regulatory issues nih (daids)...

DHHS/NIH/NIAID/DAIDS 5 October 2006

HIV Vaccine Research: Ethical and Regulatory Issues

NIH (DAIDS) Experience

Alan Fix, MD, MSChief, 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)


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.


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


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.


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


Trials Supported by DAIDS (2006/07)

Adeno DNA Pox virus Peptide Cytokine Env sub Other

HVTN 050 HVTN 045 HVTN 042 HVTN 042 HVTN 040

HVTN 502 HVTN 048 HVTN 055 HVTN 059

HVTN 503 HVTN 044 HVTN 044

HVTN 057 HVTN 052



VRC 009 HVTN/EUROV HVTN/EUROV

VRC 010 VRC 007

VRC 008 VRC 008

RV 156 RV 144 RV144

ABL ABL


RV 172 RV 172

IAVI V001 IAVI V001

IAVI V002 IAVI V002

PAVE 100 PAVE 100

HVTN/SAAVI HVTN/SAAVI



HVTN 065 HVTN 065

HVTN 067 HVTN 067

HVTN 069 HVTN 069


HVTN: A Global Network


DAIDS Protocol Review(general steps)

• DAIDS Prevention Sciences Review Committee (PSRC)

• DAIDS regulatory review• FDA• Host country regulatory reviews• EC/IRBs• IBCs


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


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


Non-US Host Country Requirements

• National ethical and/or scientific review(s)

• Pharmacy Boards (or equivalent)• Biosafety review• Local review


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


Multi-Network Phase I/II Trials ofVRC 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)


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


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


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.


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


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.


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

dhhs/nih/niaid/daids 5 october 2006 hiv vaccine research: ethical and regulatory issues nih (daids)...

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