HIV Vaccine Research: Ethical and Regulatory Issues Brasília, 4-5 October 2006 Panel 2

1. HIV Vaccine Research: Ethical and Regulatory IssuesBrasília, 4-5 October 2006Panel 2 International experience: the role of the regulatory agencies in research, technological development, production, research material importation and approval of new products The DCVRN experience Sérgio Nishioka, MD, PhD ANVISA, Brazil DCVR Network Chairman

2. I am currently manager of the Office of New Drugs, Research and Clinical Trials at ANVISA (National Health Surveillance Agency), but this presentation is made on behalf of the Developing Country Vaccine Regulators Network (DCVRN). The views herein expressed are not necessarily those of ANVISA. Disclaimer

3. The following presentation was prepared by James Southern, from the South African NRA, also a member from the DCVRN, for an HIV/AIDS session on the AVAREF (AFRO Vaccine Regulatory Forum), held in Accra, Ghana, in September 2006. Acknowledgement

4. DCVRN • Objectives • Strengthen capacity in DCVRN member NRAs • Develop mutual understanding of policies • Improve skills and knowledge of members - e.g. Training • Integrate best practice into member NRA activities • Transfer strengths to other non-member DC NRAs • Report & disseminate DCVRN regulatory perspectives • Current Membership • Brazil • China • Cuba • India • Indonesia • Korea • Russia • South Africa • Thailand • WHOfacilitation

5. DCVRN Meeting in Bangkok - 2005 • Clinical evaluation of HIV Vaccines • Reports of trials in progress • Regulatory perspective of developed countries • Regulatory issues for developing countries • Clinical evaluation of rotavirus vaccines • Background on human papilloma disease and vaccine development. • Strengthening the DCVRN

6. Clinical evaluation of HIV vaccines • Scientific Reports Session • Reports of trials in progress: • MRK-Ad5 Cl-B gag(pol/nef) • Vaxgen gp120/140 in Thailand • NIH & WHO perspectives • Experience of India, Thailand and Indonesia • Expectations of USA-FDA • Member discussions of problem areas

7. Primary concerns of regulatory authorities • Regulation of Clinical Trials • Registration of Medicines – HIV Vaccines • An URGENT issue for many countries

8. Registration of an HIV vaccine • An ideal HIV vaccine • Quality of manufacture • Safe • Efficacious in protection from infection • Affordable, available and acceptable • But it may be necessary to modify expectations

9. HIV vaccine clinical trials - 1 • Requirements for registration drive clinical trial design • Safety issues for HIV vaccines: • Generally accepted criteria • Infants – adolescents - adults • Danger of disease exacerbation in individuals that may become HIV infected • Spread, persistence and effects of GMOs • Inappropriate behavioural changes

10. HIV vaccine clinical trials - 2 • Efficacy in protection from diseas • So far no human vaccine has shown protection • There is no agreed marker of efficacy • Antibody response to envelope protein – no good? • Cellular immune responses (to what) current goal • Uncertainty regarding cross-clade protection

11. HIV vaccine clinical trials - 3 Clinical trials remain exploratory • Develop new types of vaccine • Pre-clinical evaluation • Clinical trials • Find protective vaccine • Analyse immune responses • Define mechanism and correlates of protection

12. HIV vaccines – Another perspective • Expectation of protection from infection – may be unrealistic • Disease modification: [therapeutic] vaccines • Reduction of viral load • Maintained CD4+ count • Reduced intercurrent infections • Extended time to treatment – Quality of life • Improved ARV efficacy • Transmission – infectivity reduction

13. The other perspective • Most current clinical trials include • Rates of new HIV infections (protection) • Changes in dynamics of viral load • Changes in dynamics of CD4+ count • Viral load in transmissable body fluids • Rates of intercurrent diseases • However some outcomes need Extended trials • Development of AIDSRequirement for ARV treatmentReponse to ARV treatment • Intercurrent infections

14. DCVRN concerns discussed in Bangkok • Ensuring that clinical trials lead to a licence • Definition of an efficacy end point • Preventive vaccine • Therapeutic vaccine • Can a phase II study be a basis for registration? • The definition of surrogate markers of immunity • The definition of “clinical benefits” of a vaccine • Registration problems of heterogenous prime-boost vaccines

15. Further DiscussionPhase II as basis for registration • Normal expectation is successful completion of phase III studies • Suggestions that extended phase II-b studies may be sufficient was challenged • In some countries the urgency may mandate registration and follow-up phase IV • This would bring further problems of sponsorship and monitoring • No consensus exists on this issue

16. Further discussion- Surrogate markers • Preventive vaccines • No protective vaccines are known • Thus markers of protection are unknown • Therapeutic vaccines • Complex issue • Viral load and CD4+ count most likely • Much more experience with vaccines needed • Responsibility for long-term treatment of trial participants must be defined

17. Further discussion • Clinical benefits as a vaccine end-point • This is difficult to define and impractical • “Quality of Life” would depend on external factors – e.g. disease environment • Combination prime-boost vaccines • Would need to registered as a combo-package

18. Conclusions • The DCVRN Bangkok meeting enabled • Provision of up-to-date information • Discussion of undefined / problem areas • Insight into WHO, EU and FDA perspectives • Identification of issues of concern for members • Debate that may lead to future consensus • These are critically important issues, particularly for DCVRN member coutries and should be the subject of further workshops

19. Thank you! sergio.nishioka@anvisa.gov.br