1. Ministério da Saúde The Brazilian HIV Vaccine Program: Ethical and Regulatory Challenges Cristina de A. Possas Research and Development Unit National Program STD-AIDS Ministry of Health, Brazil International Seminar HIV Vaccine Research: Ethical and Regulatory Issues Brasília, October 4-5, 2006

2. Vision Vision Brazil aims to participate in an outstanding way in the international effort towards Vaccine Research and Development and to conduct HIV Vaccine Research with the highest possible scientific, ethical and regulatory standards

3. IMPACT UNIVERSAL ACCESS TO ARV IN BRAZIL (1996 - 2002)  R eduction of Mortality  70%  Reduction of Morbidity  80%   58,000 new cases avoided  90,000 deaths avoided  Hospitalization  Reduced in 70%  358.000 hospitalizations avoided (1997- 2001) Economy: U$ 2.2 billion

4. International scenario for HIV vaccine development Over 30 clinical trials with vaccine candidates are now under way worldwide Over 30 clinical trials with vaccine candidates are now under way worldwide There are still some important scientific challenges for vaccine R & D (HIV hypervariability; Neutralizing Antibodies; Retrovirus; Animal Models; Correlate of protective immunity; HIV Antigens; Clinical Trials) There are still some important scientific challenges for vaccine R & D (HIV hypervariability; Neutralizing Antibodies; Retrovirus; Animal Models; Correlate of protective immunity; HIV Antigens; Clinical Trials) Source: IAVI - Aids Vaccine Blueprint 2006

5. New Paradigm: International Cooperation for a Dynamic Global R & D Program in HIV Vaccine WHO WHO UNAIDS UNAIDS IAVI IAVI NIH-HVTN NIH-HVTN ANRS ANRS The Global HIV/AIDS Enterprise –endorsed by the G-8 in June 2004 The Global HIV/AIDS Enterprise –endorsed by the G-8 in June 2004 The Collaboration for AIDS Vaccine Discovery (CAVD) – Bill and Melinda Gates Foundation – network of 11 vaccine discovery consortia The Collaboration for AIDS Vaccine Discovery (CAVD) – Bill and Melinda Gates Foundation – network of 11 vaccine discovery consortia

6. HIV Vaccine Strategies Vaccines from HIV Genes (Naked DNA, Viral Vectors, Bacterial Vectors) Vaccines from HIV Genes (Naked DNA, Viral Vectors, Bacterial Vectors) Vaccines from HIV Proteins (Proteins, Peptides) Vaccines from HIV Proteins (Proteins, Peptides) Vaccines from Whole HIV (Whole Inactivated HIV, Live Atenuated HIV) Vaccines from Whole HIV (Whole Inactivated HIV, Live Atenuated HIV) Combination (Combining different vaccine designs and/or different antigens) Combination (Combining different vaccine designs and/or different antigens)

7. Two approaches tested in large-scale efficacy trials VaxGen Phase III Trial – Sanofy Aventis (to induce cellular helper and humoral immune response) – Thailand VaxGen Phase III Trial – Sanofy Aventis (to induce cellular helper and humoral immune response) – Thailand Merck Phase II B Trial -Ad 5 HIV Vaccine - (first test of vaccine candidate inducing cellular – cytotoxic mediated immune response in the majority of vaccinees) – U.S, Canada, Peru, Dominican Republic, Haiti, Puerto Rico, Australia, Jamaica and Brazil. Merck Phase II B Trial -Ad 5 HIV Vaccine - (first test of vaccine candidate inducing cellular – cytotoxic mediated immune response in the majority of vaccinees) – U.S, Canada, Peru, Dominican Republic, Haiti, Puerto Rico, Australia, Jamaica and Brazil.

8. Obstacles to overcome, but a safe and effective HIV vaccine is possible Recent discoveries and promising studies of candidate vaccines in animal models indicate that a safe and effective HIV vaccine is possible and new advances in this area can be expected in the next 3-5 years Recent discoveries and promising studies of candidate vaccines in animal models indicate that a safe and effective HIV vaccine is possible and new advances in this area can be expected in the next 3-5 years Possible combined strategies: initial HIV vaccines will probably be partially efficacious (from low – 40% to high – 95% efficacy) Possible combined strategies: initial HIV vaccines will probably be partially efficacious (from low – 40% to high – 95% efficacy) Partially efficacious vaccines will probably require very high coverage Partially efficacious vaccines will probably require very high coverage

9. Brazil: National HIV Vaccine Committee The National Committee for HIV Vaccine supports the Brazilian National STD-AIDS in this area and has an outstanding role in national scientific and technological development in HIV research (representatives of scientific community and civil society) The National Committee for HIV Vaccine supports the Brazilian National STD-AIDS in this area and has an outstanding role in national scientific and technological development in HIV research (representatives of scientific community and civil society) The Committee is elaborating the new HIV Vaccine Plan for 2007-2012, with new priorities for research, development and production in this area The Committee is elaborating the new HIV Vaccine Plan for 2007-2012, with new priorities for research, development and production in this area

10. National HIV Vaccine Plan 2007-2012: guidelines Support to preventive and therapeutic vaccines Support to preventive and therapeutic vaccines Stimulate innovation: identify gaps in research and the main challenges to be addressed Stimulate innovation: identify gaps in research and the main challenges to be addressed Strengthen national and international collaboration Strengthen national and international collaboration Build national capacity for larger scale trials Build national capacity for larger scale trials Create national technological capacity for technology transfer for future recombinant HIV vaccines. Create national technological capacity for technology transfer for future recombinant HIV vaccines. Identification and support to potential new sites Identification and support to potential new sites Support to cohorts Support to cohorts Stimulate public-private partnership Stimulate public-private partnership Reinforcement of existing infrastructure Reinforcement of existing infrastructure Guarantee of access to evaluated products Guarantee of access to evaluated products Compatibility to ongoing activities Compatibility to ongoing activities Create adequate environment for scientific, ethical and regulatory evaluations, supported by stable funding mechanisms Create adequate environment for scientific, ethical and regulatory evaluations, supported by stable funding mechanisms

11. The new National HIV Vaccine Plan 2007-2012 - Strategies 1. Capacity building 2. Improve Laboratory & Clinical trial infra-structure 3. Adopt accreditation procedures 4. 4. Facilitate importation of equipment and materials. 5. Provide Sustainability of Funding 6. Organize site evaluation, selection and development for efficacy trials 7. Increase understanding of trial participation

12. The Brazilian strategy for developing local HIV Vaccine R & D Select a few scientific priorities and concentrate on them Select a few scientific priorities and concentrate on them Vaccine research: identification of gaps in research and development and feasible topics Vaccine research: identification of gaps in research and development and feasible topics Capacity building: research methodology and support to research (GLP, Bioinformatics, Data management, criopreservation) Capacity building: research methodology and support to research (GLP, Bioinformatics, Data management, criopreservation) Support to local implementation of research project Support to local implementation of research project Community preparedeness Community preparedeness

13. Funding HIV vaccine research The Brazilian government is giving priority to funding research in this area The Brazilian government is giving priority to funding research in this area The National STD-AIDS Program in the Ministry of Health has significant funding available for Scientific and Technological Development (14,5 million dollars 2004-2006) The National STD-AIDS Program in the Ministry of Health has significant funding available for Scientific and Technological Development (14,5 million dollars 2004-2006) A National Call for HIV Vaccine Research was just launched by the National STD-AIDS Program in June 2006 and preparatory studies for vaccine research were included as an item of this competitive process A National Call for HIV Vaccine Research was just launched by the National STD-AIDS Program in June 2006 and preparatory studies for vaccine research were included as an item of this competitive process

14. New National Call for HIV Vaccine R & D June 13 2006 - funding of 4 million dollars June 13 2006 - funding of 4 million dollars Broad range of topics in 14 thematic lines of research, including : Broad range of topics in 14 thematic lines of research, including : Research on mucosal immunity Research on mucosal immunity Central memory cells - phenotypes induced by HIV vaccines Central memory cells - phenotypes induced by HIV vaccines Studies to support the development of preventive vaccines (new Brazilian products) Studies to support the development of preventive vaccines (new Brazilian products) Correlates of immunity for mapping relevant epitopes for vaccine candidates Correlates of immunity for mapping relevant epitopes for vaccine candidates Therapeutic vaccines (Immunotherapy research with dendritic cells) Therapeutic vaccines (Immunotherapy research with dendritic cells) Bioinformatics (HIV sequencing for identification of genic segments for development of vaccine prototipes) Bioinformatics (HIV sequencing for identification of genic segments for development of vaccine prototipes) Chimeric antigens of HIV related to Major Histocompatibility Complex (MHC) Chimeric antigens of HIV related to Major Histocompatibility Complex (MHC) Molecular adjuvants for activation of dendritic cells ex-vivo, Molecular adjuvants for activation of dendritic cells ex-vivo, Clinical study phase I of therapeutic vaccine for treatment of co- infection TB-HIV Clinical study phase I of therapeutic vaccine for treatment of co- infection TB-HIV Behavioral studies supporting development of preventive and therapeutic vaccines. Behavioral studies supporting development of preventive and therapeutic vaccines.

15. FUNDING CLINICAL RESEARCH IN BRAZIL The Brazilian government (Ministry of Health and Ministry of Science and Technology) just approved funding for a network of 14 university hospitals for clinical research The Brazilian government (Ministry of Health and Ministry of Science and Technology) just approved funding for a network of 14 university hospitals for clinical research This initiative will provide adequate infra-structure for vaccine and microbicide research in some of these university hospitals This initiative will provide adequate infra-structure for vaccine and microbicide research in some of these university hospitals The National STD/AIDS Program just launched three large Call for Proposals in Clinical Research The National STD/AIDS Program just launched three large Call for Proposals in Clinical Research

16. 58% 12% 1% 3% 26% 93% 1% 2%4% 72% 3% 24% 1% 82,5% 11% 1%,5% 5% NorthNortheast Southeast S outh B F C D nd/rec National Network for HIV isolation and Characterization HIV-1 clades in Brazil Distinct frequencies among regions of the country

17. Potential Vaccine sites have been identified and are under evaluation RORAIMA (1) Potential phase 3 sites identified RS, PR, SC, PE, CE,AM Factibility cohort in Belo Horizonte (UFMG, former WHO seroincidence study) Phase 1/2 HVTN sites in Rio and São Paulo (international multicentric studies - UFRJ, UNIFESP, CRT-SP)

18. Civil society organizations Participation in National Vaccine Advisory Committee Participation in National Vaccine Advisory Committee Community Advisory Boards (CABS): participation in preparation of studies, support and recruiting of volunteers, in follow-up and advocacy for ethics in research Community Advisory Boards (CABS): participation in preparation of studies, support and recruiting of volunteers, in follow-up and advocacy for ethics in research

19. Ethical and regulatory evaluations: Strengths Brazil has well established national systems for scientific, ethical and regulatory evaluation Brazil has well established national systems for scientific, ethical and regulatory evaluation CONEP – Resolution 196/96 – National Commission for Ethics in Research with a network of local ethical research commitees - CEPS – supported and legitimated by the scientific community and civil society CONEP – Resolution 196/96 – National Commission for Ethics in Research with a network of local ethical research commitees - CEPS – supported and legitimated by the scientific community and civil society ANVISA – the National Health Surveillance Agency ANVISA – the National Health Surveillance Agency CTNBio – the National Biosafety Technical Commission – genetic engineering evaluations CTNBio – the National Biosafety Technical Commission – genetic engineering evaluations

20. Ethical and regulatory evaluations: challenges Lengthy review timeline - process could be more efficient and effective Unclear pathways and procedures - need for adequate institutional and legislative frameworks line of communication with ethical and regulatory authorities Lack of adequate communication between ethical and regulatory agencies and investigators – need for an open line of communication with ethical and regulatory authorities Lack of information - incomplete applications/ inadequate reply to information requests

21. Conclusion: need for harmonization and “fast- track” procedures in ethical and regulatory evaluations Emerging Infectious Diseases such as HIV/AIDS and Avian Flu require “fast track” procedures in ethical and regulatory evaluations Emerging Infectious Diseases such as HIV/AIDS and Avian Flu require “fast track” procedures in ethical and regulatory evaluations Ethical and regulatory evaluations in collaborative and international projects should consider the time frame of evaluations in the different countries involved in the project Ethical and regulatory evaluations in collaborative and international projects should consider the time frame of evaluations in the different countries involved in the project Need to overcome difficulties in imports of technology and inputs Need to overcome difficulties in imports of technology and inputs Need for expedite biosafety evaluations in recombinant HIV vaccines Need for expedite biosafety evaluations in recombinant HIV vaccines Overcome intellectual property rights barriers to access – legal constraints Overcome intellectual property rights barriers to access – legal constraints

22. The contribution of this Seminar This Seminar can provide significant inputs to the international guidelines on ethics and regulation of HIV Vaccine R & D This Seminar can provide significant inputs to the international guidelines on ethics and regulation of HIV Vaccine R & D It will also provide an environment for sharing successful experiences in this area It will also provide an environment for sharing successful experiences in this area We will prepare a final report with the main recommendations resulting from the seminar and it will certainly contribute to improve the quality of ethical and regulatory frameworks worldwide We will prepare a final report with the main recommendations resulting from the seminar and it will certainly contribute to improve the quality of ethical and regulatory frameworks worldwide