Ministério da Saúde

The Brazilian HIV Vaccine The Brazilian HIV Vaccine Program: Ethical and Regulatory Program: Ethical and Regulatory ChallengesChallenges

Cristina de A. PossasCristina de A. PossasResearch and Development UnitResearch and Development UnitNational Program STD-AIDSNational Program STD-AIDSMinistry of Health, BrazilMinistry of Health, Brazil

International SeminarHIV Vaccine Research: Ethical and Regulatory Issues Brasília, October 4-5, 2006

VisionVision

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

IMPACT UNIVERSAL IMPACT UNIVERSAL ACCESS TO ARV IN ACCESS TO ARV IN BRAZIL (1996 - 2002)BRAZIL (1996 - 2002)

IMPACT UNIVERSAL IMPACT UNIVERSAL ACCESS TO ARV IN ACCESS TO ARV IN BRAZIL (1996 - 2002)BRAZIL (1996 - 2002)

Reduction 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

International scenario International scenario for HIV vaccine for HIV vaccine developmentdevelopment Over 30 clinical trials with vaccine Over 30 clinical trials with vaccine

candidates are now under way worldwidecandidates are now under way worldwide

There are still some important scientific There are still some important scientific challenges for vaccine R & D (HIV challenges for vaccine R & D (HIV hypervariability; Neutralizing Antibodies; hypervariability; Neutralizing Antibodies; Retrovirus; Animal Models; Correlate of Retrovirus; Animal Models; Correlate of protective immunity; HIV Antigens; protective immunity; HIV Antigens; Clinical Trials)Clinical Trials)

Source: IAVI - Aids Vaccine Blueprint 2006

New Paradigm: International Cooperation New Paradigm: International Cooperation for a Dynamic Global R & D Program in for a Dynamic Global R & D Program in

HIV VaccineHIV Vaccine WHOWHO UNAIDSUNAIDS IAVIIAVI NIH-HVTNNIH-HVTN ANRSANRS

The Global HIV/AIDS Enterprise –endorsed by The Global HIV/AIDS Enterprise –endorsed by the G-8 in June 2004the G-8 in June 2004

The Collaboration for AIDS Vaccine Discovery The Collaboration for AIDS Vaccine Discovery (CAVD) – Bill and Melinda Gates Foundation – (CAVD) – Bill and Melinda Gates Foundation – network of 11 vaccine discovery consortia network of 11 vaccine discovery consortia

HIV Vaccine StrategiesHIV Vaccine Strategies

Vaccines from HIV Genes (Naked DNA, Viral Vaccines from HIV Genes (Naked DNA, Viral Vectors, Bacterial Vectors)Vectors, Bacterial Vectors)

Vaccines from HIV Proteins (Proteins, Vaccines from HIV Proteins (Proteins, Peptides)Peptides)

Vaccines from Whole HIV (Whole Inactivated Vaccines from Whole HIV (Whole Inactivated HIV, Live Atenuated HIV)HIV, Live Atenuated HIV)

Combination (Combining different vaccine Combination (Combining different vaccine designs and/or different antigens) designs and/or different antigens)

Two approaches tested in Two approaches tested in

large-scale efficacy trialslarge-scale efficacy trials VaxGen Phase III Trial – Sanofy Aventis (to VaxGen Phase III Trial – Sanofy Aventis (to

induce cellular helper and humoral immune induce cellular helper and humoral immune response) –Thailand response) –Thailand

Merck Phase II B Trial -Ad 5 HIV Vaccine - Merck Phase II B Trial -Ad 5 HIV Vaccine - (first test of vaccine candidate inducing (first test of vaccine candidate inducing cellular –cytotoxic mediated immune cellular –cytotoxic mediated immune response in the majority of vaccinees) – U.S, response in the majority of vaccinees) – U.S, Canada, Peru, Dominican Republic, Haiti, Canada, Peru, Dominican Republic, Haiti, Puerto Rico, Australia, Jamaica and Brazil.Puerto Rico, Australia, Jamaica and Brazil.

Obstacles to overcome, but a safe Obstacles to overcome, but a safe and effective HIV vaccine is possibleand effective HIV vaccine is possible

Recent discoveries and promising studies of Recent discoveries and promising studies of candidate vaccines in animal models indicate candidate vaccines in animal models indicate that a safe and effective HIV vaccine is that a safe and effective HIV vaccine is possible and new advances in this area can possible and new advances in this area can be expected in the next 3-5 yearsbe expected in the next 3-5 years

Possible combined strategies: initial HIV Possible combined strategies: initial HIV vaccines will probably be partially efficacious vaccines will probably be partially efficacious (from low – 40% to high – 95% efficacy)(from low – 40% to high – 95% efficacy)

Partially efficacious vaccines will probably Partially efficacious vaccines will probably require very high coverage require very high coverage

Brazil: National HIV Brazil: National HIV Vaccine CommitteeVaccine Committee

The National Committee for HIV Vaccine The National Committee for HIV Vaccine supports the Brazilian  supports the Brazilian  National STD-AIDS in National STD-AIDS in this area and this area and has an outstanding role in has an outstanding role in national scientific and technological national scientific and technological development in HIV research (representatives development in HIV research (representatives of scientific community and civil society)of scientific community and civil society)

The Committee is elaborating the new HIV The Committee is elaborating the new HIV

Vaccine Plan for 2007-2012, with new priorities Vaccine Plan for 2007-2012, with new priorities for research, development and production in for research, development and production in this areathis area  

National HIV Vaccine Plan 2007-2012: National HIV Vaccine Plan 2007-2012:

guidelinesguidelines Support to preventive and therapeutic vaccinesSupport to preventive and therapeutic vaccines Stimulate innovation: identify gaps in research and the main Stimulate innovation: identify gaps in research and the main

challenges to be addressed challenges to be addressed Strengthen national and international collaborationStrengthen national and international collaboration Build national capacity for larger scale trialsBuild national capacity for larger scale trials Create national technological capacity for technology transfer for Create national technological capacity for technology transfer for

future recombinant HIV vaccines. future recombinant HIV vaccines. Identification and support to potential new sites Identification and support to potential new sites

Support to cohortsSupport to cohorts

Stimulate public-private partnershipStimulate public-private partnership

Reinforcement of existing infrastructureReinforcement 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 Create adequate environment for scientific, ethical and regulatory

evaluations, supported by stable funding mechanisms evaluations, supported by stable funding mechanisms

The new National HIV The new National HIV Vaccine Plan 2007-2012Vaccine Plan 2007-2012 - - StrategiesStrategies

1.1. Capacity buildingCapacity building2.2. Improve Laboratory & Clinical trial infra-Improve Laboratory & Clinical trial infra-

structure structure 3.3. Adopt accreditation proceduresAdopt accreditation procedures4. Facilitate importation of equipment and

materials.5.5. Provide Sustainability of Funding Provide Sustainability of Funding 6.6. Organize site evaluation, selection and Organize site evaluation, selection and

development for efficacy trialsdevelopment for efficacy trials7.7. Increase understanding of trial participationIncrease understanding of trial participation

The Brazilian strategy for The Brazilian strategy for developing local HIV Vaccine R & D developing local HIV Vaccine R & D

Select a few scientific priorities and Select a few scientific priorities and concentrate on them concentrate on them

Vaccine research: identification of gaps in Vaccine research: identification of gaps in research and development and feasible research and development and feasible topics topics

Capacity building: research methodology and Capacity building: research methodology and support to research (GLP, Bioinformatics, support to research (GLP, Bioinformatics, Data management, criopreservation) Data management, criopreservation)

Support to local implementation of research Support to local implementation of research projectproject

Community preparedenessCommunity preparedeness

Funding HIV vaccine Funding HIV vaccine researchresearch

The Brazilian government is giving priority to The Brazilian government is giving priority to funding research in this areafunding research in this area

The National STD-AIDS Program in the The National STD-AIDS Program in the Ministry of Health has significant funding Ministry of Health has significant funding available for Scientific and Technological available for Scientific and Technological Development (14,5 million dollars 2004-Development (14,5 million dollars 2004-2006)2006)

A A National Call for HIV Vaccine ResearchNational Call for HIV Vaccine Research was was just launched by the National STD-AIDS just launched by the National STD-AIDS Program in June 2006 and preparatory Program in June 2006 and preparatory studies for vaccine research were included studies for vaccine research were included as an item of this competitive processas an item of this competitive process

New National Call for HIV Vaccine R & New National Call for HIV Vaccine R & D D

June 13  2006 - June 13  2006 - funding of 4 million dollarsfunding of 4 million dollars Broad range of topics in Broad range of topics in 14 thematic lines of research14 thematic lines of research, including : , including : Research on mucosal immunityResearch on mucosal immunity Central memory cells - phenotypes induced by HIV vaccinesCentral memory cells - phenotypes induced by HIV vaccines Studies to support the development of preventive vaccines (new Studies to support the development of preventive vaccines (new

Brazilian products)Brazilian products) Correlates of immunity for mapping relevant epitopes for vaccine Correlates of immunity for mapping relevant epitopes for vaccine

candidatescandidates Therapeutic vaccines (Immunotherapy research with dendritic cells)Therapeutic vaccines (Immunotherapy research with dendritic cells) Bioinformatics (HIV sequencing for identification of genic segments for Bioinformatics (HIV sequencing for identification of genic segments for

development of vaccine prototipes)development of vaccine prototipes) Chimeric antigens of HIV related to Major Histocompatibility Complex Chimeric antigens of HIV related to Major Histocompatibility Complex

(MHC)(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-Clinical  study phase I of therapeutic vaccine for treatment of co-

infection TB-HIVinfection TB-HIV Behavioral studies supporting development of preventive and Behavioral studies supporting development of preventive and

therapeutic vaccines.   therapeutic vaccines.  

FUNDING CLINICAL RESEARCH FUNDING CLINICAL RESEARCH IN BRAZILIN BRAZIL

The Brazilian government (Ministry of Health The Brazilian government (Ministry of Health and Ministry of Science and Technology) just and Ministry of Science and Technology) just approved funding for a network of 14 approved funding for a network of 14 university hospitals for clinical research university hospitals for clinical research

This initiative will provide adequate infra-This initiative will provide adequate infra-structure for vaccine and microbicide structure for vaccine and microbicide research in some of these university research in some of these university hospitals hospitals

The National STD/AIDS Program just The National STD/AIDS Program just launched three large Call for Proposals in launched three large Call for Proposals in Clinical ResearchClinical Research

58%

12%1%

3%

26%

93%

1%2% 4%

72%

3%

24% 1%

82,5%11%

1% ,5% 5%

North Northeast

Southeast South

BFCDnd/rec

National Network for HIV isolation and National Network for HIV isolation and CharacterizationCharacterization

HIV-1 clades in Brazil

Distinct frequencies among regions of the country

Potential Vaccine sites have been Potential Vaccine sites have been identified and are under evaluationidentified and are under evaluation

RORAIMARORAIMA

(1)(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 Rioand São Paulo (international multicentric studies - UFRJ, UNIFESP, CRT-SP)

Civil society Civil society

organizations organizations Participation in National Vaccine Participation in National Vaccine

Advisory CommitteeAdvisory Committee

Community Advisory Boards (CABS): Community Advisory Boards (CABS): participation in preparation of participation in preparation of studies, support and recruiting of studies, support and recruiting of volunteers, in follow-up and volunteers, in follow-up and advocacy for ethics in researchadvocacy for ethics in research

Ethical and regulatory Ethical and regulatory evaluations: Strengthsevaluations: Strengths

Brazil has well established national systems for Brazil has well established national systems for scientific, ethical and regulatory evaluation scientific, ethical and regulatory evaluation

CONEP – Resolution 196/96 – National CONEP – Resolution 196/96 – National Commission for Ethics in Research with a Commission for Ethics in Research with a network of local ethical research commitees - network of local ethical research commitees - CEPS – supported and legitimated by the CEPS – supported and legitimated by the scientific community and civil societyscientific community and civil society

ANVISA – the National Health Surveillance ANVISA – the National Health Surveillance AgencyAgency

CTNBio – the National Biosafety Technical CTNBio – the National Biosafety Technical Commission – genetic engineering evaluations Commission – genetic engineering evaluations

Ethical and regulatory Ethical and regulatory evaluations: challengesevaluations: challenges

Lengthy review timeline - process could be more efficient and effective

Unclear pathways and procedures - need for adequate institutional and legislative frameworks

Lack of adequate communication between ethical and regulatory agencies and investigators – need for an open line of communicationline of communication with ethical with ethical and regulatory authorities and regulatory authorities

Lack of information - incomplete applications/ inadequate reply to information requests

Conclusion: need for Conclusion: need for harmonization and “fast- harmonization and “fast- track” procedures in ethical track” procedures in ethical and regulatory evaluationsand regulatory evaluations Emerging Infectious Diseases such as HIV/AIDS and Emerging Infectious Diseases such as HIV/AIDS and

Avian Flu require “fast track” procedures in ethical Avian Flu require “fast track” procedures in ethical and regulatory evaluations and regulatory evaluations

Ethical and regulatory evaluations in collaborative Ethical and regulatory evaluations in collaborative and international projects should consider the time and international projects should consider the time frame of evaluations in the different countries frame of evaluations in the different countries involved in the project involved in the project

Need to overcome difficulties in imports of technology Need to overcome difficulties in imports of technology and inputs and inputs

Need for expedite biosafety evaluations in Need for expedite biosafety evaluations in recombinant HIV vaccines recombinant HIV vaccines

Overcome intellectual property rights barriers to Overcome intellectual property rights barriers to access – legal constraintsaccess – legal constraints

The contribution of The contribution of this Seminarthis Seminar This Seminar can provide significant inputs to This Seminar can provide significant inputs to

the international guidelines on ethics and the international guidelines on ethics and regulation of HIV Vaccine R & Dregulation of HIV Vaccine R & D

It will also provide an environment for It will also provide an environment for sharing successful experiences in this areasharing successful experiences in this area

We will prepare a final report with the main We will prepare a final report with the main recommendations resulting from the seminar recommendations resulting from the seminar and it will certainly contribute to improve the and it will certainly contribute to improve the quality of ethical and regulatory frameworks quality of ethical and regulatory frameworks worldwide worldwide