The Brazilian experience: the role of national regulatory agency in technology development, production, importation and

1. Dr. Akira Homma Diretor Bio-Manguinhos Fundação Oswaldo Cruz Ministério da Saúde Brasília, DF, 4-5 Outubro 2006 The Brazilian experience: the role of national regulatory agency in technology development, production, importation and in the approval of future products

2. % Fonte: Ministério da Saúde, SI-PNI.

3. Vacinas do Calendário Básico e Campanhas - Aquisições do PNI - 2006 Domínio de todas tecnologias de produção de vacinas do calendário básico de imunização – exceto rotavirus

4. IN PRODUCTION - BRAZILIAN REGULATION (RDC 210 & 315) & INTERNATIONAL: PRODUCTION PROCEDURES; RAW MATERIAL; INTERMEDIATE PRODUCTS - PURITY; FINAL PRODUCT; EFFICACY & POTENCY; CONSISTENCY OF PRODUCTION; STABILITY, THERMAL-STABILITY; PERSONNEL; OPERATION VALIDATION; PRODUCT VALIDATION; - PRE-CLINICAL STUDIES; - CLINICAL TRIALS – PHASE 1, 2 AND 3; - POS-MARKETING REGULATION OF VACCINES IN PRODUCTION & NEW VACCINES - HIV Facilities & Equipments BIOSAFETY ENVIRONMENT • ANTI- HIV/aids vaccines – Prophylatic and Therapeutic - New and complex, requires new regulatory approach with early participation of regulatory authority

5. Proof of concept - 2 - STEPS FOR VACCINE DEVELOPMENT > 10-20 years Experimental Lots – clinical studies - GMP - 4 - Phase II - 6 - Clinical Studies Phase I - 5 - Fase III - 7 - Pre-Clinical - 3 - Discovery - 1 - License - 8 - Producion - 9 - Characteristics: multiples steps; multiple specialized teams; each step, specific requirement; long period; not linear --- need strong coordination Early participation of Regulatory Authority is essential !!! Phase IV - 10 -

6. The scientific strategic plan of the Enterpriseidentifies six key challenges to the development of an effective AIDS vaccine, and proposes the formation of consortia or centers to further accelerate vaccine research. Adapted with permission from a figure created by the Bill & Melinda Gates Foundation

7. DIVERSITY OF TECHNOLOGICAL APPROACH

8. Potential advantages and disadvantages of major HIV vaccine design strategies.

9. Declan Butler - Nature 442, 610-611(10 August 2006) HIV poses a formidable challenge for vaccine developers: it mutates rapidly, attacks immune cells that might destroy it, An effective vaccine will be two-pronged: generating antibodies, stimulate immune cells. Gates Funding: 11 consortia selected. five will seek ways of generating effective antibodies when the immune system is exposed to HIV. a consortium led by Robin Weiss of University College London, ($25.3-million), will screen antibodies from humans and animals that seem naturally active against HIV, and then work backwards to see which regions they target and design new vaccine candidates. a consortium led by Leo Stamatatos at Seattle Biomedical Research Institute ($19.4-million ) will use computers to design molecules that might trigger antibodies against the virus. six consortia will focus on stimulating a cellular response. Timothy Zamb of the International AIDS Vaccine Initiative ($23.7 million) to try to modify other viruses to act as vectors for the vaccine. Giuseppe Pantaleo at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, ($15.3-million ) hopes to improve the ability of poxvirus, a known vaccine vector, to trigger a response to HIV.

10. Lancet 2006; 368: 511–21 Mother-to-child transmission (MTCT) of HIV-1 is the major mode of paediatric infection. The rapidly increasing incidence of MTCT worldwide has resulted in an urgent need for preventive strategies. Antiretroviral regimens can prevent intrapartum HIV transmission; however, these regimens do not prevent HIV transmission through breastfeeding. Furthermore, children who escape MTCT are again at risk of infection when they become sexually active as adolescents. An infant vaccine regimen, begun at birth, would hence be a more attractive strategy and might also provide the basis for lifetime protection. Unique features of MTCT and paediatric HIV disease could be helpful in understanding correlates of immune protection and could facilitate rapid assessment of vaccine e. cacy. Thus, there is compelling rationale to develop safe, e. ective HIV vaccines for use in infants and children.

11. CANARYPOX VECTOR -ALVAC vCP 1452 (Sanofi Pasteur) DNA PLASMIDIAL -Clade C Gag-Env plasmids (Chiron) -EP HIV-1090 (Epimmune) -pGA2/JS2 DNA (Emory) -VRC-HIVDNA-009 (NIH VRC) -WLV003 (Wyeth) -Gag and Env DNA/PLG microparticles (Chiron) ANTI-HIV UNDER DEVELOPMENTJULY 2006

12. FOWLPOX VECTOR -TBC-F357;TBC-F349(Therion Biologics) LIPOPEPTIDE -LIPO-5 (Sanofi Pasteur/ ANRS) MAV (Ankara) -MVA pGA/JS2 (NIAID-LVD) -TBC-M358; TBC-M335 (Therion Biologics) ADENOVIRUS VECTOR NO REPLICABLE -MRKAd5 HIV-1 Gag (Merck) -VRC-HIVADV-010 (NIH VRC) PEPTIDE -Multi-epitope CTL peptide vaccine (Wyeth) ANTI-HIV UNDER DEVELOPMENT JULY 2006

13. PROTEIN -AIDSVAX B/B (VaxGen) -Clade C Env subunit (Chiron) -gp120 MN (VaxGen) -AIDSVAX B/B (VaxGen) -gp140 SF-162 -- oligomeric, V2-deleted (Chiron) -gp120W61D (GlaxoSmithKline) -NefTat (GlaxoSmithKline) YEAST VECTOR -HIVAX-GS (GlobeImmune) ANTI-HIV UNDER DEVELOPMENTJULY 2006

15. Variety of technologies used for anti HIV/aids vaccines The establishment of ANVISA is relatively new - gaining experience; BIOLOGICAL AND IMMUNOLOGICAL COMPLEXITY OF HIV/aids Each country has to establish their own regulations; RELATIVE SMALL NUMBER OF RESERCHERS INVOLVED IN HIV/aids CHALLENGES: ANVISA FACING NEW VACCINES HIV

16. For live attenuated virus vaccine there are general requirements established; For DNA vaccines there is FDA´s guidance; For subunits and recombinant vaccines there are requirements established; For viral and bacterial vector vaccines there is no requirement established; Lack of information on technology aspects from developer laboratories. CHALLENGES: ANVISA FACING NEW HIV VACCINES

17. SIX-SYSTEM INSPECTION MODEL FDA – Pharmaceutical CGMPs – Sept. 2006

18. POLICY, LEGAL, ETHICAL OPERATIONAL: Organization of Technical Advisory Committee with participation of Anvisa, MoH, MC&T, MRE, MF, R&D institutions with following functions: Identification and selection of the most promising technological approach for development in Brazil; Identification of anchor institutions that must take part in R&D of anti-HIV/aids vaccines. Set out specific projects, with defined tasks and schedules, with participation of the correspondent authority, to follow, monitor, evaluate the steps up to production process. PROPOSAL FOR TECHNOLOGICAL DEVELOPMENT STRENGTHENING

19. Establishment of technical cooperation among countries and companies that work with HIV/aids vaccine development; Establish specific technical projects dealing with improvement of regulatory issues involved; Networking/consortium should be organized in order to address different aspects of development; Globalization must contribute to facilitate the R&D. PROPOSAL FOR TECHNOLOGICAL DEVELOPMENT STRENGHTHENING

20. PROPOSAL TO STRENGTHEN TECHNOLOGICAL DEVELOPMENT • A strong coordination and project management procedures with definition of specific targets and timetable for each institution; • Strengthen the administrative (professional) management • Integration of related R&D activities – Research institution&technological development & regulatory authority + Ministry of Finance/Science &Technology/External Relations

21. THANK YOU FOR YOUR ATTENTION !!!