1. Brazilian experiences in collaborative and preventive multicentric studies: present situation and ethical issues Paulo Feijó Barroso HUCFF-Faculdade de Medicina Universidade Federal do Rio de Janeiro Projeto Praça Onze http://www.pracaonze.ufrj.br

3. HIV Vaccine?

4. Clinical Trials of HIV Preventive Vaccines, 1988-2005 * * includes AVEG, HIVNET, HVTN, Merck, VRC, & selected USMHRP trials ** Other includes: Alphavirus, and Salmonella vectors 2004-2008 Phase IIB: MRK Ad5 2003-2008 Phase III: vCP 1521/gp120 1998-2003 Phase III: AIDSVAX B/B + B/E **

5. An international program to develop and test HIV preventive vaccines San Francisco, CA Seattle, WA Birmingham, AL Nashville, TN Chicago, IL Rochester, NY New York, NY Baltimore, MD Providence, RI Washington, DC Fairfax, VA *Kingston, Jamaica Port of Spain, Trinidad & Tobago Lima, Peru Rio de Janeiro, Brazil Durban, South Africa *Pune, India Chiang Mai, Thailand Nanning, China St. Louis, MO Soweto, South Africa Gaborone, Botswana *Santo Domingo, Dominican Republic San Juan, Puerto Rico Sao Paulo, Brazil Boston, MA Blantyre, Malawi *Tegucigalpa, Honduras *Potential Expansion Sites Port-au-Prince, Haiti HIV VACCINE TRIALS NETWORK *Yunnan, China *Capetown, South Africa

6. HIV Preventive Vaccines Trials in Brazil (2000-06) Protocol number PhaseCandidatesTrials UnitDates# subjects 026I ALVAC-HIV vCP1452 e HIV-1 rgp120 UFRJ_40 050I Adenovírus 5 UFRJ/CRT/ UNIFESP 200455 055I MVA+FPV UFRJ/CRT 12/0540 204II DNA +AD5 UFRJ/CRT 03/0624 502IIb Adenovírus 5 UFRJ/CRT/ UNIFESP 03/06240 063I gag DNA, IL-15 DNA, IL-12 DNA,Vacina CTL MEP UFRJ/CRT07/06~40 Total~=440

7. HIVNET 026 Projeto Praça Onze -UFRJ HIVNET 026- A MULTISITE PHASE II CLINICAL TRIAL TO EVALUATE THE IMMUNOGENICITY AND SAFETY OF ALVAC-HIV vCP1452 ALONE AND COMBINED WITH MN rgp120

8. IRBs evaluation prior to study initiation USA: NIH, Pittsburgh, Cornell, Maryland, UCSF Brasil: UFRJ, Comitê Nacional de Vacinas, CONEP Evaluation during study Community Advisory Board IRBS: USA: NIH, Pittsburgh, Cornell, Maryland, UCSF Brasil: UFRJ, Comitê Nacional de Vacinas, CONEP HIVNET 026 Projeto Praça Onze -UFRJ

9. Protocolo 026 Projeto Praça Onze Recrutamento de participantes Indivíduos contatados434 Indivíduos triados 77 Indivíduos incluídos 40

10. Vaccine trials in Brazil: Regulatory Process I.I nvestigators II.CAB II.IRB III.IBS IVCONEP V.CTnBio VI.ANVISA

11. Vaccine trials in Brazil: Before Regulatory Process I. I nve stigators Network committees Writing Protocols Adapting docs to local legislation (e.g: Sample storage, compenantion, insurance, etc) II.CAB Reviewing protocols Consent Forms, etc... Recruitment strategies, etc etc

12. HIV Preventive Vaccines Trials in Brazil (2000-06) Protocol number PhaseCandidatesTrials UnitDates# subjects 026I ALVAC-HIV vCP1452 e HIV-1 rgp120 UFRJ_40 050I Adenovírus 5 UFRJ/CRT/ UNIFESP 200455 055I MVA+FPV UFRJ/CRT 12/0540 204II DNA +AD5 UFRJ/CRT 03/0624 502IIb Adenovírus 5 UFRJ/CRT/ UNIFESP 03/06240 063I gag DNA, IL-15 DNA, IL-12 DNA,Vacina CTL MEP UFRJ/CRT07/06~40 Total~=440

13. HVTN 050- Regulatory process SubmissionApproval# days Conep May 27, 2003 February 11, 2004 ~ 270 days CTnBio May 27, 2003 September 18, 2003 ~120 days Anvisa March 30, 2004 May 05, 2004 ~45 days Total May 27, 2003 May 05, 2004 ~340 days

15. HVTN 055- Regulatory process SubmissionApproval# days Conep December 13, 2004 May 23, 2005~ 160 days CTnBio January 05, 2005 April 19, 2006 ~ 450 days Anvisa July 11, 2005 October 1, 2005 ~90 days Total May 27, 2003 May 05, 2004 ~480 days

16. HVTN Protocols in Field – 2006

17. Ongoing HIV Vaccine Trials;Non HVTN Eurovac NYVAC/MVA with matched DNAClade B and Clade C prototypes:gag/pro/envgag- IAVI AAV 2 PR-delta RT, clade C IAVI AAV1Starting trials this year St Judes Multienv. VacciniaEnrolling Aaron Diamond DNA / MVA Clade CCompleted phase 1 Karolinska Institute DNA/MVACompleted phase 1; DNA plus USMRP A/E USMRP MVA Clade A; A/E; DA/E clinical trials; others starting China CDC DNA Vaccinia :replication competantEnrolling China CDC Vaccinia replication defectiveEnrolling

18. HIV-1 Vaccines in Advanced Clinical Trials in 2006 - Phase IIA/B/ and III Phase II trial of VRC multiclade DNA followed by R Ad5 boost (75% enrolled):qualifying trial for Test of Concept Efficacy trial. Phase IIB trial in North and South America, and Caribbean of MRK gag-pol-nef vaccine (75% enrolled) Phase IIB trial in Republic of South Africa of MRK gag-pol-nef vaccine (start 10/06) Phase III trial in Thailand of canarypox/ gp120.(16,000 enrolled)

21. HVTN 204- Regulatory process SubmissionApproval# days Conep September 26, 2005 March 29, 2006~180 days CTnBio September 29, 2005 April 19, 2006 ~210 days Anvisa April 03, 2006 June 06, 2006 ~ 90 day Total September 26, 2005 June 06, 2006 ~270 days

22. HVTN 204- CONEP Regulatory process First evaluation:~60 days –25 clarifications requested E.g “ Why Dr. Barroso is not the Principal investigator”? Second evaluation:~70 days –1 clarification requested re blood volumes Third evaluation: ~20 days –Approved

23. Phase IIB test of concept trial: HVTN/Merck trivalent Ad5 vaccine (Step Trial) 1.5 x 10 10 at 0, 1, 6 months in high and low titer Ad5 N = 3000, clade B regions (Americas, Aust)

24. Current Status of STEP Trial 15 sites in North America: Caribbean sites: Puerto Rico, Haiti, Dominican Republic, Jamaica South America: Peru, Brazil Currently 2,200 persons enrolled with target of 3,000 persons Enrollment averaging 175 per month; trial to be fully enrolled by end of the year

25. First Brazilian volunteer

26. Challenges Interaction of investigators, MOH and regulatory bodies during review Interaction between agencies Standardized reviews Infrastructure development

28. Acknowledgements: Projeto Praça Onze-UFRJ HVTN Monica Barbosa Mauro Schechter Ann Duerr Larry Corey Regina Ferro S. Buchbinder Alan Fix www.pracaonze.ufrj.br