Brazilian experiences in collaborative and preventive multicentric studies: present situation and ethical issuesPaulo Feijó Barroso
HUCFF-Faculdade de MedicinaUniversidade Federal do Rio de Janeiro
Projeto Praça Onze
http://www.pracaonze.ufrj.br
06/06 e 10
Over 11 000 new HIV infections a day in 2005
• More than 95% are in low and middle income countries
• About 1500 are in children under 15 years of age
• About 10 000 are in adults aged 15 years and older of whom:
— almost 50% are among women
— over 40% are among young people (15-24)
HIV Vaccine?
Clinical Trials ofHIV Preventive Vaccines, 1988-2005*
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
OtherAdenovirus
DNAPox Envelope Proteins & Peptides
0
1
2
3
4
5
Nu
mb
er o
f P
roto
cols
Year
Other
Adenovirus
DNA
Pox
Envelope Proteins & Peptides
*includes AVEG, HIVNET, HVTN, Merck, VRC, & selected USMHRP trials** Other includes: Alphavirus, and Salmonella vectors
2004-2008 Phase IIB: MRK Ad5
2003-2008Phase III:vCP 1521/gp120
1998-2003Phase III: AIDSVAX B/B + B/E
**
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, DCFairfax,
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 VACCINETRIALS NETWORK
*Yunnan, China
*Capetown, South Africa
HIV Preventive Vaccines Trials in Brazil (2000-06)
Protocol
number
Phase Candidates
Trials Unit Dates
# subjects
026 I ALVAC-HIV vCP1452 e HIV-1 rgp120
UFRJ _ 40
050 I Adenovírus 5
UFRJ/CRT/UNIFESP
2004 55
055 I MVA+FPV UFRJ/CRT 12/05
40
204 II DNA +AD5 UFRJ/CRT 03/06
24
502 IIb Adenovírus 5
UFRJ/CRT/UNIFESP
03/06
240
063 I gag DNA, IL-15 DNA, IL-12 DNA,Vacina CTL MEP
UFRJ/CRT 07/06
~40
Total~=440
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
• 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
Protocolo 026Projeto Praça Onze
Recrutamento de participantes
• Indivíduos contatados 434
• Indivíduos triados 77
• Indivíduos incluídos 40
Vaccine trials in Brazil:Regulatory Process
• I. Investigators• II. CAB• II. IRB• III. IBS• IV CONEP• V. CTnBio• VI. ANVISA
Vaccine trials in Brazil:Before Regulatory Process
• I. Investigators• 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
HIV Preventive Vaccines Trials in Brazil (2000-06)
Protocol
number
Phase Candidates
Trials Unit Dates
# subjects
026 I ALVAC-HIV vCP1452 e HIV-1 rgp120
UFRJ _ 40
050 I Adenovírus 5
UFRJ/CRT/UNIFESP
2004 55
055 I MVA+FPV UFRJ/CRT 12/05
40
204 II DNA +AD5 UFRJ/CRT 03/06
24
502 IIb Adenovírus 5
UFRJ/CRT/UNIFESP
03/06
240
063 I gag DNA, IL-15 DNA, IL-12 DNA,Vacina CTL MEP
UFRJ/CRT 07/06
~40
Total~=440
HVTN 050- Regulatory process
Submission
Approval # 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
HVTN 055- Regulatory process
Submission
Approval # 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
HVTN Protocols in Field – 2006
Developer Vaccine Design Prot. # US Non-US Total Current Status
VRC/NIAID DNA + IL2 DNA 044 70 0 70 Follow-up
Chiron DNA/PLG + gp140 049 60 0 60 Follow-up
VRC/NIAID Multiclade Ad5 replicon 054 48 0 48 Follow-up
Wyeth multiepitope peptides + GMCSF 056 96 0 96 Follow-up
Alphavax Alphavirus replicon 059 48 48 96 Follow-up
Merck Adeno5 vector (gag Clade B) 050 87 348 435 Follow-up
Therion MVA + Fowlpox 055 120 30 150 Follow-up
VRC/NIAID DNA + Adeno 068 66 66 Follow-up
Wyeth DNA/IL-12/CTL MEP 060 134 22 156 Enrolling
Wyeth DNA/IL-15/IL-12/or CTL MEP 063 116 40 156 Enrolling
Pharmexa-Epimmune
Multiepitope protein: Multiepitope DNA
064 84 36 120 Enrolling
GeoVax DNA, MVA 065 84 36 120 EnrollingVRC/NIAID DNA + Adeno 204 180 300 480 Enrolling
Merck Adeno 5 vector (gag/pol/nef Clade B)
502 780 1220 3000 (2000 HVTN, 1000 Merck)
Enrolling
Total Enrollment 1973 2080 4053
Ongoing HIV Vaccine Trials;Non HVTN
Eurovac NYVAC/MVA with matched DNA Clade B and Clade C prototypes:gag/pro/envgag-
IAVI AAV 2 PR-delta RT, clade C
IAVI AAV1 Starting trials this year
St Judes Multienv. Vaccinia Enrolling
Aaron Diamond DNA / MVA Clade C Completed phase 1
Karolinska Institute DNA/MVA Completed phase 1; DNA plus USMRP A/E
USMRP MVA Clade A; A/E; D A/E clinical trials; others starting
China CDC DNA Vaccinia :replication competant Enrolling
China CDC Vaccinia replication defective Enrolling
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)
0 1 2 18-25Months 3 6 9
Env AEnv BEnv C gag/pol (B)
DNA PrimeCMV/R (007) rAd5 Boost
Env AEnv B Env C gag Bpol Bnef B
VRC 6-plasmid
VRC DNA Prime/rAd5 Boost Pilot Studies
HIV Vaccine Trials Network (HVTN)US Military HIV Research Program (USMHRP)
International AIDS Vaccine Initiative (IAVI)
Birmingham, AL
Nashville, TN
Rochester, NY Baltimore, MD
Kingston, Jamaica
Rio de Janeiro, Brazil
KOSH*, South Africa Soweto, South Africa
Sao Paulo, Brazil
Boston, MA
Port-au-Prince, Haiti
* Klerksdorp, Orkney, Stiflontein, Hartbeesfontein
Capetown, South Africa
Kigali, Rwanda
Kericho, Kenya
Kampala, Uganda
Mbeya, Tanzania
Phase I/II Evaluation of the VRC Candidate HIV Vaccine
Nairobi, Kenya
Providence, RI
HVTN 204- Regulatory process
Submission Approval # 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
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
Phase IIB test of concept trial:
HVTN/Merck trivalent Ad5 vaccine (Step Trial) ITRL ITRR
gaghCMV
pAMRKAd5 HIV-1 gag
ITRL ITRR
polhCMV
pAMRKAd5 HIV-1 pol
ITRL ITRRnefhCMV
pA
E1
MRKAd5 HIV-1 nef
1.5 x 1010 at 0, 1, 6 months in high and low titer Ad5
N = 3000, clade B regions (Americas, Aust)
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
The STEP StudyProjected vs. Actual Enrollment
0
500
1000
1500
2000
2500
3000
3500
Projected
Actual
www.stepstudies.com
First Brazilian volunteer
Challenges
• Interaction of investigators, MOH and regulatory bodies during review
• Interaction between agencies
• Standardized reviews
• Infrastructure development
06/06 e 10
Over 11 000 new HIV infections a day in 2005
• More than 95% are in low and middle income countries
• About 1500 are in children under 15 years of age
• About 10 000 are in adults aged 15 years and older of whom:
— almost 50% are among women
— over 40% are among young people (15-24)
Acknowledgements:• Projeto Praça Onze-UFRJ• HVTN
• Monica Barbosa• Mauro Schechter• Ann Duerr• Larry Corey• Regina Ferro• S. Buchbinder• Alan Fix
www.pracaonze.ufrj.br
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