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