Oct 06

Ethical and Regulatory Approval Process in HIV Vaccine Clinical Research

India Experience

HIV Vaccine Clinical Research Ethical and Regulatory Issues

Brasilia, October 4-5, 2006

Dr. Sonali Kochhar

Senior Medical Project Manager International AIDS Vaccine Initiative, India

Oct 06

Approval Process in India

• Well-delineated pathway with published guidelines and forms for

regulatory and ethical bodies available

• Regulatory Agency - Drug Controller General of India (DCGI)

(www.cdsco.nic.in)

• Drugs and Cosmetics Act 1940 was to prevent sub-standardization in

drugs.

• Drugs and Cosmetic Rule 1945 provided rules to Act. In latest

amendment in January 2005, existing Schedule Y substituted.

• Schedule Y – Provides specific guidelines for permission to import or

manufacture new drugs for clinical trials

• No separate guidelines for vaccines

Oct 06

Approval Process in India

Phase I trials with imported product

• Normally no Phase I with new product if not first tested outside

India.

• Need to submit Phase I data generated outside India, obtain

permission to repeat Phase I trials and /or Phase II trials followed

by Phase III trials concurrently with other global trials for product.

• Phase III trials must be conducted in India before permission to

market product in India is granted

• Exceptions on case-by-case basis for vaccines or drugs targeting

diseases of major public health threat or life threatening/serious

diseases e.g. HIV, Malaria, TB, Cancer

Oct 06

Export Permit from USA to India

• India is not on US FDA list for export of investigational products

without IND

• Two scenarios are possible:

• India is site of joint trial with countries where dossier was

approved by European agency (A001 trial, Pune)

• Obtain export approval from FDA

• Submit abbreviated dossier and letter to FDA providing

evidence that all steps have been taken to get approvals

from Indian regulatory authorities and ethics committees

(D001 trial, Chennai)

Oct 06

Approval Process in India

Mandatory, transparent

• Institutional Scientific Committee

• Ethics committees

• Institutional

• National

• Import permit of vaccine (DCGI) – MOH&FW

• National Regulatory Authority (DCGI) - MOH&FW

• Genetic Engineering Approval Committee

• Ministry of Environment & Forest

• Health Ministry’s Screening Committee

Oct 06

Preclinical Data

Institutional Scientific Committee •Protocol •IB

Institutional Ethics Committee•Protocol & IB•Toxicology Report Summary•Clinical documents

DCGI• Reviews standard clinical documents• Schedule Y with Form 44 (IND equivalent)• Form 12 (Import of test vaccine)

Central Ethics CommitteeProtocol & IBToxicology Report SummaryClinical documents

DCGI: Drug Controller General of India HMSC: Health Ministry Screening CommitteeGEAC: Genetic Engineering Approval Committee

LetterPermission to use material for clinical trial

HMSC•TRC cover letter•Special HMSC form•All approvals

Regulatory Process in India

GEAC GEAC dossier

1

2

3

3

Approval Steps

4

TK-02-24-05

Oct 06

Institutional Ethics Committee

At least 7 members including Chairperson (from outside

institution)

• Basic medical scientist

• Clinician

• Legal Expert

• Social Scientist/ representative of NGO

• Lay person from community

Sch Y requirement that committee function according to

• Good Clinical Practice Guidelines issued by Central Drugs

Standard Control organization

• Ethical Guidelines for Biomedical Research on Human Subjects, issued by Indian Council of Medical Research

Committee to have SOP’s and maintain record of proceedings

Oct 06

Genetic Engineering Approval Committee

Genetically Engineered Products

• If vaccine is manufactured locally by using recombinant DNA technology, approval of Review Committee for Gene Manipulation (RCGM) and GEAC is mandatory.

• If vaccine is imported into country, approval required from GEAC.

• Consists of members from Dept. of Biotechnology, Agricultural Research, Pollution Control, Food Technology etc.

• Need to confirm that product is free of contamination

• Measures taken to avoid release or damage of environment by product.

Oct 06

Heath Ministry’s Screening Committee

• Provides final approval for foreign-funded and/or collaborative

project submitted by Indian collaborator.

• Proposals are considered for review and approval after ICMR’s

technical review.

• In the case of projects on HIV/AIDS, review by National AIDS

Control Organization required.

• Information collected on

– Role/Status/Expertise of the Indian Principal Investigator.

– Type of infrastructure and manpower in institution

– Sources of foreign collaboration and funding.

– If material to be sent abroad; purpose/need of transfer; nature

of investigation to be conducted

– Material Transfer Agreement (MTA)

Oct 06

AIDS Vaccine Research in India

• First ever AIDS Vaccine trial being conducted in India raised lot of First ever AIDS Vaccine trial being conducted in India raised lot of

apprehensions amongst Regulatory and Ethics committees and apprehensions amongst Regulatory and Ethics committees and

investigatorsinvestigators

• Institutional committees required numerous meetings to address Institutional committees required numerous meetings to address

concerns (e.g. for first trial, four meetings of Institutional Scientific concerns (e.g. for first trial, four meetings of Institutional Scientific

Committee held before members satisfied)Committee held before members satisfied)

• Committees gained confidence with experience with trial process Committees gained confidence with experience with trial process

(e.g. for second trial, members from the first trial site’s Ethics (e.g. for second trial, members from the first trial site’s Ethics

Committee invited to attend meeting. Shared experience and Committee invited to attend meeting. Shared experience and

concerns with second ethics committee members. Process was concerns with second ethics committee members. Process was

faster).faster).

• National Ethics Committee reviewed trial because of public National Ethics Committee reviewed trial because of public

significancesignificance

Oct 06

AIDS Vaccine Approval Process Timelines - India

Task Name

Nari Ethic Committee

Nari Scientific Committee

Central Ethics Committee

Meeting with ICMR, NACO, DCGI, Secretary of Health, IAVI

Drug Controller of India

Genetic Engineering Approval Committee

Health Ministry's Screening Committee

Form 11

11/10

Jun '04 Jul '04 Aug '04 Sep '04 Oct '04 Nov '04 Dec '04 Jan '05 Feb '05

Task Name

TRC Ethics Committee

TRC Scientific Committee

Central Ethics Committee

Meeting with ICMR, NACO, DCGI, Union Minister of Health, Secretary of Health, TRC and IAVI

Drug Controler General of India

Genetic Engineering Approval Committee

Health Ministry's Screening Committee

Form 11

6/22

Nov '04 Dec '04 Jan '05 Feb '05 Mar '05 Apr '05 May '05 Jun '05 Jul '05 Aug '05 Sep '05 Oct '05 Nov '05 Dec '05 Jan '06

D001 Clinical Trial, TRC, Chennai

A001 Clinical Trial, NARI, Pune

Oct 06

AIDS Vaccine Trial Approval Timelines

Approval Timelines in India

0 50 100 150 200

EC

SAC

CEC

DCGI

GEAC

HMSC

Import Permit

Days from Submission to Letter of Approval

A001

D001

Oct 06

IAVI’s Clinical Research in India

• Institutional and Central Committee’s should have procedures Institutional and Central Committee’s should have procedures

and maintain record of proceedings as per GCPand maintain record of proceedings as per GCP

• Committees should provide approval letters according to GCP Committees should provide approval letters according to GCP

requirements. requirements.

• Committees are often overworked and understaffedCommittees are often overworked and understaffed

• Committee's might lack technical expertise amongst Committee's might lack technical expertise amongst

members. Simple and coherent presentations by investigators members. Simple and coherent presentations by investigators

and sponsors asked to attend sessions to answer questions.and sponsors asked to attend sessions to answer questions.

Oct 06

IAVI’s Clinical Research in India

• IAVI in partnership with Government of India and trial sites in IAVI in partnership with Government of India and trial sites in

Government institutions. Distrust amongst committees for Government institutions. Distrust amongst committees for

private agencies (e.g. CRO’s). Need to address concerns. private agencies (e.g. CRO’s). Need to address concerns.

• IAVI built capacity amongst trial investigators and staff on IAVI built capacity amongst trial investigators and staff on

GCP (via basic and advanced GCP courses) including on GCP (via basic and advanced GCP courses) including on

submissions and correspondence with committees. submissions and correspondence with committees.

• Framework and learning's useful for future HIV vaccine and Framework and learning's useful for future HIV vaccine and

Vaccine research conducted in India. Vaccine research conducted in India.

Oct 06

Key Learning’s from AIDS Vaccine Research in India*

• Importance of working with local experts/ agentsImportance of working with local experts/ agents

• Be aware of cultural differences and sensitivitiesBe aware of cultural differences and sensitivities

• Deal with long approval process & bureaucracy

• Discuss development plans and dossiers with regulatory Discuss development plans and dossiers with regulatory

agencies and scientific committees when possibleagencies and scientific committees when possible

• Understand local concerns and address them even if not Understand local concerns and address them even if not

scientifically valid scientifically valid

• Despite ICH and WHO, technical requirements and capacities Despite ICH and WHO, technical requirements and capacities

varyvary

• Global dossiers not still a reality. Need to prepare documents Global dossiers not still a reality. Need to prepare documents

according to local requirements according to local requirements

• Prepare well in advance and be prepared to be flexiblePrepare well in advance and be prepared to be flexible

*Acknowledgment Jim Ackland

Oct 06

IAVI India Team