Approval Process in India

1. Ethical and Regulatory Approval Process in HIV Vaccine Clinical ResearchIndia ExperienceHIV Vaccine Clinical Research Ethical and Regulatory IssuesBrasilia, October 4-5, 2006 Dr. Sonali KochharSenior Medical Project ManagerInternational AIDS Vaccine Initiative, India

2. 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

3. 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

4. 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)

5. 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

6. 3 3 2 1 4 Regulatory Process in India • Preclinical Data GEAC GEAC dossier • Institutional Scientific Committee • Protocol • IB • DCGI • Reviews standard clinical documents • Schedule Y with Form 44 (IND equivalent) • Form 12 (Import of test vaccine) • HMSC • TRC cover letter • Special HMSC form • All approvals Letter Permission to use material for clinical trial • Institutional Ethics Committee • Protocol & IB • Toxicology Report Summary • Clinical documents Central Ethics Committee Protocol & IB Toxicology Report Summary Clinical documents DCGI: Drug Controller General of India HMSC: Health Ministry Screening Committee GEAC: Genetic Engineering Approval Committee Approval Steps TK-02-24-05

7. 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

8. 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.

9. 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)

10. AIDS Vaccine Research in India • First ever AIDS Vaccine trial being conducted in India raised lot of apprehensions amongst Regulatory and Ethics committees and investigators • Institutional committees required numerous meetings to address concerns (e.g. for first trial, four meetings of Institutional Scientific Committee held before members satisfied) • Committees gained confidence with experience with trial process (e.g. for second trial, members from the first trial site’s Ethics Committee invited to attend meeting. Shared experience and concerns with second ethics committee members. Process was faster). • National Ethics Committee reviewed trial because of public significance

11. AIDS Vaccine Approval Process Timelines - India A001 Clinical Trial, NARI, Pune D001 Clinical Trial, TRC, Chennai

12. AIDS Vaccine Trial Approval Timelines

13. IAVI’s Clinical Research in India • Institutional and Central Committee’s should have procedures and maintain record of proceedings as per GCP • Committees should provide approval letters according to GCP requirements. • Committees are often overworked and understaffed • Committee's might lack technical expertise amongst members. Simple and coherent presentations by investigators and sponsors asked to attend sessions to answer questions.

14. IAVI’s Clinical Research in India • IAVI in partnership with Government of India and trial sites in Government institutions. Distrust amongst committees for private agencies (e.g. CRO’s). Need to address concerns. • IAVI built capacity amongst trial investigators and staff on GCP (via basic and advanced GCP courses) including on submissions and correspondence with committees. • Framework and learning's useful for future HIV vaccine and Vaccine research conducted in India.

15. Key Learning’s from AIDS Vaccine Research in India* • Importance of working with local experts/ agents • Be aware of cultural differences and sensitivities • Deal with long approval process & bureaucracy • Discuss development plans and dossiers with regulatory agencies and scientific committees when possible • Understand local concerns and address them even if not scientifically valid • Despite ICH and WHO, technical requirements and capacities vary • Global dossiers not still a reality. Need to prepare documents according to local requirements • Prepare well in advance and be prepared to be flexible *Acknowledgment Jim Ackland

16. IAVI India Team