The document discusses regulatory requirements and procedures for approval of new vaccines in India. It provides definitions of key terms like drugs, new drugs and vaccines. It describes the information and data required to be submitted for approval, including safety and efficacy data from clinical trials. It also discusses post-marketing surveillance requirements and procedures for investigating and reporting adverse events following immunization.

1. S.P. SHANI TECHNICAL OFFICER (Drugs) CENTRAL DRUGS STANDARD CONTROL ORGANIZATION (DIRECTORATE GENERAL OF HEALTH SERVICES) MINISTRY OF HEALTH & FAMILY WELFARE, NEW DELHI

2. 01123062648 www.cdsco.nic.in

4. Surveillance of Adverse Event following Immunization ( Regulatory Issues)

5. Authorities Responsible for Regulations under Drugs and Cosmetics Act & Rules thereunder Central Drug Authority State Licensing Authority Regulation of Vaccine is regulated by both the Authorities.

6. Definition of Drugs All medicines for internal or external use of human beings or animals and all substances intended to be used for or in the diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings or animals, including preparations applied on human body for the purpose of repelling insects like mosquitoes. Including vaccines

7. Definition of New Drug As per under Rule 122-E New Drug is defined “ A drug, including bulk drug substance which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labeling thereof and has not been recognised as effective and safe by the licensing authority mentioned under Rule 21 for the proposed claims. A drug already approved by the Licensing Authority mentioned in Rule 21 for certain claims , which is now proposed to be marketed with modified or new claims , namely , indications, dosage, dosage form ( including sustained release dosage form) and route of administration.

8. All vaccines are also classified as New Drug. Indigenously as well as Imported Vaccines are covered under the definition of New Drug. Definition of New Drug

9. Application on Form-44 duly filled in . Information to be submitted as per Schedule-Y ( Requirement and Guidelines on Clinical Trial for import and manufacture of Vaccine). Need for generation of Safety / Efficacy data as per GCP Guidelines under Schedule ‘Y’ Approval of Manufacturing facility/containment facility by way of joint inspection along with experts ( Rule 68 A). Approval accorded under Form-28 D ( For Indigenously developed vaccine ) or Form-10 ( for Imported Vaccine) Batch to Batch testing Generation of Post Marketing Surveillance Data Regulatory requirements for clearance under New Drug (Vaccine)

10. Requirements for Schedule-Y (Apendix I) Physico-chemical aspects Animal Pharmacology Animal Toxicology Human/Clinical Pharmacology Any special studies to be investigated. Regulatory status in other countries Marketing information

11. Physico-Chemical Aspects Authenticity of Seed Strain Characterization method Viability , Consistency and Quality Estimation of Molecular weight Peptide mapping Product based impurities

12. Production of Vaccine Seed lot techniques ( Bacterial Vaccine) Tissue Culture Technique ( Viral Vaccine) Conjugation Technique Recombinant Technique Contd..2..

13. Production of Vaccine Selection of Seed Strain Propagation Harvesting Purification Inactivation Addition of preservative Preparation of Bulk Finished Formulation Quality Control Release

14. Evaluation Procedures Review of Safety & Efficacy data in consultation with NIB, CDL, ICMR , Renowned Clinicians etc. Recombinant Drug Advisory Committee (RDAC) Panel constituted by Ministry of Health, evaluates data generated on safety and efficacy before deciding its market authorization ( In case of Recombinant based vaccine) . Results are also compared with International Published Data. Statistical Significance of end variables sufficient to demonstrates safety and efficacy . Contd..2...

15. Approval Procedures Approval accorded under Form-45 ( Imported Formulation) Form-46 ( For indigenously developed) Advice for generation of PMS Data Evaluation of product by CDL/CDTL Mumbai. Evaluation of manufacturing facility by way of Joint Inspection involving experts. Approval accorded under Form-28 D ( for Indigenously developed ) or Form-10 ( for Imported Formulation).

16. Procedures involved in approving Manufacturing Facility Compliance with Schedule M Requirements Checklist ( As per WHO Norms) Regulatory Inspection along with State Licensing Authority involving experts Validation Method SOPs Sampling of Product Demonstrate to show consistency in batch to batch production. Pharmocopoeal Specifications USP, BP, Eur. Ph.

17. CDL is responsible for Pre-release Certification of Vaccine in the Country

18. Safety Issues All serious events reported during the studies or after post marketing are reported to DCGI office as per statutory norms. Periodic submission Product Safety Update Reports (PSURs) – Post Licensing Condition. SAEs are also reported through a pharmocovigilence centre. Investigation of SAEs .

19. Why Monitor AEFI? No vaccines are 100% safe and without any risks It is important to know the risks and how to handle such an event when it occurs Informing people correctly on AEFI helps keep public’s confidence in the immunization programmes Monitoring AEFI also helps improve the quality of service

20. Adverse events following immunization are events or reactions observed following immunization. Some of these events may be due to the vaccine, some due to error in the administration of the vaccine Definition of Adverse Events Following Immunization

21. Types of Adverse Drug Reaction - Fatal Life-threatening Results in persistent or significant disability, incapacity Results in or prolongs hospitalisation Congenital anomalies/birth defects Other: Medical judgment should be exercised in deciding whether a reaction is serious in other situations. Important adverse reactions that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the patient should be considered as serious.

22. HOW THE ADVERSE EVENTS ARE REPORTED AND INVESTIGATED

23. COORDINATION ACTIVITIES AT THE LEVEL OF DCGI DURING REPORTING OF ADVERSE EVENTS DCGI Reporting of Adverse Events State Licensing Authority Zonal Office of CDSCO STATE EPI CDL Statutory Action Manufacture r

24. Steps in AEFI Surveillance Detection and reporting Temporary suspension of Product Regulatory Investigation/Inspection Causality Analysis based on Medical Investigation. CDL Testing Data Analysis Recall of batch: In case death linked with vaccine quality Statutory action proposed (Suspension or cancellation) Review of quality Investigation Data analysis

25. Major Player in Reporting Adverse Events Patients Health Professionals Media Marketing Authorization Holders Manufacturers Local Health Authorities, Agencies NRA of Exporting Country WHO (World Health Organization )

26. Investigation Ask about the vaccine Ask about immunization services Ask about the patient Observe the service in action Observe the storage procedures for vaccines and diluents in the relevant locations. Are other drugs stores with the vaccine or diluent that may have mistakenly been used. Contd..2..

27. Investigation Take an inventory of drugs/chemicals in storage at the location. Collect Urine, blood, tissue specimens as appropriate from the patient. Formulate a hypothesis as to the cause of the AEFI. Collect the sample of Vaccine used. Withdraw the entire lot Regulatory Inspection at Manufacturer’s end. Test from National Control Laboratory , CDL, Kasauli

28. Data Analysis Obtain laboratory ( pathological & CDL) results. Review clinical findings. Review on site investigation. Review epidemiological findings e.g. clustering. of cases in time or space or by vaccine manufacturer or lot. Summarize and report findings. Consult WHO or other experts for assistance when needed.

29. Barriers in Investigations Inadequate sampling Cold Chain conditions Short expiry vaccine Delay in reporting Logistic problems in sending samples Inadequate information Absence of casualty analysis report

30. Suggestions Time Frame for reporting different episodes of adverse events (Reference: National Child Vaccine Injury Act) e.g. In case of TT containing vaccine, anaphylaxis should be reported within 0-7 days and brachial neuritis within 0-28 days. Causality analysis be performed before statutory action is warranted Proper coordination and Faster Investigation Instant reporting by CDL, Kasauli Contd..2..

31. Validation of refrigerators for vaccine storage Telephone number of informer Recording of proper batch number of vaccine, diluents, Syringes , Needles and other related accessories. Linkage with Pharmaco-vigilance centre

32. The National Pharmacovigilance Programme is largely based on the recommendations made in the WHO document titled “ Safety Monitoring of Medicinal Products – Guidelines for Setting Up and Running a Pharmacovigilance Centre ”.

33. National Pharmacovigilance Programme was Launched by Honourable Union Health Minister Dr Anbumani Ramadoss on 23rd November, 2004

34. Aims and Objectives of National Pharmacovigilance Programme To generate broad based ADR data on the Indian population and share the information with global health-care community through WHO- UMC. To ensure optimum safety of drug products in the Indian market . To provide technical expertise for evaluating statutory AE reports furnished by sponsors conducting clinical trials in India.

35. National Pharmacovigilance Programme NPAC = National Pharmacovigilance Advisory Committee , ZRP = Zonal Pharmacovigilance Centre , RPC = Regional Pharmacovigilance Centre , PPC = Peripheral Pharmacovigilance Centre

36. Responsibilities of National Pharmacovigilance Advisory Committee Examine the ADR data generated by centres Risk-benefit analysis of drugs marketed in the country Advise Government regarding safe use of drugs Monitor functioning of National Pharmacovigilance Programme and give inputs for the better functioning of the programme from time to time

37. Location of Centers Zonal 2 Delhi, Mumbai Regional 5 Delhi, Kolkata, Mumbai, Nagpur, Pondicherry Peripheral 24 Orissa, Kolkata (3), Assam, Goa, Gujrat, Ahmedabad, Maharashtra (2), Delhi (3), U.P. (2), M.P., Tamil Nadu, Karnataka (5), Kerela, A.P.

38. THANK YOU - National Childhood Vaccine Injury Act of the Public Health Service. Section 2125, 1986; codified at 42 USC Section 300aa-26 - CDC, Food and Drug Administration. Vaccine Adverse Reporting System: updated reportable events table. - Stetler HC, Mullen JR, Brennan J-P, Livengood JR, Orenstein WA, Hinman AR. Monitoring system for adverse events following immunization. Vaccine 1987;5:169--74. - Faich GA. Adverse-drug-reaction monitoring. New Engl J Med 1986;314:1589--92. - Chen RT, Rastogi SC, Mullen JR. The Vaccine Adverse Event Reporting System (VAERS). Vaccine 1994;12:542--50. - Braun MM, Ellenberg SS. Descriptive epidemiology of adverse events after immunization: reports to the Vaccine Adverse Event Reporting System (VAERS), 1991--1994. J Pediatr 1997;131:529--35. - Singleton JA, Lloyd JC, Mootrey GT, Salive ME, Chen RT, VAERS Working Group. An overview of the Vaccine Adverse Event Reporting System (VAERS) as a surveillance system. Vaccine 1999;17:2908--17. - Varricchio FE. The Vaccine Adverse Event Reporting System. J Toxicol Clin Toxicol 1998;36:765--8. - Food and Drug Administration. 21 CFR Part 600.80. Postmarketing reporting of adverse experiences. Federal Register 1997;62:52252--3. - World Health Organization. Side effects: adverse reaction. Geneva, Switzerland: National Centres participating in the WHO International Drug Monitoring Programme, September 1991.. - SAS Institute Inc. SAS/STAT® user's guide. Version 6, 4th ed. Cary, NC: SAS Institute Inc, 1989. - Silvers LE, Ellenberg SS, Wise RP, Varricchio FE, Mootrey GT, Salive ME. The epidemiology of fatalities reported to the Vaccine Adverse Event Reporting System 1990--1997. Pharmacoepidemiology and Drug Safety 2001;10:279--85. - Fleming PJ, Blair PS, Platt MW, et al. The UK accelerated immunisation programme and sudden unexpected death in infancy: case-control study. BMJ 2001;322:822--5. - Institute of Medicine. Adverse effects of pertussis and rubella vaccines: a report of the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines. Howson CP, Howe CJ, Fineberg HV, eds. Washington, DC: National Academy Press, 1991:125--43. - Griffin MR, Ray WA, Livengood JR, Schaffner W. Risk of sudden infant death syndrome after immunization with the diphtheria-tetanus-pertussis vaccine. New Engl J Med 1988;319:618--23. - Hoffman HJ, Hunter JC, Damus K, et al. Diphtheria-tetanus-pertussis immunization and sudden infant death: results of the National Institute of Child Health and Human Development Cooperative Epidemiological Study of Sudden Infant Death Syndrome Risk Factors. Pediatrics 1987;79:598--611. - Institute of Medicine. Adverse events associated with childhood vaccines: evidence bearing on causality. Stratton KR, Howe CJ, Johnston RB, Jr, eds. Washington, DC: National Academy Press, 1994:274--304.