SCHEDULE Y REGULATORY TOOL TO MANAGE RISK 1252020

SCHEDULE Y REGULATORY TOOL TO MANAGE RISK 12/5/2020 1

SCENARIO FOR TODAY’S DISCUSSION: Schedule Y IEC SCOPE UTILITY NEW DRUG DEVELOPMENT PROCESS IN INDIA RISKS 12/5/2020 RIGHTS SAFETY WELL BEING OF HUMAN SUBJECTS FUTURE DIRECTION BENEFITS 2

SCHEDULE Y v DEFINE NEW DRUG v SCOPE: REGULATE THEIR INTRODUCTION BASED ON SAFETY AND EFFICACY CONSIDERATIONS v ENSURE QUALITY v IMPLEMENTATION 12/5/2020 3

SCHEDULE Y (RULE 122 E) NEW DRUG SUBSTANCE(API) DRUG PRODUCT(FORMULATION) NOT USED IN COUNTRY * • SR/FDC/VACCINES • USE < 4 YEARS EFFICACY=? ? ? 12/5/2020 SAFETY=? ? ? 4

SCOPE OF SCHEDULE Y Rule 122 -A, 122 -B, 122 -D, 122 -E under Drugs & Cosmetics Rules 1945 in 1988/2000/2001/2002/2005 DRUG SUBSTANCE DRUG PRODUCT DEVELOPMENT STUDIES /PRECLINICAL DATA IMPORT FOR TESTING ANALYSIS & EXAMINATION CLINICAL STUDIES/BE STUDIES DECISIONS BASED ON BEST AVAILABLE SCIENTIFIC EVIDENCE 12/5/2020 5

SCOPE OF SCHEDULE Y v. HERBALS: INDIAN SYSTEM OF MEDICINE & HOMEOPATHY : APPROVAL BY STATE DRUG CONTROLLER v. BIOTECHNOLOGY PRODUCTS: RECOMBINANT PRODUCTS: DCGI DBT RDAC RCGM IBSC GEAC 12/5/2020 6

Ethical Guidelines for Biomedical Research on Human Subjects ICMR 2000 STATEMENT GENERAL PRINCIPLES SPECIFIC PRINCIPLES • DRUGS • DEVICES • HERBALS • VACCINES PURPOSE CLINICAL EVALUATION CONDUCT EPIDEMIOLOGICAL STUDIES GENETICS RESEARCH EVALUATION 12/5/2020 TRANSPLANTATION INCLUDING FOETAL TISSUE TRANSPLANTATION ASSISTED REPRODUCTIVE TECHNOLOGIES 7

SPECIFIC GUIDELINES Ø Guidelines by DBT under DST: Biotechnology Products (Preclinical, clinical data for r-DNA based vaccines; diagnostics and other biological products Ø DCGI guidelines : BA/BE Studies Ø DCGI guidelines: Pharmacovigilance 12/5/2020 8

PROCESS OF NEW DRUG DEVELOPMENT IN INDIA NDA vs. ANDA Review Process Brand Name Drug NDA Requirements Generic Drug ANDA Requirements 1 Chemistry √ 2. Manufacturing √ 3 Controls √ 4. Labeling √ 5. Testing √ 6 Animal Studies √ ? Bioequivalence Studies √ 7 Clinical Studies √ ? 8 Bioavailability Studies √ ? 12/5/2020 9

IMPLEMENTATION: SCHEDULE Y Application Form 44 Submission Rule 122 A Rule 122 B Rule 122 DA Purpose: Marketing Authorisation Import Manufacture Clinical Study Drug Substance Form 45 A Form 46 A Drug Product Form 45 Form 46 Application Form 12 Submission Purpose Import For Examination, Test and Analysis Drug Product Form 11 12/5/2020 10

DOCUMENT SUBMISSION TO DCGI IN ADDITION TO FORM 44 v PROTOCOL v CASE REPORT FORMS v PRODUCT INFORMATION (Appendix I, III) v INVESTIGATOR UNDERTAKING [Appendix IV) v IEC APPROVAL [Appendix V] [Amendments/approvals] v INFORMED CONSENT FORMS(TRANSLATIONS): [Appendix VI ] v MARKETING /REGULATORY STATUS IN OTHER COUNTRIES 12/5/2020 11

Which studies ? When ? Phase II Product Already approved/ marketed in another country Product neither approved/ nor marketed in another country but phase III /II studies are in progress Phase III √ Therapeutic confirmatory studies √ if phase II Studies Are over √ if phase III Studies Are over Trials are generally allowed to be initiated at one phase earlier to the phase of trials in other countries 12/5/2020 12

Which studies ? When ? Phase I For new drug substances discovered in other countries Phase I trials are not usually allowed to be initiated in India unless Phase I data from other countries are available. Exception will be if product is of special relevance to the health problem of India. For new drug substances discovered in India √ Allowed in stages 12/5/2020 13

Which studies ? When ? Phase IV Post Marketing Surveillance Periodic Safety Update Reports Mandatory Unexpected SAE 12/5/2020 14 days Other investigators 14

ENSURE QUALITY: STABILITY STUDIES STORAGE CONDITIONS LONG ACCELERATED TEMPERATURE 30± 2°c 40 ± 2°c RH 65 ± 5% 75 ± 5% MONTHS 12 06 5 ± 3°c 25 ± 2°c GENERAL REFRIGERATOR TEMPERATURE RH MONTHS 60 ± 5% 12 06 FREEZER TEMPERATURE -20 ± 5°c MONTHS 12 12/5/2020 15

RESPONSIVE IEC COMPOSITION FUNCTION DOCUMENTATION APPROVAL REVISED SCHEDULE Y(2005): PROTOCOL BASED ON INDIAN GCP(2002) & ICMR ETHICAL GUIDELINES(2000) SPONSOR INDIAN GCP IEC SCIENTIFIC GCP INVESTIGATOR ETHICAL HUMAN SUBJECT ICMR GUIDELINES 12/5/2020 16

THERAPEUTIC EXPERIMENTAL BIOEQUIVALENCE ELECTIVE CLINICAL PRACTICE Operations on donors for live donor organ transplants, aesthetic surgery, and non-therapeutic sterilization RESEARCH NON ELECTIVE 12/5/2020 NON THERAPEUTIC 17

Before CONSIDERING the study : IEC SHOULD OBTAIN Investigator Sponsor Human Subject CV IB Advertisem ent Protocol ICF Updates Compensat ion 12/5/2020 18

WHILE CONSIDERING the study : IEC : HOW IT SHOULD FUNCTION LIST MEMBERS SOPS SCHEDULE PROCEDURE & NOTIFY INVESTIGATOR REVIEW QUORUM NON MEMBER 12/5/2020 INITIAL VOTING CONTINUOUS FINAL 19

AFTER CONSIDERING the study : IEC : HOW IT SHOULD COMMUNICATE APPROVAL OR FAVOURABLE OPINION NOTIFY MODIFICATIONS REQUIRED PRIOR TO APPROVAL PROVIDE REASONS PROCEDURES FOR APPEAL UNFAVORABLE OPINION PROVIDE REASONS PROCEDURES FOR APPEAL TERMINATION OR SUSPENSION OF PRIOR APPROVAL PROVIDE REASONS PROCEDURES FOR APPEAL 12/5/2020 20

Adverse Drug Reaction (ADR) All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i. e. the relationship cannot be ruled out. 12/5/2020 21

Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product 12/5/2020 22

Serious adverse event (SAE) Any adverse experience occurring that results in any of the following outcomes Death (irrespective of initial impression of causality) Life-threatening REPORT IMMEDIATELY Hospitalization or prolongation of existing hospitalization A persistent or significant disability/incapacity A congenital anomaly or birth defect. 12/5/2020 23

SAE/AR Reporting • Related to or associated with the use of the investigational product • There is a reasonable possibility that the event was caused by the investigational product. • Reasonable: Temporal Relationship Known Pattern 12/5/2020 24

UNEXPECTED SAE • Expected/unexpected/unanticipated An expected event is one where the specificity and severity of the event are consistent with the information in the investigator brochure, labeling for the product, or contained else where in the investigational plan. Unexpected events are all other occurrences. 12/5/2020 25

FUTURE DIRECTION: PRDC (1999) Recommendations on CDSCO v. PROTOCOL : ADVISORY BOARD v. FULL TIME EXPERTS/EXPERT PANELS v. TIME SCHEDULE FOR DRUG APPROVAL * IND PHASE I : WITH IN 3 MONTHS * IND PHASE II: WITHIN 6 MONTHS * MARKETING APPROVAL: 3 MONTHS Pharmaceutical Research & Development Committee (PRDC) 12/5/2020 26

FUTURE DIRECTION: INVESTIGATOR SPONSOR REGULATOR RISK MANAGEMENT IEC 12/5/2020 ACCESSIBILITY HUMAN SUBJECT 27

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