Amended Schedule “Y”

Dr. Surinder Singh

(Drugs Controller General of India)

Directorate General Health Services(Ministry of Health & Family Welfare)

Govt. of India

Overview

• Schedule Y – what it covers and associated rules

• Application for permission under form 44, regulatory authorities and fees

• Important consideration

• Appendices of Schedule Y

• Loopholes & further refinement

SCHEDULE “Y”

WHAT IT COVERS & ASSOCIATED RULES

What is Schedule Y

• Regulation and guidelines for permission to import and / or manufacture of new drugs for sale or to undertake clinical trials

• It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines

• REFER TO RULES 122A, 122B, 122D, 122DA, 122DAA and 122E

Part X-A of D & C Rules, 1945

• 122-A Application for permission to import new drug

• 122-B Application for approval to manufacture new drug

• 122-D Permission to import or manufacture FDC/NDC

• 122-DA Permission to conduct clinical trials for New Drug / Investigational New Drug

Clinical trial

• 122-DAA

– “Clinical trial” means a systematic study of new drug(s) in human subject(s) to generate data for discovering and / or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and /or adverse effects with the objective of determining safety and / or efficacy of the new drug.

New drug• 122-E

• Not been used in the country under labeling conditions

• Approved but now proposed to be marketed with modified or new claims – indications, dosage, dosage form , route of administration

• FDC, individually approved, to be combined for the first time in a fixed ratio or if ratio is changed

• Vaccines are new drugs unless otherwise certified

• Considered new drug for 4 years from date of first approval or inclusion in IP

Investigational new drug

• New chemical entity or a product having therapeutic indication but which has never been earlier tested on human beings

APPLICATION FOR PERMISSION UNDER FORM

44, REGULATORY AUTHORITIES, & FEES

Regulatory authorities

Ministry of Chem & Fertilizers

(NPPA)National

Pharmaceutical Pricing Authority

Pricing Regulations

Ministry of Sci & Tech

(DBT)Department of Biotechnology

Ministry of Enviro

Additional Secretary

State Drug Regulatory Authority :FDA

(GEAC)Genetic

Engineering Approval

Committee

(DCGI)Drug Controller General of India

(DGHS)Director General of

Health Services

Health Secretary

Ministry of Health

(CDL/CDTL)Gov. Drug Testing

Laboratories

PROCESS

APPLICATION FORM 44

-Imp ff-Imp rm-Mfg ff-Mfg rm-CT

NOC FOR CT + Test Licence for Import

Application Form 46 A (MFG RM)

Approval Form 46 (MFG FF)

Approval Form 45 A (IMP RM)

Approval Form 45 (IMP FF)

FEES• Import ff/ Mfg ff/ Import bulk + Mfg ff = Rs

50,000/- of new drug

• Application by same applicant, = Rs 15,000/-for modified dosage form or with new claim

• Secondary applicants after 1 = Rs 15,000/-year of approval

• Import / Mfg FDC = Rs 15,000/-

• Conduct Clinical trial with ND/IND – Phase I = Rs 50,000/-– Phase II = Rs 25,000/- – Phase III = Rs

25,000/-– No separate fee to be paid along with application for import / mfg

based on successful completion

Application Form 44FORM 44

(See Rules 122A, 122B, 122D and 122DA)

Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial

I/We..……….. of ……….., hereby apply for grant of permission for import and / or clinical trial or for approval to manufacture of a new drug or fixed dose combination or subsequent permission of already approved new drug. The necessary information / data is given below :

• 1. Particulars of New Drug :– Name of the drug : – Dosage Form : – Composition of the formulation : – Test specifications :

• Active ingredients : • Inactive ingredients :

– Pharmacological classification of the drug : – Indications for which proposed to be used :– Manufacturer of the raw material :– Patent status :

FORM 44 Contd2. Data submitted along with the application

A. Permission to market new drug

1. Chemical and Pharmaceutical information2. Animal Pharmacology 3. Animal Toxicology 4. Human / Clinical Pharmacology5. Exploratory Clinical Trials6. Confirmatory Clinical Trials 7. Bioavailability / dissolution and stability data 8. Regulatory status in other countries 9. Marketing information :

(a) Proposed product monograph(b) Drafts of labels and cartons

10. Application for test license :

FORM 44 Contd

B. Subsequent approval / permission for manufacture of already approved new drug

a) Formulation :– Bioavailability / bioequivalence– Name of the investigator / centre– Source of raw mat and stability

b) Raw Material– Manufacturing Method– QC parameters, specs, stability– Animal toxicity

FORM 44 Contd

D. Subsequent approval or approval for new indication – new dosage form :

• Number and date of Approval already granted• Justification• Data on safety, efficacy and quality

• A total fee of Rs………………… has been credited to the Government under the Head of Account …… (receipt enclosed)

• Signature• Designation• Date

FORM 44 Contd

C. Approval / permission for FDC

• Justification• P’cokinetic / P’codynamic data • Any other data

Important Considerations - 1• HUMAN CLINICAL PHARMACOLOGY :-

a) Phase I (Human Pharmacology) – Safety and Tolerability with the initial administration of IND – MTD, Kinetics and Dynamics

b) Phase II (Therapeutic Exploratory Trials) – Effectiveness for a particular indication, small group

c) Phase III (Therapeutic Confirmatory Trials) – Therapeutic benefit in large number of patients

d) Phase IV (Post Marketing Trials) – Related to approved indication

IMPORTANT CONSIDERATIONS

• HUMAN CLINICAL PHARMACOLOGY :- a) for new drug substances discovered in India : Trials are required to

be carried out in India right from phase 1 and required data needs to be submitted.

b) for new drug substances discovered in countries other than India : Phase I data generated outside India, permission may be granted to repeat phase 1. Application for permission to initiate specific phase of clinical trial should also accompany Investigator’s brochure, proposed protocol, case record form, study subject’s informed consent document's) investigator’s undertaking and ethics committee clearance, if available

c) Sample size depends on type of studyd) EC application can be in parallel to DCGI applicatione) Drugs indicated in life-threatening, serious disease or diseases of

special relevance to Indian health scenario, toxicological / clinical data abbreviated, deferred or omitted

f) Administrative/Logistic Amendments notified to DCGI and EC within 30 days and approval obtained

Important Considerations - 2

PSUR :- New drugs should be closely monitored for their clinical safety;

submission of Periodic Safety Update Reports (PSUR’s) in order to-• report all the relevant new information (patient exposure)• summarize the market authorization status in different countries and

any significant variations related to safety; and• indicate whether changes should be made to product information  PSURs shall be submitted every 6 months for the first two years after approval

For subsequent two years – the PSURs need to be submitted annually

PSURs due for a period must be submitted within 30 calendar days of the last day of the reporting period.

IMPORTANT CONSIDERATIONS - 3

BA/BE

i. For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out.

ii. Evaluation of the effect of food iii. Dissolution and bioavailability data to be submittediv. All bioavailability and bioequivalence studies should

be conducted according to the Guidelines for Bioavailability and Bioequivalence studies as prescribed (ICMR guidelines)

TEST LICENCE

Application :

• Form 12 application

• Material Justification Plan

• Treasury Challan of Rs 100 for first drug, followed by Rs 50 for additional drug

• Test License obtained in FORM 11