Schedule Y

INDIAN DRUG REGULATION: SCHEDULE Y Dr. A.K.Agarwal ICRI, Bangalore

Schedule Y Requirements and Guidelines for permission to import / manufacture of new drug for sale or Clinical Trial Responsibilities Applications Appendices Refinements

Drug Regulatory Laws 1940 1985

- Drugs and Cosmetic act - Narcotic drugs and psychotropic substances act 2000 - Ethical guidelines for biomedical research on human subjects, ICMR 2001 - Indian GCP guidelines 2002 - Amendment to D & C act 2005 - Revised schedule Y Future :  Guidelines for pre-clinical data for r- DNA vaccines, diagnostics & biologicals, DBT.  Draft guidelines for 5 tem cell research/ regulation, ICMR.

Schedule Y 2005 Revised

Old

1. Application for permission

1.1 Nature of trials

2. Clinical trial

1. Clinical trials

(1) Approval for clinical trial

1.2 Permission for trials

(2) Responsibilities of Sponsor (3) Responsibilities of the Investigator(s)

1.3 Responsibilities of Sponsor/Investigator

(4) Informed Consent – New (5) Responsibilities of ECs - New (6) Human Pharmacology (Phase I) (7) Therapeutic exploratory trials (Phase II) (8) Therapeutic confirmatory trials (Phase II) (9) Post Marketing Trials (Phase IV) – New 3. Studies in special populations

5. Human clinical pharmacology (Phase I) 6. Exploratory trials (Phase II) 7. Confirmatory trials (Phase II) 8. Special studies

(1) Geriatrics (2) Pediatrics (3) Pregnant or nursing women 4. Post Marketing Surveillance 5. Special studies: BA/BE Studies – New

12. Post-marketing surveillance study

Schedule Y 2005 Revised

Old

Data to be submitted along with the application Data required to be submitted with application to to conduct clinical trials/import/manufacture of for permission to market a new drug new drugs for marketing in the country 2.1 Information on active ingredients

2.3 Specifications of active and inactive ingredients

2.2 Physicochemical Data

2.1 Physicochemical proportion

2.3 Analytical data – New 2.4 Monograph specification

2.4 Tests for identification of the active ingredient and method of its assay

2.5 Validations – new 2.7 Data on Formulation

2.2 and 2.5

3.4 Safety Pharmacology – New 4.3 Male Fertility Studies – New 4.6 Allergenicity/Hypersensitivity – New 11. Samples and Testing Protocols

10.3 Sample…with testing protocol

Regulatory Authorities MINISTRY OF HEALTH Health Secretary

M/O Chemistry & Fertilizer

NPPA DBT

DGHS

DCGI

CDTL

M/O Science & Technology

M/O Environment

GEAC ADD. SECRETARY

State Drug Regulatory Authority FDA

Investigational New Drug (IND) New chemical entity or product having therapeutic indication but never tested on human beings

Importan t conc erns SAE / SADR Event associated with death, hospitalization disability, congenital anomaly or otherwise life- threatening. Adverse Event (AE) Untoward medical (I/S/D) occurrence that does NOT necessarily have relationship with the treatment.

ADVERSE DRUG REACTION Noxious / unintended response at therapeutic doses for approved product, or any dose for unapproved product, and a possible Adverse Event

Drugs and Cosmetics Act 1945 Rule 2 A B

Permission for

– Import – Manufacture [except drugs under schedule C and C(1)] D – Fixed dose combination DA – Clinical trial DAA – CT definition E – New drug definition

122 – DAA Clinical Trial Definition Systematic study of new drugs in human subjects; To generate data for discovering/verifying clinical, pharmacological (PK & PD) or adverse effects; & To determine safety and efficacy of the new drug

122 – E New drug definition Not used in the country Approved drug : 1. New claims (Indications,dosage, dosage form, route) 2. FDCs (New / Modified) Note : Vaccines are new drugs unless 1. Certified 2. Till 4 year or 3. Included in IP

SPONSOR’S RESPONSIBILITIES Quality Assurance : Adopt GCP Guidelines Trial Status Report to Licensing Authority : Annually Premature Termination : Summary report within 3 m ( Study, Pt. no., Dose, Duration, ADR & reasons for discontinuation ) Serious Adverse Event : Report to LA & other investigators within 14 days

INVESTIGATOR’S RESPONSIBILITIES Adhere to approved Protocol & GCP Guidelines Document SOPs Management of all ADR / AE Reporting unexpected AE to : - Sponsor within 24 hours - EC within 7 days

EC RESPONSIBILITIES Safeguard rights, safety & well being Protect vulnerable subjects Obtain and maintain record of SOPs Ongoing review based on Periodic progress report If EC revokes its approval - Record reasons for it - Inform the Investigator & LA immediately

ESSENTIAL STEPS OF CLINICAL PHARMACOLOGY Phase I (Human Pharmacology) Safety & Tolerability ( PK, PD & MTD Phase II (Th. Exploratory Trial) Therapeutic benefits in few patients Phase III (Th. Confirmatory Trial) Therapeutic benefit in more patients Phase IV (Post Marketing Trials) Related to Approved indication

REGULATORY REQUIREMENTS FOR CLINICAL PHARMACOLOGY Drug discovered in India

: Phase I data

Drug discovered outside India : Foreign Phase I data required for Phase II/III permission Accompanying documents

: Protocol, CRF, IB, IC, EC Clearance, Investigator’s undertaking

Sample size :

Depending upon type of study

REGULATORY REQUIREMENTS FOR CLINICAL PHARMACOLOGY EC application can parallel DCGI application Toxicological / clinical data abbreviate, deferred or omitted for life threatening diseases (or diseases of special relevance to Indian health Scenario) Amendments notified to DCGI & EC within 30 days & approval obtained

BA / BE INFORMATION Drugs approved elsewhere require BE studies with the reference formulation Effect of Food Dissolution and BA data Compliance with ICMR guidelines for BA / BE Studies

APPLICATION FORM 44 -Imp ff -Imp rm -Mfg ff -Mfg rm -CT

PROCESS APPROVAL FORM 45 (IMP FF) APPROVAL FORM 45 A (IMP RM) APPROVAL FORM 46 (MFG FF) APPLICATION FORM 46 A (MFG RM)

NOC FOR CT + Test License for Import

Application Fees Import ff/ Mfg ff/ Import bulk + Mfg ff of new drug

= Rs 50,000/-

Application by same applicant, for modified dosage form or with new claim

= Rs 15,000/-

Secondary applicants after 1 year of approval

= Rs 15,000/-

Import / Mfg FDC

= Rs 15,000/-

Conduct Clinical trial with ND/IND Phase I Phase II Phase III

= Rs 50,000/= Rs 25,000/= Rs 25,000/-

No separate fee to be paid along with application for import / mfg based on successful completion

TEST LICENCE Application form No. 12 Material Justification Plan Treasury Challan ( Rs. 100 )

Test License obtained in form 11

PERIODIC SAFETY UPTAKE REPORTS ( PSUR) Report all relevant new information following patient exposure Summarize the market authorization status in different countries and any significant variations related to safety Suggest changes in Product Information

PSUR TIME FRAME ( within 30 days ) First 2 years – Next 2 years –

Half yearly Annually

Drafts of Labels & Cartons Comply with Rules 96 of D & C rules , 1945 No changes in Package insert once approved

Appendices I

: Data required for import/manufacture/

conduct CT of new drugs I A : …. Drugs approved in other country II : Format for clinical study reports(ICH E6) III : Animal toxicology IV : Animal pharmacology V : Informed consent

Appendices VI : VII : VIII : IX : X : XI :

FDC Undertaking by the investigator Ethics committee Stability testing Proposed protocol SAE Reporting

Loopholes in Schedule Y New drug remains new for 4 years. Thus, Phase IV trials require permission. However, Approved drug and indication need not require permission. Approval of Amendment could be a problem. SOPs for investigators and documentation of tasks – Template required. Unmet medical needs to be added to CT waiver.

Loopholes in schedule Y EC chairman outside institute is a rarity. Exhaustive species data (App.I-A)and comparative evaluation (App. I) not helpful for differentiation. All CT supplies to be included in Form 11. Requirement to support data protection

Unattended Areas Regulations for : 1. Biologics : vaccines Blood products Tissue Cellular/gene therapy 6. Herbals 7. Medical devices 8. Pharmacovigilance 9. Electronic records