INDIAN DRUG REGULATION: SCHEDULE

Y

Dr. A.K.AgarwalICRI, Bangalore

Schedule Y

Requirements and Guidelines for permission to import / manufacture of new drug for sale or Clinical Trial

ResponsibilitiesApplicationsAppendicesRefinements

Drug Regulatory Laws1940 - Drugs and Cosmetic act

1985 - 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 1.3 Responsibilities of Sponsor/Investigator(3) Responsibilities of the Investigator(s)

(4) Informed Consent – New

(5) Responsibilities of ECs - New

(6) Human Pharmacology (Phase I) 5. Human clinical pharmacology (Phase I)

(7) Therapeutic exploratory trials (Phase II)

6. Exploratory trials (Phase II)

(8) Therapeutic confirmatory trials (Phase II)

7. Confirmatory trials (Phase II)

(9) Post Marketing Trials (Phase IV) – New

3. Studies in special populations 8. Special studies

(1) Geriatrics

(2) Pediatrics

(3) Pregnant or nursing women

4. Post Marketing Surveillance 12. Post-marketing surveillance study

5. Special studies: BA/BE Studies – New

Schedule Y 2005

Revised Old

Data to be submitted along with the application to conduct clinical trials/import/manufacture of new drugs for marketing in the country

Data required to be submitted with application to for permission to market a new drug

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 AuthoritiesMINISTRY OF HEALTH

DGHS

Health Secretary

DCGI

CDTL

M/O Chemistry & Fertilizer

M/O Environment

M/O Science & Technology

State Drug Regulatory AuthorityFDA

NPPA

DBT

ADD. SECRETARY

GEAC

Investigational New Drug (IND)

New chemical entity or product having therapeutic indication but never tested on human beings

Important concerns

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 Permission for122 A – Import B – 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 countryApproved 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 RESPONSIBILITIESQuality 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 GuidelinesDocument SOPsManagement of all ADR / AEReporting unexpected AE to :

- Sponsor within 24 hours - EC within 7 days

EC RESPONSIBILITIES

Safeguard rights, safety & well beingProtect vulnerable subjectsObtain and maintain record of SOPsOngoing review based on Periodic progress reportIf 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 FoodDissolution and BA dataCompliance with ICMR guidelines for

BA / BE Studies

PROCESS

APPLICATION FORM 44

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

NOC FOR CT + Test License for Import

APPLICATION FORM 46 A (MFG RM)

APPROVAL FORM 46 (MFG FF)

APPROVAL FORM 45 A (IMP RM)

APPROVAL FORM 45 (IMP FF)

Application FeesImport 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

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 – Half yearly

Next 2 years – Annually

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

Appendices

I : Data required for import/manufacture/

conduct CT of new drugs I A : …. Drugs approved in other countryII : Format for clinical study reports(ICH

E6)III : Animal toxicologyIV : Animal pharmacologyV : Informed consent

Appendices

VI : FDCVII : Undertaking by the

investigatorVIII : Ethics committeeIX : Stability testingX : Proposed protocolXI : 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 AreasRegulations for :1. Biologics : vaccines

Blood products Tissue Cellular/gene therapy

2. Herbals3. Medical devices 4. Pharmacovigilance5. Electronic records