Download - Schedule Y
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