Amended

Schedule Y

Corporate Headquarters:
Max House, G.F.
1 Dr. Jha Marg, Okhla
New Delhi – 110020 In Force Jan 2005
India
 PRESENTATION OVERVIEW

• SCHEDULE Y – WHAT IT COVERS AND ASSOCIATED RULES

• RESPONSIBILITIES OF SPONSOR, INVESTIGATOR AND ETHICS

COMMITTEE

• APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY

AUTHORITIES, FEES AND TEST LICENCE

• LOOPHOLES & FURTHER REFINEMENT

• SCHEDULE Y – WHAT IT COVERS AND ASSOCIATED RULES
 WHAT IS SCHEDULE Y
• REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT
AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO
UNDERTAKE CLINICAL TRIALS

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

 PART XA of D & C RULES 1945
• 122-A Application for permission to import new drug
• 122-B Application for approval to manufacture new drug
• 122-C Deleted
• 122-D Permission to import or manufacture FDC
• 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.
• 122-E. NEW DRUG
- 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 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
• RESPONSIBILITIES OF SPONSOR, INVESTIGATOR AND ETHICS
COMMITTEE
 RESPONSIBILITIES OF THE SPONSOR

• Implementing and maintaining quality assurance systems - Good Clinical Practice (GCP)
Guidelines issued by CDSCO, INDIA
• Sponsors are required to submit a status report on the clinical trial to the Licensing
Authority at the prescribed periodicity (annual).
• In case of studies prematurely discontinued for any reason including lack of commercial
interest in pursuing the new drug application, a summary report should be submitted
within 3 months. The summary report should provide a brief description of the study, the
number of patients exposed to the drug, dose and duration of exposure, details of adverse
drug reactions and the reason for discontinuation of the study or non-pursuit of the new
drug application
• Any unexpected serious adverse event (SAE) (as defined in GCP Guidelines) occurring
during a clinical trial should be communicated promptly (within 14 calendar days) by the
Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study
 DEFINITION SAE / SADR / AE / ADR
• SAE / SADR: An adverse event / adverse reaction associated with death, in patient
hospitalisation, prolongation of hospitalisation, persistant or significant disability or
incapacity , a congenital anomaly or birth defect or is otherwise life threatening
• Adverse Event (AE ) : any untoward medical occurrence (including a symptom /
disease or an abnormal lab finding) during treatment with a pharmaceutical product in
a patient or a human volunteer that does not necessarily have a relationship with the
treatment being given.
• Adverse Drug Reaction (ADR) :
– Approved product: Noxious / unintended response at doses normally
used or tested in humans
– Unapproved product: Noxious / unintended response at any dose
– There is reasonable possibility that the adverse event is related with
medicinal product studied
 RESPONSIBILITIES OF INVESTIGATOR
• Responsible for the conduct of the trial according to the protocol and the
GCP Guidelines and also for compliance.
• Standard operating procedures are required to be documented by the
investigators for the tasks performed by them.
• Ensure that adequate medical care is provided to the participant for any
adverse events.
• Report all serious and unexpected adverse events to the Sponsor within
24 hours and to the Ethics Committee that accorded approval to the
study protocol within 7 working days of their occurence.
 RESPONSIBILITIES OF ETHICS COMMITTEE
• Safeguard the rights, safety and well being of all trial subjects.
• Particular care to protect the rights, safety and well being of all vulnerable subjects
• Obtain ‘standard operating procedures’ and maintain a record
• Ongoing review based on periodic study progress reports
• In case an ethics committee revokes its approval it must record the reasons for doing
so and at once communicate such a decision to the Investigator as well as to the
Licensing Authority.
• APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY
AUTHORITIES, FEES AND TEST LICENCE
REGULATORY AUTHORITIES
Ministry of Chem & Ministry of Health Ministry of Sci &
Fertilizers Tech Ministry of
Health Secretary Enviro
DBT
NPPA DGHS Department of Additional
National Director General of Biotechnology Secretary
Pharmaceutical Health Services
Pricing Authority GEAC
DCGI Genetic
Drug Controller Engineering
Pricing General of India Approval
Regulations Committee
CDL/CDTL
Gov. Drug Testing
Laboratories

State Drug Regulatory Authority :FDA

 PROCESS

APPLICATION APPROVAL FORM 45

FORM 44 (IMP FF)
-Imp ff APPROVAL FORM 45 A
-Imp rm (IMP RM)
-Mfg ff
-Mfg rm
-CT APPROVAL FORM 46
(MFG FF)

APPLICATION FORM 46 A
(MFG RM)

NOC FOR CT + Test Licence

for Import
 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 IN FORM 44
FORM 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 :
1. Name of the drug :
2. Dosage Form :
3. Composition of the formulation :
4. Test specifications :
• Active ingredients :
• Inactive ingredients :
5. Pharmacological classification of the drug :
6. Indications for which proposed to be used :
7. Manufacturer of the raw material :
8. Patent status :
 FORM 44 Contd
2. Data submitted along with the application

A Permission to market new drug

1. Chemical and Pharmaceutical information

2. Animal Pharmacology
3. Animal Toxicology
4. Human / Clinical Pharmacology
5. Exploratory Clinical Trials
6. 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 licence :
 FORM 44 Contd

B Subsequent approval / permission for manufacture of

already approved new drug
a) Formulation :
a) Bioavailability / bioequivalence
b) Name of the investigator / centre
c) Source of raw mat and stability
b) Raw Material
• Manufacturing Method
• QC parameters, specs, stability
• Animal toxicity

C Approval / permission for FDC

1. Justification
2. P’cokinetic / P’codynamic data
3. Any other data
 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
 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 : Data from Phase I
(b) for new drug substances discovered in countries other than India :
Phase I data generated outside India, permission may be granted for
Phase II trials and subsequently Phase III trials concurrently with other
global trials
(c) 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
(d) Sample size depends on type of study
(e) EC application can be in parallel to DCGI application
(f) Drugs indicated in life-threatening, serious disease or diseases of
special relevance to Indian health scenario, toxiciological / clinical data
abbreviated, deferred or omitted
(g) 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 (PSURs) 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

DRAFTS OF LABEL AND CARTONS :-

• Should comply with Rules 96 of the D&C Rules, 1945

• After Approval no changes in the package insert shall be effected

without such changes being approved
 TEST LICENCE

Application :
¾Form 12 application
¾Material Justification Plan
¾Treasury Challan of Rs 100 for first
drug, followed by Rs 50 for additional
drug
¾Test Licence obtained in FORM 11
• LOOPHOLES AND FURTHER REFINEMENT
 LOOPHOLES and FURTHER REFINEMENT

• New Drug remains to be New Drug for 4 years. Phase IV trials require
permission? Approved drug and approved indication need not require
permission
• Unmet medical needs also to be added for CT waiver
• All clinical trial supplies to be included in FORM 11
• Approvals of Amendments could be a problem
• SOPs for investigators and documentation of tasks – templates
required
• EC chairperson outside institute is a rarity
 LOOPHOLES and FURTHER REFINEMENT

• SUSARS within 15 calendar days (Suspected unexpected serious adverse

event). 24 hour timeline for reporting to sponsor required.

• PSURs instead of PMS data for new drug. International PSURs to be

accepted

• Requirement to support data protection

Thank You