Submitted by-Neelotpal Sharma

What Is Schedule Y ?It is “Schedule under Part X-A of Drugs & Cosmetics Rule

1945 describe the information/data required –

Requirements and guidelines for permission to import and/or manufacture of new drugs for sale

or undertake clinical trials

Salient Features of Schedule Y

• For new drug substances discovered in countries other than India, Phase I data as required under items 1, 2, 3, 4, 5 (data from other countries) and 9 of Appendix I should be submitted along with the application.

• After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials concurrently with other global trials for that drug. Phase III trials are required to be conducted in India before permission to market the drug in India is granted;

• Provides statutory support to Indian GCP Guidelines• Stipulates responsibilities of EC, Investigators and Sponsor.• Structure, contents and formats for CT protocols, reports, EC approvals, ICF,

SAE reporting are incorporated .

In Drugs & Cosmetics Rules (Schedule y) : 122A-122E

• 122-A Application for permission to import new drug

• 122-B Application for approval to manufacture new drug other than the drugs classifiable under Schedules C (biologics, etc.)

• 122-C Deleted

• 122-D Permission to import or manufacture Fixed Dose combination: Defined FDC

• 122-DA Application for permission to conduct clinical trials for ND/IND.

• 122-DAA Definition of Clinical trial

• 122-E Definition of New Drug

Amendments on Schedule Y rules

• 122 DAB Compensation in case of trial related injury or death

• 122 DAC Condition of clinical trial permission and inspection

• 122 DD Registration of ethics committee

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.

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 occurrence.

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

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 = 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 44Application 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 Contd….

2.Data submitted along with the application

A) Permission to market new drug1.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 cartons10.Application for test licence:

FORM 44 Contd….

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

Formulation :a)Bioavailability / bioequivalenceb)Name of the investigator / centrec)Source of raw materials and stability

Raw Materiala)Manufacturing Methodb)QC parameters, specifications, stabilityc)Animal toxicity

C) Approval / permission for FDC

1.Justification2.P’cokinetic/ P’codynamic data3.Any other data

FORM 44 Contd……D) Subsequent approval or approval for new indication –new dosage form :1. Number and date of Approval already granted2. Justification3. Data on safety, efficacy and quality

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

SignatureDesignationDate

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 -2PSUR• 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; andindicate 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.

PSUR Structure:-

(a) A title page stating: Periodic safety update report for the product, applicant’s name, period covered by the report, date of approval of new drug, date of marketing of new drug and date of reporting;(b) Introduction,(c) Current worldwide market authorization status,(d) Update of actions taken for safety reasons,(e) Changes to reference safety information,(f) Estimated patient exposure,(g) Presentation of individual case histories,(h) Studies,(i) Other information,(j) Overall safety evaluation,(k) Conclusion,(l) Appendix providing material relating to indications, dosing, pharmacology and other

related information.

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.

IMPORTANT CONSIDERATIONS -4

BIOEQUIVALENCE / BIOAVAILABILTY

(i) For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out. (ii) Dissolution and bioavailability data to be submitted. (iii) All bioavailability and bioequivalence studies should be

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