Schedule Y(1)

8/6/2019 Schedule Y(1)

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Corporate Headquarters:

Max House, G.F.

1 Dr. Jha Marg, Okhla

New Delhi 110020

India

Amended

In Force Jan 2005

Schedule Y


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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 APPENDICE OF SCHEDULE Y LOOPHOLES & FURTHER REFINEMENT


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SCHEDULE Y WHAT IT COVERS AND ASSOCIATED RULES


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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


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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


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CLINICAL TRIAL

122-DAA

Clinical trial means a systematic study of new

drug(s) in human subject(s) to generate data fordiscovering and / or verifying the clinical,pharmacological (including pharmacodynamic andpharmacokinetic) and /or adverse effects with theobjective of determining safety and / or efficacy ofthe new drug.


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NEW DRUG 122-E.- 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 ifratio is changed

Vaccines are new drugs unless otherwise certified

Considered new drug for 4 years or inclusion in IP


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INVESTIGATIONAL NEW DRUG

New chemical entity or a product having therapeutic indication but whichhas never been earlier tested on human beings


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RESPONSIBILITIES OF SPONSOR, INVESTIGATOR AND ETHICSCOMMITTEE


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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 LicensingAuthority at the prescribed periodicity (annual).

In case of studies prematurely discontinued for any reason including lack of commercialinterest 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, thenumber of patients exposed to the drug, dose and duration of exposure, details of adversedrug reactions and the reason for discontinuation of the study or non-pursuit of the newdrug 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 theSponsor to the Licensing Authority and to the other Investigator(s) participating in the study


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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 orincapacity , 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 ina patient or a human volunteer that does not necessarily have a relationship with thetreatment 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


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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 theinvestigators for the tasks performed by them.

Ensure that adequate medical care is provided to the participant for anyadverse events.

Report all serious and unexpected adverse events to the Sponsor within24 hours and to the Ethics Committee that accorded approval to thestudy protocol within 7 working days of their occurence.


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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.


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APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY

AUTHORITIES, FEES AND TEST LICENCE


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Ministry of Chem &Fertilizers

NPPANationalPharmaceutical

Pricing Authority

Pricing Regulations

Ministry of Sci &Tech

DBT

Department ofBiotechnology

Ministry ofEnviro

AdditionalSecretary

State Drug Regulatory Authority :FDA

GEACGenetic

EngineeringApproval

Committee

DCGIDrug ControllerGeneral of India

DGHSDirector General of

Health Services

Health Secretary

Ministry of Health

CDL/CDTL

Gov. Drug TestingLaboratories

REGULATORY AUTHORITIES


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PROCESS

APPLICATIONFORM 44

-Imp ff

-Imp rm-Mfg ff-Mfg rm-CT

NOC FOR CT + Test Licence

for Import

APPLICATION FORM 46 A(MFG RM)

APPROVAL FORM 46(MFG FF)

APPROVAL FORM 45 A

(IMP RM)

APPROVAL FORM 45(IMP FF)


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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 50,00 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


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APPLICATION IN FORM 44FORM 44(See Rules 122A, 122B, 122D and 122DA)

Application for grant of permission to import or manufacture a New Drug orto 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 fixeddose combination or subsequent permission of already approved newdrug. 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 :


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FORM 44 Contd2. Data submitted along with the application

A Permission to market new drug

1. Chemical and Pharmaceutical information2. Animal Pharmacology3. Animal Toxicology4. Human / Clinical Pharmacology

5. Exploratory Clinical Trials6. Confirmatory Clinical Trials7. Bioavailability / dissolution and stability data8. Regulatory status in other countries9. Marketing information :

(a) Proposed product monograph(b) Drafts of labels and cartons

10. Application for test licence :


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FORM 44 Contd

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

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

b) Raw Material

Manufacturing Method QC parameters, specs, stability Animal toxicity

C Approval / permission for FDC

1. Justification2. Pcokinetic / Pcodynamic data3. Any other data


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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)

SignatureDesignationDate


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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 particularindication, small group

(c) Phase III (Therapeutic Confirmatory Trials) Therapeutic benefit in largenumber of patients

(d) Phase IV (Post Marketing Trials) Related to approved indication


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IMPORTANT CONSIDERATIONSHUMAN 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 forPhase II trials and subsequently Phase III trials concurrently with otherglobal trials

(c) Application for permission to initiate specific phase of clinical trial shouldalso accompany Investigators brochure, proposed protocol, caserecord form, study subjects informed consent document(s)investigators undertaking and ethics committee clearance , ifavailable

(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 dataabbreviated, deferred or omitted

(g) Amendments notified to DCGI and EC within 30 days and approvalobtained


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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 anysignificant 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 ofthe reporting period.


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DRAFTS OF LABEL AND CARTONS :-

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

After Approval no changes in the package insert shall be effected

without such changes being approved


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IMPORTANT CONSIDERATIONS - 4BE / BA

(i) For drugs approved elsewhere in the world and absorbed systemically,bioequivalence with the reference formulation should be carried out.

(ii) Evaluation of the effect of food

(iii) Dissolution and bioavailability data to be submitted

(iv) All bioavailability and bioequivalence studies should be conductedaccording to the Guidelines for Bioavailability and Bioequivalence studiesas prescribed (ICMR guidelines


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TEST LICENCE

Application :

Form 12 applicationMaterial Justification Plan

Treasury Challan of Rs 100 for firstdrug, followed by Rs 50 for additionaldrug

Test Licence obtained in FORM 11


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APPENDICE OF SCHEDULE Y


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APPENDIX I / IA - REFER WORD DOCUMENT


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APPENDIX II FORMAT OF STUDY REPORT1.Title Page : Protocol code, name of the investigational product tested,development phase, indication studied, a brief description of the trial design,

the start and end date of patient accrual, names of the Sponsor and theparticipating Institutes (Investigators).

2. Study Synopsis (1 to 2 pages): summarize important conclusions

3. Statement of compliance with the Guidelines for Clinical Trials onPharmaceutical Products in India GCP Guidelines issued by CDSCO.

4. List of Abbreviations and Definitions

5.Table of contents

6.Ethics Committee: Study conducted in accordance with the ethical principles of

Declaration of Helsinki. A detailed description of the Ethics Committeeconstitution and date(s) of approvals of trial documents for each of theparticipating sites should be provided. A declaration should state that ECnotifications as per Good Clinical Practice Guidelines issued by CentralDrugs Standard Control Organization and Ethical Guidelines for BiomedicalResearch on Human Subjects, issued by Indian Council of Medical Researchhave been followed.


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APPENDIX II FORMAT OF STUDY REPORT contd7. Study Team: Administrative structure of the study (Investigators, site staff,

Sponsor/ designates, Central laboratory etc.).

8. Introduction: Description of the product development rationale

9.Study Objective: Overall purpose of the study, primary and secondaryobjectives

10.Investigational Plan: Trial design, the Subject selection criteria, thetreatment procedures, blinding / randomization techniques if any, allowed/

disallowed concomitant treatment, the efficacy and safety criteriaassessed, the data quality assurance procedures and the statisticalmethods planned for the analysis of the data obtained.

11.Trial Subjects : Enumerate the patients screened, randomised, andprematurely discontinued. State reasons for premature discontinuation oftherapy in each applicable case.

12. Efficacy evaluation : Results


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APPENDIX II FORMAT OF STUDY REPORT contd13. Safety Evaluation : Complete list13.1 all serious adverse events, whether expected or unexpected and13.2 unexpected adverse events whether serious or not

14. Discussion and overall Conclusion

15. List of References

16. Appendices

a. Protocol and amendmentsb. Specimen of Case Record Formc. Investigators name with contact addresses, phone, emaild. Patient data listingse. List of trial participants treated with investigational product

f. Discontinued participantsg. Protocol deviationsh. CRFs of cases involving death / life threatening AE casesi. Publications from the trialj. Important publications referenced in the study

k. Audit certificate, if availablel. Investigators certificate on accuracy of the study


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APPENDIX III ANIMAL TOXICOLOGY

Toxicity studies to comply with GLP

Systemic Toxicity Studies

Single dose ( 2 rodent species); 2g/kg or 10 timesdose in humans 14 days observation; Minimum lethaldose / Maximum tolerated dose

Repeated dose (2 mammalian species, 1 non-rodent);administration for 7 days)

Dose Ranging Study : Identify target organ and establishMTD

Male Fertility Study

Female Reproduction and Developmental Toxicity Study


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APPENDIX III ANIMAL TOXICOLOGY

Perinatal study

Local toxicity Dermal, vaginal, rectal, ocular, inhalation

Allergenicity / hypersensitivityGenotoxicity

Carcinogenicity


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APPENDIX IV ANIMAL PHARMACOLOGY

Cardiovascular System

Central Nervous System

Respiratory System

Follow up and Supplemental Safety Pharmacology


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APPENDIX V INFORMED CONSENTEssential Elements:

Study involves research and its purposeExpected duration of participationDescription of the procedures

Description of foreseeable risks or discomfortsDescription of any benefits to subject / mankindAlternative procedures or therapiesStatement describing confidentiality of records

Trial treatment schedule(s)Compensation and/or treatment(s) in the event of a trial-relatedinjuryWhom to contact, rights of Subjects and in the event of any injuryanticipated prorated payment, if any, to the Subject for participatingin the trialSubject's responsibilities

Voluntary participation, no penalty or loss of benefits to which theSubject is otherwise entitled


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APPENDIX V INFORMED CONSENT contdAdditional elements, which may be required

Foreseeable circumstances under which the Subject'sParticipation may be terminated without the Subject's consentAdditional costs to the Subject

Consequences to withdraw from the research and procedures fororderly terminationNotification in a timely manner if significant new findings develop

which may affect the Subject's willingness to continue participationParticular treatment or procedure may involve risks to the Subject

(or to the embryo or fetus, if the Subject is or may become

pregnant), which are currently unforeseeableApproximate number of Subjects enrolled in the study


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APPENDIX VI FIXED DOSE COMBINATIONS

Fixed Dose Combinations refer to products

containing one or more active ingredients usedfor a particular indication(s).


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APPENDIX VI FIXED DOSE COMBINATIONS contd

GROUP 1 : One or more of the active ingredients is

a new drug.

Marketing data will be similar to data required for

any new drug (including clinical trials)


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GROUP 2 : Active ingredients already approved/marketed individually,combined for the first time, for a particular claim and where theingredients are likely to have significant interaction of apharmacodynamic or pharmacokinetic nature

If Marketed abroad : Clinical trial reports of other countries Regulatory status in other countries

If not Marketed abroad : Chemical and pharmaceutical data will be submitted - chemical andpharmaceutical data, stability of the proposed dosage form Clinical trials (pharmacological, toxicological and clinical data on theindividual ingredients along with the rationale for combining them inthe proposed ratio. Acute toxicity data (LD 50) and pharmacologicaldata should be submitted on the individual ingredients as well as theircombination in the proposed ratio.

APPENDIX VI FIXED DOSE COMBINATIONS d


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GROUP 3 : Already marketed, but in which it is proposedeither to change the ratio of active ingredients or to make a

new therapeutic claim. For such FDCs, the appropriaterationale including published reports (if any) should besubmitted to obtain marketing permission. Permission will

be granted depending upon the nature of the claim anddata submitted.

APPENDIX VI FIXED DOSE COMBINATIONS d


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GROUP4 : Individual active ingredients (or drugs from thesame class) have been widely used in a particular

indication(s) for years , their concomitant use is oftennecessary and no claim is proposed to be made other thanconvenience. It will have to be demonstrated that theproposed dosage form is stable and the ingredients areunlikely to have significant interaction of apharmacodynamic or pharmacokinetic nature.

No additional animal or human data are generally requiredfor these FDCs, and marketing permission may be grantedif the FDC has an acceptable rationale.

APPENDIX VII UNDERTAKING BY INVESTIGATOR


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APPENDIX VII UNDERTAKING BY INVESTIGATOR

1. Full name, address, title2. Name / address of medical college, hospital or other facility

where the clinical trial will be conducted. Education, training &

experience, qualification and MCR number3. Name / address of clinical laboratory facilities

4. Name / address of the Ethics Committee

5. Names of other members of the research team

6. Protocol Title and Study number (if any) of the clinical trial to beconducted by the Investigator.

APPENDIX VIII ETHICS COMMITTEE


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APPENDIX VIII ETHICS COMMITTEEAt least seven members

Should appoint Chairperson (who is from outside the institution)and a Member Secretary .Quorum at least 5 members with the following representations:

1. basic medical scientists (preferably one pharmacologist).2. clinicians3. legal expert4. social scientist / representative of NGO voluntary agency

/philosopher / ethicist / theologian or a similar person5. lay person from the community.

Must include at least one non-scientific member and at least onemember who is independent of the institution / trial site.Appropriate gender representation on the Ethics Committee.EC members who are independent of trial and sponsor should vote/ provide opinion in matters related to the study.

APPENDIX IX STABILITY TESTING OF NEW DRUGS


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APPENDIX IX STABILITY TESTING OF NEW DRUGS

Evidence on how the quality of a drug substance or formulationvaries with time under the influence of various environmentalfactors

To establish shelf life for the formulation / recommended storageValidated stability-indicating analytical procedures

Stress testing of the drug substance on single batch to identifydegradation products

Photostability on at least one primary batch of the drug substance

as well as the formulation,Pilot Batch : 1/10 th of commercial / production batch

Primary Batch : Batch used in stability study for registration / establish

shelf life.


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APPENDIX X PROPOSED PROTOCOL contd


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7. Study Population

8. Subject Eligibilitya. Inclusion Criteria

b. Exclusion Criteria9.Study Assessments

10. Study Conduct

11.Discontinued Subjects

12.Study Treatment (Dosing Schedule, Drug supplies, administration,dose modification, possible drug interactions, concomitanttherapy, blinding / unblinding procedures)

APPENDIX X PROPOSED PROTOCOL contd


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13. Adverse Events

14. Ethical Considerations (Risk/benefit assessment, EC review andcommunications, Informed consent process, Statement of Subjectconfidentiality including ownership of data and coding procedures)

15. Study Monitoring and Supervision

16. Investigational Product Management

17. Data Analysis

18. Undertaking by the Investigator

19. Appendices (Study synopsis, patient information sheet, informedconsent form, CRF, other data collection forms, a summary of

relevant pre-clinical safety information and any other documentsreferenced)

APPENDIX XI DATA FOR REPORTING SAE1 Patient Details


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1. Patient DetailsInitials & other relevant identifier (hospital/OPD record number etc.)

GenderAge and/or date of birthWeightHeight

2. Suspected Drug(s)Generic name of the drugIndication(s) for which suspect drug was prescribed or testedDosage form and strengthDaily dose and regimen (specify units - e.g., mg, ml, mg/kg)

Route of administrationStarting date and time of dayStopping date and time, or duration of treatment

3. Other Treatment(s)

Provide the same information for concomitant drugs (including non prescription/OTCdrugs) and non-drug therapies, as for the suspected drug(s).

4. Details of Suspected Adverse Drug Reaction(s)Full description of reaction(s) including body site and severity, as well as the criterion

(or criteria) for regarding the report as serious. In addition to a description of thereported signs and symptoms, whenever possible, describe a specific diagnosis forthe reaction.*

APPENDIX XI DATA FOR REPORTING SAE contd


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Start date (and time) of onset of reaction Stop date (and time) or duration of reaction Dechallenge and rechallenge information Setting (e.g., hospital, out-patient clinic, home, nursing home)

5. OutcomeInformation on recovery and any sequelae; results of specific tests

and/or treatment that may have been conductedFor a fatal outcome, cause of death and a comment on its possible

relationship to the suspected reaction; Any post-mortem findings.

6. Details about the InvestigatorNameAddressTelephone numberProfession (specialty)Date of reporting the event to Licensing Authority:Date of reporting the event to Ethics Committee overseeing the site:Signature of the Investigator


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LOOPHOLES AND FURTHER REFINEMENT


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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 requirepermission

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 templatesrequired

EC chairperson outside institute is a rarity


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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

Appendix IA minimal data, exhaustive specs demanded from Innovator(Appendix I) ; not useful for differentiation with generic

Comparative evaluation to be omitted in Appendix 1

Requirement to support data protection


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Thank You

Schedule Y(1)

Documents

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