BY PRAGNYA,(M.pharm)

PHARMACOLOGY(Iyr),GPRCP

Schedule Y of DRUG & COSMETICS ACT 1940 detailed the requirements and guidelines

•Import/manufacture of New Drugs for sale

•For conducting a “clinical trial”

122E - NEW DRUG

Not been used in country under label

Approved but now proposed to be marketed with modified /new claims indications dosage form , route of administration.

Application for permission to import NEW DRUG.

(a) No new drug shall be imported, except under, and in accordance with, the permission granted by the Licensing Authority.

(b) An application for the grant of permission to import a new drug shall be made in Form 44 to the Licensing Authority, accompanied by a fee of

Rs 50, 000.

DATA TO BE  SUBMITTED ALONG WITH THE APPLICATION FORM 44

Chemical &Pharmaceutical Info Animal Pharmacology –1)Specific Pharmacological Actions Dose response rel ED50 s 2)General Pharmacological Actions

Animal Toxicology DataSystemic toxicity studies - Single Dose Toxicity Repeated Dose

Toxicity

Male fertility studiesFemale reproduction and developmental studiesLocal toxicity - Dermal Toxicity , Vaginal Toxicity,

rectal Toxicity ,Ocular ToxicityAllergenicityGenotoxicitycarcinogenicity

HUMAN CLINICAL PHARMACOLOGY DATA Human / Clinical pharmacology (Phase I)• Maximum tolerated dose • PK –ADME• PD• Early measurement of drug activity

 Therapeutic exploratory trials (Phase II)To determine dose and regimen

Therapeutic confirmatory trials (Phase III)Confirmation of therapeutic benefits

“For new drug substances discovered in India, clinical trials are required to be carried out in India right from phase I and data should be submitted”

 FOR NEW DRUG SUBSTANCES

DISCOVERED IN COUNTRIES OTHER THAN INDIA

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

Permission to carry out these trials shall be given in stages

Study report should be certified by the principal investigator

Regulatory Status In Other Countries

The Full Prescribing Information should be submitted

Complete Testing Protocol/S For Quality Control Testing together with a Complete Impurity Profile And Release Specifications

For drugs indicated in life threatening / serious diseases/ diseases of special references to Indian health scenario , toxicological and clinical data requirements may be abbreviated ,deffered , ommitted as deemed appropriate by the licensing authority .

Clinical Trial is 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

• LICENSING AUTHORITY• ETHICS COMMITTEE• INVESTIGATOR• SPONSORSUBJECT

Approval from ethics committeeApproval from licensing authority under rule

21(b)

• LICENSING AUTHORITY• ETHICS COMMITTEE• INVESTIGATOR• SPONSORSUBJECT

Approval from ethics committeeApproval from licensing authority under rule

21(b)

Ethics CommitteeShould have atleast 7 members-

chairperson, member & secretary For review of each protocol the quorum of EC

should be at least 5 members with the following representations:

(a)   Basic Medical Scientists (Preferably One Pharmacologist).

(B)   Clinicians(C)   Legal Expert(D)   Social Scientist / Representative Of Non-

governmental Voluntary Agency /Philosopher / Ethicist / Theologian Or A Similar Person

(E)   Lay Person From The Community.

Responsibilities of the Ethics Committee

• Reviews and accords its approval to a trial protocol

• To protect the rights, safety and well being of all vulnerable subjects participating in the study

• An ongoing review of the trials for which they review the protocol(s). 

• Revokes its approval accorded to a trial protocol

INVESTIGATORS

Study not to begin until EC / DCGI approvalAdherence to protocolPersonal supervisionReport of ADE to sponsorUnderstanding of investigator’s brochureMaintenance of records and availability foraudits / sponsor inspection / EC and DCGI

SPONSOR• Responsible for implementing and maintaining quality

assurance systems • Data generated, documented and reported in compliance

with the protocol and good clinical practice (GCP) guidelines issued by the “CDSCO”, “DIRECTORATE GENERAL OF HEALTH SERVICES”, “GOI” as well as with all applicable statutory provisions

• Submit a status report • Discontinued – 3 months• Serious adverse event (SAE)-14 days

INFORMED CONSENT TO PARTICIPANT

That the study involves research and explanation of the purpose of the research

DurationProcedures to be followedReasonably foreseeable risks or discomforts Trial treatment schedule

Statement that participation is voluntary, that the subject can withdraw from the study at any time and that refusal to participate will not involve any penalty or loss of benefits to which the subject is otherwise entitled

MULTI-NATIONAL CLINICAL DEVELOPMENT:

The number of sites & the patients as well as the justification for undertaking such trials in India shall be provided to the licensing authority.

For new drugs approved outside India, Phase III studies need to be carried out primarily to generate evidence of efficacy and safety of the drug in Indian patients when used as recommended in the prescribing information.

STUDIES IN SPECIAL POPULATIONS

Information supporting the use of the drug in Geriatrics ,

Paediatrics Pregnant or Nursing women children & patients with renal or other organ systems

failure, and those on specific concomitant medication is required to be submitted if relevant to the clinical profile of the drug and its anticipated usage pattern.

POST MARKETING SURVEILLANCE PSUR :- New drugs should be closely monitored for their clinical safety

submission of 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 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.

SPECIAL STUDIES: BIOAVAILABILITY / BIOEQUIVALENCE STUDIESFor drugs approved elsewhere in the world:Data regarding the BE with reference formulation

should be submitted whereever applicableData on the extent of systemic absorption may be

required for formulations other than those designed for systemic absorption

Data on effect of food on absorption Data on Dissolution studies (oral dosage forms)

Dissolution and bioavailability data submitted with the new drug application must provide information that

Assures bioequivalence Establishes bioavailability and dosage

correlations between the formulation(s) sought to be marketed and those used for clinical trials during clinical development of the product

FIXED DOSE COMBINATIONS

1st group New drug

2nd group

Already approved /marketed but combined for the first time

3rd group

Already approved or marketed as FDC but now changed the ratio or make a new claim

4th group

Active ingredients combination becomes necessary

APPENDIX -I

Data To Be Submitted Along With The Application To Conduct Clinical Trials / Import / Manufacture Of New Drugs For Marketing In The Country.

Chemical and pharmaceutical informationPhysicochemical DataAnalytical DataComplete monograph specificationValidationsMaterial safety dataRegulatory status in other countriesSamples and Testing Protocol/s

Appendix II FORMAT FOR CLINICAL STUDY REPORTS

Title PageStudy SynopsisList of Abbreviations and DefinitionsStudy TeamIntroductionStudy objectiveInvestigational PlanTrial SubjectsSafety Evaluation

Appendix III : Animal Toxicology (non-clinical toxicity)

Systemic toxicity studies - Single Dose Toxicity Repeated Dose Toxicity

Male fertility studiesFemale reproduction and developmental studiesLocal toxicity - Dermal Toxicity , Vaginal

Toxicity,rectal Toxicity ,Ocular ToxicityAllergenicityGenotoxicitycarcinogenecity

Route of administration Duration of proposed human administration

Human Phase(s) for which study is proposed to be conducted

Long term toxicity requirements

Oral or Parenteral or Transdermal

Single dose or several doses in one day, Upto 1wk

I,II,III 2sp,2wk

> 1 wk but upto 2wk I,II,III 2sp;4wk

> 2 wk but upto 4wk I,II,III 2sp;12wk

Over 1moI,II,III 2sp;24wk

Inhalation (general anaesthetics, aerosols)

Upto 2 wk I,II,III 2sp;1mo; (Exposure time 3h/d, 5d/wk)

Upto 4wk I,II,III 2sp;12wk, (Exposure

time 6h/d, 5d/wk)

> 1 4wk I,II,III 2sp;24wk, (Exposure time 6h/d, 5d/wk)

Single dose toxicity studies DATA

Local Toxicity Studies data

Route of administration

Duration of proposed human administration

Human Phase(s) for which study is proposed to be conducted

Long term toxicity requirements

Dermal Upto 2 wk I,II 1sp;4wk

III 2sp;4wk

> 2 wk I,II,III 2sp;12wk

Ocular or Otic or Nasal

Upto 2 wk I,II 1sp;4wk III

2sp;4wk

> 2 wk I,II,III 2sp;12wk

Vaginal or Rectal Upto 2 wk I,II 1sp;4wk

III 2sp;4wk

> 2 wk I,II,III 2sp;12wk

Repeated-dose Toxicity Studies Data 

14-28 days 84-182 days

Group Rodent (Rat) Non-rodent(Dog or Monkey)

Rodent (Rat) Non-rodent(Dog or Monkey)

 M F M F M F M F

Control 6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6

Low dose 6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6

Intermediate dose

6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6

High dose 6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6

LABORATORY PARAMETERS TO BE INCLUDED IN TOXICITY STUDIES.1. Haematological

parameters

2. Urinalysis Parameters

3. Blood Biochemical Parameters

4. Gross and Microscopic Pathology

 Haemoglobin,haematocrit,blood PICTURE

Colour, appearance, albumin, bilirubin

Proteins ,cholestrol. urea Ca,P,K

Brain,spinalcord,spleen,

trachea,lungs,pancreas

Appendix IV : Animal PharmacologySPECIFIC PHARMACOLOGICAL ACTION

GENERAL PHARMACOLOGY ( CVS ,CNS ,RESPIRATORY) SAFETY PHARMACOLOGY

Appendix V : INFORMED CONSENT

Format of informed consent form for Subjects participating in a clinical trial

 Informed Consent form to participate in a clinical trialStudy Title:Study Number: Subject’s Initials: _______________         Subject’s Name:_______________ Date of Birth / Age: _________________   

      

Signature (or Thumb impression) of the Subject/Legally Acceptable Representative:_____________                

 

 

Date: _____/_____/______

 

Signatory’s Name: ______________________________________________________

 

Signature of the Investigator: ____________________________                   Date: _____/_____/______

 

Study Investigator’s Name: __________________________________________________

 

Signature of the Witness ______________________               Date:_____/_____/_______     

 

Name of the Witness: _______________________________________________________

 

 

Appendix VIFIXED DOSE COMBINATIONS (FDCs)

Appendix VIIUNDERTAKING BY THE INVESTIGATOR

Appendix VIIIETHICS COMMITTEE

Format for Approval of Ethics Committee 

a.         Trial Protocol( including protocol amendments), dated____________ Version no (s).__________

b.         Patient Information Sheet and Informed Consent Form

c.         Investigator’s Brochure, dated_________, Version no.________

d.         Proposed methods for patient accrual including advertisement (s) etc. proposed to be used for the purpose.

e.         Principal Investigator’s current CV.f.          Insurance Policy / Compensation for participation and for serious

adverse events occurring during the study participation.g.         Investigator’s Agreement with the Sponsor.

 

Appendix IX : Stability Testing Of New Drugs

Storage conditions and the length of studies

Photostability on at least one primary batch of the drug

The susceptibility of the drug substance to hydrolysis across a wide range of ph values when in solution or suspension

Appendix XCONTENTS OF THE PROPOSED PROTOCOL FOR CONDUCTING CLINICAL TRIALS

  Title Page Table of Contents Background and

Introduction• a.      Preclinical

experience• b.      Clinical experience• C.    Study rationale  Study Design  Subject Eligibility a.      Inclusion Criteria b.      Exclusion Criteria

Cont…..

Study Treatment  Adverse Events Ethical Considerations Study Monitoring And Supervision Investigational Product Management Data Analysis

APPENDIX XIData Elements for reporting serious adverse events occuring in a clinical trial1. Patient Details2. Suspected Drug(s) & Its complete information3. Details of Suspected Adverse Drug Reaction(s) Start date (and time) of onset of reaction Stop date (and time) or duration of reaction Dechallenge and rechallenge information

4. Outcome

5.Details about the Investigator

REFERENCES

http://cdsco.nic.in/html/schedule-y%20(amended%20version-2005)%20original.htm

http://202.54.104.237/intranet/eip/legislation/uploads/SCHEDULE-Y.pdf