Indian Regulations :

Schedule Y 2016

Dr Arun Bhatt MD FICP FICR (UK)

Consultant –
Clinical Research & Development
Clinical Trial – 2 Billion Blockbuster?
 Life of P I

CDSCO
EC
Indian Regulatory Organization
Minister
of Health

Secretary
Health

DCGI

DDC Zonal State

Offices CDL
ADC FDA
TO
 Regulatory Stakeholders
DC
Product DBT Other ICMR
GI
NCE √ Phase I
√ √ √ (GEAC)
Biotech
National
√ Health
√ priorities
Vaccines (rDNA) √ (rDNA)

√ Complex
Devices issues
 The Drugs And Cosmetics
Act And Rules
• The Drugs And Cosmetics Act, 1940 (23 Of
1940) (As Amended Up To The 30th June,
2005) And
• The Drugs And Cosmetics Rules, 1945 (As
Amended Up To The 30th June, 2005)

• An Act to regulate the import, manufacture,

• distribution and sale of drugs [and cosmetics]
 CDSCO
Central Drugs Standard
Control Organisation

www.cdsco.nic.in
 Regulatory Landscape
• Act
• Rules
• Schedules
• Amendments – gazette notifications
• Guidelines
• Office orders
 Important Schedules
Schedule Description
A Application/licenses for import, manufacture,
stock, sale, etc. of drugs/cosmetics
D I & D II Registration of manufacturing site/product
H Lists of drugs to be sold by prescription
M Good manufacturing practice (GMP)
X Psychotropic drugs list
Y Permission to import and / or manufacture of
new drugs for sale or to undertake clinical trials
SCHEDULE Y
 Schedule Y
• Requirements And Guidelines For Permission
to
– Import and / or
– Manufacture of New Drugs
– For Sale or
– To Undertake Clinical Trials
 Schedule Y Structure
• Major sections 3
• Application for permission
• Clinical trial
• Studies in special populations

• Appendices12
 Section 1 Application for
Permission
• Data required for clinical trial application
– Relevant appendices for documents/data to be
submitted as Appendix
– I / II / III / IV
– Accompanied by
• V informed consent document(s)
• VII investigator„s undertaking
• VIII ethics committee clearance
• X protocol
• Investigator„s brochure / case record form
 Section 2 Clinical trial
1) Approval for clinical trial – Regulatory and EC
2) Responsibilities of sponsor
3) Responsibilities of investigator
4) Informed consent process
5) Responsibilities of ethics committee
5A) Serious Adverse Events
6) Human Pharmacology (Phase I)
7) Therapeutic exploratory trials (Phase II)
8) Therapeutic confirmatory trials (Phase III)
9) Post Marketing Trials (Phase IV)
 Responsibility of Sponsor
I. Quality assurance to ensure compliance to
GCP guidelines of CDSCO
II. Submission of status report at prescribed
periodicity
III. Summary report for premature termination to
be communicated
IV. Serious adverse event to be communicated
within 14 calendar days to DCGI, Chairman of
the Ethics Committee and the Head of the
institution
V. Payment for medical management / financial
compensation for trial related injury or death
Responsibilities of Investigator
• Responsible for conduct of trial according to
protocol and GCP
• SOPs to be documented by Investigators for the
tasks performed by them
• Compliance as per undertaking format Appendix VII
• Medical care for AEs
• Serious and unexpected adverse events
reporting to
– DCGI, EC, Head of Institute and Sponsor within 24 hrs.
and 14 days of occurrence
• Informed consent
 Informed Consent
• Freely given, informed, written consent
required to be obtained from each study
subject.
• A checklist of essential elements as per
Appendix V
 Responsibilities of EC
• Safeguard rights, safety, wellbeing of subjects
• Special care for vulnerable subjects
• Ongoing review
• Reason‟s for revoking approval and information to
investigator / regulatory authority
• Causality / Compensation to DCGI within 30 days of
occurrence of serious adverse event.
 Serious Adverse Events
• Definition
• Reporting requirements / timelines
 3 Special Studies
• Geriatrics
• Paediatrics population
• Pregnant or nursing women
• Post marketing surveillance of new drugs and
Periodic Safety Update Reports (PSURs)
• Bioavailability/bioequivalence studies

21
 Schedule Y : Important Rules
Rule Description
122 A Application for permission to import new drug
122 B Application for approval to manufacture new drug
122 D Application for permission to import or manufacture
fixed dose combination
122 DA Application for permission to conduct clinical trials for
New Drug/Investigational New Drug
122 E Definition of new drug
122 DAB Compensation for injury / death during clinical trial
122 DAC Permission to conduct clinical trials
122 DD Registration of Ethics Committees
 Drug – Definition
• All medicines for internal or external use of
human beings and all substances intended to
be used for or in the
• diagnosis,
• treatment,
• mitigation or
• prevention
of any disease or disorder
122 E Categories of New Drugs

New Drug

New Indication
New Fixed Dose Vaccine
Dosage form
Chemical Combination rDNA drugs
Route

A new drug shall be considered as new drug for a period of four years
from the date of its first approval or its inclusion in the Indian
Pharmacopoeia, whichever is earlier.
 Rule 122DA : Application for permission to
conduct clinical trials for New Drug/
Investigational New Drug
(a) “Clinical Trial” means a systematic study of any 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;
(b) “Global Clinical Trial” means any clinical trial which is conducted
as part of multi-national clinical development of a drug;
(c) “Investigational New Drug” means a new chemical entity or a
product having therapeutic indication but which has never been
tested earlier on human being;
(d) “New Chemical Entity” means an active substances in
developmental stage which may be specified as a drug under the
Act, after undergoing any clinical trial
 Rule 122DA

• An application for grant of permission to conduct

– (a) human clinical trials (Phase-I) on a new drug shall be
made to the Licensing Authority in Form 44 accompanied
by a fee of fifty thousand rupees and such information
and data as required under Schedule Y.
– (b) exploratory clinical trials (Phase-II) on a new drug
shall be made on the basis of data emerging from Phase-I
trial, accompanied by a fee of twenty-five thousand
rupees;
– (c) confirmatory clinical trials (Phase-III) on a new drug
shall be made on the basis of the data emerging from
Phase-II and where necessary, data emerging from
Phase-I also, and shall be accompanied by a fee of
twenty-five thousand rupees:
 Appendices
I Data to be submitted along with the application to
conduct clinical trials / import / manufacture of new
drugs for marketing in the country
I-a Data required to be submitted by an applicant for
grant of permission to import and / or manufacture a
new drug already approved in the country
I-B Data To Be Submitted Along With Application To
Conduct Clinical Trial Or Import Or Manufacture Of A
Phytopharmaceutical Drug In The Country
II Structure, Contents And Format For Clinical Study
Reports
III Animal Toxicology (Non-clinical Toxicity Studies)
IV Animal Pharmacology
 Appendices
V Informed Consent
VI Fixed Dose Combinations (FDCs)
VII Undertaking by Investigator
VIII Ethics Committee
IX Stability Testing Of New Drugs
X Contents Of The Proposed Protocol For Clinical
Trial
XI Data Elements For Reporting Serious Adverse
Events Occurring In A Clinical Trial
XII Compensation for clinical trial related injury/death
Appendix I : Data for Application for Clinical Trials
/ Import / Manufacture of New Drugs for Marketing
1. Introduction
• A brief description of the drug and the therapeutic class to
which it belongs.
2. Chemical and pharmaceutical information
2.1. Information on active ingredients
2.2. Physicochemical Data
2.3. Analytical Data
2.4. Complete monograph specification (not required for clinical
trial application)
2.5. Validations (not required for clinical trial application)
2.6. Stability Studies
2.7. Data on Formulation
Appendix I : Data for Application for Clinical Trials
/ Import / Manufacture of New Drugs for Marketing
3. Animal Pharmacology
3.1. Summary
3.2. Specific pharmacological actions
3.3. General pharmacological actions
3.4. Follow-up and Supplemental Safety
Pharmacology Studies
3.5. Pharmacokinetics: absorption, distribution;
metabolism; excretion
Appendix I : Data for Application for Clinical Trials
/ Import / Manufacture of New Drugs for Marketing
4. Animal Toxicology (as applicable for relevant Phase
of trial)
4.1. General Aspects
4.2. Systemic Toxicity Studies
4.3. Male Fertility Study
4.4. Female Reproduction and Developmental Toxicity
Studies
4.5. Local toxicity
4.6. Allergenicity/Hypersensitivity
4.7. Genotoxicity
4.8. Carcinogenicity
Appendix I : Data for Application for Clinical Trials
/ Import / Manufacture of New Drugs for Marketing

5. Human / Clinical pharmacology (Phase I)

6. Therapeutic exploratory trials (Phase II)
7. Therapeutic confirmatory trials (Phase III)
8. Special studies
8.1. Summary
8.2. Bio-availability / Bio-equivalence.
8.3 Other studies e.g. geriatrics, paediatrics, pregnant
or nursing women (If relevant to Phase of trial)
Appendix I : Data for Application for Clinical Trials
/ Import / Manufacture of New Drugs for Marketing

9. Regulatory status in other countries

9.1. Countries where the drug is
a. Marketed
b. Approved
c. Approved as IND
d. Withdrawn, if any, with reasons
9.2. Restrictions on use, if any, in countries where
marketed /approved
9.3. Free sale certificate or certificate of analysis, as
appropriate.
Appendix I : Data for Application for Clinical Trials
/ Import / Manufacture of New Drugs for Marketing
10. Prescribing information
10.1 Proposed full prescribing information
10.2 Drafts of labels and cartons

11 Samples and Testing Protocol/s

11.1 Samples of pure drug substance and finished
product (an equivalent of 50 clinical doses, or
more number of clinical doses if prescribed by
the Licensing Authority), with testing protocol/s,
full impurity profile and release specifications.
Regulatory Submission Process
• Undertakings/Declaration : Sponsor
– application of marketing authorization in India after
successful completion of clinical trial
– to provide medical management and compensation
in case of clinical trial related injury or death
– financial status of the applicant vis-à-vis medical
management and compensation to be paid to the trial
participants
– financial contract / support plan with the site
– revised ICD in the view of compensation clause
– whether the subjects will receive the Standard Care
 Documents for Approval
• Sponsor details / Authorization Letter from Sponsor:
• Treasury Challan along with Form 44 / Form 12
• Copy of valid manufacturing license
• Details the Study Drug / formulation / Dosage form /
Therapeutic class
• Study Protocol / Phase of Study
• Undertaking by the Investigator
• Undertaking by the Investigator
• Details of Ethics Committee (same location)
• Patient Information Sheet (PIS)/ Informed consent form (ICF)
 Documents for Approval
• Justification for conducting the study in India
• Application for Export NOC for biological samples
• List of Investigators in India
• Name of the Participating Countries / Approvals regulatory
and/or EC
• Total Number of patients to be enrolled globally / to be
enrolled in India
• Status of Drug in India & other countries
• Status of the proposed study in other participating countries
– rejection / suspension
• Investigators Brochure: / Investigational Medicinal Products
Dossier
• Affidavit for Investigators Brochure / study status
 Forms
Form Description
44 Application for grant of permission to import or
manufacture a New Drug or to undertake clinical trial.
12 Application for licence to import drugs for purpose
of examination, test or analysis
11 Licence to import drugs for the purposes of
examination, test or analysis
29 Licence to manufacture drugs for purposes of
examination, test or analysis
 Compensation Rule 122 DAB

40
 Of course the death was study related. He was
reading the patient information sheet when the
bus hit him
41
 Serious Adverse Event
• An untoward medical occurrence during
clinical trial that is associated with
– death
– in patient hospitalisation (in case the study was
being conducted on out-patient)
– prolongation of hospitalisation (in case the study
was being conducted on in-patient)
– persistent or significant disability or incapacity
– a congenital anomaly or birth defect or
– is otherwise life threatening.
42
 Compensation For Injury
• In the case of an injury occurring to the clinical trial
subject,
– he or she shall be given free medical management as
long as required or till such time it is established that the
injury is not related to the clinical trial, whichever is
earlier..
– such subject shall also be entitled for financial
compensation over and above any expenses incurred on
the medical management of the subject
• In case there is no permanent injury, the quantum of
compensation shall commensurate with the nature of
the non-permanent injury, loss of wages and
transportation
43
 Compensation for Death
• (3) In the case of clinical trial related death of
the subject, his/her nominee(s) would be
entitled for financial compensation

44
 Compensation Payment for
• (5) Any injury or death of the subject occurring in
clinical trial due to following reasons shall be
considered as clinical trial related injury or death:

– adverse effect of investigational product(s);

– violation of the approved protocol, scientific misconduct or

negligence by the Sponsor or his representative or the
investigator;

– failure of investigational product to provide intended

therapeutic effect, where standard care, though available,
was not to be provided to the subject as per the clinical
trial protocol

45
 SAE Reporting Timelines
Head of Chair EC DCGI
Institute
Investigator : 24 hrs of   
occurrence of SAE
Investigator : 14   
calendar days
occurrence of SAE
Sponsor : 14 calendar   
days occurrence of
SAE
EC : 30 calendar days 
occurrence of SAE
47
 Compensation Decision Process
Expert Committee
within 30 days of Ethics Committee
Report

DCGI
within 3 months of receiving SAE

30
days
Sponsor
48
 Compensation -
Clinical Trial Related Death
• Compensation = (B x F x R)/ 99.37
– B = Base amount (i.e. 8 lacs)
– F = Factor depending on the age of the subject as
per Annexure 1 (based on Workmen Compensation
Act)
– R = Risk Factor depending on the seriousness and
severity of the disease, presence of co-morbidity and
duration of disease of the subject at the time of
enrolment in the clinical trial between a scale of 0.5
to 4
 Risk Factor for SAE – Death
1) 0.50 terminally ill patient (expected survival
not more than (NMT) 6 months)
2) 1.0 Patient with high risk (expected survival
between 6 to 24 months)
3) 2.0 Patient with moderate risk
4) 3.0 Patient with mild risk
5) 4.0 Healthy Volunteers or subject of no risk
 Permanent Disability
• Compensation for 100% disability should be 90% of
the compensation for death
• Compensation for less than 100% disability will be
proportional to the actual percentage disability the
subject has suffered.
• Compensation =(CXDx90)/ (100x100)
– D= Percentage disability the subject has suffered.
– C= Quantum of Compensation which would have been
due for payment to the subject‟s nominee(s) in case of
death
 Compensation – Injury
• Life-threatening disease
• Reversible SAE Resolved
• Compensation = 2 X N x W
– N= Number of days for which the trial subject remained
under life-threatening situation requiring medical care,
irrespective of number of days of hospitalization.
– W= Minimum wage per day of the unskilled worker (in
Delhi)
 Congenital Anomaly or
Birth Defect
• Lump sum amount such that if that amount is kept
by way of fixed deposit or alike, it should bring a
monthly interest amount which is approximately
equivalent to half of minimum wage of the unskilled
worker (in Delhi).

• Quantum of compensation in such cases of SAE

should be half of the base amount of Rs 8 lacs as
per formula for compensation for SAE resulting into
death
 Schedule Y : Amendments
• Definition of SAE
• Responsibility of sponsor, investigator, ethics
committee
• Responsibility of licensing authority
• Appendix V Consent
• Appendix XII Compensation in case of Injury
or death during clinical trial

54
Clinical Trial Approval : 3 tiers
Apex
Committee

Technical
Committee

SEC
 Regulations are written for
the obedience of fools and
the guidance of the wise men