REGULATION OF CLINICAL RESEARCH

1. Schedule Y
Presented By-MANISH KUMAR SHARMA
Presented To
CENTER FOR CLINICAL RESEARCH
SHARDA UNIVERSITY, GREATER NOIDA,UP
6/1/2012

2. Outline of Presentation
1. History
2. Drug and cosmetic Act,1940 and Schedules
3. What actually Schedule Y is ?
4. Old/New(amended) Schedule Y
5. Why Changes in Schedule Y ?
6. Rules under it
7. Divisions of Schedule Y
8. New Amendments
9. Conclusion
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3. Lets revise the History
 Drug and Cosmetic Act, 1940 was enacted(D/C
Act)
 Pharmacy Act , 1948
 Drug and Magic Remedies Act, 1954
 The Narcotic and Psychotropic Substance Act and
Rules, 1985
 Ethical guidelines for Biomedical Research on
Human Participants,2000 by ICMR
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4.  Indian GCP Guidelines,2001
 Amendments to Drug and Cosmetic
Act,2002
 Revised Schedule Y, 2005
 Guidelines for Pre Clinical Data for r-DNA
Vaccines,2007
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5. Drug and Cosmetics Act,1940
In 1940 D/C Act Was enacted
in 1945 Drug Rules were Promulgated in December
and enforcement Start in 1947
Now have been called as D/C Act
Objective- To ensure that the drug is available to the
People are safe and cosmetics marketed for safer use.
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6. Schedules to Rules, 1945
 Schedule A- Forms for marketing application for licenses, issue, and
renewal
 B- Fee for test/analysis by CDL or SDL
 C/C1- talk about I/M/S/D of sera, vaccines
 D-List of drugs exempted from the provisions that are applicable to
import of other drug
 E- Omitted , E1- list of poisonous substance under
Ayurveda,Unani,Sidha system
 F- Production/testing/storage/packaging/labeling
F1-biological preparations F2- SD F3- umbilical tapes
 G- List of drug used under medical supervision
 H- List of drug sold under Prescription
 I-Omitted
 J-Diseases may not cure/prevent by drugs
 K-List of drugs exempted from the provisions that are applicable to
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manufacture of other drug

7.  M-GMP
 N-List of minimum equipment in Pharmacy
 O-Standards for disinfections
 P- Life period of drug
 Q-List of dyes/coloring agents in soap/cosmetics
 R-Standards for Mechanical contraceptives
 S-Standards for cosmetics
 T-GMP for A/U/S system of medicines
 U- Records for manufacturing/raw materials in drugs
 V- Standards for potent medicines
 X- List of drugs whose I/M/S are governed by special
provision
 W- Omitted
 Y- About CT
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8. Schedule Y
 The enforcement that came into existence in 1988
was an essential provision for providing support to
the upscale of generic pharma scenario present in
those days.
 With the entry of large pharmaceutical companies
along with the multiple multinationals in field of
clinical research the needs changed and a revised
version of Schedule Y in line with ICH-GCP
(International Council of Harmonization and Good
Clinical Practice) standard was put forth in 1995.
 Since then multiple revisions to Schedule Y took
place to provide a healthy environment for clinical
research to be conducted in India.
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9. 6/1/2012

10. Schedule Y
It’s a Law
not merely
a Guideline
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11. Schedule Y
Schedule Y ,the current regulator (of
CDSCO), enforced law in India has
been established under Drug and
Cosmetic Act,1945.
The regulations to be followed when
conducting Clinical Trial in India.
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12. contt..
‘REQUIREMENTS AND
GUIDELINES FOR PERMISSION
TO IMPORT AND / OR
MANUFACTURE OF NEW
DRUGS FOR SALE OR TO
UNDERTAKE CLINICAL TRIALS
IN INDIA’
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13. Amended Schedule Y
 ‘Regulations and
Guidelines for permission
for development (preclinical
and/or clinical), import and
manufacture of New Drugs
for Marketing in India’
DATE- 20TH JAN,2005
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14. Why Changes in Schedule Y
 To frame guidelines for the current scenario of Clinical
research.
 CDSCO and DTAB formulated GCP under Schedule Y in 2005.
 Schedule Y 1988 relevant to predominantly generic industry.
 GCP trials since 1995, and arrival of IPR regime in 2005.
 Integration of India in global clinical development and legal
support to GCP guidelines.
 Improvements in quality of clinical trials.
 It has outlined extensive study criteria in line with the globally
accepted formats such as ICH and US FDA guidelines.
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15. Rules under Schedule Y
Rule Permission
122 A To Import New Drugs
122 B To manufacture New Drugs
To import or manufacture fixed dose
122 D
Combinations
122 DA To conduct Clinical Trials
for New Drug/Investigational New
Drug
122DAA
Definition of Clinical Trial
122 E
Definition of New Drug
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16. Rule 122DA To conduct Clinical Trials
for New Drug/Investigational New Drug
New chemical entity or a product having therapeutic
indication but which has never been earlier tested on
human beings.
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17. 122-E.
 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 if ratio is changed
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18. 6/1/2012

19. Old schedule Y
in the older version there are only 5 appendices
Appendix I: Declaration of Helsinki
Appendix II: Schedule Y
Appendix III: Format for submission of Pre-clinical and
clinical data for r-DNA based vaccines, diagnostics and
other biologicals.
Appendix IV: Investigator’s Brochure
Appendix V: Essential Documents
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20. 6/1/2012

21. Significant changes
New concept Older concept
1)Clinical trials 1.1 Nature of CT
a) Definition of CT 1.2 Permission of CT
b) ICD – New 1.3 ICD but no details
c) responsibilities of ethical 1.4 Responsibilities of
committee- New sponsor/investigator
d) PMS- New
2) Studies in special populations No PMS
a) Geriatric 2) Special Studies
b) Pediatrics No Separation
c) Pregnant
d) PMS - New
e) BA/BE - New
3)Formats for critical documents
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22. Appendix I
Data to be submitted along with the application to conduct clinical
trials / import / manufacture of new drugs for marketing in the
country.
a. Introduction about the drug
b. Chemical and pharmaceutical information (e.g.
Enatiometry)
c. Animal pharmacology
d. Animal toxicology
e. Human /clinical pharmacology(Phase-I)
f. Therapeutics exploratory(Phase-II)
g. Therapeutics confirmatory(Phase-III)
h. Special studies( paediatrics, pregnant)
i. Regulatory status in other countries if available
j. Prescribing information(drug labeling and prescribing inf.)
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23. APPLICATION FOR PERMISSION
UNDER FORM 44, REGULATORY
AUTHORITIES, FEES AND TEST
LICENCE
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24. Regulatory authorities
Ministry of Chem & Ministry of Health Ministry of Sci & Ministry of
Fertilizers Tech Enviro
Health Secretary
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
CDRL/CDTL
Gov. Drug Testing
Laboratories
State Drug Regulatory Authority :FDA

25. PROCESS
Approval Form 45
APPLICATION
(IMP FF)
FORM 44
-Imp FF Approval Form 45
-Imp Rm A (IMP RM)
-Mfg FF
-Mfg Rm Approval Form 46
-CT (MFG FF)
Application Form
NOC FOR CT + Test 46 A (MFG RM)
Licence for Import

26. Fee according to Schedule Y
 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

27. Appendix I-A
Data required to be submitted by an applicant for grant of
permission to import
&/or manufacture a new drug already approved
in the country.
a) Introduction
b) Chemical and pharmaceutical information
c) Marketing information
d) Special studies
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28. Appendix III
Animal toxicology (Non-clinical toxicity studies)
1) SDTS- Minimum 5 animal, 24hr observation
2) DRS- On one Rodent Species
3) RDTS- a) 14 to 28 days- on 1 Rodent and 1 Non Rodent
b)90 days- same as above but introduction of HIGH
DOSE REVERSAL .
4) MFS- Rodent Species, Dose selection should be done on
basis of 14 to 28 days studies.
5) FFS- should be carried out for all drugs( Appendix I- 4.4)
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29. Animal toxicology (Non-clinical toxicity studies)
Other Studies
a. Hypersensitivity
b. Genotoxicity
c. Carcinogenicity
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30. Appendix IV-Animal Pharmacology
Animal pharmacology studies are done to see the effect if
IP on different systems like
CVS
CNS
ANS
RS
US
GIT
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31. Appendix V- INFORM CONSENT
 Trial involves research
 Purpose
 Trial treatments and randomization
 Trial procedures
 Risk
 Benefit
 Alternative treatments
 Compensation / treatment for injury
 Subject’s responsibilities
 Experimental aspects
 Any payment
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32. Essential Elements of Informed Consent
 Confidentiality
 New information
 Voluntary participation
 Person/s to contact for study information
 Rights of subject, if study related injury
 Reasons for termination
 Duration of study
 Number of subjects
 Any other pertinent information
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33. Format of Informed Consent Form
 Study Title
 Subject’s Initials e.g. Subject’s Name/ Date of Birth / Age
 Consent Statements with initials in
a) Signature (or Thumb impression) of the Subject
b) Legally Acceptable Representative
 Signature of the Investigator
 Study Investigator’s Name
 Signature of the Witness
 Name of the Witness
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34. Appendix VI- FDC’s
Combination therapy with two or more agents
having complementary mechanisms of action is an
example of incremental innovation that may extend
the range of therapeutic options in the treatment of
almost every human disease
Data requirements of Fixed Dose Combinations
Fixed Dose combinations (FDC) fall into four groups and
their data requirements accordingly.
 The first group of FDC includes those in which one or more
of the active ingredients is a new drug.
 The second group of FDC includes those in which active
ingredients already approved/marketed .
 The third group of FDC includes those which are already
marketed
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35. Appendix VII
Undertaking By The Investigator
1) Full name, address and title of the Principal Investigator
2) Name and address of the medical college, hospital or other
facility where the clinical trial will be conducted: Education,
training &experience that qualify the Investigator for the
clinical trial (Attach details including Medical Council
registration number, and / any other statement of
qualification
3) Name and address of all clinical laboratory facilities to be
used in the study.
4) Name and address of the Ethics Committee ,responsible
for approval and continuing review of the study.
5) Names of the other members of the research team (Co- or
sub-Investigators) who will be assisting the Investigator in
the conduct of the investigation.

36. VII.2 Commitments by The Investigator
a. Study not to begin until EC / DCGI approval
b. Adherence to protocol
c. Personal supervision
d. Ensure requirements of IC and EC review
e. Report of AE to sponsor
f. Understanding of investigator’s brochure
g. Ensure that all associates, colleagues and
employees suitably qualified and experienced and
aware of their obligations
h. Report all unexpected serious adverse events to
the Sponsor in 24 hrs and EC within 7 days.
i. Maintenance of records and availability for audits /
sponsor inspection / EC and DCGI. Cooperation in
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audits

37. Appendix VIII
ETHICS COMMITTEE COMPOSITION
ICH GCP Indian GCP Schedule-Y
• At least 5 members. •Fairly small (5-7 •At least 7 members.
•At least 1 member - members).
nonscientific area. • 1 member from non- •Not Explained.
•Quorum members scientific area •The quorum should
number not detailed. have at least 5
•The quorum should have a members.
•Maximum number is minimum of 5 members. •Maximum number is
not detailed. not detailed.
•12 to 15 is the maximum
•Not recommended. recommended number. •Not recommended.
•Member Secretary
belongs to the same
Institution.
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38. Appendix IX- Stability testing of New
Drugs
Stability testing is to be performed to provide evidence
on how the quality of a drug substance or
formulation varies with time under the influence of
various environmental factors such as-
a. Temperature
b. Humidity and
c. Light
Objective. - To establish shelf life for the formulation
and recommended storage conditions.
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39. STABILITY TESTING
Stress testing of the drug substance should be conducted to
identify-
a. The degradation pathways
b. Evaluate the intrinsic stability of the molecule and
c. Validate the stability indicating power of the analytical
procedures used.
Stress testing may generality be carried out on a single batch
of the drug substance. It should include the effect of-
Temperature, humidity, oxidation, photolysis on the drug
substance.
TWO TYPES OF STUDY IS DONE
1)Long-term testing should cover a minimum of 12
months’ duration on at least three primary batches of
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40. STABILITY TESTING
2)Accelerated testing should cover a minimum of 6
months duration at the time of submission.
Study conditions for drug substances and formulations
intended to be stored under general conditions.
Study conditions and Duration of study
i)Long term 30 C 2 C/65% RH 5%RH 12 months
ii)Accelerated 40 C 2 C/75% RH 5% RH 6 months
If at any time during 6 months’ testing under the
accelerated storage condition, such changes occur
then further studies are done.
NOTE- The nature of the stress testing will depend
on the individual drug substance and the type of
formulation involved.
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41. Appendix X – Contents of the Proposed
Protocol
 Title page
 Table of content
a) a) introduction
b) Study rationale
c) Study design
d) Study population
e) Subject eligibility
f) Study treatment
g) AE
h) Data analysis
i) Undertaking by investigator
NOTE- Protocol is assigned by sponsor after getting CDA from
investigator
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42. Appendix XI- Data Elements For Reporting SAE in a
Clinical Trial
a) Patient details(Age, sex, weight, height)
b) Suspected drug( Generic name, DFD, ROA)
c) Detail of SUSPECTED ADR( severity, start date, stop
date, hospitalization or not)
d) Details about investigator
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43. New Amendments on 30.06.2009
CLINICAL RESEARCH ORGANISATION –
REGISTRATION
These guidelines have been approved by DTAB
1)Rule 122 DAB. – Registration of clinical research
organization for conducting clinical trials.
The clinical research organisation, contracted in
writing by the sponsor to carry out any or all
obligations transferred to it by the sponsor, shall
perform such functions only, if it is duly registered,
under the rules, by the Licensing Authority defined in
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44. Schedule Y-1-Requirements and Guidelines
for registration of clinical research
2. Criteria for
organisations Registration
(I) The Clinical Research Organisation shall be
under the charge of a person who is responsible
for the overall activities of the organisation. He
shall be thoroughly familiar with the
investigational product(s), the protocol, written
informed consent forms or other information
provided to the subjects, the standard operative
procedures by the sponsors, GCP guidelines and
other rules applicable to the conduct of clinical
trials.
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(ii)

45. (iii) The organisation shall ensure that the trials are
adequately monitored and the trial related
responsibilities transferred to it, partially or fully,
by the sponsor are discharged effectively and
efficiently.
(iv) The organisation shall implement quality
assurance and quality control as per standard
operative procedures designed for the purpose.
Such SOPs shall be well documented.
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46. New Amendments on 18th Nov.2011
1)Rule 122-DAB- compensation during injury or death during
clinical trial
In case of injury in clinical trial the compensation is based as
per the recommendation of EC/IRB , it may be financial or
medical.
2) In case of death his/her legal heirs are entitled for the
financial compensation, subject to the confirmation to EC
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47. Conclusion
With the Schedule Y, efforts are
aligned in a single direction to ensure
that irrespective of the country, the
data generated is of good quality and
standard which can be accepted
worldwide
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48. References
Gupta S.K, Basic principles of Clinical research and
Methodology, 2007.
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49. QUERIES????
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