SCHEDULE Y

PRESENTED BY-
AKSHDEEP SHARMA
CLINICAL RESEARCH
(STUDENT)
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
Lets Revise the History

• 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
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.
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.
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 manufacture
of other drug
Schedules to Rules, 1945
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
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.
What actually Schedule Y is?
 Schedule Y

यह एक कानून
न केवल एक It’s a Law
दिशाननिे श है
not merely
a Guideline
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.
Schedule Y

‘REQUIREMENTS AND GUIDELINES FOR

PERMISSION TO IMPORT AND / OR
MANUFACTURE OF NEW DRUGS FOR
SALE OR TO UNDERTAKE CLINICAL
TRIALS IN INDIA’
 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
Why Changes in Schedule Y
To frame guidelines for the current scenario of Clinical research.
CDSCO and DTAB(Drug Testing Advisory Board) 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.
Application for permission
It shall made in Form 44 accompanied with the following data
in accordance with appendices, namely
Clinical and pharmaceutical information
Animal pharmacology data
Animal Toxicology data
 Human Clinical pharmacology data
Regulatory status in other countries
Prescribing information

FORM 12- To import Study drug for examination , test or

analysis
Clinical Trial
1. Approval for clinical trials
2. Responsibilities of sponsor
3. Responsibilities of Investigator
4. Informed Consent
5. Responsibilities of Ethics Committee
6. Human Pharmacology (Phase l)
7. Therapeutic Exploratory Trials (Phase ll)
8. Therapeutic confirmatory Trials (Phase lll)
9. Post Marketing Trials (lV)
Clinical Trials : Special Studies

 Clinical trials required if the indication is relevant to

special population e.g. pediatrics, geriatrics,and
pregnancy

 Members knowledgeable about pediatric, ethical,

clinical and psychosocial issues
 Mature minors and adolescents to sign an assent form
 Other – Post-marketing surveillance, BA/BE
Approval for Clinical Trials

 Clinical trial on a new drug shall be initiated only after the

permission has been granted by the Licensing Authority under
rule 21 (b), and the approval obtained from the respective ethics
committees.
 The Licensing Authority as defined shall be informed of the
approval of the respective institutional ethics committees as
prescribed in Appendix VIII, and the trial initiated at each
respective site only after obtaining such an approval for that site.
Responsibility of Sponsor
 Quality assurance to ensure compliance to GCP guidelines of
CDSCO(Central Drug Standard Control Organization)
Submission of status report at prescribed periodicity; reasons for
premature termination to be communicated
Serious adverse event to be communicated promptly (within 14
calendar days) to DCGI(Drug Controller General Of India) and other
investigators
Responsibilities of Investigator
Responsible for conduct of trial according
to protocol and GCP
 Compliance as per undertaking format
Medical care for AEs
SAE reporting to
Sponsor within 24 hrs
EC within 7 days
Informed consent
Responsibilities of EC
Safeguard rights, safety, wellbeing of
subjects
Special care for vulnerable subjects
Reason’s for revoking approval and information to investigator /
regulatory authority
Ongoing review
 Clinical Trial

1.Human Pharmacology (Phase l)

Safety and tolerability – Objective
2.Therapeutic Exploratory Trials (Phase ll)
To evaluate the effectiveness of a drug for particular
indication.
To determine the short term side effects and risk
associated with the drug
To determine the dose and regimen for phase lll trials.
Clinical Trial

6.Therapeutic confirmatory Trials (Phase lll)

Demonstration of therapeutic benefit
Drug is safe and effective for use and Provide and
adequate basis for marketing approval
7.Post Marketing Trials (lV)
Performed after drug approval and related to the
approved indication
Includes drug-drug interaction, dose-response or
safety studies, mortality/morbidity studies
Studies in Special Population
Information supporting the use of the drug in children, pregnant women,
nursing women, elderly patients, 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 (Appendix I, item 8.3).

Types
1. Geriatrics
2. Pediatrics
3. Pregnant or Nursing Women
 Geriatrics
Geriatric patients should be
included in Phase III clinical trials
(and in Phase II trials, at the
Sponsor's option) in meaningful
numbers, if-
the disease intended to be treated
is characteristically a disease of
aging; or
the population to be treated is
known to include substantial
numbers of geriatric patients
Pediatrics

The timing of pediatric

studies in the new drug
development program
will depend on the
medicinal product, the
type of disease being
treated, safety
considerations, and the
efficacy and safety of
available treatments.
The pediatric studies should include –

clinical trials,
relative bioequivalence comparisons of the
pediatric formulation with the adult formulation
performed in adults
definitive pharmacokinetic studies for dose
selection across the age ranges of pediatric
patients in whom the drug is likely to be used.
These studies should be conducted in the
pediatric patient population with the disease
under study.
Pregnant or Nursing Women
Pregnant or nursing women should be
included
in clinical trials only when the drug is
intended for use by pregnant/nursing
women or fetuses/nursing infants and
where the data generated from women who
are not pregnant
or nursing, is not suitable.
For new drugs intended for use during
pregnancy, follow-up data (pertaining to a
period appropriate for that drug) on the
pregnancy, fetus and child will be required
Post Marketing Surveillance

PSUR : Periodic Safety Update Reports

New drugs should be closely monitored for their clinical safety;
submission of 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; and
indicate whether changes should be made to product information
PSURs shall be submitted every 6 months for the first two years
after
approval
PSUR : Periodic Safety Update Reports

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.
Rules under Schedule Y
Rule Permission

122 A To Import New Drugs

122 B To manufacture New Drugs

122 D To import or manufacture fixed dose Combinations

To conduct Clinical Trials

122 DA for New Drug/Investigational New Drug

122DAA Definition of Clinical Trial

Definition of New Drug

122 E
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.
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
APPLICATION FOR PERMISSION UNDER
FORM 44, REGULATORY AUTHORITIES,
FEES AND TEST LICENCE
 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

DRUG REGULATION IN INDIA
Ministry of Health and Family
Welfare

• Directorate General of Health Services

CDSCO-Central Drugs Standard

Control Organization

• Drugs Controller General of India.

Retail and Manufacturing Clinical Trials and

new drug
Distribution Practice development
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
 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
 Appendix III
Animal toxicology (Non-clinical toxicity studies)
1) SDTS(Single Dose Toxicity Study)- Minimum 5 animal, 24hr observation
2) DRS(Dose Ranging Study)- On one Rodent Species
3) RDTS(Repeated Dose Systemic Toxicity Study)- 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)
Appendix IV-Animal Pharmacology

Animal pharmacology studies are done to see the effect if

IP on different systems like
 CVS-(Cardiovascular System)
 CNS-(Central Nervous System)
 ANS-(Autonomic Nervous System)
 RS-(Respiratory System)
 US-(Urinary System)
 GIT-(Gastrointestinal System)
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
 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
 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
Appendix VI- FDC’s
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
The fourth group of FDC includes those whose individual active
ingredients have been widely used.
 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.
6) Protocol Title and Study number (if any) of the clinical trial to be conducted by the
Investigator.
7) Signature with Date.
Appendix 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 audits
 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.
scientific area

•Quorum members •The quorum should have •The quorum should

number not detailed. a minimum of 5 members. have at least 5
members.

•Maximum number is •12 to 15 is the maximum •Maximum number is

not detailed. recommended number. not detailed.

•Not recommended. •Member Secretary •Not recommended.

belongs to the same
Institution.
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.
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 the drug substance or the formulation at
the time of submission
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.
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
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
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 organization, 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 Clause (b) of Rule 21.
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