Name: Dr.

Wasim Ismail Kamate

Roll no.: 17700002
Module Number – 7
Regulations in Clinical Research

1. Food , Drug and Cosmetic Act

The major crisis during this period was evoked by the use of elixir of Sulfanilamide.
Sulfanilamide was a tablet - very large tablet - used to treat infections. The manufacturer
wanted to make a formulation for use among children, but the tablet was too big for them to
swallow, so the company decided to make a liquid preparation by adding diethylene glycol, the
principal ingredient of antifreeze. The company was able to get a liquid form and tested it for
flavor- it tasted just fine. Unfortunately, it never tested the resulting liquid for toxicity. It was
very toxic, causing the deaths of more than a hundred people, many of them children.

The FDA had no authority to withdraw this product from the market for safety reasons, as there
were no regulations regarding safety at that time. The agency could, however, remove it for
mislabeling. It was called an elixir. Elixirs had to contain alcohol; however Elixir Sulfanilamide
did not contain alcohol. Based only on this labeling error, the FDA was able to have this unsafe
product removed from the market.

As a direct result of this tragedy, congress passed the 1938 'Food, Drug and Cosmetic Act'. For
the first time, a pre-market approval of 'new drugs' was required for safety. 'New drugs' meant
new chemical entities or combinations. Drugs marketed prior to 1938 were specifically
exempted ('grandfathered' in) as long as their labeling didn't change. There was no definition of
safety in the act; however, the general understanding was that the benefits must outweigh the
risk. The act also did not require active approval by the FDA. Unless the FDA objected within
sixty days of the New Drug Application (NDA) being filed, the manufacturer could automatically
begin marketing. No proof of efficacy was required. Between 1938 and 1962, most NDAs filed
were essentially just testimonials from the physicians.
2. Belmont Report

The Belmont report

The National Research Act, passed bt Congress in 1974, created the National Commission for
the Protection of Human Subjects of Biomedical and Behavioral Research. This commission
wrote a document entitled 'Ethical principles & guidelines' for the protection and human
subjects of biomedical and behavioral research; which became known as the 'Belmont report'
when it was published in 1979. The three basic principles of the Belmont report are respect for
persons, beneficence, and justice.
 Respect for persons is manifested by the informed consent process, as
well as in safeguards for vulnerable populations, such as children,
pregnant women, mentally disabled adults, and prisoners. Other
important concerns of respect for persons are privacy and confidentially.
 Beneficence has two general characteristics: do no harm, and maximize
benefit while minimizing risk. Beneficence is manifested in the use of
good research design, competent investigators, and a favorable
risk/benefit ratio.
 Justice implies fairness and is manifested in the equitable selection of
subjects for research, ensuring that no group of people is "selected in" or
"selected out" unfairly based on factors unrelated to the research. This
means that there must be appropriate inclusion/exclusion criteria and a
fair system of recruitment.
 The Belmont report forms the cornerstone for the ethical treatment of human subjects of
research.
3. Law and Regulation in India
(CDSCO). The Drugs Control General (India) (DCGI) has the authority to give permission to
conduct a clinical trial. After submitting the clinical trial report this authority gives
permission to manufacture and marketing the drug in India; approve new drug; develop
quality standards for drugs and vaccines and issue drug import license. The DCGI also
evaluates various documents of quality of drug as per standard and as per the national and
international guidelines. Regulatory authority may conduct the inspections in-between or
after the completion of the clinical trial. Regulatory authority evaluates the clinical trial for
the compliance of Good Clinical Practice (GCP) guidelines of country. India has its own GCP
guidelines that are similar to those of the ICH-GCP. Regulatory agencies have their own
procedures and the process of documentation. In India Schedule-Y regulation and ICMR,
'Guidelines for Ethical Biomedical Research' need to be adhered to in conduct the clinical
trials. Any study conducted for US-FDA submission and implemented in India must also
comply with the national regulations and guidelines in addition to the US-FDA regulations.
4. Clinical Trial Registry of India
According to the recent amendments to Schedule Y vide GSR 63 (E) and GSR 364 (E), all clinical
trials must be registered with the 'Clinical Trial Registry of India (CTRI)' that is operated by the
Indian Council of Medical Research before the first participant is enrolled in the study. This
needs to be done online on www.ctri.in. The CTRI, launched in July 2007, is maintained by the
National Institute of Medical Statistics, New Delhi. The Indian CTRI is a part of the International
Clinical Trial Registry Platform (ICTRP) devised by the 'World Health Organisation', Geneva. The
clinical trial has been defined (as one that follows WHO/ICJME 2008 definition) as studies done
among human beings involving any health related intervention to evaluate effects on health
outcome. The health related interventions include drugs, surgical procedures, devices,
behavioral treatments, etc. Thus, any interventional clinical trials, involving drugs, devices,
biologicals, vaccines, herbal compounds etc are required to be registered.
CTRI registration involves provision of information on following salient issues:
a. Title of the study (including acronym)
b. Name and address of Principal investigator
c. Name of IEC and approval status
d. Regulatory clearance status from DCGI
e. Phase of the trial
f. Duration of trial
g- Study sites
h. Summary of the trial
i. Method of generating random sequence
j- Method of allocation concealment
k. Blinding and masking
l. Sponsor and source of funding
m. Date of first enrollment
n. Type of study
o. Sample size
p- Intervention agent
q. Inclusion and exclusion criteria
r. Primary and secondary end points
s. Status of trial
 C TRI registration involves provision of information on following salient issues:

a. Title of the study (including acronym)

b. Name and address of Principal investigator
c. Name of IEC and approval status
d. Regulatory clearance status from DCGI
e. Phase of the trial
f. Duration of trial
g- Study sites
h. Summary of the trial
i. Method of generating random sequence
j- Method of allocation concealment
k. Blinding and masking
l. Sponsor and source of funding
m. Date of first enrollment
n. Type of study
0. Sample size
P- Intervention agent
q. Inclusion and exclusion criteria
r. Primary and secondary end points
s. Status of trial

On provision of the information about the study, the CTRI issues a Universal Trial Number
(UTN). Even if the trial has been registered in some other country, it is necessary that it is
registered with CTRI. The CTRI issues a secondary ID number. The CTRI registration is a
responsibility of the principal investigator. The CTRI registration is free. In case the trial
information including design changes, CTRI needs to be informed through email to make
suitable changes in the information.

• Protocol
The protocol shall contain the following:
 General administrative information
 Background to and objective(s) of the trial
 Type of trial
 Inclusion and exclusion criteria
 Treatment, intervention
 Enrollment of study subjects
 Evaluation procedures
 Statistical considerations - including sample size calculation and
assumptions
 End points registration of efficacy and evaluation of safety

 Direct access to source documentation

 Data Management procedures including quality assurance and
o quality control
o Ethical considerations
 Data handling and storage
 Financing and insurance coverage and
 Plan for publication of results (publication plan)

It shall also be specified whether the trial forms part of an international study.
• Supplementary information about the trial
In addition to the information provided in the protocol, the regulatory agency (of specific
country) shall be informed of:
a. Principal investigator's professional qualifications for the trial in
question.
b. Plan for termination of earlier treatment, if relevant
c. Follow-up of subjects after the trial
d. Plan for information to personnel concerned
e. Preparedness in the event of complications
f. Plan for handling medicinal products
g. Review of which listings that will be kept for subjects in the trial, and
overview of case record forms
h. Insurance of subjects
i. Labelling of the medicinal product packaging, and
j. The place of the trial in the product manufacturer's overall plan for development of the
product in question

• New drug advisory committee

The proposed clinical trial protocol is reviewed by the 'New Drug Advisory Committee' that
is constituted by DCGI which comprises subject experts. The DCGI has recently proposed to
change the name of this committee to 'Subject Expert Committee'. All the applications
submitted to DCGI for approval shall be first reviewed by this committee. The
recommendations of this committee shall be reviewed by Technical Review Committee
(TRC)'. The TRCs will be constituted by the 'Director General of Health Services (DGHS)'
comprising of pool of subject experts. Based on the recommendation of TRC, the CDSCO
will grant approval for any clinical trial. The TRC is expected to review the protocol to
determine definitive need of the drug in the country. CDSCO is also planning to establish
such review committees at regional level. It is also proposed that a facility of video
conferencing will be established in near future to enable experts to deliberate without
losing time in travel and minimize delays is approvals. A database of subject experts is being
developed. This database will be revised every year.

It is also proposed that the decision to approve or disapprove conduct of clinical trial will be
done within six months. In case, the process requires a longer period, the reason for delay
will be recorded. This is being proposed to ensure that the approval time will be brought to
one month in near future.

CDSCO is planning to develop criteria to waive the approval of TRC if the mechanisms for
protection of human subjects are in place for certain trials. Trials focusing on public health
emergencies due to epidemics or a disaster (e.g. bioterrorism) are good examples of the
same. However, CDSCO has committed to develop the criteria for such trials in near future.
5. Principles of ICH GCP
 Clinical trials should be conducted in accordance with the ethical principles that have their
origin in the declaration of Helsinki, and that are consistent with GCP and the applicable
regulatory requirement(s).
 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against
the anticipated benefit for the individual trial subject and society. A trial should be initiated
and continued only if the anticipated benefits justify the risks.
 The rights, safety, and well-being of the trial subjects are the most important considerations
and should prevail over interests of science and society.
 The available nonclinical and clinical information on an investigational product should be
adequate to support the proposed clinical trial.
 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
 A trial should be conducted in compliance with the protocol that has received prior
institutional review board / independent ethics committee approval/favourable opinion.

 The medical care given to, and medical decisions made on behalf of, subjects should always
be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
 Each individual involved in conducting a trial should be qualified by education, training, and
experience to perform his or her respective task(s).
 Freely given informed consent should be obtained from every subject prior to clinical trial
participation.
 All clinical trial information should be recorded, handled, and stored in a way that allows its
accurate reporting, interpretation and verification.
 The confidentiality of records that could identify subjects should be protected, respecting
the privacy and confidentiality rules in accordance with the applicable regulatory
requirement(s).
 Investigational products should be manufactured, handled, and stored in accordance with
applicable Good Manufacturing Practice (GMP). They should be used in accordance with the
approved protocol.
 Systems with procedures that assure the quality of every aspect of the trial should be
implemented.
6. Health Insurance and Accountability Act (HIPAA)
The purpose of the Health Insurance Portability and Accountability Act (HIPAA) is to improve
the efficiency and effectiveness of the healthcare system by encouraging the development of
healthcare information systems using electronic data interchange for health- related
administrative and financial transactions. In addition, HIPAA seeks to establish the required use
of national transaction standards while maintaining patient privacy when business and patient
information is transmitted electronically between organizations.

All vendors of Electronic Medical Record (EMR)' systems must conform to the standards in the
administrative simplification component of HIPAA. This component encompasses four
standards:
1. Electronic transactions and code sets
2. Privacy of individually identifiable health information

3. Security to preserve patient confidentiality

4. Creation of unique health identifiers for patients, health plans, providers and employers

The fourth standard is one part of HIPAA that will directly affect clinical research. It addresses
standards by which unique patient- identifying information can be transmitted electronically,
possibly over the internet.

The final HIPAA rule was released on August 14, 2002 and has a compliance date of April 14,
2003. Specific areas of the final regulation that will affect researches are: de-identification of
patient health information, as mentioned above, single authorization from the patient required
for all uses and disclosures of patient health information the combining of patient authorization
forms with the informed consent document; and the elimination of an expiration date or event
for research authorization. The final regulation also now has one set of transition provisions for
all forms of research regardless of whether they involve treatment or not.
7. Responsibilities of the ethics committee

Basic responsibilities of EC's

a. To protect the dignity, rights and well being of the potential research
participants.
b. To ensure that universal ethical values and international scientific standards are expressed
in terms of local community values and
customs.
c. To assist in the development and education of a research community to local health care
requirements.

Composition
a. IEC should be kept fairly small (8-12)
b. Should be multidisciplinary and multi sectorial in composition
c. Minimum 5 persons required to form the quorum
d. Basic layout of EC composition may be as follows:
Chairperson (from outside the institution) 11 -2 persons from basic medical
science 1 -2 clinicians from various institutes 1 legal person or retired Judge 1
social scientist/representative of NGO 1 philosopher/ethicist/theologian 1 lay
person Member secretary

• Review procedures
a. EC should review every research proposal on human participants
before the research is initiated.
b. Risk/benefit ratio should be evaluated.
c. Depending on the risk involved, the proposal may fall into any of below
mentioned categories:
• Exemption from review
• Expedited review
• Full review

• Decision making
a. The decision must be taken by a board.
b. Any decision should be communicated in writing.
c. Conflict of interest should be submitted before EC meeting by PI.
d. If any one member has his own proposal for review or has any conflict
of interest then he should withdraw from IEC while the project is being
discussed.
e. Negative decision should be supported by defined reason.
f. As per ICMR / Indian GCP, IEC can go for a discontinuation call if IEC
finds that goals of the trial have already been achieved.
g. Proper notice for premature termination of trial.

• Review process
a. Periodic process
b. Continuing process
c. Interim review

• Monitoring
a. Once IEC gives a certificate of approval, it is the duty of the IEC to monitorthe approved
studies.

• Record keeping
a. All communication of an IEC, should be filed.
b. Records must be safely maintained after the completion/ termination
of study for a period of 3 years.

• Administration and management

a. A full time secretariat
b. Space for keeping records
c. Reasonable compensation for members for the time spared for
reviewing proposals
c. Reasonable amount of fund for smooth functioning of the IEC

• Special considerations
a. Vulnerable populations

• General ethical issues

a. Informed consent
b. Compensation for participants
c. Conflict of interest
d. Selection of special groups as research participants
e. Essential information on confidentiality for prospective research
participants
f. Compensation for accidental injury
g. Post -Trial access
h. International collaboration/assistance in biomedical/health research
i. Researcher's relations with the media and publication practices

Few additions in the revised guidelines

• Chapter 5: Statement of specific principles for epidemiological studies
• Chapter 6: Statement of specific principles for human genetics and genomics
research
• Chapter 7: Statement of specific principles for research in transplantation
• Chapter 8: Statement of specific principles for assisted reproductive technologies
8. Regulations of Clinical Trial in India-
Regulatory approvals in India can usually take 3 months, which is comparable to most Asian and
European countries. Although the US FDA gives approval in 30 days, most US trials are delayed
because suitable subjects are not available in adequate numbers. The timelines for approval are
often unpredictable in India as the Drug Controller's office depends on external experts and
other government agencies such as the Indian Council of Medical Research (ICMR) and the
Department of Biotechnology (DBT) for advice and there are additional permissions required
for the import of trial samples and export of blood samples to foreign central laboratories.

The potential for fast recruitment can partly offset the delay in the regulatory approval.
Nevertheless the regulatory situation is a major concern for all pharmaceutical sponsors and
Contract Research Organizations (CROs), who continue to press for improvements in the
regulatory approval process to make it predictable, accountable and less cumbersome. The
other aspects of regulatory revisions such as adoption of Good Clinical Practices (GCP)
guidelines, removal of import duty on clinical trial samples, elimination of restrictions on
concurrent trials, anticipated patent law changes have shown India's seriousness about
becoming a hub of global clinical trials.

Regulations for Clinical Trials in India

The ICMR has planned to review and audit the functioning of ECs and to introduce a national
accreditation system for them. Additionally, the ICMR has also established an independent
Forum for Ethics Review Committees, which will organize training programs for the members of
ECs. The revised Schedule Y of Drugs and Cosmetic Rules devotes significant attention to the
roles and responsibilities of ECs, prescribes the composition of ECs as per the ICMR guidelines
and provides formats for the approval letter of ECs. These government initiatives are likely to
improve the current situation.

In 2002, there were 200-250 GCP trained investigators and 40-50 GCP clinical studies were
conducted. These small numbers imply that many potential clinical investigators do not have
the experience of conducting GCP trials. Though this s not considered negative, it does require
a major investment in training during study start-up. For the investigators struggling to balance
patient care and research activities, compliance to GCP is an additional new responsibility. In
addition, low literacy levels and poverty amongst the patients and the pressure of quick patient
recruitment from the sponsors pose significant challenges to an investigator making efforts to
obtain proper informed consent from the patients. The stress on the responsibilities of
investigators for the implementation and documentation of the informed consent process in
the GCP training programs, and the adverse media publicity to several recent clinical trial
mishaps and subsequent government enquiries have increased the awareness amongst the
investigators about ethical and regulatory issues and the need for adequate patient protection.
Although the US FDA has yet to inspect any clinical trials in India, most sponsors and CROs carry
out their own audits of clinical trials. Numerous audits in India are a testimony to the level of
quality. Data from clinical studies in India have been successfully filed with international
regulatory agencies.

Since quality is the hallmark of global acceptance, most sponsors and CROs invest heavily in
monitoring, quality control and investigator training. The overall impression is that the data
quality is usually excellent.
2. Discuss in Detail
a. Investigational New Drug

Investigational New Drugs (INDs)

Content and Format of Investigational New Drug Applications (INDs)
The clinical investigation of a drug that is not marketed requires submission of an IND
application to FDA. An IND can be issued to a company, a government agency such as NIH or
NCI, or an individual investigator (sponsor-investigator). The clinical investigation of an
investigational new drug may not begin until the IND goes into effect. FDA notifies the sponsor
in writing of the date it receives the IND application. An IND goes into effect 30 days after FDA
receives the IND application, unless the FDA notifies the sponsor that the investigations
described in the IND application are subject to a clinical hold. A clinical hold is an order issued
by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing
investigation. Investigators are responsible for promptly notifying the PHRC whenever FDA
issues a clinical hold. An IND may also go into effect before the 30-day period when FDA notifies
the sponsor that the clinical investigations may begin. The PHRC must ascertain that the IND
has been issued and is not subject to a clinical hold before final approval can be given for the
clinical investigation to begin. An IND submission for human studies is required by regulation to
contain the sections enumerated below. Clarifications are described when appropriate beneath
each section heading.

Documents to help prepare INDs include

• Guidance for industry: INDs-Approaches to complying with CGMP's for Phase 1 Drugs
(Draft)
• Guidance for industry: Exploratory IND studies
• Content and format of INDs for phase 1 studies of drugs including well characterized,
therapeutic, biotechnology-derived products. Provides description of required sections of
an application.
• Q & A - Content and format of INDs for Phase 1 studies of drugs, including well-
characterized, therapeutic, biotechnology-derived products. This guidance is intended to
clarify when sponsors should submit final, quality-assured toxicology reports and/or update
the Agency on any changes in findings since submission of non-quality-assured reports or
reports based on non-quality-assured data.
• Bioavailability and bioequivalence studies for orally administered drug products - general
considerations. This guidance should be useful for applicants planning to conduct
bioavailability and bioequivalence studies during the IND period for an NDA, BE studies
intended for submission in an ANDA, and BE studies conducted in the postapproval period
for certain changes in both NDAs and ANDAs.
• IND Exemptions for studies of lawfully marketed drug or biological products for the
treatment of cancer.
• Drug master files –A Drug Master File (DMF) is a submission to the FDAthat may be used to
provide confidential detailed information about facilities, processes, or articles used in the
manufacturing, processing, packaging, and storing of one or more human drugs.
• Required specifications for FDA's IND, NDA, and ANDA Drug Master binders.
• Immunotoxicology evaluation of investigational new drugs. This guidance makes
recommendations to sponsors of investigational new drugs on
a. the parameters that should be routinely assessed in toxicology studies to
determine effects of a drug on immune function,
b. when additional immunotoxicity studies should be conducted, and
c. when additional mechanistic information could help characterize the
significance of a given drug's effect on the immune system.

IND application format

• Cover sheet
• Table of contents
• Introductory statement and general investigational plan
• Investigator's brochure
• Protocols
• Chemistry, manufacturing, and control information
• Pharmacology and toxicology information
• Previous human experience with the investigational drug
• 21 CFR312.23(a)(10),(11)and(b),(c),(d),and(e)

Information on the drug substance should be submitted in a summary report containing the
following items.
a. A description of the drug substance, including its physical, chemical, or
biological characteristics: A brief description of the drug substance and
some evidence to support its proposed chemical structure should be
submitted. It is understood that the amount of structure information will
be limited in the early stage of drug development.
b. The name and address of its manufacturer: The full street address of
the manufacturer of the clinical trial drug substance should be
submitted.
c. The general method of preparation of the drug substance: A brief
description of the manufacturing process, including a list of the
reagents, solvents, and catalysts used, should be submitted. A
detailed flow diagram is suggested. More information may be needed
to assess the safety of biotechnology-derived drugs or drugs extracted
from human or animal sources.
d. The acceptable limits and analytical methods used to assure the
identity, strength, quality, and purity of the drug substance: A brief
description of the test methods used should be submitted. Proposed
acceptable limits supported by simple analytical data, (e.g., IR
spectrum to prove the identity, and HPLC chromatograms to support
the purity level and impurities profile) of the clinical trials material
should be provided. Submission of a copy of the certificate of analysis
is also suggested. The specific methods will depend on the source and
type of drug substance (e.g., animal source, plant extract,
radiopharmaceutic, other biotechnology-derived products). Validation
data and established specifications ordinarily need not be submitted
at the initial stage of drug development. However, for some well-
characterized, therapeutic biotechnology-derived products,
preliminary specifications and additional validation data may be
needed in certain circumstances to ensure safety in phase 1.

Toxicological studies and the proposed clinical study(ies): A brief description of the stability
study and the test methods used to monitor the stability of the drug substance should be
submitted. Preliminary tabular data based on representative material may be submitted.
Neither detailed stability data nor the stability protocol should be submitted.
b. Schedule Y
Data to be submitted along with the application to conduct clinical trial / import / manufacture
of new drugs for marketing in the country

Data to be submitted along with the application to conduct clinical trials/import/manufacture

of new drugs for marketing in the country
All items may not be applicable to all drugs. For more information, refer text of Schedule Y. For
requirements of data to be submitted with application for clinical trials, refer text of this
schedule.
• Introduction
A brief description of the drug and the therapeutic class to which it belongs

• Chemical and pharmaceutical information

a. Information on active ingredients
Drug information (generic name, chemical name or international nonproprietary
name)

b. Physicochemical data
• Chemical name and structure
a. Empirical formula
b. Molecular weight
• Physical properties
a. Description
b. Solubility
c. Rotation
d. Partition coefficient
e. Dissociation constant

• Analytical data
a. Elemental analysis
b. Mass spectrum
c. NMR spectra
d. IR spectra
e. UV spectra
f. Polymorphic identification

Complete monograph specification including

a. Identification
b. Identity/quantification of impurities
c. Enantiomeric purity
d. Assay
Validations
a. Assay method
b. Impurity estimation method
c. Residual solvent/other volatile impurities estimation method

Stability Studies
a. Final release specification
b. Reference standard characterization
c. Material safety data sheet

Data on formulation
a. Dosage form
b. Composition
c. Master manufacturing formula
d. Details of the formulation (including inactive ingredients)
e. In process quality control check
f. Finished product specification
g. Excipient compatibility study
h. Validation of the analytical method
i. Comparative evaluation with international brand(s) or approved n brands, if applicable
j. Pack presentation
k. Dissolution
I. Assay
m. Impurities
n. Content uniformity
o. pH
p. Force degradation study
q. Stability evaluation in market intended pack at proposed storage conditions
r. Packing specifications
s. Process validation
When the application is for clinical trials only, the international non-proprietary name or
generic name, drug category, dosage form and data supporting stability in the intended
container-closure system for the duration of the clinical trial (information covered in item nos.
2.1,2.3,2.6,2.7) are required.
 Animal pharmacology (for details refer Appendix IV)
a. Summary
b. Specific pharmacological actions
c. General pharmacological actions
d. Follow-up and supplemental safety pharmacology studies
e. Pharmacokinetics: absorption, distribution; metabolism; excretion
o
Animal toxicology (for details refer Appendix III)
a. General aspects
b. Systemic toxicity studies
c. Male fertility study
d. Female reproduction and developmental toxicity studies
e. Local toxicity
f. Allergenicity/hypersensitivity
g. Genotoxicity
h. Carcinogenicity

• Human / clinical pharmacology (Phase I)

a. Summary
b. Specific pharmacological effects
c. General pharmacological effects
d. Pharmacokinetics, absorption, distribution, metabolism, excretion
e. Pharmacodynamics/early measurement of drug activity

• Therapeutic exploratory trials (Phase II)

a. Summary
b. Study report(s) as given in Appendix 11

• Therapeutic confirmatory trials (Phase III)

a. Summary
 b. Individual study reports with listing of sites and investigators.

• Special studies
c. Summary
b. Bio-availability / bio-equivalence.
c. Other studiese.g. geriatrics, paediatrics, pregnant or nursing women

• Regulatory status in other countries

a. Countries where the drug is marketed, approved, approved as IND
withdrawn, if any, with reasons
b. Restrictions on use, if any, in countries where marketed /approved
c. Free sale certificate or certificate of analysis, as appropriate

• Prescribing information
a. Proposed full prescribing information

• Samples and testing protocol/s

a. 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.

Unattended areas in schedule Y

Regulations for:
• Biologies: vaccines. Blood products, Tissue, Cellular/gene therapy
a. Herbals
b. Medical devices
c. Pharmacovigilance
d. Electronic records
 FORM 44

Application for grant of permission to import or manufacture a new drug or to undertake

clinical trial.

I/We* ................................................ of M/s .......................................

(address) hereby apply for grant of permission for import of and/or clinical trial or for approval
to manufacture a new drug or fixed dose combination or subsequent permission for already
approved new drug. 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 specification, (i) Active ingredients (ii) Inactive ingredients
(5) Pharmacological classification of the drug
(6) Indications for which proposed to be used

(7) Manufacturer of the raw material (bulk drug substances)

(8) Patent status of the drug

2. Data submitted along with the application (as per Schedule Y with indexing and page
numbers:)

A. Permission to market a new drug:

(1) Chemical and pharmaceutical information
(2) Animal pharmacology
(3) Animal toxicology
(4) Human / clinical pharmacology (Phase I)
(5) Exploratory clinical trials (Phase II)
(6) Confirmatory clinical trials (Phase III) (including published review articles)
(7) Bio-availability, dissolution and stability study data
(8) Regulatory status in other countries
 (9) Marketing information:
(a) Proposed product monograph
(b) Drafts of labels and cartons
(10) Application for test license

B. Subsequent approval / permission for manufacture of already approved

new drug:
(a) Formulation:
(1) Bio-availability/bio-equivalence protocol
(2) Name of the investigator/center
(3) Source of raw material (bulk drug substances) and stability study data.
(b) Raw material (bulk drug substances):
(1) Manufacturing method
(2) Quality control parameters and/or analytical specification, stability report
(3) Animal toxicity data

(C) Approval / permission for fixed dose combination:

(1) Therapeutic Justification (authentic literature in pre-reviewed journals/text books)
(2) Data on pharmacokinetics / pharmacodynamics combination
(3) Any other data generated by the applicant on the safety and efficacy of the
combination
(D) Subsequent approval or approval for new indication -new dosage form:
(1) Number and date of Approval / permission already granted
(2) Therapeutic justification for new claim / modified dosage form
(3) Data generated on safety, efficacy and quality parameters

A total fee of rupees ................................. (in words) .......................

has been credited to the Government under the Head of Account

........................... (Photocopy of receipt is enclosed).

Dated:... Signature ...................

Designation ..............
Note: *Delete whichever is not applicable

The reader should also note that CDSCO recently released guidelines for Common
Technical Document (CTD) for marketing, import and manufacturing new drug.
c. Phases of Clinical Trials.
Ans –

Phases of Clinical Trial Human pharmacology (Phase I)

• The objective of studies in this phase is the estimation of safety and tolerability with the
initial administration of an investigational new drug into human(s). Studies in this phase of
development usually have non-therapeutic objectives and may be conducted in healthy
volunteer subjects or certain types of patients. Drugs with significant potential toxicity e.g.
cytotoxic drugs are usually studied in patients. Phase I trials should preferably be carried
out by investigators trained in clinical pharmacology with access to the necessary facilities
to closely observe and monitor the subjects.

• Studies conducted in phase I, usually intended to involve one or a combination of the

following objectives:-
a. Maximum tolerated dose: To determine the tolerability of the dose
range expected to be needed for later clinical studies and to
determine the nature of adverse reactions that can be expected.
These studies include both single and multiple dose administration.
b. Pharmacokinetics, i.e., characterization of a drug's absorption,
distribution, metabolism and excretion. Although these studies
continue throughout the development plan, they should be
performed to support formulation development and determine
pharmacokinetic parameters in different age groups to support
dosing recommendations.
c. Pharmacodynamics: Depending on the drug and the endpoints
studied, pharmacodynamic studies and studies relating to drug
 blood levels (pharmacokinetic/ pharmacodynamic studies) may be
conducted in healthy volunteer subjects or in patients with the
target disease. If there are appropriate validated indicators of
activity and potential efficacy, pharmacodynamic data obtained
from patients may guide the dosage and dose regimen to be applied in
later studies.
d. Early measurement of drug activity: Preliminary studies of activity or
potential therapeutic benefit may be conducted in Phase I as a
secondary objective. Such studies are generally performed in later
phases but may be appropriate when drug activity is readily
measurable with a short duration of drug exposure in patients at this
early stage.

Therapeutic exploratory trials (Phase II)

• The primary objective of phase II trials is to evaluate the effectiveness of a drug for a
particular indication or indications in patients with the condition under study and to
determine the common short-term side-effects and risks associated with the drug. Studies
in phase II should be conducted in a group of patients who are selected by relatively
narrow criteria leading to a relatively homogeneous population. These studies should be
closely monitored. An important goal for this phase is to determine the dose(s) and
regimen for phase III trials. Doses used in phase II are usually (but not always) less than the
highest doses used in phase I.

• Additional objectives of phase II studies can include evaluation of potential study

endpoints, therapeutic regimens (including concomitant medications) and target
populations (e.g. mild versus severe disease) for further studies in phase II or III. These
objectives may be served by exploratory analyses, examining subsets of data and by
including multiple endpoints in trials.
• If the application is for conduct of clinical trials as a part of multi-national clinical
development of the drug, the number of sites and the patients as well as the justification
for undertaking such trials in India shall be provided to the licensing authority.

Therapeutic confirmatory trials (Phase III)

• Phase III studies have primary objective of demonstration or confirmation of therapeutic
benefit(s). Studies in phase III are designed to confirm the preliminary evidence
accumulated in phase II that a drug is safe and effective for use in the intended indication
and recipient population. These studies should be intended to provide an adequate basis
for marketing approval. Studies in phase III may also further explore the dose-response
relationships (relationships among dose, drug concentration in blood and clinical response),
use of the drug in wider populations, in different stages of disease, or the safety and
efficacy of the drug in combination with other drug(s).

• For drugs intended to be administered for long periods, trials involving extended exposure
to the drug are ordinarily conducted in Phase III, although they may be initiated in phase II.
These studies carried out in phase III complete the information needed to support
adequate instructions for use of the drug (prescribing information).

• 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. Prior to conduct of phase III studies in Indian
subjects, licensing authority may require pharmacokinetic studies to be undertaken to
verify that the data generated in Indian population is in conformity with the data already
generated abroad.

• If the application is for the conduct of clinical trials as a part of multinational clinical
development of the drug, the number of sites and patients as well as the justification for
undertaking such trials in India should be provided to the licensing authority along with the
application.
Post marketing trials (Phase IV)
Post marketing trials are studies (other than routine surveillance) performed after drug
approval and related to the approved indication(s). These trials go beyond the prior
demonstration of the drug's safety, efficacy and dose definition. These trials may not be
considered necessary at the time of new drug approval but may be required by the licensing
authority for optimizing the drug's use. They may be of any type but should have valid scientific
objectives. Phase IV trials include additional drug-drug interaction(s), dose-response or safety
studies and trials designed to support use under the approved indication(s), e.g.
mortality/morbidity studies, epidemiological studies etc.

Post marketing surveillance

• Subsequent to approval of the product, new drugs should be closely monitored for their
clinical safety once they are marketed. The applicants shall furnish Periodic Safety Update
Reports (PSURs) in order to-
a. Report all the relevant new information from appropriate sources;
b. Relate these data to patient exposure
c. Summarize the market authorization status in different countries
and any significant variations related to safety
d. Indicate whether changes should be made to product information in
order to optimize the use of the product.
• Ordinarily all dosage forms and formulations as well as indications for new drugs should be
covered in one PSUR. Within the single PSUR separate presentations of data for different
dosage forms, indications or separate population need to be given.

• All relevant clinical and non-clinical safety data should cover only the period of the report
(interval data). The PSURs shall be submitted every six months for the first two years after
approval of the drug is granted to the applicant. For subsequent two years - the PSURs
need to be submitted annually. Licensing authority may extend the total duration of
submission of PSURs if it is considered necessary in the interest of public health. PSURs due
for a period must be submitted within 30 calendar days of the last day of the reporting
period.

The data requirements stated in this schedule are expected to provide adequate
information to evaluate the efficacy, safety and therapeutic rationale of new drugs (as
defined under rule 122-E) prior to the permission for sale. Depending upon the nature of
new drugs and disease(s), additional information may be required by the licensing
authority. The applicant shall certify the authencity of the data and documents submitted
in support of an application for new drug. The licensing authority reserves the right to
reject any data or any document(s) if such data or contents of such documents are found to
be of doubtful integrity.
d. Declarations of Helsinki & Write basic principles of all medical research

Declaration of Helsinki
The 'World Medical Association (WMA)' has developed the 'Declaration of Helsinki' as a
statement of ethical principles for medical research involving human subjects, including
research on identifiable human material and data. The Declaration is intended to be read as a
whole and each of its constituent paragraphs should not be applied without consideration of all
other relevant paragraphs. Although the declaration is addressed primarily to physicians, the
WMA encourages other participants in medical research involving human subjects to adopt
these principles. It is the duty of the physician to promote and safeguard the health of patients,
including those who are involved in medical research. The physician's knowledge and
conscience are dedicated to the fulfillment of this duty. The 'Declaration of Geneva' of the
WMA binds the physician with the words, "The health of my patient will be my first
consideration," and the International Code of Medical Ethics declares that, "A physician shall
act in the patient's best interest when providing medical care." Medical progress is based on
research that ultimately must include studies involving human subjects. Populations that are
under represented in medical research should be provided appropriate access to participation
in research. In medical research involving human subjects, the well-being of the individual
research subject must take precedence over all other interests. The primary purpose of medical
research involving human subjects is to understand the causes, development and effects of
diseases and improve preventive, diagnostic and therapeutic interventions (methods,
procedures and treatments). Even the best current interventions must be evaluated continually
through research for their safety, effectiveness, efficiency, accessibility and quality. In medical
practice and in medical research, most interventions involve risks and burdens. Medical
research is subject to ethical standards that promote respect for all human subjects and protect
their health and rights.
Some research populations are particularly vulnerable and need special protection. These
include those who cannot give or refuse consent for themselves and those who may be
vulnerable to coercion or undue influence. Physicians should consider the ethical, legal and
regulatory norms and standards for research involving human subjects in their own countries as
well as applicable international norms and standards. No national or international ethical, legal
or regulatory requirement should reduce or eliminate any of the protections for research
subjects set forth in this declaration.

• Basic principles for all medical research

a. It is the duty of physicians who participate in medical research to protect
the life, health, dignity, integrity, right to self-determination, privacy, and
confidentiality of personal information of research subjects.
b. Medical research involving human subjects must conform to generally
accepted scientific principles, be based on a thorough knowledge of the
scientific literature, other relevant sources of information, and adequate
laboratory and, as appropriate, animal experimentation. The welfare of
animals used for research must be respected.
c. Appropriate caution must be exercised in the conduct of medical
research that may harm the environment.
d. The design and performance of each research study involving human
subjects must be clearly described in a research protocol. The protocol
should contain a statement of the ethical considerations involved and
should indicate how the principles in this declaration have been addressed.
The protocol should include information regarding funding, sponsors,
institutional affiliations, other potential conflicts of interest, incentives for
subjects and provisions for treating and/or compensating subjects who are
harmed as a consequence of participation in the research study. The
protocol should describe arrangements for post-study access by study
subjects to interventions identified as beneficial in the study or access to
other appropriate care or benefits.

e. The research protocol must be submitted for consideration, comment,

guidance and approval to a research ethics committee before the study
begins. This committee must be independent of the researcher, the
sponsor and any other undue influence. It must take into consideration
 the laws and regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standards but these must not be allowed to reduce or eliminate any of the
protections for research subjects set forth in this declaration. The
committee must have the right to monitor ongoing studies. The
researcher must provide monitoring information to the committee,
especially information about any serious adverse events. No change to the protocol may be
made without consideration and approval by the committee.
f. Medical research involving human subjects must be conducted only by
individuals with the appropriate scientific training and qualifications.
Research on patients or healthy volunteers requires the supervision of a
competent and appropriately qualified physician or other health care
professional. The responsibility for the protection of research subjects
must always rest with the physician or other health care professional and
never the research subjects, even though they have given consent.
g. Medical research involving a disadvantaged or vulnerable population or
community is only justified if the research is responsive to the health
needs and priorities of this population or community and if there is a
reasonable likelihood that this population or community stands to benefit
from the results of the research.
h. Every medical research study involving human subjects must be
preceded by careful assessment of predictable risks and burdens to the
individuals and communities involved in the research in comparison with
foreseeable benefits to them and to other individuals or communities
affected by the condition under investigation.
i. Every clinical trial must be registered in a publicly accessible database
before recruitment of the first subject.
j. Physicians may not participate in a research study involving human subjects unless they are
confident that the risks involved have been adequately assessed and can be satisfactorily
 managed. Physicians must immediately stop a study when the risks are found to outweigh
the potential benefits or when there is conclusive proof of positive and beneficial results.
k. Medical research involving human subjects may only be conducted if the importance of the
objective outweighs the inherent risks and burdens to the research subjects.
l. Participation by competent individuals as subjects in medical research must be voluntary.
Although it may be appropriate to consult family members or community leaders, no
competent individual may be enrolled in a research study unless he or she freely agrees.
m. Every precaution must be taken to protect the privacy of research subjects and the
confidentiality of their personal information and to minimize the impact of the study on
their physical, mental and social integrity.
n. In medical research involving competent human subjects, each potential subject must be
adequately informed of the aims, methods, sources of funding, any possible conflicts of
interest, institutional affiliations of the researcher, the anticipated benefits and potential
risks of the study and the discomfort it may entail, and any other relevant aspects of the
study.

The potential subject must be informed of the right to refuse to participate in the study or to
withdraw consent to participate at any time without reprisal. Special attention should be given
to the specific information needs of individual potential subjects as well as to the methods used
to deliver the information. After ensuring that the potential subject has understood the
information, the physician or another appropriately qualified individual must then seek the
potential subject's freely-given informed consent, preferably in writing. If the consent cannot
be expressed in writing, the non-written consent must be formally documented and witnessed.
For medical research using identifiable human material or data, physicians must normally seek
consent for the collection, analysis, storage and/or reuse. There may be situations where
consent would be impossible or impractical to obtain for such research or would pose a threat
to the validity of the research. In such situations the research may be done only after
consideration and approval of a research ethics committee.
When seeking informed consent for participation in a research study the physician should be
particularly cautious if the potential subject is in a dependent relationship with the physician or
may consent under duress. In such situations the informed consent should be sought by an
appropriately qualified individual who is completely independent of this relationship.
For a potential research subject who is incompetent, the physician must seek informed consent
from the legally authorized representative. These individuals must not be included in a research
study that has no likelihood of benefit for them unless it is intended to promote the health of
the population represented by the potential subject, the research cannot instead be performed
with competent persons, and the research entails only minimal risk and minimal burden.
When a potential research subject who is deemed incompetent is able to give assent to
decisions about participation in research, the physician must seek that assent in addition to the
consent of the legally authorized representative. The potential subject's dissent should be
respected.

Research involving subjects who are physically or mentally incapable of giving consent, for
example, unconscious patients, may be done only if the physical or mental condition that
prevents giving informed consent is a necessary characteristic of the research population. In
such circumstances the physician should seek informed consent from the legally authorized
representative. If no such representative is available and if the research cannot be delayed, the
study may proceed without informed consent provided that the specific reasons for involving
subjects with a condition that renders them unable to give informed consent have been stated
in the research protocol and the study hasbeen approved by a research ethics committee.
Consent to remain in the research should be obtained as soon as possible from the subject or a
legally authorized representative, t. Authors, editors and publishers all have ethical obligations
with regard to the publication of the results of research. Authors have a duty to make publicly
available the results of their research on human subjects and are accountable for the
completeness and accuracy of their reports. They should adhere to accepted guidelines for
ethical reporting. Negative and inconclusive as well as positive results should be published or
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of
interest should be declared in the publication. Reports of research not in accordance with the
principles of this declaration should not be accepted for publication.

Additional principles for medical research combined with medical care

• The physician may combine medical research with medical care only to the extent that the
research is justified by its potential preventive, diagnostic or therapeutic value and if the
physician has good reason to believe that participation in the research study will not
adversely affect the health of the patients who serve as research subjects.
• The benefits, risks, burdens and effectiveness of a new intervention must be tested against
those of the best current proven intervention, except in the following circumstances:
a. The use of placebo, or no treatment, is acceptable in studies where no
current proven intervention exists; or
b. Where for compelling and scientifically sound methodological reasons
the use of placebo is necessary to determine the efficacy or safety of
an intervention and the patients who receive placebo or no treatment
will not be subject to any risk of serious or irreversible harm. Extreme
care must be taken to avoid abuse of this option.
• At the conclusion of the study, patients entered into the study are entitled to be informed
about the outcome of the study and to share any benefits that result from it, for example,
access to interventions identified as beneficial in the study or to other appropriate care or
benefits.
• The physician must fully inform the patient which aspects of the care are related to the
research. The refusal of a patient to participate in a study or the patient's decision to
withdraw from the study must never interfere with the patient-physician relationship.

In the treatment of a patient, where proven interventions do not exist or have been
ineffective, the physician, after seeking expert advice, with informed consent from the
patient or a legally authorized representative, may use an unproven intervention if in the
physician's judgment it offers hope of saving life, re-establishing health or alleviating
suffering when possible, this intervention should be made the object of research, designed
to evaluate its safety and efficacy. In all cases, new information should be recorded and,
where appropriate, made publicly available.
e. Institutional Ethics Committee
All clinical trials shall be reviewed and approved by the 'Institutional Ethics Committee (IEC)'
before commencement, globally. 'Indian Council of Medical Research' developed ethics
guidelines in 2006. The ICMR guideline recommends the composition of IEC that consists of
medical, non-medical, social and legal members. In addition to the chairman, there should one
or two members each from basic medical science disciplines and clinicians. Additionally, there
should be one member who is a legal expert, one social scientist or a representative from non-
governmental organization, a philosopher or ethicist, a lay person representing the community
and a member secretary. Schedule Y recommends that preferably a pharmacologist should be a
member in place of one or two basic scientists. Efforts should be made to maintain gender
balance in the IEC. According to the recent amendments made through GSR 52 (E) in 122 D, the
IEC must be registered with DCGl. The DCGI is empowered to reject the application of IEC after
giving reasons.

Following information needs to be provided to DCGI with a request to regis the IEC:

Name of the Ethics Committee

Authority under which the IEC is being constituted, membersh requirements, the terms of
reference, conditions of appointment ar quorum required
The procedure for resignation, replacement and removal of members Address of the office of
IEC
Name, address, qualification, organizational title, phone and fax numben email and address of
the Chairman along with his/her CV

Name, address, qualification, organizational title, phone and fax numbers email and address of
the members along with their special grou| representation (e.g. patient, social science, law etc)

The details of the support staff of IEC

If the IEC was existent before the amendments (before February 8 2013), they will additionally
be required to submit;

a. Type of clinical research that they have reviewed in the past.

b. Documents reviewed prior in clinical trials including informed consent.

 c. Information regarding the minutes of the past meetings and their
documentation.

d. Information regarding review of serious adverse events in the past.

The Standard Operating Procedures (SOPs) that are followed by the IEC

 Policy regarding training of the new and existent members of IEC along with SOPs.

 Policy to monitor conflict of interest along with SOPs for it.

 Documents regarding inspections or audits, if they have been done in the past.

The registration with DCGI is valid for three years unless it has been suspended for penal
reasons in the interim. The renewal for registration should be submitted 90 days in
advance of date of its expiry. The IEC registration shall be considered as extended until they
receive communication from DCGI if it has been submitted 90 days in advance. Any change
in membership of IEC should be intimated to the DCGI. The IEC registration can be
cancelled by DCGI by issuing a notice to IEC. The IEC can appeal to the central government
within 90 days of receipt of the cancellation and the central government can provide an
opportunity to defend in order to reverse, confirm or modify cancellation of registration of
IEC. The notification to the IEC shall be drawn up in conformity with the lEC's mandate. No
trials may commence before receiving an approval from the a IEC.

DCGI is developing long-term strategies to strengthen quality implementation of clinical

trials in India. Quality Council of India will be mandated to create systems for accreditation
of investigators, ethics committees and clinical trial sites in India.

The IEC shall consider the following:

a. The relevance and design of the clinical trial.

b. That the presumed risks and inconveniences are weighed up against the
benefits to the individual subject and to other present and future patients of
that disease.
c. Protocol.
d. Investigator's qualifications.
e. Investigator's brochure.
f. The suitability of the trial site.
g. The relevance and completeness of the informed consent form and the
information process in connection with the obtaining of informed consent.

h. Justification for research on persons who are unable to give informed

consent.

i. Provisions concerning indemnity or compensation in the event of the injury

or death of a subject as a result of a clinical trial.

j. Insurance or compensation to cover the liability of the investigator and the sponsor.

k. The amount of, and the detailed rules for payment of any fee or compensation to
investigators and subjects.

I. Relevant clauses in any intended agreement between the sponsor and trial site.

m. Arrangements for the recruitment of subjects.

The IEC is expected to maintain all the documents with dates. It is expected to ensure that
confidentiality is maintained while accessing or retrieving records. The IEC is expected to
maintain following records of work in accordance with the GSR 53(E);

a. The constitution and composition of IEC

b. The bio-data of all the members

c. ALL SOPs

d. Copies of all National and International guidelines

e. Copies of the protocol, data collection formats, 'Case Reporting Forms'

(CRFs), investigator's brochure and any other document/s submitted for
review to IEC

f. Copy of communication of members and investigators regarding

application, decision and follow up
g. Agenda of all IEC meetings
h. Minutes of IEC meetings with chairman's signature
i. Copy of communication of decisions made by IEC
j. Records of all notifications issued where premature termination of trial has been ordered
along with summary of reasons
k. Final reports of the trial in any formats - documents, CDs, microfilms or video

The hard as well as soft copies of all study (trial) related documents need to be maintained for
five years after completion or termination of trial.

Every year the principal investigator of a trial /study is expected to inform the IEC about the
progress in implementation and also obtain approval for the informed consent template. Any
modification of the protocol, emergence of any new finding relevant to the protocol that can
potentially impact study participants must be presented in IEC meetings. IEC will review the
findings and decide whether it needs to be notified to the study participants and decide
whether reconsenting is required in view of emergence of new findings.

IEC will also receive all the adverse events occurring in a clinical trial. According to the recent
changes in the GSR 53 (E), the DCGI has made it mandatory that the sponsor shall report any
serious adverse event including hospitalization or death to the chairman, IEC expert committee
(constituted i n DCGI) and should notify DCGI within 24 hours of occurrence or knowledge. An
addendum has been issued recently that a reasonable explanation should be given in cases
where it is filed after 24 hours and should be acceptable to the DCGI. However, report of any
adverse event other than death needs to be submitted to the IEC within 10 days of its
occurrence after due analysis. The IEC is expected to submit its report that includes issues such
as relatedness and compensation to the DCGI within 21 days of its occurrence. The serious
adverse event reports submitted to the expert committee must be sent in different coloured
envelopes depending on the nature of adverse events. In case of death, the envelope should be
red colored and for all other adverse events in white colored cover.

The IEC should permit inspections (as and when they occur) from authorized persons from
Central Drugs Standard Control Organization that may also include those officers from state
level.
f. Approaches to Pharmacovigilance
Maximum attention needs to be paid to assess the ADRs immediately following the launch of a
new product. The Committee on Safety of Medicines (CSM) of U.K., the successor to the Dunlop
committee has set up a yellow card scheme which is a reporting system under which, all
suspected adverse reactions, post-treatment with a drug is reported. Currently on an average,
over 25000 reports are registered per year in U.K. These reports, could have many false
positives, nevertheless, they still provide early warnings of drug hazards. Such warnings make it
possible to further carry out prospective and systematic studies to validate the claims of drug -
related adverse reactions. In the past, these reports have led to the identification of a large
number of drug- related side effects, such as thromboembolism with oral contraceptives,
hypotension with ACE inhibitors, fatal blood dyscrasias with co-trimoxazole and mianserin,
acute dystonias with metoclorpropamide, hepatitis with zimelidine the first selective serotonin
uptake inhibitor, asthma with beta agonists, endometrial cancer with hormone replacement
therapy, gastro-intestinal haemorrhage with NSAIDS, agranulocytosis with clozapine, the anti-
psychotic drug etc.

The National Pharmacovigilance Programme for India, sponsored by the World Health
Organization (WHO) and funded by the World Bank, became operational from January 1,2005.
This programme was launched on 23rd Nov 2004 in Delhi. It will be overseen by the National
Pharmacovigilance Advisory Committee (NPAC) based at the Central Drugs Standard Control
Organization (CDSCO), New Delhi. The Central ministry has announced formation of a NPAC
under the chairmanship of Director General of Health Services in October 2004.
The Drug Controller General of India function as the member secretary of the committee. NPAC
has been given the sole responsibility of putting in place machinery for monitoring of the
pharmacovigilance programme throughout the country.

• When to start reporting:

As per the timeline designated in the protocol (1st dose of the study drug)
• When to stop reporting SAE's:
 SAE that occur after the patient has discontinued from the study, but prior to the 30-day
post study follow up must be reported & the matter will be handled by sponsor.
• Investigator reporting timeline:
It is the responsibility of the investigational site to report a SAE to the sponsor within 24
hrs of becoming aware. This timeline is applicable to both initial and follow up reports.

ADRs/ADEs Reporting Format

Study information, investigator & patient information

• Patient details: Date of birth, gender, medical history
• Study drug: Dose, start date, end date, duration, indication, Concomitant medications &
associated disease

SAE information

• Event description, onset date, end date, dechallenge, rechallenge & patient outcome
Investigator opinion of relatedness to the study drug and protocol procedures
• Concomitant drugs should be listed

Event page: Investigator's opinion of relatedness

• The investigator is to provide an opinion of relatedness, with rationale, for all events to
study drug and protocol procedures though in the opinion of the investigator, the event
was not related to the study drugs or protocol procedures, but a result of disease
progression.
• Investigators are informed of every possible related, unexpected case.
• Receiving a MedWatch form detailing the case.
• Upon receipt of a safety report, the investigator participating in a sponsored LG study is
required to notify their EC & /or drug regulators.