Contents

INTRODUCTION .......................................................................................................... 5
DEFINITIONS .............................................................................................................. 6
PREREQUISITES FOR THE STUDY ........................................................................ 21
2.1 Investigational Pharmaceutical Product .......................................................................... 21
2.2 Pre-clinical supporting data .............................................................................................. 21
2.3 Protocol ............................................................................................................................... 21
2.3.1 Relevant components of Protocol ............................................................................................... 21
2.3.2 Supplementaries and appendices ................................................................................................. 25
2.3.1 Academic clinical study/research ................................................................................................ 25
2.4 Ethical & Safety Considerations ....................................................................................... 26
2.4.1 Ethical Principles ........................................................................................................................ 26
2.4.2 Ethics Committee ........................................................................................................................ 34
2.4.3 Informed Consent Process ........................................................................................................... 38
P2.4.5 Reimbursement/payment for Participation ................................................................................ 41
2.4.6 Clinical trials with marginalized community .............................................................................. 43
2.4.7 Compensation in case of injury or death in clinical study/research or bioavailability or
bioequivalence study of new drug or investigational new drug. .......................................................... 43
RESPONSIBILITIES .................................................................................................. 48
3.1 Sponsor: .............................................................................................................................. 48
3.1.1 Investigator and clinical study site Selection: ............................................................................. 48
3.1.2 Agreement/ Contract: .................................................................................................................. 48
3.1.3 Sponsor Oversight ....................................................................................................................... 49
3.1.4. Allocation of activities ............................................................................................................... 50
3.1.5 Study management, data handling and record keeping ............................................................... 50
3.1.6 Reimbursement/payment for Participation .................................................................................. 51
3.1.7 Confirmation of review by the Ethics Committee ....................................................................... 51
3.1.8 Information on Investigational Products ..................................................................................... 52
3.1.9 Supply, storage and handling of Pharmaceutical Products ......................................................... 52
3.1.10 Safety assessment and reporting: .............................................................................................. 53
3.1.11 Study Reports ............................................................................................................................ 54
3.1.12 Audit ......................................................................................................................................... 54
3.1.13 Premature Termination or Suspension of a Study ..................................................................... 54
3.1.14 Transfer of activities to Service Provider(s) ............................................................................. 54
3.2 The Monitoring .................................................................................................................. 55
3.2.1 Qualifications .............................................................................................................................. 55
3.2.2 Responsibility ............................................................................................................................. 55
3.2.3 Investigator Site Monitoring........................................................................................................ 58
3.2.4Centralised Monitoring................................................................................................................. 58
3.3 Investigator......................................................................................................................... 58
3.3.1 Qualifications, resource, and responsibility ................................................................................ 58
3.3.2 Medical care of the study participants ......................................................................................... 59
3.3.3 Monitoring and Auditing of Records........................................................................................... 60
3.3.4 Communication with Ethics Committee...................................................................................... 60
3.3.5 Compliance with the protocol ..................................................................................................... 60
3.3.6 Investigational Product(s) management ...................................................................................... 61
3.3.7 Selection and recruitment of study participants ........................................................................... 61
3.3.8 Randomisation Procedures and Unblinding ................................................................................ 62
3.3.9 Records/Reports .......................................................................................................................... 62
RECORD KEEPING AND DATA HANDLING .......................................................... 65
4.1. Documentation .................................................................................................................. 65

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 4.2 Corrections ......................................................................................................................... 65
4. 3 Electronic Data Processing ............................................................................................... 65
4.4 Validation of Electronic Data Processing Systems .......................................................... 65
4.4.1 Computerised Systems ................................................................................................................ 65
4.4.2 Validation of Computerised Systems .......................................................................................... 66
4.4.3 System Failure ............................................................................................................................ 67
4.4.4 Technical Support ....................................................................................................................... 67
4.4.5. User Management ...................................................................................................................... 67
4.5 Language ............................................................................................................................ 67
QUALITY ASSURANCE ............................................................................................. 69
Quality Assurance and Quality Control ................................................................................ 69
STATISTICS ............................................................................................................... 72
6.1 Role of a Biostatistician ..................................................................................................... 72
6.2 Study Design ....................................................................................................................... 72
6.2.1 Randomisation and blinding: ...................................................................................................... 72
6.3 Statistical Analysis ............................................................................................................. 73
SPECIAL CONCERNS................................................................................................ 74
7.1 Clinical Study/research of Vaccines ................................................................................. 74
7.1.1 Phases of Vaccine Study/research ............................................................................................... 74
7.1.2 Guidelines ................................................................................................................................... 74
7.2 Clinical Study/research of Contraceptives ....................................................................... 75
7.3 Clinical study/research with surgical procedures/ medical devices ............................... 75
7.4 Clinical study/research for Diagnostic Agents .......................................................... 76
7.4.1 Guidelines ................................................................................................................................... 77
7.5 Clinical study/research of Herbal Remedies and Medicinal Plants............................... 77
7.5.1 Categories of Herbal Products ..................................................................................................... 78
7.5.2 Guidelines ................................................................................................................................... 78
7.6 Clinical study/research of Stem Cell ................................................................................ 79
DISCLOSURE OF SITE SPECIFIC SAFETY/EFFICACY DATA .......................... 85
8.1 Disclosure of site specific safety/efficacy data: ................................................................ 85
APPENDICES ............................................................................................................. 86
Appendix I ................................................................................................................................ 86
World Medical Association - Declaration of Helsinki ......................................................................... 86
Appendix II ............................................................................................................................... 91
New Drugs and Clinical Trials Rules, 2019......................................................................................... 91
Appendix III. Animal toxicology (Non-clinical toxicity studies).......................................... 95
Appendix IV - Conduct of Clinical Study/Research ............................................................ 112
Appendix V Information To Be Submitted By An Applicant And Format ...................... 117
TABLE 1: INFORMATION TO BE SUBMITTED BY AN APPLICANT FOR GRANT OF
REGISTRATION OF ETHICS COMMITTEE AND FORMAT FOR ACCORDING TO
APPROVAL ...................................................................................................................................... 117
TABLE 2: CONTENTS OF THE PROPOSED PROTOCOL FOR CONDUCTING CLINICAL
STUDY/RESEARCH ........................................................................................................................ 118
TABLE 3 UNDERTAKING BY THE INVESTIGATOR ................................................................ 124
TABLE 4: DATA ELEMENTS FOR REPORTING SERIOUS ADVERSE EVENTS OCCURRING
IN A CLINICAL STUDY/RESEARCH OR BIOAVAILABILITY OR BIOEQUIVALENCE
STUDY .............................................................................................................................................. 126
TABLE 5: STRUCTURE, CONTENT AND FORMAT FOR CLINICAL STUDY/RESEARCH

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 REPORT ............................................................................................................................................ 127
TABLE 6 INVESTIGATOR'S BROCHURE .................................................................................... 129
TABLE 7 PRESCRIBING INFORMATION .................................................................................... 132
APPENDIX VI: Format For Submission Of Preclinical And Clinical Data ..................... 134
APPENDIX V: Essential documents for the conduct of a clinical study/research ............. 137

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 Good Clinical Practice Guidelines

INTRODUCTION
The history of Good Clinical Practice (GCP) statute traces back to one of the oldest
enduring traditions in the history of medicine: The Hippocratic Oath. As the guiding
ethical code, it is primarily known for its edict to do no harm to the patient. However, the
complexities of modern medicine research necessitate a more elaborate set of guidelines
that address an investigator’s ethical and scientific responsibilities such as obtaining
informed consent or disclosing risk while involved in biomedical/clinical research.

Good Clinical Practice is a set of guidelines for biomedical studies which encompasses the
design, conduct, termination, audit, analysis, reporting and documentation of the studies
involving human participants. The fundamental tenet of GCP is that in research on human
subject/participant, the interest of science and society should never take precedence over
considerations related to the well-being of the study participant. It aims to ensure that the
studies are scientifically and ethically sound and that the clinical properties of the
pharmaceutical substances under investigation are properly documented. The guidelines
seek to establish two cardinal principles: protection of the rights, safety and well-being of
participants/subjects and authenticity of biomedical/clinical data generated.

The principles of GCP are designed to be flexible and applicable to a broad range of
clinical research. This guideline, along with other global guidelines encourages thoughtful
consideration and planning to address specific and potentially unique aspects of an
individual clinical study/research. This includes evaluation of study/research
characteristics, such as the design elements, the investigational product being evaluated,
the medical condition being addressed, the characteristics of the participants, the setting in
which the clinical study/research is being conducted, and the type of data being collected.
Careful consideration of various aspects relevant to ensuring study/research quality is
needed for each clinical study/research.

The principles are intended to support efficient approaches to study/research design and
conduct. For example, innovative digital health technologies, such as wearables and
sensors, may expand the possible approaches to study/research conduct. Such technologies
can be incorporated into existing healthcare infrastructures and enable the use of a variety
of relevant data sources in clinical study/research. This will aid in keeping clinical
study/research conduct in line with advancing science and technological developments.
The use of technology in the conduct of clinical study/research should be adapted to fit the
participant/subject characteristics and the particular study/research design.
The use of innovative clinical study/research designs and technologies may help include
diverse patient populations, as appropriate, and enable wider participation. The design of
the study/research, to ensure appropriate quality and meaningful study/research outcomes,
may be supported by the perspectives of all stakeholders; (for example, patients,
participant/subjects, healthcare providers, regulators and others). Their input can increase
the likelihood of meaningful study/research outcomes, which are relevant to both
study/research participants and future patients. This input will also guide decisions on the
feasibility of data collection and assure that participation in the study/research does not
become unduly burdensome for those involved.

These guidelines have been evolved in consideration of various national and global

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guidelines and in line with NDCT Rules 2019, WHO, ICH, USFDA and European GCP
guidelines as well as the Ethical Guidelines for Biomedical research on Human
Participants issued by the Indian Council of Medical Research. They should be followed
for carrying out all biomedical research in India at all stages of drug development,
whether prior or subsequent to product registration in India.

DEFINITIONS

Academic Clinical Study/research:

Clinical study/research of a drug already approved for a certain claim and initiated by any
investigator, academic or research institution for a new indication or new route of
administration or new dose or new dosage form, where the results of such a study/research
are intended to be used only for academic or research purposes and not for seeking approval
of the Central Licensing Authority or regulatory authority of any country for marketing or
commercial purpose;

Act

Wherever relevant, the Act means Drugs & Cosmetics Act 1940 (23 of 1940) and the Rules
made thereunder.

Adaptive Clinical Study/research:

An adaptive design is defined as a clinical study/research design that allows for
prospectively planned modifications to one or more aspects of the design based on real time
data generated from participants in the study/research.

Adverse Event (AE)

Any untoward medical occurrence (including a symptom / disease or an abnormal
laboratory finding) during treatment with a investigational product in a patient or a human
volunteer that does not necessarily have a relationship with the treatment being given. Also
see Serious Adverse Event

Adverse Drug Reaction (ADR)

(a) In case of approved pharmaceutical products/medical device: A noxious and
unintended response at doses normally used or tested in humans.
(b) In case of new unregistered investigational/ pharmaceutical products/medical devices
(or those products which are not yet approved for the medical condition where they are
being tested): A noxious and unintended response at any dose(s)
The phrase ADR differs from AE, in case of an ADR there appears to be a reasonable
possibility that the adverse event is related with the medicinal product being studied.

In clinical study/research, an untoward medical occurrence seemingly caused by

overdosing, abuse / dependence and interactions with other medicinal products is also
considered as an ADR.

Assent
To agree or approve after thoughtful consideration an idea or suggestion to participate in
research by a young person below the age of 18 years who is old enough to understand the
implications of any proposed research but not legally eligible to give consent. The assent

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has to be corroborated with informed consent of parent/ LAR.

Audit
A systematic and independent examination of study/research-related activities and records
performed by the sponsor, service provider (including clinical/contract research organization
(CRO)) or institution to determine whether the evaluated study/research-related activities
were conducted and the data were recorded, analyzed and accurately reported according to
the protocol, applicable standard standard operating procedures (SOPs), Good Clinical
Practice (GCP) guidelines and the applicable regulatory requirement(s).

Audit Certificate
A declaration of confirmation by the auditor that an audit has taken place.

Audit Report
A record describing the conduct and outcome of the audit.

Audit Trail
Metadata records that allow reconstruction of the course of events by capturing details on
actions (manual or automated) performed relating to information and data collection and,
where applicable, to activities in computerized systems. The audit trail should show
activities, initial entry, and changes to data fields or records, by whom, when and, where
applicable, why. In computerized systems, the audit trail should be secure, computer
generated and timestamped.

Bioavailability study:
bioavailability study” means a study to assess the rate and extent to which the drug is
absorbed from a pharmaceutical formulation and becomes available in the systemic
circulation or availability of the drug at the site of action.

Bioequivalence study:
Bioequivalence study” means a study to establish the absence of a statistically significant
difference in the rate and extent of absorption of an active ingredient from a pharmaceutical
formulation in comparison to the reference formulation having the same active ingredient
when administered in the same molar dose under similar conditions.

Bioequivalence/Bioavailability study centre:

“Bioavailability and Bioequivalence study centre” means a centre created or established to
undertake bioavailability study or bioequivalence study of a drug for either clinical part or
for both clinical and analytical part of such study.

Blinding / Masking
A method of “control experimentation” in which one or multiple stakeholders involved are
not informed of the treatment being given.

Case Record Form (CRF)

A document designed in consonance with the Protocol, to record data and other
information on each study/research participant. The Case Record Form should be in such
a form and format that allows accurate input, presentation, verification, audit, and
inspection of the recorded data. A CRF may be in printed or electronic format.

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Certified Copy
A copy (irrespective of the type of media used) of the original record that has been
verified (i.e., by a dated signature or by generation through a validated process) to have
the same information as the original, including relevant metadata, where applicable.

Clinical Study/clinical research

Research that directly involves a particular person or group of people to study the effect of
interventions, or uses materials/data from humans indirectly, such as their behavior or
biological samples for prevention, treatment and diagnosis of a disease condition/health
disorder.

Clinical Study/research
clinical study/research” in relation to a new drug or investigational new drug means any
systematic study of such new drug or investigational new drug in human participants to
generate data for discovering or verifying its, - (i) clinical or (ii) pharmacological including
pharmacodynamics, pharmacokinetics or; (iii) adverse effects, with the objective of
determining the safety, efficacy or tolerance of such new drug or investigational new drug;

Micro-dose:
The concept of micro-dosing involves the use of extremely low, non-pharmacologically
active doses of a drug to define the pharmacokinetic profile of the medication in human
participants.

Phase Zero
First-in-human testing of new investigational agents at subtherapeutic doses based on
reduced manufacturing and toxicologic requirements, allowing the demonstration of drug-
target effects and assessment of pharmacokinetic–pharmacodynamic relationships in
humans earlier in clinical development.

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 humans. Studies in this phase of
development usually have non-therapeutic objectives and may be conducted in healthy
participants or certain types of patients. Drugs with significant potential toxicity e.g.
cytotoxic drugs are usually studied in patients. Phase I study/research should preferably be
carried out by investigators trained in clinical pharmacology with access to the necessary
facilities to closely observe and monitor the participants. 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 or
pharmacodynamic studies) may be conducted in healthy volunteer participants or in
patients with the target disease. If there are appropriate validated indicators of activity and

8
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.

Phase II
(i) The primary objective of Phase II study/research 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 and regimen for Phase
III study/research. Doses used in Phase II are usually (but not always) less than the highest
doses used in Phase I. (ii) 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 study/research.

Phase III
(i) Phase III studies have primary objective of demonstration or confirmation of therapeutic
benefits. 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 drugs. (ii) For drugs intended to be administered for long
periods, study/research 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.

Phase IV
Phase IV or post marketing study/research of new drugs are performed after the approval of
the drug and related to the approved indication. Such study/research go beyond the prior
demonstration of the drug’s safety, efficacy and dose definition. Such study/research might
not have been considered essential at the time of new drug approval due to various reasons
such as limitation in terms of patient exposure, duration of treatment during clinical
development of the drug, need for early introduction of the new drug in the interest of
patients etc. Phase IV study/research include additional drug-drug interaction, dose response
or safety studies and study/research design to support use under the approved indication e.g.
mortality or morbidity studies, epidemiological studies, etc.

Clinical study/research inspection:

Inspection of site of clinical study/research, sponsor/ CRO/ ethics committees involved in
clinical study/research to verify the compliance with various regulatory provisions as per
New Drugs and Clinical Trials Rules, 2019, GCP compliance to protect the rights, safety
and wellbeing of the participants involved in clinical study/research and to verify the

9
credibility and integrity of clinical study/research data generated.

Clinical study/research protocol

Clinical study/research Protocol is a document containing the background, objective,
rationale, design, methodology including matters concerning performance, management,
conduct, analysis, adverse event, withdrawal, statistical consideration, and record keeping
pertaining to clinical study/research.

Clinical trial registry

An official platform for registering clinical trial/study/research, such as Clinical trial
Registry-India (CTRI).

Clinical Investigation
Clinical investigation means the systematic study of an investigational medical device in or
on human participants to assess its safety, performance, or effectiveness.

Clinical Investigation Plan

Clinical investigation plan means a document which contains the information about the
rationale, aims and objective, design and the proposed analysis, conduct, methodology
including performance, management, adverse event, withdrawal and statistical consideration
and record keeping pertaining to clinical investigation.

Clinical performance evaluation

Clinical performance evaluation means the systematic performance study of a new in vitro
diagnostic medical device on a specimen collected from human participants to assess its
performance.

Controlled Human Infection studies (CHIS):

Controlled Human Infection studies (CHIS) refers to the research methodology that involves
intentionally exposing healthy human volunteers to a specific pathogen or infectious agent
under controlled conditions. These studies aim to understand disease pathophysiology &
immune responses, develop vaccines, test treatment modalities, and evaluate the safety and
efficiency of potential New Chemical Entities (NCE)

Comparator Product:
A pharmaceutical product (including placebo) used as a reference in clinical study/research.

Compensation:
Provision of financial payment to the research participants or their legal heirs when
temporary or permanent injury or death occurs due to participation in biomedical and health
research.

Confidentiality:
Maintenance of privacy of study participants including their personal identity and all
medical information, from individuals other than those prescribed in the Protocol.
Confidentiality also covers the prevention of disclosure of sponsor’s proprietary
information to unauthorised persons.

Confidentiality agreement:

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Secrecy or non-disclosure agreements designed to protect trade secrets, information, and
expertise from being misused by those who have learned about them.

Clinical Research Organization/Contract Research Organization (CRO)

Clinical/Contract Research organization means a body commercial or academic or of other
category owned by an individual or an organization having status of legal entity by
whatsoever name called to which the sponsor may delegate or transfer some or all of tasks,
duties and/or obligations regarding clinical study/research or bioavailability or
bioequivalence study, such transfer or delegation of contractual transfers or obligations must
be in writing.

Contract
A written, dated, and signed document describing the agreement between two or more
parties involved in a biomedical study, namely Investigator, Sponsor, Institution.
Typically, a contract sets out delegation / distribution of responsibilities, financial
arrangements, and other pertinent terms. The “Protocol” may form the basis of
“Contract”.

Computerized Systems Validation

A process of establishing and documenting that the specified requirements of a
computerized system can be consistently fulfilled from design until decommissioning of
the system or transition to a new system. The approach to validation should be based on a
risk assessment that takes into consideration the intended use of the system and the
potential of the system to affect study/research participant’s protection and the reliability
of study/research results.

Co-Investigator
A person legally qualified to be an investigator, to whom the Investigator delegates a part of
his responsibilities.

See Principal Investigator

Data Acquisition Tool (DAT)

A paper or electronic tool designed to collect data and associated metadata from a data
originator in clinical study/research according to the protocol and to report the data to the
sponsor. The data originator may be a human (e.g., the participant/subject or study/research
staff), a machine (e.g., wearables and sensors) or an electronic transfer of data from one
system to another (e.g., extraction of data from an electronic health record or laboratory
system). Examples of DATs include but are not limited to CRFs, interactive response
technologies (IRTs), patient-reported outcomes (PROs), clinical outcome assessments
(COAs) and wearable devices, irrespective of the media used.

Decentralized clinical study/research

Decentralized clinical study/research (DCT) are study/research where some or all of a
clinical study/research’s activities occur at locations other than a traditional clinical
study/research site. These alternate locations can include the participant’s home, a local
health care facility, or a nearby laboratory.

Direct Access
Permission to examine, analyse and verify records that are important to the evaluation of a
clinical study/research and may be performed in person or remotely. Any party (e.g.,

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domestic, and foreign regulatory authorities, sponsor’s monitors and auditors) with direct
access should take reasonable precautions within the constraints of the applicable regulatory
requirement(s) to maintain the confidentiality of participants’ identities and their data and
sponsor’s proprietary information.

Data Monitoring Committees (DMCs)/ Data and Safety Monitoring Boards (DSMBs)/
Data and Safety Monitoring Committees (DSMCs)
A clinical study/research DMC is a group of individuals with pertinent expertise that
reviews on a regular basis accumulating data from one or more ongoing clinical
study/research. The DMC advises the sponsor regarding the continuing safety of
study/research participants and those yet to be recruited to the study/research, as well as the
continuing validity and scientific merit of the study/research. When a single DMC is
responsible for monitoring multiple study/research, the considerations for establishment and
operation of the DMC are generally similar to those for a DMC monitoring a single
study/research, but the logistics may be more complex. For example, in case of multiple
conflict of interest determinations may be needed for each DMC member.

Independent Data Monitoring Committee (IDMC)

An independent data monitoring committee (e.g., data safety monitoring board) that may be
established by the sponsor to assess at intervals the progress of a clinical study/research, the
safety data and the critical efficacy endpoints, and to recommend to the sponsor whether to
continue, modify or stop study/research.

Development Safety Update Report (DSUR)

DSUR prepared by the sponsor presents a comprehensive, thoughtful annual review and
evaluation of pertinent safety information collected during the reporting period related to a
drug under investigation, whether or not it is marketed, by: (1) examining whether the
information obtained by the sponsor during the reporting period is in accordance with
previous knowledge of the investigational drug’s safety; (2) describing new safety issues
that could have an impact on the protection of clinical study/research participants; (3)
summarizing the current understanding and management of identified and potential risks;
and (4) providing an update on the status of the clinical investigation/development program
and study results. A DSUR should be concise and provide information to assure regulators
that sponsors are adequately monitoring and evaluating the evolving safety profile of the
investigational drug. All safety issues discovered during the reporting period should be
discussed in the text of the DSUR.

Documentation
All records (including physical records (dry & wet – like pathological slides/blocks, as
applicable)/electronic data scans, x-rays etc.) that describe or record the methods, conduct
and results of the study, and the actions taken. The Documents include Protocol, copies of
submissions and approvals from the office of the Drugs Controller General of India, ethics
committee, investigator(s)’ particulars, consent forms, monitor reports, audit certificates,
relevant letters, reference ranges, raw data, completed CRFs and the final report. Also see:
Essential Documents.

e-Consent
electronic informed consent refers to the use of electronic systems and processes that may
employ multiple electronic media, including text, graphics, audio, video, podcasts, passive
and interactive Web sites, biological recognition devices, and card readers, to convey

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information related to the study and to obtain and document informed consent.

Electronic Case Record Form (e-CRF)

The eCRF is an auditable electronic record of information that generally is reported to the
sponsor on each trial subject, according to a clinical investigation protocol. The eCRF
enables clinical investigation data to be systematically captured, reviewed, managed,
stored, analyzed, and reported.

Escape/rescue medicine /treatment

A supplementary treatment, usually given to alleviate pain in placebo-controlled
study/research, to relieve the study/research participant/subject of the symptoms caused by
the investigated disease in a study.

Essential document/Record
Essential records are the documents and data (and relevant metadata), in any format,
associated with a clinical study/research that facilitate the ongoing management of the
study/research and collectively allow the evaluation of the methods used, the factors
affecting a study/research and the actions taken during the study/research conduct to
determine the reliability of the study/research results produced and the verification that the
study/research was conducted in accordance with GCP guidelines and applicable regulatory
requirements (Annexure/checklist)

Ethics Committee (EC)

An ethics committee is an multi displiniary/ multi sectorial committee responsible to
undertake scientific and ethical review of clinical research. Ethics committee could be an
institutional ethics committee (EC) or an independent (Ind EC) (with no institutional
affiliation). The EC comprising of medical / scientific and non-medical / non-scientific
members, whose responsibility is to verify the protection of the rights, safety and well-
being of human participants involved in a study. The EC ensures an independent fair and
un-biased review The independent review provides public reassurance by objectively,
independently and impartially reviewing and approving the “Protocol”, the suitability of the
investigator(s), facilities, methods and material to be used for obtaining and documenting
“Informed Consent” of the study participants and adequacy of confidentiality safeguards.
The legal status, composition, function, operations and regulatory requirements pertaining
to ECs is defined in New Drugs and Clinical Trials Rules 2019 which allow the EC to act
in agreement with GCP as described in this guideline.

Interim analysis
An interim analysis is any examination of data obtained from participants in study/research
while that study/research is ongoing and is not restricted to cases in which there are formal
between-group comparisons. The observed data used in the interim analysis can include
one or more types, such as baseline data, safety outcome data, pharmacokinetic,
pharmacodynamic or other biomarker data, or efficacy outcome data.

Final Report
A complete and comprehensive written description of the study/research/study of any
therapeutic, prophylactic, or diagnostic agent conducted in human participants, in which
the clinical and statistical description, presentations, and analyses are fully integrated into a
single report after its completion. It includes description of experimental and statistical
methods and materials, presentation and evaluation of the results, statistical analyses, and a

13
critical ethical, statistical and clinical appraisal. The Investigator’s declaration closing the
study is a part of the Final Report.

Good Clinical Practice (GCP)

It is a standard for clinical studies or study/research that encompasses the design, conduct,
monitoring, termination, audit, analyses, reporting and documentation of the studies. It
ensures that the studies are implemented and reported in such a manner that there is public
assurance that the data are credible, accurate and that the rights, integrity and
confidentiality of the participants are protected. GCP aims to ensure that the studies are
scientifically authentic and that the clinical properties of the “Investigational Product” are
properly documented.

Impartial Witness
A literate person, who is independent of the research and would not be unfairly
influenced by people involved with the study, who attends the informed consent
process if the participant and/or
their LAR cannot read, and understand the informed consent form and any other
written information supplied to the participant.

Informed Consent
Written signed and dated paper confirming a participant’s willingness to voluntarily
participate in a particular research, after having been informed of all aspects of the research
that are relevant for the participant’s decision to participate.

Inspection –
See Clinical study/research inspection

Institution/ Clinical study/research site

“Clinical study/research site” means any hospital or institute or any other clinical
establishment having the required facilities to conduct clinical study/research.

Interim clinical study/research report: - see interim analysis.

Investigator
A person responsible for the conduct of the study at the study/research site. Investigator is
responsible for the rights, health and welfare of the study participants. In case the study is
conducted by a team of investigators at the study site then the designated leader of the team
should be the Principal Investigator. Also see Principal Investigator.

See co-investigator

Investigational product Labelling

Labelling developed specifically for products involved in the study.

Investigational Product
A pharmaceutical product (including the Comparator Product) being tested or used as
reference in a clinical study. An Investigational Product may be an active chemical entity
or a formulated dosage form or placebo.

14
Investigational new drug
“Investigational new drug” means a new chemical or biological entity or substance that has
not been approved for marketing as a drug in any country.

Investigator’s Brochure
A collection of data (including justification for the proposed study) for the Investigator
consisting of all the clinical as well as non-clinical information available on the
Investigational Product(s) known prior to the onset of the study/research. There should be
adequate data to justify the nature, scale and duration of the proposed study/research and to
evaluate the potential safety and need for special precautions. If new substantially relevant
data is generated during the study/research, the information in the Investigator’s Brochure
must be updated.

Legally authorized representative (LAR)/Legally acceptable representative (LAR)

A person who, under applicable law or judicial authority, can give consent on behalf of a
prospective participant/subjectwho, for either legal or medical reasons, is unable to give
consent herself/himself to participate in research or to undergo a diagnostic, therapeutic or
preventive procedure as per research protocol, duly approved by the ethics committee.

Medical Device
Medical device means substances used for in vitro diagnosis and surgical dressings, surgical
bandages, surgical staples, surgical sutures, ligatures, blood and blood component collection
bag with or without anticoagulant covered under subclause (i) of Medical Device Rules
2017; substances including mechanical contraceptives (condoms, intrauterine devices, tubal
rings), disinfectants and insecticides notified in the Official Gazette under sub-clause (ii) of
medical device rules 2017; (C) devices notified from time to time under sub-clause (iv), of
clause (b) of section 3 of the Act and medical device rules

Medical Management
medical management” means treatment and other necessary activities for providing the
medical care to complement the study/research treatment.

Metadata
The contextual information required to understand a given data element. Metadata is
structured information that describes, explains, or otherwise makes it easier to retrieve, use
or manage data. For this guideline, relevant metadata are those needed to reconstruct the
study/research conduct.

Monitor
A person appointed by the Sponsor or Contract Research Organisation (CRO) for
monitoring and reporting the progress of the study/research and for verification of data.
The monitor ensures that the study/research is conducted, recorded and reported in
accordance with the Protocol, Standard Standard operating procedures (SOPs), Good
Clinical Practice (GCP) and the applicable regulatory requirements.

Monitoring Plan
A document that describes the strategy, methods, responsibilities and requirements for
monitoring the clinical study/research.

Monitoring Report

15
A documented report following site and/or centralized monitoring activities.

Multi-Centre Study
Clinical study/research conducted according to one single protocol in which the
study/research is taking place at different investigational sites, therefore carried out by
more than one investigator.

Global clinical study:

Global clinical study means any clinical study which is conducted as part of a clinical
development of a drug in more than one country.

Non-Clinical Study
Biomedical studies that are not performed on human participants.

Non interventional studies

Non-interventional studies are defined as studies, in the context of which findings resulting
from individuals' treatment with medicinal products are analysed using epidemiological
methods; the treatment, including the diagnosis and monitoring, does not follow a
predetermined study/research protocol but results exclusively from current medical practice.

Periodic Safety Update Report (PSUR)

A Periodic Safety Update Report (PSUR) is a systematic review of the safety data of an
approved medicine which include all relevant new information from appropriate sources,
patient exposure data and summarizes marketing authorization status of product.

Pharmaceutical Product(s)
Any substance or combination of substances which has a therapeutic, prophylactic or
diagnostic purpose or is intended to modify physiological functions and presented in a
dosage form suitable for administration to humans.

Phytopharmaceutical drug
Phytopharmaceutical drug includes purified and standard fraction with defined minimum
four bio-active or phyto-chemical compound (qualitatively and quantitatively assessed) of
an extract of a medicinal plant or its part, for internal or external use of human beings or
animals for diagnosis, treatment, mitigation or prevention of any disease or disorder but
does not include administration by parenteral route as specified in Rule 2 (eb) of the Drugs
& Cosmetics (D&C) Rules, 1945.

Post marketing surveillance

PMS is practice of monitoring the safety of a pharmaceutical drug or medical device after it
has been released on the market. PMS can be active or by way of spontaneous reporting.

Post marketing surveillance study or observational or non-interventional study for

active surveillance:
Such studies are conducted with a new drug under approved conditions of its use under a
protocol approved by Central Licencing Authority with scientific objective. Inclusion or
exclusion of subject are decided as per the recommended use as per prescribing information
or approved package insert. In such studies the study drugs are the part of treatment of
patient in the wisdom of the prescriber included in the protocol. The regulatory provisions
and guidelines applicable for clinical trial of a new drug are not applicable in such cases as
drugs are already approved for marketing.

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Principal Investigator
The investigator who has the responsibility to co-ordinate between the different
Investigators involved in a study at one site or different sites in case of a multi-center
study.

Protocol
A document that states the background, objectives, rationale, design, methodology
(including the methods for dealing with AEs, withdrawals etc.) and statistical
considerations of the study. It also states the conditions under which the study shall be
performed and managed.

A list of items to be included in the Protocol is compiled in a subsequent chapter.

The content and format of the protocol should take into consideration the adopted
SOPs, the regulatory requirements and the guiding principles of GCP.

The term Protocol, unless otherwise specified, relates to the latest amended version of
the document, read in conjunction with all its appendices and enclosures.

Protocol Amendment(s)
Any changes or formal clarifications appended to the protocol. All Protocol Amendments
should be agreed upon and signed by the persons who were the signatories to the Protocol.

Quality Assurance (QA)

The systematic and independent examination of all study/research-related activities and
documents. These audits determine whether the evaluated activities were appropriately
conducted, and that the data were generated, recorded, analyzed, and accurately reported
according to protocol, standard standard operating procedures (SOPs), applicable
regulations and GCP guideline.

Quality Control (QC)

Periodic operational examination of the study/research related processes carried out
proactively by the process owners to verify that clinical data are generated, collected,
handled, analyzed, and reported according to protocol, SOPs, applicable regulation and
GCP guideline.

Randomisation
The process of assigning study participants t o either the treatment or the
control group. Randomisation gives all participants the same chance of being in either
group to reduce bias.

Regulatory Authority
The Drugs Controller General of India or an office nominated by him is the regulatory
authority for the purpose of carrying out Clinical Study/research in India. The Regulatory
Authority approves the study Protocol, reviews the submitted data and conducts
inspections.

Raw Data
It refers to all records or certified copies of the original clinical and laboratory findings or
other activities in a clinical study necessary for the reconstruction and evaluation of

17
the study/research. Also see Source Data.

Real-world data
RWD are data relating to patient health status and/or the delivery of health care routinely
collected from a variety of sources. Examples of RWD include data derived from electronic
health records, medical claims data, data from product or disease registries, and data
gathered from other sources (such as digital health technologies) that can inform on health
status.

Real-world evidence
RWE is the clinical evidence about the usage and potential benefits or risks of a medical
product derived from analysis of RWD.

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR)

An AE or ADR that is associated with death, inpatient hospitalisation (in case the study was
being conducted on out-patients), prolongation of hospitalisation (in case the study was
being conducted on in-patients), persistent or significant disability or incapacity, a
congenital anomaly or birth defect, or is otherwise life threatening.

Sever adverse event:

The term "severe" is often used to describe the intensity (severity) of a specific event. This
is not the same as "serious," which is based on patient/event outcome or action criteria
usually associated with events that pose a threat to a patient's life or functioning.
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

Service Provider
A person or organisation (commercial, academic or other) providing a service used during
the conduct of a clinical study/research to either the sponsor or CRO or the investigator or
any other related entity to fulfil one or more of their study/research-related activities.

Source Data
Original documents or data (which includes relevant metadata) or certified copies of the
original documents or data, irrespective of the media used. This may include study/research
participants’ medical/health records/notes/charts; data provided/entered by study/research
participants (e.g., electronic patient-reported outcome (ePROs)); healthcare providers’
records from pharmacies, laboratories and other facilities involved in the clinical
study/research; and data from automated instruments, such as wearables and sensors.

Sponsor
An individual or a company or an institution that takes the responsibility for the initiation,
management of a Clinical Study.

Sponsor-Investigator
An individual who both initiates and conducts, alone or with others, a clinical
study/research/clinical investigation/ clinical research, and under whose immediate
direction the investigational product is administered to, dispensed to, or used by a
participant. The term does not include any person other than an individual (e.g., the term
does not include a corporation or an agency). The obligations of a sponsor-investigator
include both those of a sponsor and those of an investigator.

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Sub-Investigator
See Co-Investigator

Participant/subjectFiles / Patient Files

A file containing demographic and medical information about a study participant. It
includes hospital files, consultation records or special participant/subjectfiles allowing the
authenticity of the information presented in CRF to be verified and where necessary
allowing it to be completed or corrected. The conditions regulating the use and consultation
of such documents must be honoured as prescribed under Confidentiality.

Study Participant/subject(Participant)
An individual participating in clinical study/research as a recipient of the Investigational
Product.

A Study Participant/subjectmay be a healthy person volunteering in study/research or a

person with a medical condition that is unrelated to the use of the Investigational Product
or a person whose medical condition is relevant to the use of the Investigational Product.

Standard Standard operating procedures (SOP)

Standard elaborate written instructions to achieve uniformity of performance in the
management of clinical studies. SOPs provide a general framework for the efficient
implementation and performance of all the functions and activities related to a particular
study.

Participant/subjectIdentification Code
A unique identification number / code assigned by the Investigator to each Study
Participant/subjectto protect the Participant’s identity. Participant/subjectIdentification
Code is used in lieu of the Participant’s name for all matters related to the study.

Study Management
Steering, supervising, data management and verification, statistical processing, and
preparation of the study report.

Suspected unexpected serious adverse reactions (SUSARs)

Adverse reactions due to medicines administered in clinical study/research that are
unexpected and serious.

Treatment Emergent Adverse Event

An event that emerges during treatment having been absent pre-treatment or worsens
relative to the pre-treatment state.

Validation
Validation of Study: The process of proving, in accordance with the principles of Good
Clinical Practice, that any procedure, process equipment, material, activity or system
actually leads to the expected results.

Validation of Data: The procedures carried out to ensure and prove that the data contained
in the final report match the original observations. The procedure is applied to Raw Data,
CRFs, computer software, printouts, statistical analyses, and consumption of Study Product
/ Comparator Product.

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Vulnerable participants
Vulnerability in research pertains to individuals who are relatively or absolutely incapable
of protecting their own interests because of personal disability, environmental burdens or
social injustice, lack of power, understanding or ability to communicate or are in a situation
that prevents them from doing so.

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 PREREQUISITES FOR THE STUDY

2.1 Investigational Pharmaceutical Product

Physical, chemical, pharmaceutical properties and the formulation of the
Investigational Product must be documented to permit appropriate safety measures
to be taken during the course of a study. Instructions for the storage and handling
of the dosage form should be documented. Any structural similarity(ies) to the
other known compounds should be mentioned.

2.2 Pre-clinical supporting data

The available pre-clinical data and clinical information on the Investigational
Product should be adequate and convincing to support the proposed study.

2.3 Protocol
A well designed study relies predominantly on a thoroughly considered, well-
structured and complete protocol.

2.3.1 Relevant components of Protocol

2.3.1.1 General information

a. Protocol title, protocol identifying number and date. All amendments should
bear amendment number and date(s)
b. Name, address & contact numbers of the sponsor and the monitor / CRO
c. Name and title of the persons authorised to sign the protocol and the protocol
amendments for the sponsor.
d. Name, title, address and contact numbers of the sponsor's medical expert for the
study
e. Name(s), title(s), address(es) and contact numbers of the investigator(s) who is /
are responsible for conducting the study, along with their consent letter(s)
f. Name(s), address(es) and contact numbers of the institution(s) - clinical
laboratories and / or other medical and technical departments along with the
particulars of the head(s) of the institution(s) and the relevant department(s)

2.3.1.2 Objectives and Justification

a. Aims and objectives of the study, indicating the Phase to which the study
corresponds.
b. Name and description of the investigational product(s)
c. A summary of findings from non-clinical studies that potentially have clinical
significance and from clinical studies that are relevant to the study.
d. Summary of the known and potential risks and benefits, if any, to human
participants
e. Description of and justification for the route of administration, dosage regimen
and treatment periods for the pharmaceutical product being studied and the
product being used as control. Dose- response relationships should be
considered and stated.
f. A statement that the study will be conducted in compliance with the protocol,
GCP and the applicable regulatory requirements.

21
 g. Description of the inclusion & exclusion criteria of the study population
h. References to the literature and data that are relevant to the study and that
provide background for the study.

2.3.1.3 Ethical Considerations

a. General ethical considerations related to the study.

b. Description of how patients / healthy volunteers will be informed and how their
consent will be obtained.
c. Possible reasons for not seeking informed consent.

2.3.1.4 Study design

The scientific integrity of the study and the credibility of the data from the study
depend substantially on the study design. Description of the study design should
include:
a. Specific statement of primary and secondary end points, if any, to be measured
during the study
b. Description of the type of the study (randomised, comparative, blinded, open,
placebo controlled), study design (parallel groups, cross-over technique),
blinding technique (double-blind, single- blind), randomisation (method and
procedure) and placebo controlled.
c. A schematic diagram of the study design, procedures, and stages
d. Medications/treatments permitted (including rescue medications) and not
permitted before and / or during the study.
e. A description of the study treatments, dosage regimen, route of administration
and the dosage form of the investigational product and the control proposed
during the study.
f. A description of the manner of packaging and labelling of the investigational
product
g. Duration of the participant/subjectparticipation and a description of the
sequence of all study periods including follow-up, if any
h. Proposed date of initiation of the study
i. Justification of the time-schedules e.g. in the light of how far the safety of the
active ingredients, medicinal products has been tested, the time course of the
disease in question
j. Discontinuation criteria for study participants and instructions on terminating or
suspending the whole study or a part of the study.
k. Accountability procedures for the investigational products including the
comparator product.
l. Maintenance of study treatment randomisation codes and procedures for
breaking codes
m. Documentation of any decoding that may occur during the study
n. Procedures for monitoring participants’ compliance

2.3.1.5 Inclusion, Exclusion and Withdrawal of Participants

a. Participant/subject inclusion criteria: specifications of the participants (patients /

healthy volunteers) including age, gender, ethnic groups, prognostic factors,

22
 diagnostic admission criteria etc. should be clearly mentioned where relevant.
b. Participant/subject exclusion criteria, including an exhaustive statement on
criteria for pre-admission exclusions.
c. Participant/subject withdrawal criteria (i.e. terminating investigational product
treatment / study treatment) and procedures specifying – when and how to
withdraw participants from the treatment, type and timing of the data to be
collected from withdrawn participants, whether and how participants are to be
replaced and the follow-up on the withdrawn participants
d. Statistical justification for the number of Participants to be included in the Study
e. justification for placebo, benefit–risk assessment, If standard therapies are to be
withheld, to be included in justification
f. justification of inclusion/exclusion of vulnerable populations

2.3.1.6 Handling of the Investigational Product(s)

a. Measures to be implemented to ensure the safe handling and storage of the

pharmaceutical products.
b. System to be followed for labelling of the product(s) (code numbering etc.)
The label should necessarily contain the following information: the words –
clinical trial supply, containers bearing labels, indicating the name of the
Investigational Product or code number, batch or lot number, wherever
applicable, date of manufacture, use before date, storage conditions, name of the
institution or organisation or the centre where the clinical trial or bioavailability
or bioequivalence study is proposed to be conducted, name and address of the
manufacturer, and the purpose for which it has been manufactured.

2.3.1.7 Assessment of Efficacy

a. Specifications of the effect parameters to be used.

b. Description of how effects are measured and recorded.
c. Time and periodicity of effect recording
d. Description of special analyses and / tests to be carried out (pharmacokinetic,
clinical, laboratory, radiological etc.)

2.3.1.8 Assessment of Safety

a. Specifications of safety parameters

b. Methods and periodicity for assessing and recording safety parameters.
c. Procedures for eliciting reports of and for recording and reporting adverse drug
reactions and / or adverse events and inter-current illnesses.
d. Type and duration of the follow-up of the participants after adverse events
e. Information on establishment of the study-code, where it will be kept and when,
how and by whom it can be broken in the event of an emergency.

2.3.1.9 Statistics

a. Description of the statistical methods to be employed, including timing of any

planned interim analysis.
b. Number of study participants needed to achieve the study objective, and
statistical considerations on which the proposed number of participants is based
c. Detailed break-up of the number of participants planned to be enrolled at each

23
 study site (in case of multi-center studies)
d. The level of statistical significance to be used
e. Procedures for managing missing data, unused data and unauthentic data
f. Procedures for reporting any deviations from the original statistical plan (any
deviations from the original statistical plan should be stated and justified in
protocol and / in the final report, as appropriate)
g. Selection of the participants to be included in the final analyses (e.g. all
randomized participants / all dosed participants / all eligible participants /
evaluable participants

2.3.1.10 Data handling and management

A statement should be clearly made in the protocol that “The investigator(s) /

institution(s) will permit study related monitoring, audits, ethics committee review
and regulatory inspection(s) providing direct access to source data / documents”.

A copy of the CRF should be included in the protocol. Besides, the following
details should be given:
a. Procedures for handling and processing records of effects and adverse events to
the product(s) under study
b. Procedures for the keeping of patient lists and patient records for each
individual taking part in the study. Records should facilitate easy identification
of the individual participants.

2.3.1.11 Quality control and quality assurance

a. A meticulous and specified plan for the various steps and procedures for the
purpose of controlling and monitoring the study most effectively
b. Specifications and instructions for anticipated deviations from the protocol
c. Allocation of duties and responsibilities with-in the research team and their co-
ordination
d. Instructions to staff including study description (the way the study is to be
conducted and the procedures for drug usage and administration)
e. Addresses and contact numbers etc. enabling any staff member to contact the
research team at any hour
f. Considerations of confidentiality problems if any arise
g. Quality control of methods and evaluation procedures

2.3.1.12 Finance and insurance

a. All financial aspects of conducting and reporting a study may be arranged and a
budget made out.
b. Information should be available about the sources of economic support (e.g.
foundations, private or public funds, sponsor / manufacturer). Likewise, it
should be stated how the expenditures should be distributed e.g. payment to
participants, refunding expenses of the participants, payments for special tests,
technical assistance, purchase of apparatus, possible fee to or reimbursement of
the members of the research team, payment of the investigator / institution etc.)
c. The financial arrangement between the sponsor, the individual researcher(s)/

24
 manufacturer involved, institution and the investigator(s) in case such
information is not stated explicitly.
d. Study Participants should be satisfactorily insured against any injury caused by
the study
e. The liability of the involved parties (investigator, sponsor / manufacturer,
institution(s) etc.) must be clearly agreed and stated before the start of the study

2.3.1.13 Publication policy

A publication policy, if not addressed in a separate agreement, should be described

in the protocol.

2.3.1.14 Evaluation

a. A specified account for how the response is to be evaluated

b. Methods of computation and calculation of effects
c. Description of how to deal with and report participants withdrawn from /
dropped out of the study

2.3.2 Supplementaries and appendices

The following documents should be appended with the protocol:

a. Information to the Study Participants and the mode of providing it
b. Instructions to staff
c. Descriptions of special procedures

2.3.1 Academic clinical study/research

(1) No permission for conducting an academic clinical study/research shall be

required for any drug from the Central Licensing Authority where,
(i) the clinical study/research in respect of the permitted drug formulation is
intended solely for academic research purposes for a new indication or new
route of administration or new dose or new dosage form; and
(ii) the clinical study/research referred to in clause (i) has been initiated after
prior approval by the Ethics Committee for clinical study/research; and
(iii) the observations generated from such clinical study/research are not required
to be submitted to the Central Licensing Authority; and
(iv) the observations of such clinical study/research are not used for promotional
purposes.

(2) In the event of a possible overlap between the academic clinical study/research
and clinical study/research or a doubt on the nature of study, the Ethics
Committee concerned shall inform the Central Licensing Authority in writing
indicating its views within thirty working days from the receipt of application to
that effect.

(3) The Central Licensing Authority shall, after receiving the communication from
the Ethics Committee examine it and issue necessary clarification, in writing,
within thirty working days from the date of receipt of such communication;
provided that where the Central Licensing Authority does not send the required

25
 communication to such Ethics Committee within thirty working days from the
date of receipt of communication from the said Ethics Committee, it shall be
presumed that no permission from the Central Licensing Authority is required.

(4) The approved academic clinical study/research shall be conducted in accordance

with the approved clinical study/research protocol, ethical principles specified in
National Ethical Guidelines for Biomedical and Health Research Involving
Human Participants, notified by the Indian Council of Medical Research with a
view to ensuring protection of rights, safety and wellbeing of study/research
participant/subjectduring conduct of clinical study/research of licenced and
approved drug or drug formulation for any new indication or new route of
administration or new dose or new dosage form for academic research purposes.

An “academic clinical study/research” means a clinical study/research of a drug

already approved for a certain claim and initiated by any investigator, academic
or research institution for a new indication or new route of administration or new
dose or new dosage form, where the results of such a study/research are intended
to be used only for academic or research purposes and not for seeking approval of
regulatory authority of any country for marketing or commercial purpose. No
permission for conducting an academic clinical study/research shall be required
for any drug from the regulatory agency provide ― (i) the clinical study/research
in respect of the permitted drug formulation is intended solely for academic
research purposes for a new indication or new route of administration or new
dose or new dosage form; and (ii) the clinical study/research has been initiated
after prior approval by the Ethics Committee for clinical study/research; and (iii)
the observations generated from such clinical study/research are not required to
be submitted to the regulatory authority; and (iv) the observations of such clinical
study/research are not used for promotional purposes. However, in the event of a
possible overlap between the academic clinical study/research and clinical
study/research or a doubt on the nature of study, the Ethics Committee concerned
shall inform the DCG (I) in writing indicating its views within thirty working
days from the receipt of application to that effect. The academic clinical
study/research shall be required to be conducted in accordance with the approved
clinical study/research protocol, ethical principles specified in National Ethical
Guidelines for Biomedical and Health Research Involving Human Participants,
notified by the ICMR with a view to ensuring protection of rights, safety and
wellbeing of study/research participant/subjectduring conduct of such clinical
study/research. Therefore, ethical principles including compensation, medical
management in case of injury or death etc. as prescribed in National Ethical
Guidelines for Biomedical and Health Research Involving Human Participants,
notified by the ICMR are applicable for academic clinical study/research.

2.4 Ethical & Safety Considerations

2.4.1 Ethical Principles

1.0 Statement of General Principles

Research on human participants pertains to a broad range of scientific enquiry aimed

26
at developing generalizable knowledge that improves health, increases
understanding of disease and is ethically justified by its social value. Every research
has some inherent risks and probabilities of harm or inconvenience to
participants/communities. Therefore, protection of participants should be built into
the design of the study. Do no harm (non-maleficence) has been the underlying
universal principle guiding health care in all systems of medicine around the world.
While conducting biomedical and health research, the four basic ethical principles
namely; respect for persons (autonomy), beneficence, non-maleficence and justice
have been enunciated for protecting the dignity, rights, safety and well-being of
research participants. These four basic principles have been expanded into 12
general principles described below, and are to be applied to all biomedical, social
and behavioural science research for health involving human participants, their
biological material and data.

1.1. General Principles

1.1.1 Principle of essentiality whereby after due consideration of all alternatives in

the light of existing knowledge, the use of human participants is considered to be
essential for the proposed research. This should be duly vetted by an ethics
committee (EC) independentof the proposed research.

1.1.2 Principle of voluntariness whereby respect for the right of the

participant/subjectto agree or not to agree to participate in research, or to withdraw
from research at any time, is paramount. The informed consent process ensures that
participants’ rights are safeguarded.

1.1.3 Principle of non-exploitation whereby research participants are equitably

selected so that the benefits and burdens of the research are distributed fairly and
without arbitrariness or discrimination. Sufficient safeguards to protect vulnerable
groups should be ensured.

1.1.4 Principle of social responsibility whereby the research is planned and

conducted soas to avoid creation or deepening of social and historic divisions or in
any way disturbsocial harmony in community relationships.

1.1.5 Principle of ensuring privacy and confidentiality whereby to maintain

privacy of the potential participant, her/his identity and records are kept confidential
and accessis limited to only those authorized. However, under certain circumstances
(suicidal ideation, homicidal tendency, HIV positive status, when required by court
of law etc.)privacy of the information can be breached in consultation with the EC
for valid scientific or legal reasons as the right to life of an individual supersedes the
right to privacy of the research participant.

1.1.6 Principle of risk minimization whereby due care is taken by all stakeholders
(including but not limited to researchers, ECs, sponsors, regulators) at all stages of
the research to ensure that the risks are minimized, and appropriate care and
compensation is given ifany harm occurs.

1.1.7 Principle of professional competence whereby the research is planned,

conducted, evaluated and monitored throughout by persons who are competent and

27
have the appropriate and relevant qualification, experience and/or training.
1.1.8 Principle of maximization of benefit whereby due care is taken to design and
conduct the research in such a way as to directly or indirectly maximize the benefits
to the research participants and/or to the society.

1.1.9 Principle of institutional arrangements whereby institutions where the

research is being conducted, have policies for appropriate research governance and
take the responsibility to facilitate research by providing required infrastructure,
manpower, funds and training opportunities.

1.1.10 Principle of transparency and accountability whereby the research plan

and outcomes emanating from the research are brought into the public domain
through registries, reports and scientific and other publications while safeguarding
the right to privacy of the participants. Stakeholders involved in research should
disclose any existing conflict of interest and manage it appropriately. The research
should be conducted in a fair, honest, impartial and transparent manner to guarantee
accountability. Related records, data and notes should be retained for the required
period for possible external scrutiny/ audit.

1.1.11 Principle of totality of responsibility whereby all stakeholders involved in

research are responsible for their actions. The professional, social, and moral
responsibilities compliant with ethical guidelines and related regulations are binding
on all stakeholders directly or indirectly.

1.1.12 Principle of environmental protection whereby researchers are accountable

for ensuring protection of the environment and resources at all stages of the research,
in compliance with existing guidelines and regulations.

2.0 General Ethical Considerations:

All research involving human participants should be conducted in accordance with

the basic and general ethical principles as outlined in section 1. The researcher and
the team are responsible for protecting the dignity, rights, safety and well-being of
the participants enrolled in the study. They should have the appropriate
qualifications and competence in research methodology and should be aware of and
comply with the scientific, medical, ethical, legal and social requirements of the
research proposal. The ECs are responsible for ensuring that the research is
conducted in accordance with the afore mentioned principles.

2.1 Benefit-risk assessment

Benefits to the individual, community or society refer to any sort of favourable
outcome of the research, whether direct or indirect. The social and scientific value of
research should justify the risk, which is the probability of causing discomfort or
harm anticipated as physical, psychological, social, economic or legal.

2.1.1 The researcher, sponsor and EC should attempt to maximize benefits and
minimize risks to participants so that risks are balanced to lead to potential benefits
at individual, societal and/or community levels.
2.1.2 The EC should assess the inherent benefits and risks, ensure a favourable
balance of benefits and risks, evaluate plans for minimizing the risk and discomfort

28
 and decide on the merit of the research before approving it.
2.1.3 The EC should also assess any altered risks in the study at the time of
continuing review.
2.1.4 The type of EC review based on risk involved in the research, is categorized as
given in Risk Table

2.2 Informed consent process

Informed consent protects the individual’s autonomy to freely choose whether or not
to participate in the research. The process involves three components – providing
relevant information to potential participants, ensuring the information is
comprehended by them and assuring voluntariness of participation. Informed
consent should explain medical terminology in simple terms and be in a language
that the participant/subjectunderstands.

Type of risk Definition/description

Less than minimal risk Probability of harm or discomfort anticipated in the research is nil or
not expected. For example, research on anonymous or non-
identified data/samples, data available in the public domain, meta-
analysis, etc.
Minimal risk Probability of harm or discomfort anticipated in the research is not
greater than that ordinarily encountered in routine daily life activities
of an average healthy individual or general population or during the
performance of routine tests where occurrence of serious harm or an
adverse event (AE) is unlikely. Examples include research involving
routine questioning or history taking, observing, physical examination,
chest X-ray, obtaining body fluids without invasive intervention,
such as hair, saliva or urine samples, etc.
Minor increase over minimal Increment in probability of harm or discomfort is only a little more
risk or Low risk than the minimal risk threshold. This may present in situations such as
routine research on children and adolescents; research on persons
incapable of giving consent; delaying or withholding a proven
intervention or standard of care in a control or placebo group during
randomized study/research; use of minimally invasive procedures that
might cause no more than brief pain or tenderness, small bruises or
scars, or very slight, temporary distress, such as drawing a small
sample of blood for testing; trying a new diagnostic technique in
pregnant and breastfeeding women, etc. Such research should have a
social value. Use of personal identifiable data in research also
imposes indirect risks. Social risks, psychological harm and
discomfort may also fall in this category.
More than minimal risk or High Probability of harm or discomfort anticipated in the research is invasive
risk and greater than minimal risk. Examples include research involving
any interventional study using a drug, device or invasive procedure
such as lumbar puncture, lung or liver biopsy, endoscopic procedure,
intravenous sedation for diagnostic procedures, etc.

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General Ethical Issues
2.2.1. The informed consent document (ICD), which includes
patient/participant/subjectinformation sheet (PIS) and informed consent form (ICF)
should have the required elements and should be reviewed and approved by the EC
before enrolment of participants. For all biomedical and health research involving
human participants, it is the primary responsibility of the researcher to obtain the
written, informed consent of the prospective participant/subjector legally
acceptable/authorized representative (LAR). In case of an individual who is not
capable of giving informed consent, the consent of the LAR should be obtained. If a
participant/subjector LAR is illiterate, a literate impartial witness should also be
present during the informed consent process.
2.2.2. In certain circumstances audio/audio-visual recording of the informed consent
process may be required, for example in certain clinical study/research as notified by
CDSCO.
2.2.3. Verbal/oral consent/waiver of consent/re-consent may be obtained under
certain conditions after due consideration and approval by the EC.

2.3 Privacy and confidentiality

Privacy is the right of an individual to control or influence the information that can
be collected and stored and by whom and to whom that information may be
disclosed or shared. Confidentiality is the obligation of the researcher/research
team/organization to the participant/subjectto safeguard the entrusted information. It
includes the obligation to protect information from unauthorized access, use,
disclosure, modification, loss or theft.

2.3.1 The researcher should safeguard the confidentiality of research related data of
participants and the community.
2.3.2 Potential limitations to ensure strict confidentiality must be explained to the
participant. Researchers must inform prospective participants that although every
effort will be made to protect privacy and ensure confidentiality, it may not be
possible to do so under certain circumstances.
2.3.3 Any publication arising out of research should uphold the privacy of the
individuals by ensuring that photographs or other information that may reveal the
individual’s identity are not published. A specific re-consent would be required for
publication, if this was not previously obtained.
2.3.4 Some information may be sensitive and should be protected to avoid
stigmatization and/or discrimination (for example, HIV status; sexual orientation
such as lesbian, gay, bisexual, and transgender (LGBT); genetic information; or any
other sensitive information).
2.3.5 While conducting research with stored biological samples or medical
records/data, coding or anonymization of personal information is important and
access to both samples and records should be limited.
2.3.6 Data of individual participants may be disclosed in certain circumstances with
the permission of the EC such as specific orders of a court of law, threat to a
person’s or community’s life, public health risk that would supersede personal rights
to privacy, serious adverse events (SAEs) that are required to be communicated to an
appropriate regulatory authority etc.

2.4 Distributive justice

2.4.1. Efforts must be made to ensure that individuals invited for research are

30
selected in such a way that the benefits and burdens of research are equitably
distributed.
2.4.2. Vulnerable individuals/groups should not be included in research to solely
benefit others who are better-off than themselves.

2.4.3 Research should not lead to social, racial or ethnic inequalities.

2.4.4 Plans for direct or indirect benefit sharing in all types of research with
participants, donors of biological materials or data should be included in the study,
especially if there is a potential for commercialization. This should be decided a
priori in consultation with the stakeholders and reviewed by the EC.

2.5 Payment for participation

2.5.1 If applicable, participants may be reimbursed for expenses incurred relating to
their participation in research, such as travel related expenses. Participants may also
be paid for inconvenience incurred, time spent and other incidental expenses in
either cash or kind or both as deemed necessary (for example, loss of wages and
food supplies).
2.5.2 Participants should not be made to pay for any expenses incurred beyond
routine clinical care and which are research related including investigations, patient
work up, any interventions or associated treatment. This is applicable to all
participants, including those in comparator/control groups.
2.5.3 If there are provisions, participants may also receive additional medical
services at no cost.
2.5.4 When the LAR is giving consent on behalf of a participant, payment should not
become an undue inducement and to be reviewed carefully by the EC.
Reimbursement may be offered for travel and other incidental expenses incurred due
to participation of the child/ward in the research.
2.5.5 ECs must review and approve the payments (in cash or kind or both) and free
services and the processes involved, and also determine that this does not amount to
undue inducement.

2.6 Compensation for research-related harm

Research participants who suffer direct physical, psychological, social, legal or
economic harm as a result of their participation are entitled, after due assessment, to
financial or other assistance to compensate them equitably for any temporary or
permanent impairment or disability. In case of death, participant’s dependents are
entitled to financial compensation. The research proposal should have an in-built
provision for mitigating research related harm.
2.6.1 The researcher is responsible for reporting all SAEs to the EC within 24 hours
of knowledge. Reporting of SAE may be done through email or fax communication
(including on non-working days). A report on how the SAE was related to the
research must also be submitted within 14 days.
2.6.2 The EC is responsible for reviewing the relatedness of the SAE to the research,
as reported by the researcher, and determining the quantum and type of assistance to
be provided to the participants.
• For clinical study/research under the purview of CDSCO, the timeline and
procedures as notified from time to time may be followed.
• All research participants who suffer harm, whether related or not, should be offered
appropriate medical care, psycho-social support, referrals, clinical facilities, etc.
• Medical management should be free if the harm is related to the research.

31
• Compensation should be given to any participant/subjectwhen the injury is related
to the research. This is applicable to participants in any of the arms of research, such
as intervention, control and standard of care.
• While deliberating on the quantum of compensation to be awarded to participants
who have suffered research-related injury, the EC should consider aspects including
the type of research (interventional, observational, etc.), extent of injury
(temporary/permanent, short/long term), loss of wages, etc.
• For other sponsored research, it is the responsibility of the sponsor (whether a
pharmaceutical company, government or non-governmental organization (NGO),
national or international/bilateral/multilateral donor agency/institution) to include
insurance coverage or provision for possible compensation for research related
injury or harm within the budget.
2.6.3 All AEs should be recorded and reported to the EC according to a pre-planned
timetable, depending on the level of risk and as recommended by the EC.
2.6.4 In investigator initiated research/student research, the investigator/institution
where the research is conducted becomes the sponsor.
• It is the responsibility of the host institution to provide compensation and/or cover
for insurance for research related injury or harm to be paid as decided by the EC.
• The institution should create in-built mechanism to be able to provide for
compensation, such as a corpus fund in the institution.
• In the applications for research grants to funding agencies – national or
international, government or non-government agencies – the researcher should keep
a budgetary provision for insurance coverage and/or compensation depending upon
the type of research, anticipated risks and proposed number of participants.

2.7 Ancillary care

2.7.1 Participants may be offered free medical care for non-research-related
conditions or incidental findings if these occur during the course of participation in
the research, provided such compensation does not amount to undue inducement as
determined by the EC.

2.8 Conflict of interest

Conflict of interest (COI) is a set of conditions where professional judgement
concerning a primary interest such as participants welfare or the validity of research
tends to be unduly influenced by a secondary interest, financial or non-financial
(personal, academic, or political). COI can be at the level of researchers, EC
members, institutions, or sponsors. If COI is inherent in the research, it is important
to declare this at the outset and establish appropriate mechanisms to manage it.
2.8.1 Research institutions must develop and implement policies and procedures to
identify, mitigate conflicts of interest and educate their staff about such conflicts.
2.8.2 Researchers must ensure that the documents submitted to the EC include a
disclosure of interests that may affect the research.
2.8.3 ECs must evaluate each study considering any disclosed interests and ensure
that appropriate means of mitigation are taken.
2.8.4 COI within the EC should be declared and managed in accordance with
standard standard operating procedures (SOPs) of that EC.

2.9 Selection of vulnerable and special groups as research participants

Vulnerable groups and individuals may have an increased likelihood of incurring
additional harm as they may be relatively (or absolutely) incapable of protecting

32
their own interests.
2.9.1 Characteristics that make individuals vulnerable are legal status – children;
clinical conditions – cognitive impairment, unconsciousness; or situational
conditions –including but not limited to being economically or socially
disadvantaged, (for example, certain ethnic, individuals/communities which have
hierarchical relationships, institutionalized persons, humanitarian emergencies,
language barriers and cultural differences).
2.9.2 In general, such participants should be included in research only when the
research is directly answering the health needs or requirements of the group. On the
other hand, vulnerable populations also have an equal right to be included in
research so that benefits accruing from the research apply to them as well. This
needs careful consideration by researchers as well as the EC.
2.9.3 The EC should determine vulnerability and ensure that additional safeguards
and monitoring mechanisms are established. It should also advise the researcher in
this regard.

2.10 Community engagement

Community can be defined as a social group of people of any size sharing the same
geographical location, beliefs, culture, age, gender, profession, lifestyle, disease, etc.
The community should be meaningfully engaged before, during and after the
research to mitigate culturally sensitive issues and ensure greater responsiveness to
their health needs and requirements.
2.10.1 The community can be engaged in many ways and can provide valuable
opinions. The degree of community engagement should depend on the type of
research that is being conducted.
2.10.2 Community advisory board/group (CAB/CAG) can act as an interface
between the community (from which participants are to be drawn), the researchers
and the concerned EC. Members of the CAB should be such that they do not coerce
the members of the community to participate in the research and also protect the
rights and serve the requirements of the group.
2.10.3 Members of the community can also be represented in the EC either as
members or special invitees.
2.10.4 Community engagement does not replace individual informed consent. It
ensures that the community’s health needs and expectations are addressed, informed
consent is appropriate, and access to research benefits are provided through research
that is designed and implemented in the best interests of science and the community.
2.10.5 After the study is completed, the researcher may communicate with the
community representative, local institution or the government department from
where the data was collected to help in dissemination of the results to the entire
community.

2.11 Post research access and benefit sharing

The benefits accruing from research should be made accessible to individuals,
communities and populations whenever relevant. Sometimes more than the benefit
to the individual participant, the community may be given benefit in an indirect way
by improving their living conditions, establishing counselling centres, clinics, or
schools, and providing education on good health practices.
2.11.1 Efforts should be made to communicate the findings of the research study to
the individuals/communities wherever relevant.
2.11.2 The research team should make plans wherever applicable for post-research

33
 access and sharing of academic or intervention benefits with the participants,
including those in the control group.
2.11.3 Post-research access arrangements or other care must be described in the
study protocol so that the EC may consider such arrangements during its review.
2.11.4 If an investigational drug is to be given to a participant/subjectpost-
study/research, appropriate regulatory approvals should be in place.

2.11.5 The EC should consider the need for an a priori agreement between the
researchers and sponsors
2.11.6 In studies with restricted scope, such as student projects, post study benefit to
the participants may not be feasible, but conscious efforts should be made by the
institution to take steps to continue to support and give better care to the participants.

2.4.2 Ethics Committee

The sponsor and / or investigator should seek the opinion of an independent Ethics
Committee regarding suitability of the Protocol, methods, and documents to be used
in recruitment of Participants and obtaining their Informed Consent including
adequacy of the information being provided to the Participants. The Ethics
Committees are entrusted not only with the initial view of the proposed research
protocols prior to initiation of the projects but also have a continuing responsibility
of regular monitoring for the compliance of the Ethics of the approved programs
till the same are completed. Such an ongoing review is in accordance with the
Declaration of Helsinki and all the international guidelines for biomedical research.

2.4.2.1 Basic Responsibilities

The basic responsibility of an EC is to ensure a competent review of all ethical
aspects of the project proposals received and execute the same free from any bias
and influence that could affect their objectivity.

The ECs should specify in writing the authority under which the Committee is
established, membership requirements, the terms of reference, the conditions of
appointment, the offices and the quorum requirements. The responsibilities of an
EC can be defined as follows:
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 the education of a research community
responsive to local health care requirements

2.4.2.2 Composition
1. EC should be multidisciplinary and multi-sectorial in composition.
Independence and competence are the two hallmarks of an EC.
2. Ethics Committee shall have a minimum of seven members from medical,
non-medical, scientific and non-scientific areas with at least,
(i) one lay person;
(ii) one woman member;
(iii) one legal expert;
(iv) one independent member from any other related field such as social
scientist or representative of non-governmental voluntary agency or

34
 philosopher or ethicist or theologian.
3. There should be adequate representation of age and gender.
4. The Ethics Committee referred to in sub-rule (1) shall consist of at least fifty
percent of its members who are not affiliated with the institute or organization
in which such committee is constituted.
5. One member of the Ethics Committee who is not affiliated with the institute or
organization shall be the Chairperson and shall be appointed by such institute or
organisation.
6. One member who is affiliated with the institute or organization shall be
appointed as Member Secretary of the Ethics Committee by such Institute or
organization.
7. The committee shall include at least one member whose primary area of interest
or specialisation is nonscientific and at least one member who is independent of
the institution.
8. The members of the Ethics Committee shall follow the provisions of these
rules, Good Clinical Practices Guidelines, and other regulatory requirements to
safeguard the rights, safety and well-being of study/research participants.
9. Every member of the Ethics Committee shall be required to undergo such
training and development programmes as may be specified by the Central
Licencing Authority from time to time; Provided that any member, who has not
successfully completed such training and developmental programmes, shall be
ineligible to hold the post of member of the Ethics Committee and shall cease
to be a member of such committee.
10. The members representing medical scientists and clinicians shall possess at
least post graduate qualification in their respective area of specialisation,
adequate experience in the respective fields and requisite knowledge and clarity
about their role and responsibility as committee members.
11. As far as possible, based on the requirement of research area such as Human
Immunodeficiency Virus (HIV) or genetic disorder, specific patient group may
also be represented in the Ethics Committee.
12. No member of an Ethics Committee, having a conflict of interest, shall be
involved in the oversight of the clinical study/research or bioavailability or
bioequivalence study protocol being reviewed by it and all members shall sign a
declaration to the effect that there is no conflict of interest.
13. While considering an application which involves a conflict of interest of any
member of the Ethics Committee, such member may voluntarily withdraw from
the Ethics Committee review meeting, by expressing the same in writing, to the
Chairperson.
14. The details in respect of the conflict of interest of the member shall be duly
recorded in the minutes of the meetings of the Ethics Committee.

2.4.2.3 Terms of Reference

The EC members should be made aware of their role and responsibilities as

committee members. Any change in the regulatory requirements should be brought
to their attention and they should be kept abreast of all national and international
developments in this regard. The Terms of References should also include a
statement on Terms of Appointment with reference to the duration of the term of
membership, the policy for removal, replacement and resignation procedure etc.
Each Committee should have its own standard operating procedures available with

35
 each member.

2.4.2.4 Review Procedures

The Ethics Committee should review every research proposal on human participants.
It should ensure that a scientific evaluation has been completed before ethical review
is taken up. The Committee should evaluate the possible risks to the participants
with proper justification, the expected benefits and adequacy of documentation for
ensuring privacy, confidentiality, and justice issues. The ethical review should be
done through formal meetings and should not resort to decisions through circulation
of proposal.

2.4.2.5 Submission of Application

The researcher should submit an appropriate application to the EC in a prescribed
format along with the study protocol at least three weeks in advance. The protocol
should include the following:

1. Clear research objectives and rationale for undertaking the investigation in

human participants in the light of existing knowledge.
2. Recent curriculum vitae of the Investigators indicating qualification and
experience.
3. Participant/subject recruitment procedures.
4. Inclusion and exclusion criteria for entry of participants in the study.
5. Precise description of methodology of the proposed research, including
intended dosages and routes of administration of drugs, planned duration of
treatment and details of invasive procedures if any.
6. A description of plans to withdraw or withhold standard therapies in the course
of research.

7. The plans for statistical analysis of the study.

8. Procedure for seeking and obtaining informed consent with sample of patient
information sheet and informed consent forms in English and vernacular
languages.
9. Safety of proposed intervention and any drug or vaccine to be tested, including
results of relevant laboratory and animal research.
10. For research carrying more than minimal risk, an account of plans to provide
medical therapy for such risk or injury or toxicity due to over-dosage should
be included.
11. Proposed compensation and reimbursement of incidental expenses.
12. Storage and maintenance of all data collected during the study/research.
13. Plans for publication of results - positive or negative - while maintaining the
privacy and confidentiality of the study participants.
14. A statement on probable ethical issues and steps taken to tackle the same.
15. All other relevant documents related to the study protocol including regulatory
clearances.
16. Agreement to comply with national and international GCP protocols for clinical
study/research.
17. Details of Funding agency / Sponsors and fund allocation for the proposed
work.

36
 18. Statement on conflict of interest, if any
19. Relevant administrative approvals (such as HMSC approval for International trials, if
applicable)
20. Indemnity policy, clearly indicating the conditions of coverage, date of commencement
and date of expiry of coverage of risk (if applicable)
21. Insurance policy (it is preferable to have the policy and not only the insurance
certificate)for study participants indicating conditions of coverage, date of
commencement and date of expiry of coverage of risk (if applicable)

2.4.2.6 Decision Making Process

The EC should be able to provide complete and adequate review of the research
proposals submitted to them It should meet periodically at frequent intervals to
review new proposals, evaluate annual progress of ongoing ones and assess final
reports of all research activities involving human beings through a previously
scheduled agenda, amended wherever appropriate.

a. The decision must be taken by a broad consensus after the quorum requirements
are fulfilled to recommend / reject / suggest modification for a repeat review or
advice appropriate steps. The Member Secretary should communicate the
decision in writing.
b. A member must voluntarily withdraw from the EC while making a decision on
an application which evokes a conflict of interest which should be indicated in
writing to the chairperson prior to the review and should be recorded so in the
minutes.
c. If one of the members has her/his own proposal for review, then the member
should not participate when the project is discussed.
d. A negative decision should always be supported by clearly defined reasons.
e. An EC may decide to reverse its positive decision on a study in the event of
receiving information that may adversely affect the benefit/risk ratio.
f. The discontinuation of a study/research should be ordered if the EC finds that
the goals of the study/research have already been achieved midway or
unequivocal results are obtained.
g. In case of premature termination of study, notification should include the
reasons for termination along with the summary of results conducted till date.
h. The following circumstances require the matter to be brought to the attention of
EC :
i. any amendment to the protocol form the originally approved protocol with
proper justification;
ii. serious and unexpected adverse events and remedial steps taken to tackle
them;
iii. any new information that may influence the conduct of the study.
i. If necessary, the applicant/investigator may be invited to present the protocol or
offer clarifications in the meeting. Representative of the patient groups or
interest groups can be invited during deliberations to offer their viewpoint.
j. Participant/subjectexperts may be invited to offer their views but should not
take part in the decision-making process. However, her/his opinion must be
recorded.
k. Meetings are to be minuted which should be approved and signed by the
Chairperson.

37
2.4.2.8 Interim Review
The EC should decide and record the special circumstances and the mechanism
when an interim review can be resorted-to instead of waiting for the scheduled time
of the meeting. However, decisions taken should be brought to the notice of the main
committee. This can be done for the following reasons:
i) re-examination of a proposal already examined by the EC;
ii) research study of a minor nature such as examination of case records etc.;
iii) an urgent proposal of national interest.

2.4.2.9 Record Keeping

All documentation and communication of an EC are to be dated, filed and
preserved according to written procedures. Strict confidentiality is to be maintained
during access and retrieval procedures. Records should be maintained for the
following:
i. the Constitution and composition of the EC;
ii. the curriculum vitae of all EC members;
iii. standing standard operating procedures of the EC;
iv. national and international guidelines;
v. copies of the Protocol, data collection formats, CRFs, investigational brochures
etc. submitted for review;
vi. all correspondence with EC members and investigators regarding application,
decision and follow up;
vii. agenda of all EC meetings;
viii. minutes of all EC meetings with signature of the Chairperson;
ix. copies of decisions communicated to the applicants;
x. record of all notification issued for premature termination of a study with a
summary of the reasons;
xi. final report of the study including microfilms, CDs and Video- recordings.

It is recommended that all records must be safely maintained after the completion /
termination of the study for at least a period of 5 years if it is not possible to
maintain the same permanently.

2.4.2.10 Special Considerations

While all the above requirements are applicable to biomedical research as a whole
irrespective of the speciality of research, there are certain specific concerns
pertaining to specialised areas of research which require additional safe guards /
protection and specific considerations for the EC to take note of. Examples of such
instances are research involving children, pregnant and lactating women,
vulnerable participants and those with diminished autonomy besides issues
pertaining to commercialisation of research and international collaboration. The
observations and suggestions of EC should be given in writing in unambiguous
terms in such instances.

2.4.3 Informed Consent Process

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2.4.3.1. Informed Consent of Participant
Prior to the beginning of the Study the Investigator(s) should obtain the Ethics
Committee’s approval for the written informed consent form and all information
being provided to the Participants and / or their legal representatives or guardians
as well as an impartial witness.

None of the oral and written information concerning the Study, including the
written informed consent form, should contain any language that causes the
Participant(s) or their legal representatives or guardians to waive or to appear to
waive their legal rights, or that releases or appears to release the Investigator, the
Institution, the Sponsor or their representatives from their liabilities for any
negligence.

The information should be given to the Participants and / or their legal

representatives or guardians in a language and at a level of complexity that is
understandable to the Participant(s) in both written and oral form, whenever
possible.

Participants, their legal representatives or guardians should be given ample

opportunity and time to enquire about the details of the Study and all questions
answered to their satisfaction.

The Investigator(s), Sponsor or staff of the Institution should not coerce or unduly
influence a potential Participant/subjectto participate or to continue to participate in
the Study. Careful consideration should be given to ensuring the freedom of
consent obtained from members of a group with a hierarchical structure- such as
medical, pharmacy and nursing students, subordinate hospital and laboratory
personnel, employees of the pharmaceutical industry, and members of the armed
forces. Persons with incurable diseases, in nursing homes, in detention, unemployed
or impoverished, in emergency rooms, homeless persons, nomads, refugees and
any ethnic or racial minority groups should be considered as vulnerable population
whose mode of consent should be carefully considered and approved by the Ethics
Committee.

Prior to the Participant’s participation in the Study the written Informed Consent
form should be signed and personally dated by

1. (i) The Participant/subjector (ii) if the Participant/subjectis incapable of giving

an Informed Consent for example children, unconscious or suffering from severe
mental illness or disability, by the Participant’s legal representative or guardian or
(iii) if the Participant/subjectand his legal representative or guardian is unable to
read / write,
2. An impartial witness who should be present during the entire informed consent
discussion
3. The Investigator

By signing the consent form the witness attests that the information in the consent
form and any other written information was accurately explained to, and apparently
understood by, the Participant/subjector the Participant’s legal representative or the
guardian, and that informed consent was freely given by the Participant/subjector

39
 the Participant’s legal representative or the guardian.

The Participant’s legal representative or guardian (if the participant/subjectis

incapable of giving an Informed Consent for example children, unconscious or
suffering from severe mental illness or disability), the inclusion of such patients in
the study may be acceptable if the ethics committee is in principle, in agreement,
and if the investigator thinks that the participation will promote the welfare and
interest of the Participant. The agreement of a legal representative or the guardian
that participation will promote the welfare and interest of the
Participant/subjectshould also be recorded with dated signature. If, however,
neither the signed Informed Consent nor the witnessed signed verbal consent are
possible – this fact must be documented stating reasons by the Investigator and also
brought to the knowledge of Ethics Committee without any delay.

2.4.3.2. Essential information for prospective research on participants

Before requesting an individual's consent to participate in research, the investigator

must provide the individual with the following information in the language he or she
is able to understand which should not only be scientifically accurate but should
also be sensitive to their social and cultural context :

i. the aims and methods of the research;

ii. the expected duration of the participant/subjectparticipation;
iii. the benefits that might reasonably be expected as an outcome of research to the
participant/subjector to others;
iv. any alternative procedures or courses of treatment that might be as advantageous
to the participant/subjectas the procedure or treatment to which she/he is being
participanted;
v. any foreseeable risk or discomfort to the participant/subjectresulting from
participation in the study;
vi. right to prevent use of his/her biological sample (DNA, cell-line, etc.) at any
time during the conduct of the research;
vii. the extent to which confidentiality of records could be able to safeguard,
confidentiality and the anticipated consequences of breach of confidentiality;
viii. free treatment for research related injury by the investigator / institution;
ix. compensation of participants for disability or death resulting from such injury;
x. freedom of individual / family to participate and to withdraw from research any
time without penalty or loss of benefits which the participant/subjectwould
otherwise be entitled to;
xi. the identity of the research teams and contact persons with address and phone
numbers;
xii. foreseeable extent of information on possible current and future uses of the
biological material and of the data to be generated from the research and if the
material is likely to be used for secondary purposes or would be shared with
others, clear mention of the same;
xiii. risk of discovery of biologically sensitive information;
xiv. publication, if any, including photographs and pedigree charts.

The quality of the consent of certain social groups requires careful consideration as

40
 their agreement to volunteer may be unduly influenced by the Investigator.

2.4.3.3. Essential Information on Confidentiality for Prospective Research Participants

Safeguarding confidentiality - The investigator must safeguard the confidentiality

of research data, which might lead to the identification of the individual
participants. Data of individual participants can be disclosed only in a court of law
under the orders of the presiding judge or in some cases may be required to
communicate to drug registration authority or to health authority. Therefore, the
limitations in maintaining the confidentiality of data should be anticipated and
assessed.

P2.4.5 Reimbursement/payment for Participation

Participants may be paid for the inconvenience and time present, and should be
reimbursed for expenses incurred, in connection with their participation in research.
They may also receive free medical services. However, payments should not be so
large or the medical services so extensive as to induce prospective participants to
consent to participate in research against their better judgement (inducement). All
payments, reimbursement and medical services to be provided to research
participants should be approved by the EC. Care should be taken:

i. when a guardian is asked to give consent on behalf of an incompetent person, no

remuneration should be offered except a refund of out of pocket expenses;
ii. when a participant/subjectis withdrawn from research for medical reasons
related to the study the participant/subjectshould get the benefit for full
participation;
iii. when a participant/subject withdraws for any other reasons, he/she should
be paid in proportion to the amount of participation.

Academic institutions conducting research in alliance with industries / commercial

companies require a strong review to probe possible conflicts of interest between
scientific responsibilities of researchers and business interests (e.g. ownership or
part-ownership of a company developing a new product). In cases where the review
board/committee determines that a conflict of interest may damage the scientific
integrity of a project or cause harm to research participants, the board should advise
accordingly. Institutions need self-regulatory processes to monitor, prevent and
resolve such conflicts of interest. Prospective participants in research should also
be informed of the sponsorship of research, so that they can be aware of the
potential for conflicts of interest and commercial aspects of the research. Undue
inducement through compensation for individual participants, families and
populations should be prohibited. This prohibition however, does not include
agreements with individuals, families, groups, communities or populations that
foresee technology transfer, local training, joint ventures, provision of health care
reimbursement, costs of travel and loss of wages and the possible use of a
percentage of any royalties for humanitarian purposes.

41
2.4.5.1 Selection of Special Groups as Research Participant/subjectPregnant or nursing women

Pregnant or nursing women should in no circumstances be the participant/subjectof

any research unless the research carries no more than minimal risk to the fetus or
nursing infant and the object of the research is to obtain new knowledge about the
foetus, pregnancy and lactation. As a general rule, pregnant or nursing women
should not be participants of any clinical study/research except such study/research
as are designed to protect or advance the health of pregnant or nursing women or
foetuses or nursing infants, and for which women who are not pregnant or nursing
would not be suitable participants.

a) The justification of participation of these women in clinical study/research

would be that they should not be deprived arbitrarily of the opportunity to
benefit from investigations, drugs, vaccines or other agents that promise
therapeutic or preventive benefits. Example of such study/research are, to test
the efficacy and safety of a drug for reducing perinatal transmission of HIV
infection from mother to child, study/research for detecting fetal abnormalities
and for conditions associated with or aggravated by pregnancy etc. Women
should not be encouraged to discontinue nursing for the sake of participation in
research and in case she decides to do so, harm of cessation of breast feeding to
the nursing child should be properly assessed except in those studies where breast
feeding is harmful to the infant.
b) Research related to termination of pregnancy: Pregnant women who desire to
undergo Medical Termination of Pregnancy (MTP) could be made participants
for such research as per as per The Medical Termination of Pregnancy Act,
GOI, 1971. and Medical Termination of Pregnancy (Amendment) Act, 2021.
c) Research related to pre-natal diagnostic techniques: In pregnant women such
research should be limited to detect the foetal abnormalities or genetic disorders
as per the The Pre-Conception and Pre-Natal Diagnostic Techniques
(Prohibition Of Sex Selection) Act (PCPNDT Act) 2003.

2.4.5.2 Children

Before undertaking study/research in children the investigator must ensure that -

a. children will not be involved in research that could be carried out equally well
with adults;
b. the purpose of the research is to obtain knowledge relevant to health needs of
children. For clinical evaluation of a new drug the study in children should
always be carried out after the phase III clinical study/research in adults. It can
be studied earlier only if the drug has a therapeutic value in a primary disease of
the children;
c. a parent or legal guardian of each child has given proxy consent;
d. the assent of the child should be obtained to the extent of the child's capabilities
such as in the case of mature minors, adolescents etc;
e. research should be conducted in settings in which the child and parent can
obtain adequate medical and psychological support;
f. interventions intended to provide direct diagnostic, therapeutic or preventive
benefit for the individual child participant/subject must be justified in relation
to anticipated risks involved in the study and anticipated benefits to society;

42
 g. the child's refusal to participate in research must always be respected unless
there is no medically acceptable alternative to the therapy provided/tested,
provided the consent has been obtained from parents/guardian;
h. interventions that are intended to provide therapeutic benefit are likely to be at
least as advantageous to the individual child participant/subject as any available
alternative interventions;
i. the risk presented by interventions not intended to benefit the individual child
participant/subject is low when compared to the importance of the knowledge
that is to be gained.

2.4.5.3 Vulnerable participants

Effort may be made to ensure that individuals or communities invited for research
be selected in such a way that the burdens and benefits of the research are equally
distributed.

a. research on genetics should not lead to racial inequalities; persons who are
economically or socially disadvantaged should not be used to benefit those
who are better off than them; rights and welfare of individual with intellectual
disability, mentally challenged and mentally differently able persons who are
incapable of giving informed consent or those with behavioral disorders must
be protected.
b. Adequate justification is required for the involvement of participants such as
prisoners, students, subordinates, employees, service personnel etc. who have
reduced autonomy as research participants.

2.4.6 Clinical trials with marginalized community

Marginalization refers to individuals or groups who are kept at or pushed beyond the
edges of society. In India, members of particular groups experience multiple socio-
economic disadvantages which limits their access to health and healthcare. Some of
the prominent factors on the basis of which individuals are discriminated in India are
structural factors, age, disability, mobility and stigma that act as barriers to health
and healthcare.
Besides this there are certain groups in Indian society that are subject to
discriminatory treatment and feel marginalized. They need special attention to avoid
exploitation as they belong to the vulnerable groups who are unable to acquire and
use their rights.

2.4.7 Compensation in case of injury or death in clinical study/research or

bioavailability or bioequivalence study of new drug or investigational new drug.

(1) Where any death of a study/research participant/subjectoccurs during a clinical

study/research or bioavailability or bioequivalence study, the legal heir of the
study/research participant/subjectshall be provided financial compensation by the
sponsor or its representative, who has obtained permission to conduct the clinical
study/research or bioavailability or bioequivalence study, in accordance with the
procedure specified in rule 42 of NDCT rule.

43
 (2) Where permanent disability or any other injury occurs to a study/research
participant/subjectduring a clinical study/research or bioavailability or
bioequivalence study, the study/research participant/subjectshall be provided
financial compensation by the sponsor or its representative, who has obtained
permission to conduct the clinical study/research or bioavailability or bioequivalence
study, in accordance with the procedure specified in rule 42 NDCT rule.

(3) The financial compensation referred to in sub-rule (1) or sub-rule (2) shall be in
addition to any expenses incurred on medical management of the study/research
participant.

(4) In the event of an injury, not being permanent in nature, the quantum of
compensation shall be commensurate with the loss of wages of the
participant/subjectas provided in the Seventh Schedule of NDCT rules.

(5) The sponsor or its representative shall give an undertaking along with the
application for clinical study/research permission to the Central Licensing Authority
to provide compensation in the case of clinical study/research related injury or death
for which participants are entitled to compensation.

(6) Where the sponsor or its representative, who has obtained permission to conduct
clinical study/research or bioavailability or bioequivalence study, fails to provide
financial compensation, as referred to in sub-rule (1) or sub-rule (2), the Central
Licensing Authority shall, after affording an opportunity of being heard, by an order
in writing, suspend or cancel the clinical study/research or bioavailability or
bioequivalence study or restrict the sponsor including its representative, who has
obtained permission to conduct clinical study/research or bioavailability or
bioequivalence study, to conduct any further clinical study/research or
bioavailability or bioequivalence study or take any other action for such period as
considered appropriate in the light of the facts and circumstances of the case.

2.4.7.1 Medical Management in clinical study/research or bioavailability and bioequivalence

study of new drug or investigational new drug

(1) Where an injury occurs to any participant/subjectduring clinical study/research or

bioavailability and bioequivalence study of a new drug or an investigational new
drug, the sponsor, shall provide free medical management to such
participant/subjectas long as required as per the opinion of investigator or till such
time it is established that the injury is not related to the clinical study/research or
bioavailability or bioequivalence study, as the case may be, whichever is earlier.

(2) The responsibility for medical management as referred to in sub-rule (1), shall be
discharged by the sponsor or the person who has obtained permission from the
Central Licensing Authority.

(3) Where the sponsor or its representative, who has obtained permission to conduct
clinical study/research or bioavailability or bioequivalence study, fails to provide
medical management, as referred to in sub-rule (1), the Central Licensing Authority
shall after affording an opportunity of being heard, by an order in writing, suspend
or cancel the clinical study/research or bioavailability or bioequivalence study or

44
 restrict the sponsor including its representative, who has obtained permission to
conduct clinical study/research or bioavailability or bioequivalence study, to conduct
any further clinical study/research or bioavailability or bioequivalence study or take
any other action for such period as considered appropriate in the light of the facts
and circumstances of the case.

2.4.7.2 Consideration of injury or death or permanent disability to be related to clinical

study/research or bioavailability and bioequivalence study

Any injury or death or permanent disability of a study/research

participant/subjectoccurring during clinical study/research or bioavailability or
bioequivalence study due to any of the following reasons shall be considered as
clinical study/research or bioavailability or bioequivalence study related injury or
death or permanent disability, namely:-
(a) adverse effect of the investigational product;
(b) violation of the approved protocol, scientific misconduct or negligence by the
sponsor or his representative or the investigator leading to serious adverse event;
(c) failure of investigational product to provide intended therapeutic effect where,
the required standard care or rescue medication, though available, was not
provided to the participant/subjectas per clinical study/research protocol;
(d) not providing the required standard care, though available to the
participant/subjectas per clinical study/research protocol in the placebo controlled
study/research;
(e) adverse effects due to concomitant medication excluding standard care,
necessitated as part of the approved protocol;
(f) adverse effect on a child in-utero because of the participation of the parent in the
clinical study/research;
(g) any clinical study/research procedures involved in the study leading to serious
adverse event.

2.4.7.3 Procedure for compensation in case of injury or death during clinical study/research,
bioavailability, and bioequivalence study

(1) The investigator shall report all serious adverse events to the Central Licencing
Authority, the sponsor or its representative, who has obtained permission from the
Central Licencing Authority for conduct of clinical study/research or bioavailability
or bioequivalence study, as the case may be, and the Ethics Committee that accorded
approval to the study protocol, within twenty-four hours of their occurrence; and if
the investigator fails to report any serious adverse event within the stipulated period,
he shall have to furnish the reasons for delay to the satisfaction of the Central
Licencing Authority along with the report of the serious adverse event.

(2) A case of serious adverse event of death shall be examined in the following
manner, namely:-
(i) the Central Licencing Authority shall constitute an independent expert committee
to examine the cases and make its recommendations to the said authority for arriving
at the cause of death and quantum of compensation in case of clinical study/research
related death;
(ii) the sponsor or its representative and the investigator shall forward their reports
on serious adverse event of death after due analysis to the Central Licencing

45
Authority and the head of the institution where the clinical study/research or
bioavailability or bioequivalence study has been conducted within fourteen days of
the knowledge of occurrence of serious adverse event of death;
(iii) the Ethics Committee for clinical study/research shall forward its report on
serious adverse event of death after due analysis along with its opinion on the
financial compensation, if any, determined in accordance with the formula specified
in the Seventh Schedule, to be paid by the said sponsor or its representative, who has
obtained permission from the Central Licencing Authority for conduct of clinical
study/research or bioavailability or bioequivalence study, as the case may be, to the
Central Licencing Authority within a period of thirty days of receiving the report of
the serious adverse event of death from the investigator;
(iv) the Central Licencing Authority shall forward the report of the investigator,
sponsor or its representative and the Ethics Committee to the Chairperson of the
expert committee;
(v) the expert committee shall examine the report of serious adverse event of death
and make its recommendations available to the Central Licencing Authority for the
purpose of arriving at the cause of the serious adverse event of death within sixty
days from the receipt of the report of the serious adverse event, and the expert
committee while examining the event, may take into consideration, the reports of the
investigator, sponsor or its representative and the Ethics Committee for clinical
study/research;
(vi) in case of clinical study/research or the bioavailability or bioequivalence study
related death, the expert committee shall also recommend the quantum of
compensation, determined in accordance with the formula specified in the Seventh
Schedule of NDCT rule 2019, to be paid by the sponsor or his representative who
has obtained the permission to conduct the clinical study/research or the
bioavailability or bioequivalence study, as the case may be;
(vii) the Central Licencing Authority shall consider the recommendations of the
expert committee and shall determine the cause of death with regards to the
relatedness of the death to the clinical study/research or the bioavailability or
bioequivalence study, as the case may be;
(viii) in case of clinical study/research or the bioavailability or bioequivalence study
related death, the Central Licencing Authority shall, after considering the
recommendations of the expert committee, by order, decide the quantum of
compensation, determined as per the formula specified in the Seventh Schedule, to
be paid by the sponsor or its representative and shall pass orders as deemed
necessary within ninety days of the receipt of the report of the serious adverse event;
(ix) the sponsor or its representative shall pay the compensation in case the serious
adverse event of death is related to clinical study/research or the bioavailability or
bioequivalence study, as specified in the order referred to in clause (viii) of the
Central Licencing Authority within thirty days of the receipt of such order.

(3) Cases of serious adverse events of permanent disability or any other injury other
than deaths shall be examined in the following manner, namely:
(i) the sponsor or its representative, and the Investigator shall forward their reports
on serious adverse event, after due analysis, to the Central Licencing Authority,
chairperson of the Ethics Committee for clinical study/research and head of the
institution where the study/research or bioavailability or bioequivalence study has
been conducted within fourteen days of the reporting of serious adverse event;
(ii) the Ethics Committee for clinical study/research shall forward its report on

46
 serious adverse event of permanent disability or any other injury other than deaths,
as the case may be, after due analysis along with its opinion on the financial
compensation, if any, determined in accordance with the formula specified in the
Seventh Schedule, to be paid by the sponsor or its representative who has obtained
permission to conduct clinical study/research or the bioavailability or bioequivalence
study, as the case may be, within thirty days of receiving the report of the serious
adverse event;
(iii) the Central Licencing Authority shall determine the cause of the injury and pass
order as specified in clause (iv), or may constitute an independent expert committee,
wherever it considers necessary, to examine such serious adverse events of injury,
and such independent expert committee shall recommend to the Central Licencing
Authority for the purpose to arrive at the cause of the serious adverse event and also
the quantum of compensation, as determined in accordance with formula as
specified in the Seventh Schedule in case of clinical study/research or bioavailability
or bioequivalence study related injury, within a period of sixty days of receipt of the
report of the serious adverse event;
(iv) in case of clinical study/research or the bioavailability or bioequivalence study
related injury, the Central Licencing Authority shall, by order, decide the quantum of
compensation, determined in accordance with the formula specified in the Seventh
Schedule, to be paid by the sponsor or his representative who has obtained the
permission to conduct the clinical study/research or the bioavailability or
bioequivalence study, as the case may be, within a period of ninety days of receipt of
the report of the serious adverse event;
(v) the sponsor or its representative, who has obtained permission to conduct the
clinical study/research or bioavailability or bioequivalence study, as the case may be,
shall pay the compensation in case of clinical study/research or bioavailability or
bioequivalence study related injury, as specified in the order of the Central
Licencing Authority referred to in clause (iv) within thirty days of receipt of such
order.

2.4.7.4 Medical management and compensation for injury or death relating to biomedical and
health research overseen by an Ethics Committee for biomedical and health research

Notwithstanding anything contained in these rules, medical management and

compensation for injury or death relating to biomedical and health research,
overseen by an Ethics Committee for clinical study/research as referred to in Chapter
IV of NDCT rules shall be in accordance with the National Ethical Guidelines for
Biomedical and Health Research Involving Human Participants specified by the
Indian Council of Medical Research from time to time.

47
 RESPONSIBILITIES

3.1 Sponsor:

3.1.1 Investigator and clinical study site Selection:

The Sponsor is responsible for selecting the Investigator(s) / Institutions taking into
account the appropriateness and availability of the study site and facilities. The
Sponsor must assure itself of the Investigator’s qualifications (including training and
experience) and availability for the entire duration of the Study. If organisation of a
co-ordinating committee and / or selection of co-ordinating investigators are to be
utilised in multi-centric studies their organisation and / or selection are Sponsor’s
responsibilities, and their roles should be documented prior to their involvement in
the study/research.

Before entering an agreement with an Investigator(s) and/or Institution(s) to conduct

a Study, the Sponsor should provide the Investigator(s)/ Institution(s) with the
Protocol and an up-to-date Investigator’s Brochure or basic product information
(e.g., prescribing information, package insert, summary of product characteristics
etc.). Sponsor should provide sufficient time to Investigator(s) to review the Protocol
and the information provided.

3.1.2 Agreement/ Contract:

The Sponsor should enter into a formal and legal agreement/ contract with the
Investigator(s)/ Institution(s) and, where applicable, service provider on the
following terms:
a) To conduct the Study in compliance with GCP, the applicable regulatory
requirements and the Protocol agreed to by the Sponsor and given approval/
favourable opinion by the Ethics Committee
b) To comply with the procedures for data recording, and reporting
c) To permit monitoring, auditing and inspection by sponsors, ECs, regulatory
authorities (domestic and foreign) including providing direct access to source
records and facilities, including to those of service providers
d) To retain the study related essential records for the required retention period in
accordance with NDCT rules or until the Sponsor informs the Investigator(s) /
Institution(s) in writing that these documents are no longer needed, whichever is
longer
The agreement should define the relationship between the investigator and the
sponsor in matters such as financial support, fees, honorarium, payments in kind
etc.

Agreements made by the sponsor with the investigator and/or institution, service
providers and any other parties (e.g., independent data monitoring committee
(IDMC), adjudication committee) involved with the clinical study/research should
be documented prior to initiating the activities.

Agreements should be updated when necessary to reflect significant changes in the

activities delegated.

In study/research with more than one sponsor, the sponsors should have a

48
 documented agreement that sets out their respective responsibilities, in accordance
with local regulatory requirements and/or practice. Where the documented
agreement does not specify to which sponsor a given responsibility is attributed,
that responsibility lies with all sponsors.

3.1.3 Sponsor Oversight

a) The sponsor should ensure that the study/research design and study/research
conduct, the process undertaken, and the information and data generated are of
sufficient quality to ensure reliable study/research results, study/research
participant’s safety and appropriate decision making.
b) The sponsor should ensure that study/research processes are conducted in
compliance with the study/research protocol and related documents as well as
with applicable regulatory requirements and ethical standards.
c) The sponsor should determine necessary study/research-specific criteria for
classifying protocol deviations as important (i.e., those that impact the rights,
safety and well-being of study/research participants and the reliability of
results).
d) Decisions related to the study/research should be appropriately assessed for
their impact on participant’s rights, safety and well-being and the reliability
of study/research results. Risks related to such decisions should be suitably
managed throughout the planning, conduct and reporting of the
study/research.
e) The range and extent of oversight measures should be fit for purpose and
tailored to the complexity of, and risks associated with the study/research.
The selection and oversight of investigators and service providers are
fundamental features of the oversight process. Oversight by the sponsor
includes quality assurance and quality control processes relating to the
study/research-related activities of investigators and service providers.
f) The sponsor should ensure appropriate and timely escalation and follow-up
of issues to allow the implementation of appropriate actions in a timely
manner.
g) The sponsor may consider establishing an IDMC to assess the progress of a
clinical study/research including the safety data and the efficacy endpoints at
intervals and to recommend to the sponsor whether to continue, modify or
stop a study/research.
h) Where appropriate, sponsors may also establish an endpoint
assessment/adjudication committee in certain study/research to review
important endpoints reported by investigators to determine whether the
endpoints meet protocol-specified criteria. Such committees should typically
be blinded to the assigned treatments when performing their assessments,
regardless of whether the study/research itself is conducted in a blinded
manner, to ensure that the data reviewed by committee are as free of bias as
possible.
i) Committees established for purposes that could impact
participant/subjectsafety or the reliability of study/research results should
include members with relevant expertise and with managed conflicts of
interest, have written standard operating procedures (e.g., charters) and
document their decisions.
j) Standard Standard operating procedures : The Sponsor should ensure t h a t

49
 detailed Standard Standard operating procedures are available for the
conduct of study/research.

3.1.4. Allocation of activities

Prior to initiating a Study the Sponsor should define and allocate all Study related
activities to the respective identified person(s) / organisation(s). The sponsor
should utilise appropriately qualified individuals for the activities to which they
are assigned (e.g., biostatisticians, clinical pharmacologists, physicians, data
scientists/data managers, auditors and monitors) throughout the study/research
process.

3.1.4.1 Medical Expertise

The sponsor should have medical personnel readily available who will be able to
advise on specific study/research-related medical questions or problems as
applicable.

3.1.5 Study management, data handling and record keeping

The Sponsor is responsible for securing agreement with all involved parties on the
allocation of Protocol related and other responsibilities like (as applicable):
a) Access to all Study related sites, source data / documents and reports for the
purpose of inspection, monitoring and auditing by the authorised parties and
inspection by national and foreign regulatory authorities
b) Data processing
c) Breaking of the Code
d) Statistical analysis
e) Preparation of the Study Report
f) Preparation and submission of materials to the Ethics Committee, Regulatory
Authorities and any other review bodies
g) Reporting the ADRs, AEs to the Ethics Committee
h) Establishing, implementing and maintaining appropriate quality assurance and
quality control processes and documented procedures to ensure that study/research
are conducted and data are generated, recorded and reported in compliance with the
protocol, GCP and the applicable regulatory requirement(s).

The sponsor should ensure that all aspects of the study/research are operationally
feasible and should avoid unnecessary complexity, procedures and data collection.
Protocols, data acquisition tools and other operational documents should be fit for
purpose, clear, concise and consistent, when applicable.

When using computerised systems in a clinical study/research, the sponsor should:

(i) have a record of the computerised systems used in a clinical study/research. This
should include the use, functionality, interfaces and validation status of each
computerised system, and who is responsible for its management should be
described. The record should also include a description of implemented access
controls and internal and external security measures; (ii) ensure that the requirements
for computerised systems deployed by the sponsor (e.g., requirements for validation,
audit trails, user management, backup, disaster recovery and IT security) are
addressed and implemented and that documented procedures and adequate training
are in place to ensure the correct development, maintenance and use of
computerised systems in clinical study/research. These requirements should be

50
 proportionate to the importance of the computerised system and the data or activities
they are expected to process;

It shall be the responsibility of sponsor to make arrangements for safe and secure
custody of all study related documents and material for a period of five years after
the completion of the study or after submission of the data to the regulatory
authority(ies), whichever is later.

The sponsor should not make changes to data entered by the investigator or
study/research participants unless justified and documented by the sponsor and
agreed upon by the investigator.
The sponsor should allow correction of errors to data, including data entered by
participants, where requested by the investigators/participants. Such data corrections
should be justified and supported by source records.
The sponsor should ensure that the investigator has access to data collected in
accordance with the protocol during the course of the study/research including
relevant data from external sources, for example, central laboratory data, centrally
read imaging data and, if appropriate, ePRO data that are necessary to enable the
investigators to make decisions (e.g., on eligibility, treatment, continuing
participation in the study/research and care for the safety of the individual
study/research participants). The sponsor should pay special attention to data that
may unblind the investigator and include the appropriate provisions in the protocol.
The sponsor should ensure that the investigator receives instructions on how to
navigate systems, data and relevant metadata for the study/research participants
under their responsibility.
The sponsor should document the data management steps to be undertaken prior to
data analysis. These steps may vary depending on the purpose of the analysis to be
conducted (e.g., data for IDMC, for interim analysis or the final analysis).
Prior to provision of the data for analysis, edit access to the data acquisition tools
should be restricted as appropriate to the purpose of the analysis; for example, for
interim analysis, the restriction may only be temporary or managed differently
compared to the final analysis.
The sponsor should use an unambiguous study/research
participant/subjectidentification code (see glossary term) that allows identification of
all the data reported for each participant.
The sponsor should ensure that study/research data are protected from unauthorised
access, disclosure, dissemination or alteration and from inappropriate destruction or
accidental loss.

3.1.6 Reimbursement/payment for Participation

Participants may be paid compensation for participation in accordance with the
guidelines listed in 2.4.5. The sponsor should provide insurance or should
indemnify (legal and financial coverage) the investigator/the institution against
claims arising from the study/research, except for claims that arise from
malpractice and/or negligence. Payment should be such that it is not seen as undue
inducement and approved by ethics committee.

3.1.7 Confirmation of review by the Ethics Committee

51
 The Sponsor shall obtain from the Investigator(s) and/ or the Institutions
a) The particulars about Ethics Committee registration issued by CDSCO
b) EC should be registered by Department of Health Research (DHR) through
Naitik portal for biomedical and health research
c) Documented approval/ favourable opinion of the Ethics Committee before the
initiation of the Studyatio
d) A copy of the recommendations in case the Ethics Committee conditions its
approval upon change(s) in any aspect of the Study such as modification(s) of
the Protocol, written Informed Consent Form, any other written information
and / or other procedures
e) Ethics Committee’s documents relating to re-evaluations/ re-approvals with
favourable opinion, and of any withdrawals or suspensions of approval/
favourable opinion

3.1.8 Information on Investigational Products

As a prerequisite to planning of a Study, the Sponsor is responsible for providing the
Investigator(s) with an Investigator’s Brochure or basic product information (e.g.
prescribing information, package insert, summary of product characteristics etc.).
The Brochure must contain the available chemical, pharmaceutical, toxicological,
pharmacological, and clinical data including the available data from previous and
ongoing clinical studies regarding the Investigational Product and, where
appropriate, the Comparator Product. This information should be accurate and
adequate to justify the nature, scale and the duration of the Study. In addition, the
Sponsor must bring any relevant new information arising during the period of Study
to the attention of the Investigator(s) as well as the Ethics Committee.

3.1.9 Supply, storage and handling of Pharmaceutical Products

The Sponsor is responsible for supplying the Investigational Product’s, including
Comparator(s) , Rescue medication(s) and Placebo if applicable. The Products
should be manufactured in accordance with the principles of GMPs and they should
be suitably packaged in the manner that will protect the product from deterioration
and safeguard blinding procedures (if applicable) and should be affixed with
appropriate investigational labelling. Manufacturing and labelling of Investigational
product(s) should comply with NDCT rules.

The Sponsor should determine the Investigational Product’s acceptable storage

conditions, reconstitution procedures and devices for product infusions if any, and
communicate them in writing to all involved parties (e.g., investigators, monitors,
pharmacists, storage managers etc.), besides stating them on the Product labels
wherever possible.

In case any significant formulation changes are made in the Investigational Product
during the course of the Study - the results of any additional studies of the new
formulation (e.g. stability, bioavailability, dissolution rate) should be provided to
the involved parties to enable them to determine their effects on the
pharmacokinetic profile of the Product prior to the use in the Study.

The Sponsor should not supply an Investigator / Institution with the Product until
the Sponsor obtains all required documentation (e.g. approval / favourable opinion
from respective Ethics Committee and study approval from Regulatory

52
 Authorities).
The Sponsor should document procedures and lay down responsibilities for
a. adequate and safe receipt, handling, storage, dispensing of the Product
b. retrieval of unused Product from the Participants and
c. return of unused Product to the Sponsor (or its alternative disposal procedure if
authorised by the sponsor).

Sponsor should maintain records for retrieval of Product (e.g. retrieval after study
completion, expired product retrieval etc.).

Sponsor should also maintain records of the quantities of Investigational Product

with proper batch numbers. The Sponsor should ensure that the Investigator is able
to establish a system within his / her Institution for proper management of the
Products as per the procedures.

The Sponsor should maintain sufficient samples from each batch and keep the
record of their analyses and characteristics for reference, so that if necessary an
independent laboratory may be able to recheck the same. The samples do not need
to be kept by the sponsor in study/research where an authorised medicinal product
is used as an investigational product unmodified from its authorised state, since
samples are kept by the manufacturer.

In blinded study/research, the sponsor should implement:

i. a process to blind the sponsor staff, study/research participant/subjectand/or
investigator as appropriate to the investigational product identity and
assignment to prevent and detect inappropriate unblinding;
ii. a procedure and mechanism that permits the investigator to rapidly identify the
product(s) in case of a medical emergency where unblinding is considered
necessary, while protecting the identity of the treatment assignment of the other
study/research participants;
iii. a mechanism that protects the blinding of the study/research where a
participant’s treatment assignment is unblinded for the purpose of safety
reporting to regulatory authorities and/or EC, where appropriate.

3.1.10 Safety assessment and reporting:

Sponsor is responsible for the ongoing safety evaluation of the Product. The
Sponsor should notify all concerned (e.g.investigator, regulatory authority etc), in a
timely manner, of findings that could adversely affect the safety of the Participants,
impact the conduct of the Study or alter the Ethics Committee’s approval /
favourable opinion to continue the Study. The Sponsor, together with
Investigator(s), should take appropriate measures necessary to safeguard the study
participants.

Safety Reporting
Any report of the serious adverse event, after due analysis shall be forwarded by
the sponsor to the Central Licencing Authority, the Chairperson of the ethics
committee and the head of the institution where the study/research has been
conducted, within fourteen days of knowledge of occurrence of the serious adverse
event as specified in Table 5 of Third Schedule NDCT Rules.

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3.1.11 Study Reports
The Sponsor should ensure the preparation and appropriate approval(s) of a
comprehensive final clinical study report suitable for regulatory and / or marketing
purposes, whether or not the study has been completed. All reports prepared should
meet the standards of the ICH E3 and/or NDCT rules for Format and Content of
Clinical Study Reports. The sponsor should also submit any safety updates and / or
periodic reports as prescribed by the regulatory authorities.

3.1.12 Audit
Sponsor should perform an audit as a part of QA system. This audit should be
conducted with the purpose of being independent and separate from routine
monitoring or quality control functions. Audit should evaluate the study conduct
and compliance with the protocol, SOPs, GCPs and applicable regulatory
requirements. For the purpose of carrying out the audit – the sponsor may appoint
individuals qualified by training and experience to conduct audits. The Auditors
should be independent of the parties involved in the study and their qualifications
should be documented.

The Sponsor should ensure that the auditing is conducted in accordance with the
Sponsor’s SOPs on what to audit, how to audit (i.e. on-site or remote), the frequency
of audit and the form & content of audit reports. Auditors should document their
observations which should be archived by the Sponsors and made available to the
Regulatory Authorities when called for.

Sponsor should initiate prompt action in case it is discovered that any party
involved has not entirely complied with the GCP, SOPs, Protocol and / or any
applicable regulatory requirements. If monitoring / auditing identifies serious and/
or persistent non-compliance - the Sponsor should terminate the defaulting party’s
participation in the study and promptly notify to the regulatory authority.

3.1.13 Premature Termination or Suspension of a Study

In case the sponsor chooses to or is required to terminate prematurely or suspend
the study, then the sponsor should notify the investigator(s), institution(s) and the
regulatory authority(ies) accordingly. The EC should also be informed promptly by
the investigator/institution. The notification should document the reason(s) for the
termination or suspension by the sponsor or by the investigator / institution.

3.1.14 Transfer of activities to Service Provider(s)

If the sponsor is a foreign company, organisation or person(s) – it shall appoint a
local representative or Service provider(s) to fulfil the appropriate local
responsibilities as governed by the national regulations. The Sponsor may transfer
any or all of the Sponsor’s study related duties and functions to a service provider
but the ultimate responsibility for the quality and the integrity of the Study Data
shall always reside with the Sponsor. Any Study related duty, function or
responsibility transferred to and assumed by a local representative, or a service
provider should be specified in writing. Any Study related duties, functions or
responsibilities not specifically transferred to and assumed by a service provider, or
a local representative shall be deemed to have been retained by the Sponsor.

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 The sponsor is responsible for assessing the suitability of and selecting the service
provider to ensure that they can adequately undertake the activities transferred to
them. The sponsor should provide the service providers with the protocol where
necessary as well as any other documents required for them to perform their
activities.

The sponsor should have access to relevant information (e.g., SOPs and
performance metrics) for selection and oversight of service providers. The sponsor
should ensure appropriate oversight of important study/research-related activities
that are transferred to service providers and further subcontracted.

The sponsor should provide information to the investigator on any service provider
identified by the sponsor to undertake any activities under the responsibility of the
investigator. However, the responsibility for such activities ultimately remains with
the investigator. Study/research-related activities performed by service providers
should be conducted in accordance with relevant GCP requirements, which may be
fulfilled by a service provider’s existing processes.

3.2 The Monitoring

The sponsor should determine the appropriate extent and nature of monitoring, based
on identified risks. Factors such as the objective, purpose, design, complexity,
blinding, number of study/research participants, investigational product, current
knowledge of the safety profile and endpoints of the study/research should be
considered. The sponsor must appoint adequately trained monitors or service
provider to supervise an ongoing study.

The monitor is the principal communication link between the sponsor and the
investigator and other parties and individuals involved in the study/research conduct
(e.g., centrally performed activities). In general, each site should have an assigned
monitor as their contact point.
Monitoring activities may include site monitoring (performed on-site or remotely)
and centralised monitoring, depending on the monitoring strategy and the design of
the clinical study/research.

3.2.1 Qualifications
The monitor should have adequate pharmaceutical and / or scientific qualifications
and clinical study/research experience. Monitors should be thoroughly familiar
with the investigational product(s), the protocol, written informed consent form and
any other written information to be provided to participants, the sponsor’s SOPs,
GCP, and Indian regulatory requirements.

3.2.2 Responsibility
The main responsibility of the monitor is to oversee the progress of the study and to
ensure that the study conduct and data handling comply with the protocol, GCPs and
applicable ethical and regulatory requirements.
a) The Monitor should verify that the investigator(s) have the adequate
qualifications, expertise and the resources to carry out the study.

55
b) Monitor should ascertain that the institutional facilities like laboratories,
equipment, staff, storage space etc. are adequate for safe and proper conduct of
the study and that they will remain available throughout the study.
c) The Monitor should verify (and wherever necessary make provisions to ensure)
that

1. the investigational product(s) are sufficiently available throughout the

study and is stored properly, and are used within their shelf-life
2. the investigational product(s) are supplied only to participants who are
eligible to receive it and at the protocol-specified dose(s), time(s) and
duration
3. the participants, investigator, investigator site staff and other relevant
parties and individuals involved in the study/research conduct are
provided with the necessary instructions on properly using, handling,
storing, returning and destroying, or alternative disposition of the
investigational product(s)
4. the receipt, use, return and destruction, or alternative disposition of the
investigational product(s) at the site are controlled and documented as
prescribed
5. the investigator receives the current Investigator’s Brochure and all
supplies needed to conduct the study as per the protocol
6. the investigator follows the protocol, and confirming that informed consent
was obtained before participation in the study/research for all enrolled
participants at the site
7. the investigator maintains the essential documents
8. all parties involved are adequately informed about various aspects of the
study and follow the GCP guidelines and the prescribed documented
procedures
9. verifying that each party is performing the specified function in accordance
with the protocol and / or in accordance with the agreement between the
sponsor and the party concerned
10. verifying that none of the parties delegate any assigned function to
unauthorised individuals
11. Determining whether adverse events are appropriately reported within the
time periods required by the protocol, GCP and the applicable regulatory
requirement(s).
12. Verifying that the blinding is maintained, where applicable
13. Confirming the arrangement for the retention of the essential records and the
final accountability of the investigational product (e.g., return and destruction
or alternative disposition, if appropriate) during site close-out activity.

d) The monitor should promptly inform the sponsor and the investigator in case any
unwarranted deviation from the protocol or any transgression of the principles
embodied in GCP is noted. Important deviations should be highlighted and
should be the focus of remediation efforts as appropriate.
e) The monitor should follow a pre-determined written set of SOPs. A written
record should be kept of the monitor’s visits, phone calls and correspondence
with the investigators and any other involved parties. The sponsor may develop a
monitoring plan, if required, that is tailored to the identified potential safety risks,

56
 the risks to data quality and/or other risks to the reliability of the study/research
results. Particular attention should be given to procedures relevant to
participant/subjectsafety and to study/research endpoints. The plan should
describe the monitoring strategy, the monitoring activities of all the parties
involved, the various monitoring methods and tools to be used, and the rationale
for their use. The monitoring strategy should ensure appropriate oversight of
study/research conduct and consider site capabilities and the potential burden.
The plan should focus on aspects that are critical to quality. The monitoring plan
should reference the sponsor’s applicable policies and procedures.
f) The monitor should assess the institution(s) prior to the study to ensure that the
premises and facilities are adequate and that an adequate number of participants
is likely to be available during the study.
g) The monitor should observe and report the participant/subjectrecruitment rate to
the sponsor.
h) The monitor should visit the investigator before, during and after the study to
make assessments of the protocol compliance and data handling in accordance
with the predetermined SOPs or monitoring plan
i) The monitor should ensure that all staff assisting the investigator in the study
have been adequately informed about and will comply with the protocol, SOPs
and other details of the study.
j) The monitor should assist the investigator in reporting the data and results of the
study to the sponsor, e.g. by providing guidance on correct procedures for CRF
completion and by providing data verification.
k) The monitor shall be responsible for ensuring that all CRFs are correctly filled
out in accordance with original observations, are legible, complete, and dated.
The monitor should specifically verify that
i. the data required by the protocol and identified as critical are reported
accurately on the CRFs and are consistent with the source documents
ii. any dose and / or therapy modifications are well documented for each
of the study participants
iii. adverse events, concomitant medications and inter-current illnesses are
promptly reported on the CRFs in accordance with the protocol and the
SOPs
iv. visits that the participants fail to make, tests that are not conducted and
examinations that are not performed are clearly reported as such on the
CRFs
v. all withdrawals and drop-outs of enrolled participants from the study
are reported and explained on the CRFs
l) Any deviations, errors or omissions should be promptly clarified with the
investigator, corrected and explained on the CRF. Monitor should also take
appropriate actions designed to prevent recurrence of detected deviations.
Monitor should ensure that investigator certifies the accuracy of CRF by signing
it at the places provided for the purpose. All procedures for ensuring accuracy
of CRFs must be maintained throughout the course of the study.
m) The monitor should submit a written report to the sponsor after each site visit
and after all telephone calls, letters and other correspondence with the
investigator. Monitor’s report should include the date, name of site, names of the
monitor and the individuals contacted, a summary of what the monitor
reviewed, findings, deviations & deficiencies observed, and any actions taken/
proposed to secure compliance. The review and follow-up of the monitoring

57
 report with the sponsor should be documented by the sponsor’s designated
representative.

3.2.3 Investigator Site Monitoring

(a) Monitoring may be performed in relation to the clinical study/research
activities at the investigator sites (e.g., including their pharmacies and
local laboratories, as appropriate). The frequency of monitoring activities
should also be determined based on identified risks. Monitoring activities
and their frequency should be modified as appropriate using knowledge
gained.
(b) This monitoring activity may be performed on-site or remotely depending
on the nature of the activity and its objectives.
(c) Monitoring may include secure, remote, direct read-only access to source
records, other data acquisition tools and essential record retention
systems.

3.2.4Centralised Monitoring

(a) Centralised monitoring is an evaluation of accumulated data, performed

in a timely manner, by the sponsor’s qualified and trained persons (e.g.,
medical monitor, data scientist/data manager, biostatistician).
(b) Centralised monitoring processes provide additional monitoring
capabilities that can complement and reduce the extent and/or frequency of
site monitoring or be used on its own. Use of centralised data analytics
can help identify systemic or site-specific issues, including protocol non-
compliance and potentially unreliable data.
(c) Centralised monitoring may support the selection of sites and/or processes
for targeted site monitoring.

3.3 Investigator

3.3.1 Qualifications, resource, and responsibility

 Qualifications
The investigator should be qualified by education, training and experience to
assume responsibility for the proper conduct of the study and should have
qualifications prescribed by the National Medical Commission (NMC)/Dental
Council of India, in case of Dentist as investigator. The investigator should
provide a copy of the curriculum vitae and / or other relevant documents
requested by the sponsor, the ethics committee, service provider or the regulatory
authorities. The investigator should also ensure that other studies do not divert
essential participants or facilities away from the study at hand.
The investigator should be thoroughly familiar with the safety, efficacy and
appropriate use of the investigational product as described in the protocol,
investigator’s brochure and other information sources provided by the sponsor
from time to time.
The investigator should be aware of and comply with protocol, GCPs, relevant
SOPs and the applicable regulatory requirements.
 Resources
The investigator should be able to demonstrate (e.g., based on retrospective or

58
 currently available data) a potential for recruiting the proposed number of eligible
participants within the recruitment period as agreed with the sponsor.
The investigator should have sufficient time, an adequate number of available
and qualified staff, and adequate facilities for the foreseen duration of the
study/research to conduct the study/research properly and safely.
 Responsibilities
The investigator may delegate study/research-specific activities to other persons
or parties.
The investigator may be supported by the sponsor to identify a suitable service
provider(s); however, the investigator retains the final decision on whether the
service provider intended to support the investigator is appropriate based on
information provided by the sponsor.
The investigator retains the ultimate responsibility and maintains appropriate
supervision of the persons or parties undertaking the activities delegated to
ensure the rights, safety and well-being of the study/research participants and
data reliability.
The investigator should ensure that persons or parties to whom the investigator
has delegated study/research-specific activities are appropriately qualified and
supervised and are adequately informed about the protocol, the investigational
product(s) and their assigned study/research activities (including activities
conducted by staff provided by other parties, for example, home nurses arranged
by the sponsor). Study/research-related training to persons assisting in the
study/research should correspond to what is necessary to enable them to fulfil
their delegated study/research activities that go beyond their usual training and
experience.
Agreements made by the investigator/institution with service providers for
study/research-related activities should be documented.

3.3.2 Medical care of the study participants

A qualified Medical Practitioner (or a Dentist, when appropriate) who is an
Investigator or a Co-/sub-Investigator for the study should be responsible for all
study related medical decisions. Investigator has to ensure that adequate medical
care is provided to a participant/subjectfor any adverse events including clinically
significant laboratory values related to the study. Investigator should inform the
participant/subjectwhen medical care is needed for inter-current illness(es) of which
the investigator becomes aware. Investigator should also inform the participant’s
other attending physician(s) about the participant’s participation in the study if the
participant/subjecthas another attending physician(s) and if the
participant/subjectagrees to such other physician(s). Subsequent to the
completion of the study or dropping out of the participant(s) the investigator should
ensure that medical care and relevant follow-up procedures are maintained as needed
by the medical condition of the participant/subjectand the study and the interventions
made.
Adverse events and/or laboratory abnormalities required for safety evaluations (as
outlined in the protocol) should be reported to the sponsor according to the reporting
requirements and within the time periods specified in the protocol.
Although a participant/subjectis not obliged to give reason(s) for withdrawing
prematurely from a study, the investigator should make a reasonable effort to
ascertain the reason(s) while fully respecting the participant’s rights.

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3.3.3 Monitoring and Auditing of Records
The investigator / institution shall allow monitoring and auditing of the records,
procedures and facilities, by the sponsor, the ethics committee, CRO or their
authorised representative(s) or by the appropriate regulatory authority. The
investigator should maintain a list of appropriately qualified person(s) to whom the
investigator has delegated study-related duties.
Investigator should ensure that all persons involved in the study are adequately
informed about the protocol, SOPs, the investigational product(s) and their study
related duties and functions.

3.3.4 Communication with Ethics Committee

Before initiating a study, the investigator/ institution must ensure that the proposed
study has been reviewed and accepted in writing by the relevant ethics committee(s)
for the protocol, written informed consent form, participant/subjectrecruitment
procedures (e.g. advertisements) and any written/ verbal information to be provided
to the participants.
As part of the investigator's/institution’s written application to the EC, the
investigator/institution should provide the EC with a current copy of the
Investigator's Brochure. If the Investigator's Brochure is updated during the
study/research, the investigator/institution should supply a copy of the updated
Investigator’s Brochure to the EC.
During the study/research the investigator/institution should provide to the EC all
documents participant/subjectto review.
The investigator should promptly report to the ethics committee, the monitor and the
sponsor:
1. deviations from or changes of, the protocol to eliminate immediate hazards
to the participants
2. changes that increase the risk to participant(s) and / or affecting
significantly the conduct of the study
3. all serious adverse events (in addition to regulatory authority)
4. new information that may adversely affect safety of the participants or
the conduct of the study
5. for reported deaths the investigator should supply any additional
information
e.g. autopsy reports and terminal medical reports.

3.3.5 Compliance with the protocol

The investigator / institution must agree and sign the protocol and / or another
legally acceptable document with the sponsor, mentioning the agreement with the
protocol, and confirm in writing that he / she has read and understood the protocol,
GCPs and SOPs and will work as stipulated in them.
The investigator should not implement any deviation from, or changes of the
protocol without agreement by the sponsor and prior review and documented
approval/favourable opinion from the EC of an amendment, except where necessary
to eliminate an immediate hazard(s) to study/research participants, or when the
change(s) involves only logistical or administrative aspects of the study/research
(e.g., change in monitor(s), change of telephone number(s)).The implemented
deviation or change, the reasons for it and if appropriate the proposed protocol
amendment(s) should be submitted by the investigator to the ethics committee (for

60
 review and approval / favourable opinion), to the sponsor (for agreement) and if
required to the regulatory authority(ies). The investigator or person designated by
him/her should document and explain any deviation from the approved protocol.

3.3.6 Investigational Product(s) management

Investigator has the primary responsibility for investigational product(s)
accountability at the study site(s). Investigator should maintain records of the
product’s delivery to the study site, the inventory at the site, the use by each
participant, and the return to the sponsor or the alternative disposal of the
unused product(s). These records should include dates, quantities, batch / serial
numbers, expiry dates if applicable, and the unique code number assigned to the
investigational product packs and study participants. Investigator should maintain
records that describe that the participants were provided the dosage specified by the
protocol and reconcile all investigational products received from the sponsor.
Investigator should ensure that the product(s) are stored under specified conditions
and are used only in accordance with the approved protocol or other document (i.e.
investigational product manual).
The investigator should assign some or all of his / her duties for investigational
product’s accountability at the study site(s) to his subordinate who is under the
supervision of the investigator / institution. The investigator or subordinate should
explain the correct use of the product(s) to each participant/subjectand should check
at intervals appropriate for the study that each participant/subjectis following the
instructions properly. The person who carries them out should document such
periodic checks.

3.3.7 Selection and recruitment of study participants

The investigator is responsible for ensuring the unbiased selection of an adequate
number of suitable participants according to the protocol. It may be necessary to
secure the co-operation of other physicians in order to obtain a sufficient number of
participants. In order to assess the probability of an adequate recruitment rate for
participants for the study it may be useful to determine prospectively or review
retrospectively the availability of the participants. Investigator should check whether
the participant(s) so identified could be included in the study according to the
protocol. The investigator should keep a confidential list of names of all Study
Participants allocated to each study. This list facilitates the investigator / institution
to reveal identity of the participant(s) in case of need and also serve as a proof of
Participant’s existence. The investigator / institution shall also maintain a
Participants’ screening log to document identification of Participants who enter pre-
study screening. A Participant’s enrolment log shall also be maintained to document
chronological enrolment of Participants in a particular Study.
The Investigator is responsible for giving adequate information to participants about
the study/research in accordance with the GCP. The nature of the investigational
product and the stage of development and the complexity of the study should be
considered in determining the nature and extent of the information that should be
provided.

Obligations of investigators regarding informed consent: The investigator has the

duty to -
a) Communicate to prospective participants all the information necessary for
informed consent. There should not be any restriction on participant's right to ask

61
 any questions related to the study as any restriction on this undermines the
validity of informed consent.
b) Exclude the possibility of unjustified deception, undue influence and
intimidation. Deception of the participant/subjectis not permissible However,
sometimes information can be withheld till the completion of study, if such
information would jeopardize the validity of research.
c) Seek consent only after the prospective participant/subjectis adequately informed.
Investigator should not give any unjustifiable participant's decision to participate
in the study.
d) As a general rule obtain from each prospective participant/subjecta signed form
as an evidence of informed consent (written informed consent) preferably
witnessed by a person not related to the study/research, and in case of
incompetence to do so, a legal guardian or other duly authorised representative.
e) Renew the informed consent of each participant, if there are material changes in
the conditions or procedures of the research or new information becomes
available during the ongoing study/research.
f) Not use intimidation in any form which invalidates informed consent. The
investigator must assure prospective participants that their decision to participate
or not will not affect the patient-clinician relationship or any other benefits to
which they are entitled.

As part of the information provided to the Participant, the Investigator should supply
participants with, and encourage them to carry with them, information about their
participation in the study/research and information about contact persons who can
assist in an emergency situation.

3.3.8 Randomisation Procedures and Unblinding

The investigator should follow the study/research’s randomisation procedures, if
any, and, in the case of an investigator-blinded study/research, should ensure that
the identification code is broken only in accordance with the protocol. In the
case of an emergency, to protect patient safety, the investigator should be
prepared and capable from the start of the study/research to perform unblinding
without undue delay and hinderance. The investigator should promptly document
and explain to the sponsor any premature unblinding (e.g., accidental unblinding,
emergency unblinding to protect study/research participant, unblinding due to an
SAE) of the investigational product(s).

3.3.9 Records/Reports
The Investigator should ensure the accuracy, completeness, legibility, and timeliness
of the data reported to the sponsor in the CRFs and in all required reports. Data
reported on the CRF, that are derived from source documents, should be consistent
with the source documents or the discrepancies should be explained.
The investigator/institution should maintain adequate and accurate source documents
and study/research records that include all pertinent observations on each of the
site’s study/research participants. Source data should be attributable, legible,
contemporaneous, original, accurate, and complete. Changes to source data should
be traceable, should not obscure the original entry, and should be explained if
necessary (e.g., via an audit trail).

Any change or correction to the CRF should be dated, signed and explained (if

62
 necessary) and should not obscure the original entry (i.e. an audit trail should be
maintained); this applies to both written and electronic changes or corrections.
Sponsor should provide guidelines to investigators and / or the investigator’s
designated representatives on making such corrections and should have written
procedures to assure that changes in CRFs are documented and endorsed by the
Investigator. The Investigator should retain records of the changes and corrections.
The investigator should have timely access to and be responsible for the timely review
of data, including relevant data from external sources (e.g., central laboratory data,
centrally read imaging data, other institution’s records and, if appropriate, electronic
patient-reported outcome (ePRO) data) which can have an impact on, for example,
participant/subjecteligibility, treatment or safety. The protocol may provide
exceptions for access, for instance, to protect blinding.
Upon request of the monitor, auditor, EC or regulatory authority, the
investigator/institution should make available for direct access all requested
study/research-related records.
The investigator should ensure that data acquisition tools and other systems deployed
by the sponsor for clinical study/research purposes are used as specified in the
protocol or study/research related instructions.
When using computerised systems in a clinical study/research, the
investigator/institution should do the following:
(a) for systems deployed by the investigator/institution, ensure that appropriate
individuals have secure and attributable access;
(b) for systems deployed by the investigator/institution specifically for the purposes
of clinical study/research, ensure that the requirements for computerised systems
are addressed;
(c) where equipment for data acquisition is provided to study/research
participants by the investigator, ensure that traceability is maintained and
participants are provided with appropriate training;
(d) ensure that incidents in the use and operation of computerised systems, which
in their judgement may have a significant and/or persistent impact on the
study/research data, are reported to the sponsor and, where applicable, to the
EC.

Progress Reports
The investigator should submit the written summaries of the study status at the
periodicity as specified by EC, the person(s)/ organisation(s) to whom the
investigator is reporting. All reportings made by the investigator should identify the
participants by unique code numbers assigned to the study participants rather than by
the participants’ name(s), personal identification number(s) and / or addresses.

Termination and final report

In case the investigator and sponsor agree to prematurely terminate or suspend the
study for any reason, the investigator / institution should promptly inform the study
Participants, the Ethics Committee as well as the Regulatory Authorities. The
investigators should also ensure appropriate therapy and follow-up for the
participants.
However, if the investigator or the sponsor or the ethics committee decide to
terminate or suspend the study without prior agreement of all parties concerned then
the party initiating the suspension / termination should promptly inform all the
concerned parties about such suspension / termination and suspension along with a

63
detailed written explanation for such termination / suspension.

The Investigator should maintain documents as specified in the essential documents’

list and take measures to prevent accidental or premature destruction.

The completion of the study should be informed by the investigator to the institution,
the sponsor and the ethics committee. The investigator should sign and forward the
data (CRFs, results and interpretations, analyses and reports, of the study from his /
her centre to the sponsor. Collaborative investigators and those responsible for the
analyses (including statistical analyses) and the interpretation of the results must also
sign the relevant portions of the study report. Investigator should submit his signed
and dated final report to the institution, the ethics committee and the sponsor verifying
the responsibility for the validity of data. In case of a multi-centre study – the
signature of the co-ordinating investigator may suffice if agreed in the protocol. In
case the investigator is the sponsor then he / she assumes the responsibilities of both
the functionaries. The investigator should familiarise himself / herself with the
various other responsibilities assigned to him/her under the protocol and ensure that
they are carried out as expected.

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 RECORD KEEPING AND DATA HANDLING

The basic concept of record-keeping and handling of data is to record, store, transfer, and
where necessary convert efficiently and accurately the information collected on the
study/research participant(s) into data that can be used to compile the Study Report.

4.1. Documentation
All steps involved in data management should be documented in order to allow step-by-
step retrospective assessment of data quality and study performance for the purpose of
audit. Following the SOPs facilitates documentation.
Documentation SOPs should include details of checklists and forms giving details of
actions taken, dates and the individuals responsible etc.

Sponsor should safeguard the blinding, if any, particularly during data entry and
processing. The Sponsor should use an explicit Participant/subjectidentification code
that allows identification of all the data reported for each Participant. Ownership of the
data and any transfer of the ownership of data should be documented and intimated to
the concerned party(ies).

4.2 Corrections
All corrections in the CRFs or any other study related documents should be made in a
way that does not obscure the original entry. The correct data should be inserted with the
reason for the correction if such a reason is not obvious. The corrections should carry
the date and initials of the Investigator or the authorised person.

4. 3 Electronic Data Processing

For electronic data processing only authorised person should be allowed to enter or
modify the data in the computer and there should be a recorded trail of the changes and
deletions made. A security system should be set-up to prevent unauthorised access to
the data. If data is altered during processing the alteration must be documented. The
systems should be designed to permit data changes in such a way that the data changes
are documented and there is no deletion of data once it has been entered. A list of
authorised persons who can make changes in the computer system should be
maintained. Adequate backup of the data should be maintained.

4.4 Validation of Electronic Data Processing Systems

If study/research data are entered directly into the computer there must always be an
adequate safeguard to ensure validation including a signed and dated printout
and backup records. Computerised systems – hardware as well as software - should be
validated and a detailed description of their use be produced and kept up-to-date.

4.4.1 Computerised Systems

As described in sections for the responsibilities of the sponsor, investigator and the
activities of other parties with respect to a computerised system used in clinical
study/research should be clear and documented. In summary, the sponsor is
responsible for ensuring that for computerised systems which they put in place, the
expectations for computerised systems as described in this section are addressed in a
risk proportionate manner. The sponsor should review whether the systems used by
the investigator/institution (e.g., electronic health records and other record keeping

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 systems for source data collection) are fit for purpose in the context of the
study/research. In the event that the investigator/institution deploys systems
specifically for the purposes of conducting clinical study/research, the
investigator/institution should ensure that the expectations are proportionately
addressed and implemented.

The responsible party should ensure that those developing computerised systems for
clinical study/research are aware of the intended purpose and the regulatory
requirements that apply to them.

It is recommended that representatives of intended participant/subjectpopulations and

healthcare professionals are involved in the design of the system, where relevant, to
ensure that computerised systems are suitable for use by the intended user population.

4.4.1.1 Procedures for the Use of Computerised Systems

Documented procedures should be in place to ensure the appropriate use of
computerised systems in clinical study/research for essential activities related to data
collection, handling and management.

4.4.1.2 Training
The responsible party should ensure that those using computerised systems are
appropriately trained in their use.

4.4.1.3 Security of Computerised Systems

The security of the study/research data and records should be managed throughout
the data life cycle. The responsible party should ensure that security controls are
maintained for computerised systems. These controls should include user
management and ongoing measures to prevent, detect and/or mitigate security
breaches. Aspects such as user authentication requirements and password
management, firewall settings, antivirus software, security patching, system
monitoring and penetration testing should be considered. The responsible party
should maintain adequate backup of the data. Procedures should cover the following:
system security measures, data backup and disaster recovery.

4.4.2 Validation of Computerised Systems

The responsible party is responsible for the validation status of the system
throughout its life cycle. The approach to validation of computerised systems should
be based on a risk assessment that considers the intended use of the system; the
purpose and importance of the data/record that is collected/generated, maintained
and retained in the system; and the potential of the system to affect the well-being,
rights and safety of study/research participants and the reliability of study/research
results.

Validation should demonstrate that the system conforms to the established

requirements for completeness, accuracy, and reliability and is consistent with
intended performance. Systems should be appropriately validated prior to use with
adequate change control procedures implemented. Validation of changes should be
based on risk and consider both previously collected and new data.

Both basic system functionality and protocol specific configurations and

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 customisations, including automated data entry checks and calculations, should be
validated. Interfaces between systems should also be defined and validated.
Different degrees of qualification/validation may be needed for bespoke systems,
systems designed to be configured or systems where no alterations are needed.
Where relevant, procedures should cover the following: system design, validation,
and functionality testing; release; setup; installation and change control until
decommissioning. The responsible party should ensure that the computerised
systems used in clinical study/research processes are qualified and validated,
including those developed by other parties. They should ensure that qualification and
validation documentation is maintained and retained.

Validation should generally include defining the requirements and specifications for
the system and their testing, along with the associated documentation, to ensure the
system is fit for purpose, especially for critical functionality, such as randomisation,
dosing and dose titrations and reductions, and collection of endpoint data.
Unresolved issues, if any, should be justified and, where relevant, addressed by
mitigations prior to and/or during the continued use of the system. The
study/research-specific systems (including updates resulting from protocol
amendments) should only be implemented to enable the conduct of the
study/research by the investigator after all necessary approvals for the clinical
study/research have been received.

4.4.3 System Failure

Contingency procedures should be in place to prevent loss or lack of accessibility to
data essential to participant/subjectsafety, study/research decisions or study/research
outcomes.

4.4.4 Technical Support

Where appropriate, there should be mechanisms (e.g., help desk support) in place to
document, evaluate and manage issues with the computerised systems (e.g., raised ,
and there should be periodic review of these cumulative issues to identify those that
are repeated and/or systemic. Defects and issues should be resolved according to
their criticality. Issues with high criticality should be resolved in a timely manner.

4.4.5. User Management

Access controls are integral to computerised systems used in clinical study/research
to limit system access to authorised users and to ensure attributability to an
individual. The security measures should be selected in such a way that they achieve
the intended security and do not unduly impact user-friendliness. Procedures should
be in place to ensure that user access rights are appropriately assigned based on a
user’s duties and functions, blinding arrangements and the organisation to which
users belong. Access rights should be revoked when they are no longer needed.
Authorised users and access privileges should be clearly documented, maintained
and retained. These records should include any updates to a user’s roles, access
rights and permissions, and time of access privileges given (e.g., time stamp).

4.5 Language

All written documents, information and other material used in the Study should be in
a language that is clearly understood by all concerned (i.e. the Participants,

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paramedical staff, Monitors etc.)

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 QUALITY ASSURANCE

Quality Assurance and Quality Control

The Sponsor is responsible for the implementation of a system of quality control and
quality assurance in order to ensure that a study is conducted, and data is generated,
recorded and reported in compliance with the approved Protocol, GCP and other
applicable requirements. Documented Standard Standard operating procedures are a
prerequisite for quality assurance.

All observations and data should be verifiable, for the credibility of the data and to
assure that the conclusions presented are correctly derived from the raw data.
Verification processes must therefore be conducted according to written down
procedures.

Statistically controlled sampling may be an acceptable method of data verification in

each Study. E ach stage of data handling must be monitored to ensure that all data are
reliable and have processed correctly.

Audit must be commissioned by the sponsor and should be conducted by person or

auditors independent of those responsible for the Study. Investigational sites,
facilities, all data and documentation should be available for audit and inspection by
the Sponsor’s auditor as well as by the Regulatory Authority(ies).

The sponsor should adopt a proportionate and risk-based approach to quality

management, which involves incorporating quality into the design of the clinical
study/research (i.e., quality by design) and identifying factors that are likely to have a
meaningful impact on participant’s rights, safety and well-being and the reliability of
the results (i.e., critical to quality factors as described in ICH E8(R1)). The sponsor
should describe the quality management approach implemented in the study/research
in the clinical study/research report (see ICH E3).

Quality assurance should be applied throughout the clinical study/research

and includes implementing strategies to identify potential or actual causes of
serious non-compliance with the protocol, GCP and/or applicable regulatory
requirements, and to enable their corrective and preventive actions.

Audit
When performed, audits should be conducted in a manner that is commensurate with
the risks associated with the conduct of the study/research. The purpose of a
sponsor’s audit is independent assessment of and separate from routine monitoring
or quality control functions.

Selection and Qualification of Auditors

The sponsor should appoint individuals as auditors who are independent of the
clinical study/research being conducted. The sponsor should ensure that the
auditors are qualified, trained and experienced to conduct audits.

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Auditing Procedures
The sponsor should ensure that the audit of clinical study/research/processes is
conducted in accordance with the sponsor’s documented procedures on what to
audit, how to audit (i.e., on-site or remote), the frequency of audits and the form and
content of audit reports. The sponsor’s audit plan, content and procedures for a
study/research audit should be guided by the importance of the study/research in
submissions to regulatory authorities, the number of participants in the
study/research, the type and complexity of the study/research, the level of risks to the
study/research participants and any identified problem(s).

The observations and findings of the auditor(s) should be documented. To preserve

the independence and value of the audit function, the regulatory authority(ies)
should not routinely request the audit reports. Regulatory authority(ies) may
seek access to an audit report on a case-by-case basis when evidence of serious GCP
non-compliance exists or in the course of legal proceedings. When required by
applicable regulatory requirements, the sponsor should provide an audit certificate.

Quality Control
Quality control should be applied to conduct and each stage of the data handling to
ensure that data are reliable and have been processed correctly. Within clinical
study/research, monitoring and data management processes are the main quality
control activities.

The quality control of study activities/procedure and study sites (other than
investigator sites, such as centralised imaging reading facilities), including on site
and/or centralised activities, may be undertaken and reported using a risk-based
approach.

Risk Management
A standardized approach to the identification and management of risk is described
below:

Risk Identification
The sponsor should identify risks that may have a meaningful impact on critical
steps of study and quality aspects of conduct and recording. Risks should be
considered across the processes used in the clinical study/research (e.g., patient
selection, informed consent process, randomisation and investigational product
administration, data handling, and service provider activities).

Risk Evaluation
The sponsor should evaluate potential risks by considering:
a) the likelihood of harm/hazard occurring;
b) the extent to which such harm/hazard would be detectable;
c) the impact of such harm/hazard on study/research
participant/subjectprotection and the reliability of study/research results.

Risk control
Risk control should be proportionate to the risk to participants’ rights, safety
and well-being and the reliability of study/research results. Risk mitigation
activities may be incorporated in protocol design and implementation,

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 monitoring plans, agreements between parties defining roles and responsibilities,
systematic safeguards to ensure adherence to SOPs, and training in processes and
procedures.

The sponsor should set acceptable ranges to support this process within which
variation can be accepted. Where deviation beyond these ranges is detected, an
evaluation should be performed to determine if there is a possible systemic issue and
if action should be initiated.

Risk Communication
The sponsor should communicate the identified risks and mitigating activities, if
applicable, to those who are involved in taking action or are affected by such
activities. Communication also facilitates risk review and continual improvement
during clinical study/research conduct.

Risk Review
The sponsor should periodically review risk control measures to ascertain whether the
implemented quality management activities remain effective and relevant, taking into
account emerging knowledge and experience.

Risk Reporting
The sponsor should summarise and report the risks and the remedial actions
taken in relation to important deviations from the acceptable ranges and
document them in the clinical study/research report.

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 STATISTICS

6.1 Role of a Biostatistician

Involvement of a appropriately qualified and experienced statistician is necessary

in the planning stage as well as throughout the Study. The Bio-statistician’s should
make a statistical model to help the Sponsor, CRO and / or the Investigator in
writing the Protocol. The number of Participants to be included in the study is
determined in relation to the statistical model on which the Protocol is based.

6.2 Study Design

The scientific integrity of a Clinical Study and the credibility of its report depends
on the design of the Study. In comparative studies the Protocol should describe:
1. an rationale for the target difference between treatments that the Study is
being designed to detect, and the power to detect that difference, taking into
account clinical and scientific information and professional judgment on the
clinical significance of statistical differences.
2. measures taken to avoid bias, particularly methods of Randomisation.

6.2.1 Randomisation and blinding:

The key idea of a clinical study/research is to compare groups of patients who differ
only with respect to their treatment. If the groups differ in some other way then the
comparison of treatment gets biased. Randomisation, as one of the fundamental
principles of experimental design, it deals with the possible bias at the treatment
allocation. It ensures that the allocation of treatment to human participants is
independent of their characteristics. Another important benefit of Randomisation is
that statistical methods of analysis are based on what we expect to happen in
random samples from populations with specified characteristics. The Protocol must
state the method used for Randomisation.

The Study should use the maximum degree of blindness that is possible. Study
participants, investigator or any other party concerned with the study may observe
and respond by knowledge of which treatment was given. To avoid such bias it is
often desired that the patient or any other person involved with the study does not
know which treatment was given. Where a sealed code for each individual
treatment has been assigned in a blinded randomized study it should be kept both
at the site of the investigation and with the sponsor.

The Protocol must state the conditions under which the code is allowed to be broken
and by whom. The system of breaking the code should be such that it allows access
to only one Participant’s treatment at a time. The coding system for the
Investigational Product(s) should include a mechanism that permits rapid
identification of the products in case of a medical emergency but does not permit

72
 undetectable breaks of the blinding.

6.3 Statistical Analysis

The type(s) of Statistical Analyses to be used must be clearly identified and should
form basis of the statistical model for the Study. Any subsequent deviation(s)
should be
described and justified in the Final Report. The need and extent of an interim
analysis must be specified in the Protocol. The results of the statistical analyses
should be presented in a manner that is likely to facilitate the interpretation of their
clinical importance, e.g. by estimates of the magnitude of the treatment effect /
difference and confidence intervals rather than sole reliance on significance
testing.

Missing, unused and spurious data should be accounted for during the statistical
analyses. All such omissions must be documented to enable review.

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 SPECIAL CONCERNS

7.1 Clinical Study/research of Vaccines

7.1.1 Phases of Vaccine Study/research

The guidelines to conduct the clinical study/research on investigational vaccines
are similar to those governing a clinical study/research. The phase of these
study/research differ from drug study/research as given below:

Phase I: This refers to the first introduction of a vaccine into a human population
for determination of its safety and biological effects including immunogenicity.
This phase includes study of dose and route of administration and should
involve low risk participants. For example, immunogenicity to hepatitis vaccine
should not be determined in high-risk participants.

Phase II: This refers to the initial study/research examining effectiveness

(immunogenicity) in a limited number of volunteers. Vaccines can be prophylactic
and therapeutic in nature. While prophylactic vaccines are given to normal
participants, therapeutic or curative vaccines may be given to patients suffering
from particular disease.

Phase III: This focuses on assessments of safety and effectiveness in the prevention
of disease, involving controlled study on a larger number of volunteers (in
thousands) in multi-centres.

7.1.2 Guidelines
a) The sponsor and investigator should be aware of the approval process(es)
involved in conduct of clinical study/research of vaccines. They should
familiarize themselves with the guidelines provided by CDSCO, Department of
Biotechnology (DBT) and Ministry of Environment and Genetic Engineering
Approval Committee (GEAC) in the case of vaccines produced by recombinant
DNA technology.
b) Some vaccines that contain active or live-attenuated microorganisms possess a
small risk of producing that particular infection. The participants to be vaccinated
should be informed of the same.
c) The participants in control groups or when participanted to ineffective vaccines
run a risk of contracting the disease.
d) The risks associated with vaccines produced by recombinant DNA techniques are
not completely known. However, for all the recombinant vaccines/products the
guidelines issued by the Department of Biotechnology should be followed.
e) Study/research should be conducted by qualified investigator with the requisite
training and experience and having necessary infrastructure for the laboratory
evaluation of seroconversion.
f) Protocols for such study/research should include appropriate criteria for selection
of participants, plan of frequency of administration of the test vaccine in
comparison to the reference vaccine. It should accompany detailed validation of
testing method to detect the antibody levels.

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 g) It should specify methodology to be adopted for the purpose of testing.
h) The investigator should be provided with Quality Control data of the
experimental batch of the vaccine made for the purpose of clinical study/research.
i) The sponsor should provide the Ethics committee approval of the nodal body
(ies) to carry out clinical study/research with the vaccine.
j) The generic version of new vaccines already introduced in the other markets after
step up clinical study/research including extensive Phase III study/research
should be compared to the reference vaccine with regard to seroconversion in a
comparative manner in a significant sample size.
k) Post Marketing Surveillance (PMS) should be conducted following completion of
seroconversion studies. PMS data should be generated in a significant sample
size sensitive to detect side effects and address other safety issues.
l) Protocols for test of new vaccine should contain a section giving details of steps
of manufacture, in-process quality control measures, storage conditions, stability
data and a flow chart of various steps taken into consideration for manufacture of
vaccine. It should also contain detailed method of quality control procedure with
the relevant references.

7.2 Clinical Study/research of Contraceptives

All procedures for clinical study/research are applicable. Participants should be
clearly informed about the alternative available.

In women where implant has been used as a contraceptive for study/research, a

proper follow up for removal of the implant should be done, whether the
study/research is over, or the participant/subjecthas withdrawn from the
study/research.

Children borne due to failure of contraceptives under study should be followed up

for any abnormalities if the woman does not opt for medical termination of
pregnancy.

7.3 Clinical study/research with surgical procedures/ medical devices

Clinical investigations should be conducted in accordance with the ethical principles

that have their origin in the declaration of Helsinki. These principles protect the
rights, safety and well-being of human participants, which are the most important
considerations and should prevail over interests of science and society. These
principles should be understood, observed, and applied at every step in the clinical
investigation.
a) No person, sponsor, clinical research organization, any other organisation or
investigator, shall conduct any clinical investigation in respect of any
investigational medical device, in human participants except under, and in
accordance with, the permission granted by the Central Licensing Authority
participant/subjectto such conditions in such form and manner as may be
prescribed.
b) Clinical investigation shall be carried out in respect of such investigational
medical devices in such manner as may be prescribed
c) The Central Licensing Authority may, in public interest, abbreviate, defer, or
waive the requirement of conducting clinical investigation for reasons to be

75
 recorded in writing.
d) Medical device requiring clinical investigation but claiming substantial
equivalence to a predicate device shall not be marketed unless the Central
Licensing Authority approves equivalence in such manner as may be prescribed.
e) A device shall be deemed to be substantially equivalent if, in comparison to a
predicate device, it has the same intended use and same technological
characteristics or has the same intended use and different technological
characteristics and also demonstrates that the device is at least as safe and
effective as the predicate device
f) The Ethics committee shall also be the Ethics Committee for the purposes of
clinical investigation and may supervise the conduct of clinical investigation.
g) Where any participant/subjectis injured on account of his participation in the
clinical investigation, the person, sponsor, clinical research organisation, any
other organisation or investigator who has obtained permission for conduct of
investigation shall provide medical management to that participant/subject
h) Where an injury is caused to the participant/subjectin the clinical investigation of
any investigational medical device and such injury is attributable to the use of
investigational medical device, the person, sponsor, clinical research
organisation, any other organisation or investigator who has obtained permission
for conduct of investigation shall provide to that participant/subjectsuch
compensation in such manner as may be prescribed
i) Where death of a participant/subjectis related to clinical investigation and is
attributable to the use of an investigational medical device, the person, sponsor,
clinical research organisation, any other organisation or investigator who has
obtained permission for conduct of investigation shall provide to the legal heir of
that participant, such compensation in such manner as may be prescribed.
j) Every person, sponsor, clinical research organization, any other organization or
investigator conducting a clinical investigation or his agent holding a permission
to conduct clinical investigation shall keep and maintain such data, record,
registers and other documents as may be prescribed and shall furnish such
information as may be required by the Central Licensing Authority or any other
officer authorized by it in this behalf.
k) Every person, sponsor, clinical research organization, any other organization or
investigator conducting a clinical investigation or his agent, as the case may be,
shall, if so required, disclose to the Medical Devices Officer or any other officer
authorized by the Central Licensing Authority the names, addresses and other
particulars of the persons involved in conducting clinical investigation and
participants in such clinical investigation.
l) Whoever himself, or by any other person on his behalf, conducts clinical
investigation of any investigational medical device, without obtaining permission
under Medical Device rules, shall be liable to penal provision as prescribed time
to time by central licensing authority.

7.4 Clinical study/research for Diagnostic Agents - Use of Radio-active Materials

and X- Rays

In human beings, for investigation and treatment, different radiations- X-rays,

gamma rays and beta rays, radio opaque contrast agents and radioactive materials

76
 are used. The relative risks and benefits of research proposal utilizing radioactive
materials or X-rays should be evaluated. Radiation limits for the use of such
materials and X-Rays should be in accordance with the limits set forth by the
regulatory authority (BARC) for such materials. (BARC-Bhabha Atomic Research
Centre, Mumbai).

7.4.1 Guidelines
§ Informed consent should be obtained before any diagnostic procedures.
§ Information to be gained should be gathered using methods that do not expose
participants to more radiation than exposed normally.
§ Research should be performed on patients undergoing the procedures for
diagnostic or therapeutic purposes.
§ Safety measures should be taken to protect research participants and others who
may be exposed to radiation.
§ The protocol should make adequate provisions for detecting pregnancies to avoid
risks of exposure to the embryo.
§ Information to participant/subjectabout possible genetic damage to offspring
should be given.
§ Non-radioactive diagnostic agents are considered as drugs and the same
guidelines should be followed when using them.
§ Ultrasound to be submitted wherever possible.

7.5 Clinical study/research of Herbal Remedies and Medicinal Plants

For the herbal remedies and medicinal plants that are to be clinically evaluated for
use in the Allopathic/modern medicine System and which may later be used in
allopathic hospitals, the procedures laid down by the CDSCO for allopathic drugs
should be followed. This does not pertain to guidelines issued for clinical evaluation
of Ayurveda, Siddha or Unani drugs by experts in those systems of medicine which
may be used later in their own hospitals and clinics. All the general principles of
clinical study/research described earlier pertain also to herbal remedies. However,
when clinical study/research of herbal drugs used in recognized Indian systems of
Medicine and Homoeopathy are to be undertaken in Allopathic Hospitals, physicians
from the concerned system as co-investigators/ collaborators/ members of the expert
group is desirable for designing and evaluating a study.

The investigator should be qualified by education, training, and experience to

assume responsibility for the proper conduct of the study and should have
qualifications prescribed by the Central Council of Indian Medicine (CCIM). While
all the other GCP requirements are applicable to ASU Medicine research irrespective
of the specialty of research, there are certain specific concerns pertaining to
specialised areas of research which require additional safeguards / protection and
specific considerations for the EC to take note of. Examples of such instances are
research involving children, pregnant and lactating women, vulnerable participants,
and those with diminished autonomy besides issues pertaining to commercialisation
of research and international collaboration. The observations and suggestions of EC
should be given in writing in unambiguous terms in such instances.

Panchakarma including Snehana, Swedana, Dhara, Pizhichil and para-surgical

77
 procedures like Ksharasutra, Leech therapy, Agni karma, Hajamat, Hammam, Nutul
Dalk, Riazat, Prachhanna, Rakta mokshana, Tarpana, Vidalaka, Varmam etc. are
special strength areas of ASU systems of medicine. Proper documentation of end
point, procedure, standardization of ASU drug / Patent or Proprietary Medicines
used in the procedures, parameters of evaluation, statistical consideration should be
given special attention while conducting clinical study/research on them.

Informed consent procedures should be followed as in drug study/research. The

patient information sheet should contain information on the procedure to be adopted
in case patient wishes to opt out of the study/research.

ASU Medical Devices: Such ASU devices having proven quality and safety and
intended for internal or external use or for the diagnosis, treatment, mitigation or
prevention of disease or disorders in human beings or animals, as may be specified
from time to time by Central Government through Gazette notification.

7.5.1 Categories of Herbal Products

The herbal products can belong to any of the three categories given below:
a) Traditional knowledge exists about the use of a plant or its extract in the ancient
Ayurveda, Siddha or Unani literature or a plant may actually be regularly used by
physicians of the traditional systems of medicine for a number of years. The
s a m e substance m a y b e clinically evaluated for same indication for which
it is being used or as has been described in the tradional texts.
b) When an extract of a plant or a compound isolated from the plant has to be
clinically evaluated for a therapeutic effect not originally described in the texts of
traditional systems or, the method of preparation is different, it has to be treated as
a new substance or new chemical entity (NCE) and the same type of acute,
subacute and chronic toxicity data will have to be generated as required by the
regulatory authority before it is cleared for clinical evaluation.
c) An extract or a compound isolated from a plant which has never been in use
before and has not ever been mentioned in traditional literature, should be treated
as a new drug, and therefore, should undergo all regulatory requirements before
being evaluated clinically.

7.5.2 Guidelines

It is important that plants and herbal remedies currently in use or mentioned in

literature of recognized Traditional System of Medicine is prepared strictly in the
same way as described in the literature while incorporating cGMP norms for
standardization. It may not be necessary to undertake phase I studies. However, it
needs to be emphasized that since the substance to be tested is already in used in
Indian Systems of Medicine or has been described in their texts, the need for testing
its toxicity in animals has been considerably reduced. Neither would any toxicity
study be needed for phase II study/research unless there are reports suggesting
toxicity or when the herbal preparation is to be used for more than 3 months. It
should be necessary to undertake 4-6 weeks toxicity study in 2 species of animals in
the circumstances pointed out in the preceding sentence or when a larger
multicentric phase III study/research is subsequently planned based on results of
phase II study.

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 Clinical study/research with herbal preparations should be carried out only after
these have been standardized and markers identified to ensure that the substances
being evaluated are always the same. The recommendations made earlier regarding
informed consent, participant, inducements for participation, information to be
provided to the participant, withdrawal from study and research involving children
or persons with diminished autonomy, all apply to study/research on plant drugs also.
These study/research have also got to be approved by the appropriate scientific and
ethics committees of the concerned Institutes. However, it is essential that such
clinical study/research be carried out only when a competent Ayurvedic, Siddha or
Unani physician is a co-investigator in such a clinical study/research. It would
neither ethically acceptable nor morally justifiable, if an allopathic physician,
based on references in ancient literature of above-mentioned traditional systems of
Medicine, carries out clinical evaluation of the plant without any concept or training
in these systems of medicine. Hence, it is necessary to associate a specialist from
these systems and the clinical evaluation should be carried out jointly.
When a Folklore medicine / Ethno-medicine is ready for commercialization after it
has been scientifically found to be effective, then the legitimate rights/ share of the
Tribe or Community from whom the knowledge was gathered should be taken care
of appropriately while applying for the Intellectual Property Rights and / Patents for
the product.

7.6 Clinical study/research of Stem Cell

In recent years, stem cell research has emerged as an important area of biomedical
science. It has potential applications in varied areas of biomedicine including
developmental biology, disease modelling, tissue engineering, drug development,
toxicity testing. Use of stem cells in regenerative medicine holds promise for
improving human health by restoring the function of cells and tissues that are
damaged due to degeneration and/or injury. Like all other medical innovations, basic
and translational research in the field not only requires a sound scientific rationale,
but also needs to take into consideration ethical, legal and social norms. Apart from
challenges of selecting the appropriate stem cells for a particular condition, there are
important concerns related to the use of embryos for creating human embryonic stem
cell (hESC) lines as these may lead to commoditization of human cells and tissues.
Further, there are challenges related to gene editing/modification, human germ-line
engineering and reproductive cloning. Besides, the robust technologies are being
developed for deriving pluripotent stem cells from a variety of sources which may be
easily accessible for clinical applications, often without rationale. The potential
danger of tumorigenicity of stem cells, considering their capacity for unlimited
proliferation, possible risk of contamination and genomic changes arising due to in
vitro manipulations, and limitations related to
immunological tissue incompatibility between individuals are all areas of serious
concern. All of these pose an inherent risk of exploitation of individuals particularly
those belonging to the underprivileged groups. Hence the guidance for stem cell
research, development and its possible application in the frame of clinical
study/research is critical.

Stem cells and their derivatives fall under definition of ‘Drug’ as per the Drugs and
Cosmetics Act 1940, and are categorized as ‘Investigational New Drug (IND)’ or

79
‘Investigational New Entity (INE)’ when used for clinical application. Hence the
principles of bioethics and regulation must be followed accordingly before initiating
clinical study/research. Adequate safeguards must be in place so that recipients of
these cells in clinical study/research are fully protected. Societal concerns regarding
compensation for research related injuries and unforeseen adverse effects are
additional concerns that need to be adequately addressed.

Based on the cell type/tissue of origin, stem cells are classified as ‘Somatic Stem
Cells’ (SSCs), and ‘Embryonic Stem Cells’ (ESCs). SSCs may have a limited
capacity of differentiation and may be multipotent or unipotent, whereas ESCs are
pluripotent. The pluripotent stem cells can also be generated in the laboratory by
reprogramming somatic cells, and the products thus generated are referred to as
‘Induced Pluripotent Stem Cells (iPSCs)’. The regulatory requirements for research
on each of these stem cells depend on their origin and potency.

Stem cells, whether autologous or allogeneic, require variable degree of in vitro or

ex vivo processing before their use for clinical
application/transplantation/translational research. This carries the risk of
contamination and may also lead to alteration in their properties which may vary
according to the degree and type of manipulation. The investigators should follow
the requirements as given in all applicable regulations including D&C Act and rules,
DBT and GEAC. All laboratory procedures should be carried out under aseptic
conditions in a CDSCO certified cGMP (schedule M) and GLP (schedule L 1)
facility for human applications. For preclinical studies on animals, the laboratory
should have GLP certification from the Department of Science and Technology
(DST).

Research involving stem cells can be conducted only after approval both from the
ICSCR (Institutional Committee for Stem Cell Research). Additional approvals as
spelt in may also be necessary depending on the research category. The proposal
should be reviewed ethics committee and EC should invite 2 additional experts in
cell and gene therapy.

Clinical study/research with Gene therapy products:

Gene therapy refers to the technique of using normal functioning gene to treat a
genetic disease either by repairing or replacing or regulating the defective gene.
Gene therapy is classified into somatic cell gene therapy and germline gene therapy.
Somatic cell gene therapy cannot be transferred to the next generation and the two
approaches followed here are ex vivo and in vivo. In germline gene therapy, the
genetically modified cells are transplanted into gametes and vertical transmission
occurs here. Due to ethical and social reasons, germline gene therapy is banned in
India.
GTP is defined as “a biological substance or therapeutic molecule which could
modify the genome, or the extra-genomic DNA or RNA segments (mitochondrial
and episomal).” It also encompasses gene modified or edited cells, tissues, organs.

Scientific and Ethical Considerations in Gene Therapy:

Mutations, insertions, deletions and similar alterations in these genes or its
regulatory elements may result in reduced or absent production of the encoded
proteins, or expression of structurally or functionally abnormal proteins, thereby

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leading to genetic disorders. GTPs work by repairing, replacing or deactivating
dysfunctional disease-causing genes aiming to restore normal function. The
biological and technical complexities of GTPs, their design and production pose
challenges for their translation into clinic.

The scientific considerations for GTPs include selection of appropriate gene delivery
vector/modality for the disease/tissue target, design of the expression cassette to
ensure clinically relevant expression levels, specificity of gene expression to prevent
unwanted side effects or off-target effects and minimising immune reactions of the
host.

The design of preclinical and clinical studies for GTP differ significantly from the
other chemical and biological drugs, because of the complexity of the vector
interaction with the host cells wherein the effects of vector uptake into host cells,
response of the host immune system, the outcome of integration of genetic material
into host chromosomes (in case of lentivirus or gamma-retrovirus) and levels of
transgene expression from the host cells determine the final therapeutic efficiency of
the GTP.

The precautions which should be followed at the various levels of preclinical and
clinical studies of GTP include appropriate selection of vector for gene delivery
depending on the target tissue. The expression cassette should be designed in a such
a way so that only clinically relevant levels must be expressed and gene expression
should be very specific to avoid unwanted adverse effects and off-target effects in
the host. There may be risk of teratogenicity, excessive immune activation and
unwanted mutations (e.g., off-target gene editing) or unwanted host-immune
response to GTP which should be informed to patient in advance.

The scientific and ethical concerns for gene therapy primarily stem from the
profound effect that genes exert on living cells by conferring novel properties and
functions. The GTP ideally should not cause harm such as teratogenicity (e.g.
integration of transgene cassette into tumour suppressor genes), excessive immune
activation (e.g. aberrant CAR-T activity), introduction of unwanted mutations (e.g.
off-target gene editing) or unwanted host immune response to GTP (e.g. neutralising
antibodies to AAV). In addition, such gene augmentation techniques have the
potential for misuse to gain unnatural advantages (e.g. in sports or defence sectors to
enhance physical function) or to select for specific traits in new-borns (designer
babies by gene editing).

All such applications are prohibited unless scientific or ethical justification can be
provided which is acceptable under socio-ethical norms and the laws of the land.

Clinical study/research with Nanoparticles:

Nanoscience is the study of materials which are in nanoscale range. Conversion of
any material in nanoscale results in alteration of its physicochemical, biological,
mechanical, optical, electronic, etc. properties. These newly acquired (novel)
properties of the materials due to conversion into nanoscale can be utilized for
different useful activities.

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Nanopharmaceutical is an emerging field that combines nanotechnology with
pharmaceutical and biomedical science with the goal of targeted drug delivery which
may improve efficacy and safety profile. Alteration of the substance into nanoscale
associated with drug delivery may also significantly alter the pharmacokinetic,
biodistribution and toxicokinetic parameters of the conventional/traditional drugs
raising various concerns related to quality, safety and efficacy of the
nanopharmaceutical products as nanopharmaceuticals have a higher tendency of
tissue sequestration.

Nanopharmaceuticals should be demonstrated clinically through appropriate design,

patient selection hypothesis and biomarkers to exploit the increased permeability and
retention of drug. Clinical development of a nanopharmaceutical using a well
characterized drug delivery system will be successful if the development plan is
designed based on clear understanding of parameters driving the efficacy of the free
drug and the in vivo behavior of the delivery system. Majority of approved
nanopharmaceuticals, especially oncology products, have been designed clinically to
exploit the increased permeability and retention effect. Such effect may minimize
the peak concentration of free drug while increasing the overall bioavailability of the
drug, providing prolong exposure of the drug at the site of action. At times, the
development of a nanopharmaceutical may fail to achieve the clinical end point in
terms of lack of adequate level of efficacy or increased toxicity due to multiple
reasons. Appropriate design of clinical trials based on proper understanding of
accumulation, retention, toxicity and efficacy profile of the agent and correlation
between the in vivo behavior and the delivery system is of paramount importance for
successful assessment of clinical profile of the drug. In general, clinical trials should
be conducted in stages. However, depending on the status of the Active
Pharmaceutical Ingredient (API), whether it is an New Chemical Entity (NCE) or an
approved drug molecule and the nano carrier, clinical trial of appropriate phase may
be conducted on a ‘case by case approach’ basis.

Clinical study/research with food supplements

Different types of clinical trials are designed by manufacturing companies and others
to explore specific product features impacting human health. Food trials are often
designed to evaluate specific marketing claims needing scientific substantiation
while drug trials document the safety and efficacy of a specific drug for a specific
intended use (e.g., to treat, mitigate or cure a human disease). Food trials tend to be
more pragmatic and exploratory as they document human experiences with specific
foods in the context of the human diet while drug trials tend to be more explanatory
as they document specific drug doses and schedules and specific disease responses.
Food trials typically enroll healthy individuals while drug trials enroll patients with a
specific disease type potentially needing the research treatment. Foods are complex
mixtures of ingredients (e.g., plant parts, meats, eggs, chemicals, beverages, whole
meals, etc.) designed to be palatable and which may have the general health effect
under investigation while drugs are highly purified and designed to have a specific
effect on a disease.

All clinical trials should be conducted using Good Clinical Practices (GCP) with
appropriate Human Subject Protections (HSPs) and all products used in human
testing should be produced under Good Manufacturing Practices (GMP) using a

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well-established Quality Management System (QMS). All clinical trial protocols
should clearly define the study objective/s, inclusion/exclusion criteria, treatments
(including stopping rules for high risk products), study measurements and statistical
analyses to be used for data analysis. The study investigator must ensure the study
staff are trained and experienced, treat only appropriate study subject’s and collect
clinical trial data in a manner allowing appropriate evaluation of product effects on
the human subject.
Principles of good clinical trial practices followed are similar between food and drug
clinical trials, including the use of: 1. Safe products for human testing (food grade
products food trials and drug products passing preclinical safety testing for drug
products). Production lines should not introduce unsafe contaminants. Formulations
should be well characterized considering the intended use, appropriate dose, batch
variability and control products (if any). Cellular and animal testing may be required
prior to first in man studies. Properly labeled test products (e.g., placebo should not
be distinguishable from the test product, if the study is blinded) should be used.
Clearly documented shelf life stability during the timeframe of the trial is important.
Appropriate trial designs, including comprehensive reviews of past clinical trials,
Clear study objectives and test methods, Well-defined eligibility criteria (inclusion
and exclusion criteria), Precise dosing schedules (e.g., the minimal effective dose to
avoid side effects), Effective randomization methods (if any), Accurate/validated
performance criteria (e.g., to measure clinical endpoints and to enable specific
statistical plans), Covering outcomes, compliance and adverse events are critical
point to consider. Enrolling study subjects should represent the population of interest
and allowing trial results to be generalizable to entire population of interest. Well-
designed Informed Consent Form is must for any food trial. Trial registration
(Listing prior to trial start) is desired.

Best practices for food clinical trials Effective food clinical trials are highly variable
and often start with the desired claim in mind during the trial design. The food trial
is built around the claim as the rationale for the study. Using thoughtful objectives
and hypotheses based on a thorough review of the scientific literature, the benefits
and risks of the food clinical trials are carefully considered as both safety and
efficacy endpoints are defined in the study protocol.

Best practices for food clinical trials include:

1. Ensuring the claim is relevant for human health and the precise meaning of the
claim has been fully supported by the food clinical trial data
2. Ensuring the quantity/pattern of food consumption is possible as part of a
balanced diet in the target population for the claim
3. Linking the claimed effect to the consumption of the food (e.g., strength,
consistency, specificity, dose-response, biological plausibility, etc. should be fully
considered)
4. Defining effects and outcomes measures clearly –although subjective measures
like cognition, pain, or hunger are more difficult to measure than objective measures
like hemoglobin levels or weight, food trials often use measures involving the
senses: food taste, texture, and feelings of satiety, bloating, GI discomfort, etc.
5. Special considerations and measurements of specific food related items (like the
food matrix for the test material, the background diet, food-related confounding
issues)
6. Considering the totality of the evidence for each specific condition of use

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Compliance is monitored by careful diet analyses and sometimes includes validated
biomarkers of exposure.

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 DISCLOSURE OF SITE SPECIFIC SAFETY/EFFICACY DATA

8.1 Disclosure of site specific safety/efficacy data:

As per ICH GCP, Indian GCP and WHO GCP requirement on reporting of site-specific safety
and efficacy data is to report individual case safety report (ICSR) to Ethics Committee, Sponsor
and Regulatory Agency in specified time period and submit follow up data in the form of follow
up safety reports and CIOMS report. Also, as per CT approval condition, site specific safety data
by way of individual case safety report and adverse event as per Adverse event reporting
requirement of NDCT rules. The same has been communicated to EC and sponsor in the timeline
define in the NDCT rules.

Efficacy data is not being reported by individual site. The efficacy data at the end of the study has
been analyzed at the end of study by statistical plan given in the protocol and compiled clinical
study report comprising of safety and efficacy assessment is being submitted to the regulatory
agencies to the sites and site submit the copy of report to EC. During the comparative clinical
study, if investigator need to know the patient is in which arm active/comparator then Investigator
can break the blind in benefit of the patient health and well being keeping the ethical principles
for Medical Research Involving Human Subjects as per Declaration of Helsinki consideration.

However, that cannot be constituted as efficacy assessment because efficacy data can not be
analyzed on single patient reporting. This need to be validated against the agreed plan/statistical
model given in the study protocol.”

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 APPENDICES

Appendix I

World Medical Association - Declaration of Helsinki

Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and
amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, SomersetWest, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly,Washington, DC, USA, October 2002 (Note of
Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013

Preamble
1. The World Medical Association (WMA) has developed the Declaration of Helsinki
as a statement of ethical principles for medical research involving human
participants, 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 be applied with consideration of all other relevant paragraphs.
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to
physicians. The WMA encourages others who are involved in medical research
involving human participants to adopt these principles.

General Principles
3. 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.”
4. It is the duty of the physician to promote and safeguard the health, well-being and
rights of patients, including those who are Involved in medical research. The
physician's knowledge and conscience are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must include studies involving
human participants.
6. The primary purpose of medical research involving human participants is to
understand the causes, development and effects of diseases and improve preventive,
diagnostic and therapeutic interventions (methods, procedures and treatments). Even
the best proven interventions must be evaluated continually through research for
their safety, effectiveness, efficiency, accessibility and quality.
7. Medical research is participant/subjectto ethical standards that promote and ensure
respect for all human participants and protect their health and rights.
8. While the primary purpose of medical research is to generate new knowledge, this
goal can never take precedence over the rights and interests of individual research
participants.

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9. It is the duty of physicians who are involved in medical research to protect the life,
health, dignity, integrity, right to self-determination, privacy, and confidentiality of
personal information of research participants. The responsibility for the protection of
research participants must always rest with the physician or other health care
professionals and never with the research participants, even though they have given
consent.
10. Physicians must consider the ethical, legal and regulatory norms and standards for
research involving human participants 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
participants set forth in this Declaration.
11. Medical research should be conducted in a manner that minimizes possible harm to
the environment.
12. Medical research involving human participants must be conducted only by
individuals with the appropriate ethics and scientific education, training and
qualifications. Research on patients or healthy volunteers requires the supervision of
a competent and appropriately qualified physician or other health care professional.
13. Groups that are underrepresented in medical research should be provided appropriate
access to participation in research.
14. Physicians who combine medical research with medical care should involve their
patients in research only to the extent that this 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 participants.
15. Appropriate compensation and treatment for participants who are harmed as a result
of participating in research must be ensured.

Risks, Burdens and Benefits

16. In medical practice and in medical research, most interventions involve risks and
burdens. Medical research involving human participants may only be conducted if
the importance of the objective outweighs the risk and burdens to the research
participants.
17. All medical research involving human participants must be preceded by careful
assessment of predictable risks and burdens to the individuals and groups involved
in the research in comparison with foreseeable benefits to them and to other
individuals or groups affected by the condition under investigation. Measures to
minimise the risks must be implemented. The risks must be continuously monitored,
assessed and documented by the researcher.
18. Physicians may not be involved in a research study involving human participants
unless they are confident that the risks have been adequately assessed and can be
satisfactorily managed. When the risks are found to outweigh the potential benefits
or when there is conclusive proof of definitive outcomes, physicians must assess
whether to continue, modify or immediately stop the study.

Vulnerable Groups and Individuals

19. Some groups and individuals are particularly vulnerable and may have an increased
likelihood of being wronged or of incurring additional harm. All vulnerable groups
and individuals should receive specifically considered protection.
20. Medical research with a vulnerable group is only justified if the research is
responsive to the health needs or priorities of this group and the research cannot be

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 carried out in a nonvulnerable group. In addition, this group should stand to benefit
from the knowledge, practices or interventions that result from the research.

Scientific Requirements and Research Protocols

21. Medical research involving human participants 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.
22. The design and performance of each research study involving human participants
must be clearly described and justified 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, potential conflicts
of interest, incentives for participants and information regarding provisions for
treating and/or compensating participants who are harmed as a consequence of
participation in the research study. In clinical study/research, the protocol must also
describe appropriate arrangements for post-study/research provisions.

Research Ethics Committees

23. The research protocol must be submitted for consideration, comment, guidance and
approval to the concerned research ethics committee before the study begins. This
committee must be transparent in its functioning, must be independent of the
researcher, the sponsor and any other undue influence and must be duly qualified. 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 participants 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 amendment to the protocol may be made without consideration and
approval by the committee. After the end of the study, the researchers must submit a
final report to the committee containing a summary of the study’s findings and
conclusions.

Privacy and Confidentiality

24. Every precaution must be taken to protect the privacy of research participants and
the confidentiality of their personal information.

Informed Consent
25. Participation by individuals capable of giving informed consent as participants in
medical research must be voluntary. Although it may be appropriate to consult
family members or community leaders, no individual capable of giving informed
consent may be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human participants capable of giving informed
consent, each potential participant/subjectmust 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, post-study provisions and any other relevant
aspects of the study. The potential participant/subjectmust 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

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 of individual potential participants as well as to the methods used to deliver the
information. After ensuring that the potential participant/subjecthas understood the
information, the physician or another appropriately qualified individual must then
seek the potential participant’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. All medical research participants should be
given the option of being informed about the general outcome and results of the
study.
27. When seeking informed consent for participation in a research study the physician
must be particularly cautious if the potential participant/subjectis in a dependent
relationship with the physician or may consent under duress. In such situations the
informed consent must be sought by an appropriately qualified individual who is
completely independent of this relationship.
28. For a potential research participant/subjectwho is incapable of giving informed
consent, 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 form unless it is intended to promote the health of the group
represented by the potential participant, the research cannot instead be performed
with persons capable of providing informed consent, and the research entails only
minimal risk and minimal burden.
29. When a potential research participant/subjectwho is deemed incapable of giving
informed consent 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
authorised representative. The potential participant’s dissent should be respected.
30. Research involving participants 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 group. In such circumstances the physician must seek informed
consent from the legally authorised 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 participants with a
condition that renders them unable to give informed consent have been stated in the
research protocol and the study has been approved by a research ethics committee.
Consent to remain in the research must be obtained as soon as possible from the
participant/subjector a legally authorised representative.
31. The physician must fully inform the patient which aspects of their 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 adversely affect the patient-physician
relationship.
32. For medical research using identifiable human material or data, such as research on
material or data contained in biobanks or similar repositories, physicians must seek
informed consent for its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracticable to obtain for such
research. In such situations the research may be done only after consideration and
approval of a research ethics committee.

Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested
against those of the best proven intervention(s), except in the following
circumstances: Where no proven intervention exists, the use of placebo, or no

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 intervention, is acceptable; or Where for compelling and scientifically sound
methodological reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary to determine the
efficacy or safety of an intervention and the patients who receive any intervention
less effective than the best proven one, placebo, or no intervention will not be
participant/subjectto additional risks of serious or irreversible harm as a result of not
receiving the best proven intervention. Extreme care must be taken to avoid abuse of
this option.

Post-Study/research Provisions
34. In advance of a clinical study/research, sponsors, researchers and host country
governments should make provisions for post-study/research access for all
participants who still need an intervention identified as beneficial in the
study/research. This information must also be disclosed to participants during the
informed consent process.

Research Registration and Publication and Dissemination of Results

35. Every research study involving human participants must be registered in a publicly
accessible database before recruitment of the first participant.
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations
with regard to the publication and dissemination of the results of research.
Researchers have a duty to make publicly available the results of their research on
human participants and are accountable for the completeness and accuracy of their
reports. All parties should adhere to accepted guidelines for ethical reporting.
Negative and inconclusive as well as positive results must be published or otherwise
made publicly available. Sources of funding, institutional affiliations and conflicts of
interest must be declared in the publication. Reports of research not in accordance
with the principles of this Declaration should not be accepted for publication.

Unproven Interventions in Clinical Practice

37. In the treatment of an individual patient, where proven interventions do not exist or
other known interventions have been ineffective, the physician, after seeking expert
advice, with informed consent from the patient or a legally authorised representative,
may use an unproven intervention if in the physician's judgement it offers hope of
saving life, re-establishing heath or alleviating suffering. This intervention should
subsequently be made the object of research, designed to evaluate its safety and
efficacy. In all cases, new information must be recorded and, where appropriate,
made publicly available.

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 Appendix II

New Drugs and Clinical Trials Rules, 2019 - GENERAL PRINCIPLES AND
PRACTICES FOR CLINICAL STUDY/RESEARCH

GENERAL PRINCIPLES AND PRACTICES FOR CLINICAL STUDY/RESEARCH

1. General Principles
(1) The principles and guidelines for protection of study/research participants as
described in Third Schedule as well as Good Clinical Practices guidelines shall
be followed in conduct of any clinical study/research.
(2) The sponsor and investigator share the responsibilities for the protection of
study/research participant/subjecttogether with ethics committee. The
responsibilities of sponsor, investigator and ethics committee are described in the
Third Schedule.
(3) The results of non-clinical studies or previous clinical study/research should be
sufficient to ensure that the new drugs or investigational new drug is safe for the
proposed clinical study/research.
(4) Throughout the clinical study/research and drug development process, the animal
toxicological data and clinical data generated should be evaluated to ensure their
impact for the safety of the study/research participant.

2. Approach in design and analysis

Clinical study/research should be planned, designed, conducted, analysed and
reported according to sound scientific and ethical principles. Following important
principles should be followed:
a. The primary objective of any clinical study/research should be clearly and
explicitly stated which may include exploratory or confirmatory characterisation
of safety, efficacy, assessment of pharmacokinetic and pharmacodynamic
parameters;
b. The clinical study/research should be designed appropriately so that it provides
the desired information;
c. Appropriate comparator may be utilised to achieve the objective with respect to
primary and secondary end points. Comparison may be made with placebo, no
treatment, active controls or of different doses of the new drug or investigational
new drug;
d. The number of participants to be included in the clinical study/research should be
adequate depending on the nature and objective of the clinical study/research.

3. Development Methodology
(1) Non clinical studies, -

(a) The nature of non-clinical studies and their timing in respect of conduct of
clinical study/research should be determined taking following aspects in to
consideration:
(i) characteristics of the new drug or investigational new drug;
(ii) disease of conditions for which the new drug or investigational new drug is
intended to be indicated;
(iii) duration and exposure in clinical study/research participant;

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 (iv) route of administration.
(b) The detailed requirements of non-clinical studies have been specified in the
Second Schedule.
(c) For first in human studies the dose should be calculated carefully based on the
non-clinical pharmacological, toxicological data generated.

(2) Phases in Clinical Study/research: Clinical drug development generally consists

of four phases (Phase I-IV). The details of these phases are described as under.

(a) 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 humans.
Studies in this phase of development usually have non-therapeutic objectives and
may be conducted in healthy participants or certain types of patients. Drugs with
significant potential toxicity e.g. cytotoxic drugs are usually studied in patients.
Phase I study/research should preferably be carried out by investigators trained in
clinical pharmacology with access to the necessary facilities to closely observe
and monitor the participants. Studies conducted in Phase I, usually intended to
involve one or a combination of the following objectives: -
 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.
 Pharmacokinetics, i.e., characterisation 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.
 Pharmacodynamics: Depending on the drug and the endpoints studied,
pharmacodynamic studies and studies relating to drug blood levels
(pharmacokinetic or pharmacodynamic studies) may be conducted in healthy
volunteer participants 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.
 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.

(b) Phase II
(i) The primary objective of Phase II study/research 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

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 and regimen for Phase III study/research. Doses used in Phase II are usually
(but not always) less than the highest doses used in Phase I.
(ii) 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
study/research.

(c) Phase III

(i) Phase III studies have primary objective of demonstration or confirmation of
therapeutic benefits. 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
drugs.
(ii) For drugs intended to be administered for long periods, study/research
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).
(iii) For new drugs approved outside India, Phase III studies may need to be
carried out if scientifically and ethically justified, 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 participants, Central Licencing 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. In
case of an application of a new drug already approved and marketed in other
country, where local clinical study/research in India is waived off or not
found scientifically justified for its approval for manufacturing first time in
the country, the bioequivalence studies of such drug, as appropriate, is
required to be carried out and the test batches manufactured for the purpose
shall be inspected before its approval.

(d) Phase IV
Phase IV or post marketing study/research of new drugs are performed after
the approval of the drug and
related to the approved indication. Such study/research go beyond the prior
demonstration of the drug’s safety, efficacy and dose definition. Such
study/research might not have been considered essential at the time of new
drug approval due to various reasons such as limitation in terms of patient
exposure, duration of treatment during clinical development of the drug, need
for early introduction of the new drug in the interest of patients etc.

Phase IV study/research include additional drug-drug interaction, dose

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 response or safety studies and study/research design to support use under the
approved indication e.g. mortality or morbidity studies, epidemiological
studies, etc.

(3) Studies in special populations: 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.

(A) Geriatrics
Geriatric patients should be included in Phase III clinical study/research (and
in Phase II study/research, at the Sponsor's option) in meaningful numbers, if_
(a) the disease intended to be treated is characteristically a disease of aging; or
(b) the population to be treated is known to include substantial numbers of
geriatric patients; or
(c) when there is specific reason to expect that conditions common in the
elderly are likely to be encountered; or
(d) when the new drug is likely to alter the geriatric patient's response (with
regard to safety or efficacy) compared with that of the non-geriatric
patient.

(B) Paediatrics
(i) The timing of paediatric 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. For a
drug expected to be used in children, evaluations should be made in the
appropriate age group. When clinical development is to include studies in
children, it is usually appropriate to begin with older children before
extending the study/research to younger children and then infants.
(ii) If the new drug is for diseases predominantly or exclusively affecting
paediatric patients, clinical study/research data should be generated in the
paediatric population except for initial safety and tolerability data, which
will usually be obtained in adults unless such initial safety studies in adults
would yield little useful information or expose them to inappropriate risk.
If the new drug is intended to treat serious or life-threatening diseases,
occurring in both adults and paediatric patients, for which there are
currently no or limited therapeutic options, paediatric population should be
included in the clinical study/research early, following assessment of initial
safety data and reasonable evidence of potential benefit. In circumstances
where this is not possible, lack of data should be justified in detail.
(iii) If the new drug has a potential for use in paediatric patients – paediatric
studies should be conducted. These studies may be initiated at various
phases of clinical development or after post marketing surveillance in
adults if a safety concern exists. In cases where there is limited paediatric
data at the time of submission of application, more data in paediatric
patients would be expected after marketing authorisation for use in
children is granted.
(iv) The paediatric studies should include,
(a) clinical study/research,

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 (b) relative bioequivalence comparisons of the paediatric formulation with
the adult formulation performed in adults, and definitive
pharmacokinetic studies for dose selection across the age ranges of
paediatric patients in whom the drug is likely to be used. These studies
should be conducted in the paediatric patient population with the
disease under study.
(v) If the new drug is a major therapeutic advance for the paediatric population
the studies should begin early in the drug development, and this data
should be submitted with the new drug application.
(vi) For clinical study/research conducted in the paediatric population, the
reviewing ethics committee should include members who are
knowledgeable about paediatric, ethical, clinical and psychosocial issues.

(C) Pregnant or nursing women

(i) Pregnant or nursing women should be included in clinical study/research
only when the drug is intended for use by pregnant or nursing women or
fetuses or nursing infants and where the data generated from women who
are not pregnant or nursing, is not suitable.
(ii) For new drugs intended for use during pregnancy, follow-up data
(pertaining to a period appropriate for that drug) on the pregnancy, foetus
and child will be required. Where applicable, excretion of the drug or its
metabolites into human milk should be examined and the infant should be
monitored for predicted pharmacological effects of the drug.

4. Conduct of Clinical Study/research

Clinical study/research should be conducted in accordance with the principles as

specified in Third Schedule of NDCT rules. Adherence to the clinical
study/research protocol is essential and if amendment of the protocol becomes
necessary the rationale for the amendment shall be provided in the form of a
protocol amendment. Serious adverse events shall be reported during clinical
study/research in accordance with NDCT Rules.

5. Analysis

The results of a clinical study/research shall be analysed according to the plan

specified in the clinical study/research protocol. Safety data should be
appropriately tabulated and all adverse events should be classified according to
their seriousness and causal relationship with the study drug.

6. Reporting

Report of clinical study/research shall be documented in accordance with the

approaches specified in Table 6 of
the Third Schedule. The report shall be certified by the principal investigator or if
no principal investigator is designate then by each of the participating
investigators of the study.

Appendix III. Animal toxicology (Non-clinical toxicity studies)

95
(1) General principles. -
Toxicity studies should comply with the norms of Good Laboratory Practices (GLP).
Briefly, these studies should be performed by suitably trained and qualified staff
employing properly calibrated and standardized equipment of adequate size and capacity.
Studies should be done as per written protocols with modifications (if any) verifiable
retrospectively. Standard standard operating procedures (SOPs) should be followed for all
managerial and laboratory tasks related to these studies. Test substances and test systems
(in-vitro or in-vivo) should be properly characterised and standardized. All documents
belonging to each study, including its approved protocol, raw data, draft report, final
report, and histology slides and paraffin tissue blocks should be preserved for a minimum
of five years after marketing of the drug.
Toxicokinetic studies (generation of pharmacokinetic data either as an integral component
of the conduct of non-clinical toxicity studies or in specially designed studies) should be
conducted to assess the systemic exposure achieved in animals and its relationship to dose
level and the time course of the toxicity study. Other objectives of toxicokinetic studies
include obtaining data to relate the exposure achieved in toxicity studies to toxicological
findings and contribute to the assessment of the relevance of these findings to clinical
safety, to support the choice of species and treatment regimen in nonclinical toxicity
studies and to provide information which, in conjunction with the toxicity findings,
contributes to the design of subsequent non-clinical toxicity studies.

(1.1) Systemic toxicity studies, -

(1.1.1) Single-dose toxicity studies These studies (see Table 1) should be carried out in 2
rodent species (mice and rats) using the same route as intended for humans. In addition,
unless the intended route of administration in humans is only intravenous, at least one more
route should be used in one of the species to ensure systemic absorption of the drug. This
route should depend on the nature of the drug. A limit of 2g/kg (or 10 times the normal
dose that is intended in humans, whichever is higher) is recommended for oral dosing.
Animals should be observed for 14 days after the drug administration, and Minimum
Lethal Dose (MLD) and Maximum Tolerated Dose (MTD) should be established. If
possible, the target organ of toxicity should also be determined. Mortality should be
observed for up to seven days after parenteral administration and up to 14 days after oral
administration. Symptoms, signs and mode of death should be reported, with appropriate
macroscopic and microscopic findings where necessary. LD10 and LD50 should be
reported preferably with 95 percent confidence limits. If LD50 cannot be determined,
reasons for the same should be stated.

The dose causing severe toxic manifestations or death should be defined in the case of
cytotoxic anticancer agents, and the post-dosing observation period should be up to 14
days. Mice should first be used for determination of MTD. Findings should then be
confirmed in rat for establishing linear relationship between toxicity and body surface area.
In case of nonlinearity, data of the more sensitive species should be used to determine the
Phase I starting dose. Where rodents are known to be poor predictors of human toxicity
(e.g., antifolates), or where the cytotoxic drug acts by a novel mechanism of action,
Maximum Tolerated Dose (MTD) should be established in non-rodent species.

(1.1.2) Repeated-dose systemic toxicity studies These studies (see Table 1) should be
carried out in at least two mammalian species, of which one should be a non-rodent. Dose

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ranging studies should precede the 14-, 28-, 90- or 180- day toxicity studies. Duration of
the final systematic toxicity study will depend on the duration, therapeutic indication and
scale of the proposed clinical study/research. If a species is known to metabolise the drug
in the same way as humans, it should be preferred for toxicity studies. In repeated-dose
toxicity studies the drug should be administered seven days a week by the route intended
for clinical use. The number of animals required for these studies, i.e., the minimum
number of animals on which data should be available.

Wherever applicable, a control group of animals given the vehicle alone should be
included, and three other groups should be given graded doses of the drug. The highest
dose should produce observable toxicity; the lowest dose should not cause observable
toxicity but should be comparable to the intended therapeutic dose in humans or a multiple
of it. To make allowance for the sensitivity of the species the intermediate dose should
cause some symptoms, but not gross toxicity or death, and should be placed
logarithmically between the other two doses.

The parameters to be monitored and recorded in long-term toxicity studies should include
PK, PD, behavioural, physiological, biochemical and microscopic observations. In case of
parenteral drug administration, the sites of injection should be participated to gross and
microscopic examination. Initial and final electrocardiogram and fundus examination
should be carried out in the non-rodent species. In the case of cytotoxic anticancer agents
dosing and study design should be in accordance with the proposed clinical schedule in
terms of days of exposure and number of cycles. Two rodent species may be tested for
initiating Phase I study/research. A non-rodent species should be added if the drug has a
novel mechanism of action, or if permission for Phase II, III or marketing is being sought.

For most compounds, it is expected that single dose tissue distribution studies with
sufficient sensitivity and specificity will provide an adequate assessment of tissue
distribution and the potential for accumulation. Thus, repeated dose tissue distribution
studies should not be required uniformly for all compounds and should only be conducted
when appropriate data cannot be derived from other sources. Repeated dose studies may be
appropriate under certain circumstances based on the data from single dose tissue
distribution studies, toxicity and toxicokinetic studies. The studies may be most appropriate
for compounds which have an apparently long half-life, incomplete elimination or
unanticipated organ toxicity.

Notes:
(i) Single dose toxicity study. - Each group should contain at least five animals of either
sex. At least four graded doses should be given. Animals should be exposed to the test
substance in a single bolus or by continuous infusion or several doses within 24 hours.
Animals should be observed for 14 days. Signs of intoxication, effect on body weight,
gross pathological changes should be reported. It is desirable to include histo-pathology of
grossly affected organs, if any.

(i i) Dose- ranging study. - Object ives of this study include the identification of target
organ of toxicity and establishment of Maximum Tolerated Dose (MTD) for subsequent
studies.

a.Rodents. - Study should be performed in one rodent species (preferably rat) by the
proposed clinical route of administration. At least four graded doses including control

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should be given, and each dose group as well as the vehicle control should consist of a
minimum of five animals of each sex. Animals should be exposed to the test substance
daily for 10 consecutive days. Highest dose should be the maximum tolerated dose of
single-dose study. Animals should be observed daily for signs of intoxication (general
appearance, activity and behavior etc), and periodically for the body weight and laboratory
parameters. Gross examination of viscera and microscopic examination of affected organs
should be done.
b. Non-rodents. - One male and one female are to be taken for ascending Phase Maximum
Tolerated Dose (MTD) study. Dosing should start after initial recording of cage-side and
laboratory parameters. Starting dose may be three to five times the extrapolated effective
dose or Maximum Tolerated Dose (MTD) (whichever is less), and dose escalation in
suitable steps should be done every third day after drawing the samples for laboratory
parameters. Dose should be lowered appropriately when clinical or laboratory evidence of
toxicity are observed. Administration of test substance should then continue for 10 days at
the well-tolerated dose level following which, samples for laboratory parameters should be
taken. Sacrifice, autopsy and microscopic examination of affected tissues should be
performed as in the case of rodents.

(iii) 14-28 Day repeated-dose toxicity studies. - One rodent (6-10/sex/group) and one non-
rodent (2-3/sex/group) species are needed. Daily dosing by proposed clinical route at three
dose levels should be done with highest dose having observable toxicity, mid dose between
high and low dose, and low dose. The doses should preferably be multiples of the effective
dose and free from toxicity. Observation parameters should include cage side observations,
body weight changes, food or water intake, blood biochemistry, haematology, and gross
and microscopic studies of all viscera and tissues.

(iv) 90 Days repeated-dose toxicity studies. - One rodent (15-30/sex/group) and one non-
rodent (4-6/sex/group) species are needed. Daily dosing by proposed clinical route at three
graded dose levels should be done. In addition to the control a “high-dose-reversal” group
and its control group should be
also included. Parameters should include signs of intoxication (general appearance, activity
and behavior etc), body weight, food intake, blood biochemical parameters, haematological
values, urine analysis, organ weights, gross and microscopic study of viscera and tissues.
Half the animals in “reversal” groups (treated and control) should be sacrificed after 14
days of stopping the treatment. The remaining animals should be sacrificed after 28 days of
stopping the treatment or after the recovery of signs or clinical pathological changes –
whichever comes later, and evaluated for the parameters used for the main study.

(v) 180-Day repeated-dose toxicity studies. - One rodent (15-30/sex/group) and one non-
rodent (4-6/sex/group) species are needed. At least four groups, including control, should
be taken. Daily dosing by proposed clinical route at three graded dose levels should be
done. Parameters should include signs of intoxication, body weight, food intake, blood
biochemistry, hematology, urine analysis, organ weights, gross and microscopic
examination of organs and tissues.

(1.2) Male fertility study: One rodent species (preferably rat) should be used. Dose
selection should be done from the results of the previous 14 days or 28 days toxicity study
in rat. Three dose groups, the highest one showing minimal toxicity in systemic studies,
and a control group should be taken. Each group should consist of six adult male animals.
Animals should be treated with the test substance by the intended route of clinical use for

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minimum 28 days and maximum 70 days before they are paired with female animals of
proven fertility in a ratio of 1:2 for mating. Drug treatment of the male animals should
continue during pairing. Pairing should be continued till the detection of vaginal plug or 10
days, whichever is earlier. Females getting thus pregnant should be examined for their
fertility index after day 13 of gestation. All the male animals should be sacrificed at the end
of the study. Weights of each testis and epididymis should be separately recorded. Sperms
from one epididymis should be examined for their motility and morphology. The other
epididymis and both testes should be examined for their histology.

(1.3) Female reproduction and developmental toxicity studies: These studies need to be
carried out for all drugs proposed to be studied or used in women of child bearing age.
Segment I, II and III studies (see below) are to be performed in albino mice or rats, and
segment II study should include albino rabbits also as a second test species. On the
occasion, when the test article is not compatible with the rabbit (e.g. antibiotics which are
effective against gram positive, anaerobic organisms and protozoas) the Segment II data in
the mouse may be substituted.

(1.3.1) Female fertility study (Segment I). - The study should be done in one rodent species
(rat preferred). The drug should be administered to both males and females, beginning a
sufficient number of days (28 days in males and 14 days in females) before mating. Drug
treatment should continue during mating and, subsequently, during the gestation period.
Three graded doses should be used, the highest dose (usually the Maximum Tolerated Dose
(MTD) obtained from previous systemic toxicity studies) should not affect general health
of the parent animals. At least 15 males and 15 females should be used per dose group.
Control and the treated groups should be of similar size. The route of administration should
be the same as intended for therapeutic use. Dams should be allowed to litter and their
medication should be continued till the weaning of pups. Observations on body weight,
food intake, clinical signs of intoxication, mating behaviour, progress of gestation or
parturition periods, length of gestation, parturition, postpartum health and gross pathology
(and histopathology of affected organs) of dams should be recorded. The pups from both
treated and control groups should be observed for general signs of intoxication, sex-wise
distribution in different treatment groups, body weight, growth parameters, survival, gross
examination, and autopsy. Histopathology of affected organs should be done.

(1.3.2) Teratogenicity study (Segment II). - One rodent (preferably rat) and one non-rodent
(rabbit) species are to be used. The drug should be administered throughout the period of
organogenesis, using three dose levels as described for segment I. The highest dose should
cause minimum maternal toxicity and the lowest one should be proportional to the
proposed dose for clinical use in humans or a multiple of it. The route of administration
should be the same as intended for human therapeutic use. The control and the treated
groups should consist of at least 20 pregnant rats (or mice) and 12 rabbits, on each dose
level. All foetuses should be participanted to gross examination, one of the foetuses should
be examined for skeletal abnormalities and the other half for visceral abnormalities.
Observation parameters should include: (Dams) signs of intoxication, effect on body
weight, effect on food intake, examination of uterus, ovaries and uterine contents, number
of corpora lutea, implantation sites, resorptions (if any); and for the foetuses, the total
number, gender, body length, weight and gross or visceral or skeletal abnormalities, if any.

(1.3.3) Perinatal study (Segment III). - This study is specially recommended if the drug is
to be given to pregnant or nursing mothers for long periods or where there are indications

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of possible adverse effects on foetal development. One rodent species (preferably rat) is
needed. Dosing at levels comparable to multiples of human dose should be done by the
intended clinical route. At least four groups (including control), each consisting of 15 dams
should be used. The drug should be administered throughout the last trimester of pregnancy
(from day 15 of gestation) and then the dose that causes low foetal loss should be
continued throughout lactation and weaning. Dams should then be sacrificed and examined
as described below. One male and one female from each litter of F1 generation (total 15
males and 15 females in each group) should be selected at weaning and treated with
vehicle or test substance (at the dose levels described above) throughout their periods of
growth to sexual maturity, pairing, gestation, parturition and lactation. Mating performance
and fertility of F1 generation should thus be evaluated to obtain the F2 generation whose
growth parameters should be monitored till weaning. The criteria of evaluation should be
the same as described earlier. Animals should be sacrificed at the end of the study and the
observation parameters should include (Dams) body weight, food intake, general signs of
intoxication, progress of gestation or parturition periods and gross pathology (if any); and
for pups, the clinical signs, sex-wise distribution in dose groups, body weight, growth
parameters, gross examination, survival and autopsy (if needed) and where necessary,
histopathology.

(1.4) Local toxicity- These studies are required when the new drug is proposed to be used
by some special route (other than oral) in humans. The drug should be applied to an
appropriate site (e.g., skin or vaginal mucous membrane) to determine local effects in a
suitable species. Typical study designs for these studies should include three dose levels
and untreated or vehicle control, preferably use of two species, and increasing group size
with increase in duration of treatment. Where dosing is restricted due to anatomical or
humane reasons, or the drug concentration cannot be increased beyond a certain level due
to the problems of solubility, pH or tonicity, a clear statement to this effect should be
given. If the drug is absorbed from the site of application, appropriate systemic toxicity
studies will also be required.

Notes:
(i) Dermal toxicity study - The study may be done in rabbit and Guinea pig . The initial
toxicity study shall be carried out by non-animal alternative tests as given in Organisation
for Economic Cooperation and Development Guidelines. In rabbit and Guinea pig studies,
daily topical (dermal) application of test substance in its clinical dosage form should be
done.; Test material should be applied on shaved skin covering not less than 10% of the
total body surface area. Porous gauze dressing should be used to hold liquid material in
place. Formulations with different concentrations (at least 3) of test substance, several fold
higher than the clinical dosage form should be used. Period of application may vary from
seven to 90 days depending on the clinical duration of use. Where skin irritation is grossly
visible in the initial studies, a recovery group should be included in the subsequent
repeated-dose study. Local signs (erythema, oedema and eschar formation) as well as
histological examination of sites of application should be used for evaluation of results.

(ii) Photoallergy or dermal photo-toxicity - It should be tested by Armstrong or Harber test

in guinea pig. This test should be done if the drug or a metabolite is related to an agent
causing photosensitivity or the nature of action suggests such a potential (e.g., drugs to be
used in treatment of leucoderma). Pretest in eight animals should screen four
concentrations (patch application for two hours ±15 min.) with and without UV exposure
(10J/cm2). Observations recorded at 24 and 48 hours should be used to ascertain highest

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non-irritant dose. Main test should be performed with 10 test animals and five controls.
Induction with the dose selected from pretest should use 0.3 ml/patch for 2 hour ±15 min.
followed by 10 J/cm2 of UV exposure. This should be repeated on day 0, 2,4,7,9 and 11 of
the test. Animals should be challenged with the same concentration of test substance
between day 20 to 24 of the test with a similar 2-hour application followed by exposure to
10 J/cm2 of UV light. Examination and grading of erythema and oedema formation at the
challenge sites should be done 24 and 48 hours after the challenge. A positive control like
musk ambrett or psoralin should be used.

(iii) Vaginal toxicity test - Study is to be done in rabbit or dog. Test substance should be
applied topically (vaginal mucosa) in the form of pessary, cream or ointment. Six to ten
animals per dose group should be taken. Higher concentrations or several daily
applications of test substance should be done to achieve multiples of daily human dose.
The minimum duration of drug treatment is seven days (more according to clinical use),
participant/subjectto a maximum of 30 days. Observation parameters should include
swelling, closure of in troit us and histopathology of vaginal wall.

(iv) Rectal tolerance test - For all preparations meant for rectal administration this test may
be performed in rabbits or dogs. Six to ten animals per dose group should be taken.
Formulation in volume comparable to human dose (or the maximum possible volume)
should be applied once or several times daily, per rectally, to achieve administration of
multiples of daily human dose. The minimum duration of application is seven days (more
according to clinical use), participant/subjectto a maximum of 30 days. Size of
suppositories may be smaller, but the drug content should be several folds higher than the
proposed human dose. Observation parameters should include clinical signs (sliding on
backside), signs of pain, blood or mucus in faeces, condition of anal region or sphincter,
gross and (if required) histological examination of rectal mucosa.

(v) Parenteral drug s- For products meant for intravenous or intramuscular or

subcutaneous or intradermal injection the sites of injection in systemic toxicity studies
should be specially examined grossly and microscopically. If needed, reversibility of
adverse effects may be determined on a case-to-case basis.

(vi) Ocular toxicity studies (for products meant for ocular instillation) - These studies
should be carried
out in two species, one of which should be the albino rabbit which has a sufficiently large
conjunctival sac. Direct delivery of drug onto the cornea in case of animals having small
conjunctival sacs should be ensured. Liquids, ointments, gels or soft contact lenses
(saturated with drug) should be used. Initial single dose application should be done to
decide the exposure concentrations for repeated-dose studies and the need to include a
recovery group. Such initial toxicity studies shall be carried out by non-animal alternative
tests as given in Organisation for Economic Cooperation and Development Guidelines.
Duration of the final study will depend on the proposed length of human exposure
participant/subjectto a maximum of 90 days. At least two different concentrations
exceeding the human dose should be used for demonstrating the margin of safety. In acute
studies, one eye should be used for drug administration and the other kept as control. A
separate control group should be included in repeated-dose studies. Slit-lamp examination
should be done to detect the changes in cornea, iris and aqueous humor. Fluorescent dyes
(sodium fluorescein, 0.25 to 1.0%) should be used for detecting the defects in surface
epithelium of cornea and conjunctiva. Changes in intra-ocular tension should be monitored

101
by a tonometer. Histological examination of eyes should be done at the end of the study
after fixation in Davidson's or Zenker's fluid.

(vii) Inhalation toxicity studies - The studies are to be undertaken in one rodent and one
non-rodent species using the formulation that is to be eventually proposed to be marketed.
Acute, subacute, and chronic toxicity studies should be performed according to the
intended duration of human exposure. Standard systemic toxicity study designs (described
above) should be used. Gases and vapours should be given in whole body exposure
chambers; aerosols are to be given by nose-only method. Exposure time and concentrations
of test substance (limit dose of 5mg/l) should be adjusted to ensure exposure at levels
comparable to multiples of intended human exposure. Three dose groups and a control
(plus vehicle control, if needed) are required. Duration of exposure may vary
participant/subjectto a maximum of 6 hours per day and five days a week. Food and water
should be withdrawn during the period of exposure to test substance. Temperature,
humidity and flow rate of exposure chamber should be recorded and reported. Evidence of
exposure with test substance of particle size of 4 micron (especially for aerosols) with not
less than 25% being 1 micron should be provided. Effects on respiratory rate, findings of
bronchial lavage fluid examination, histological examination of respiratory passages and
lung tissue should be included along with the regular parameters of systemic toxicity
studies or assessment of margin of safety.

(1.5) Allergenicity or Hypersensitivity - Standard tests include guinea pig maximization

test (GPMT) and local lymph node assay (LLNA) in mouse. Any one of the two may be
done. Notes: (i) Guinea pig maximization test. - The test is to be performed in two steps:
first, determination of maximum non-irritant and minimum irritant doses, and second, the
main test. The initial study will also have two components. To determine the intradermal
induction dose, four dose levels should be tested by the same route in a batch of four male
and four female animals (2 of each sex should be given Freund's adjuvant). The minimum
irritant dose should be used for induction. Similarly, a topical minimum irritant dose
should be determined for challenge. This should be established in two males and two
females. A minimum of six male and six female animals per group should be used in the
main study. One test and one control group should be used. It is preferable to have one
more positive control group. Intradermal induction (day 1) coupled with topical challenge
(day21) should be done. If there is no response, re-challenge should be done 7 to 30days
after the primary challenge. Erythema and oedema (individual animal scores as well as
maximization grading) should be used as evaluation criteria.
(ii) Local lymph node assay. - Mice used in this test should be of the same sex, either only
males or only females. Drug treatment is to be given on ear skin. Three graded doses, the
highest being maximum non-irritant dose plus vehicle control should be used. A minimum
of 6 mice per group should be used. Test material should be applied on ear skin on three
consecutive days and on day 5, the draining auricular lymph nodes should be dissected out
5 hours after i.v. H-thymidine or bromo-deoxy-uridine (BrdU). Increase in H-thymidine or
BrdU incorporation should be used as the criterion for evaluation of results.

(1.6) Genotoxicity: Genotoxic compounds, in the absence of other data, shall be presumed
to be transspecies carcinogens, implying a hazard to humans. Such compounds need not be
participanted to long term carcinogenicity studies. However, if such a drug is intended to
be administered for chronic illnesses or otherwise over a long period of time - a chronic
toxicity study (up to one year) may be necessary to detect early tumorigenic effects.
Genotoxicity tests are in vitro and in vivo tests conducted to detect compounds which

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induce genetic damage directly or indirectly. These tests should enable a hazard
identification with respect to damage to De-oxy Ribonucleic Acid (DNA) and its fixation.

The following standard test battery is generally expected to be conducted:

(i) A test for gene mutation in bacteria.
(ii) An in vitro test with cytogenetic evaluation of chromosomal damage with mammalian
cells or an in vitro mouse lymphomatic assay.
(iii) An in vivo test for chromosomal damage using rodent haematopoietic cells. Other
genotoxicity tests e.g. tests for measurement of De-oxy Ribonucleic Acid (DNA) adducts,
De-oxy Ribonucleic Acid (DNA) strand breaks, De-oxy Ribonucleic Acid (DNA) repair or
recombination serve as options in addition to the standard battery for further investigation
of genotoxicity test results obtained in the standard battery. Only under extreme conditions
in which one or more tests comprising the standard battery cannot be employed for
technical reasons, alternative validated tests can serve as substitutes provided sufficient
scientific justification should be provided to support the argument that a given standard
battery test is not appropriate.
(iv) Both in-vitro and in-vivo studies should be done. In-vitro studies should include Ames
Salmonella assay and chromosomal aberrations (CA) in cultured cells. In-vivo studies
should include micronucleus assay (MNA) or chromosomal aberrations (CA) in rodent
bone marrow. Data analysis of chromosomal aberrations (CA) should include analysis of
“gaps”.
(v) Cytotoxic anticancer agents. - Genotoxicity data are not required before Phase I and II
study/research. But these studies should be completed before applying for Phase III
study/research.
Notes: Ames’ Test (Reverse mutation assay in Salmonella): S. typhimurium tester strains
such as TA98, TA100, TA102, TA1535, TA97 or Escherichia coli WP2 uvrA or
Escherichia coli WP2 uvrA (pKM101) should be used.
(vi) In-vitro exposure (with and without metabolic activation, S9 mix) should be done at a
minimum of 5 log dose levels. “Solvent” and “positive” control should be used. Positive
control may include 9-amino-acridine, 2-nitrofluorine, sodium azide and mitomycin C,
respectively, in the tester strains mentioned above. Each set should consist of at least three
replicates. A 2.5 fold (or more) increase in number of revertants in comparison to
spontaneous revertants would be considered positive.
(vii) In-vitro cytogenetic assay. - The desired level of toxicity for in vitro cytogenetic tests
using cell lines should be greater than 50% reduction in cell number or culture confluency.
For lymphocyte cultures, an inhibition of mitotic index by greater than 50% is considered
sufficient. It should be performed in Chinese Hamster Ovary (CHO) cells or on human
lymphocyte in culture. In-vitro exposure (with and without metabolic activation, S9 mix)
should be done using a minimum of 3 log doses. “Solvent” and “positive” control should
be included. A positive control like Cyclophosphamide with metabolic activation and
Mitomycin C for without metabolic activation should be used to give a reproducible and
detectable increase clastogenic effect over the background which demonstrates the
sensitivity of the test system. Each set should consist of at least three replicates. Increased
number of aberrations in metaphase chromosomes should be used as the criteria for
evaluation.
(viii) In-vivo micronucleus assay. - One rodent species (preferably mouse) is needed.
Route of administration of test substance should be the same as intended for humans. Five
animals per sex per dose groups should be used. At least three dose levels, plus “solvent”
and “positive” control should be tested. A positive control like mitomycin C or
cyclophosphamide should be used. Dosing should be done on day one and two of study

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followed by sacrifice of animals six hours after the last injection. Bone marrow from both
the femora should be taken out, flushed with fetal bovine serum (20 min.), pelletted and
smeared on glass slides. Giemsa-May Gruenwald staining should be done and increased
number of micronuclei in polychromatic erythrocytes (minimum 1000) should be used as
the evaluation criteria.
(ix) In-vivo cytogenetic assay. - One rodent species (preferably rat) is to be used. Route of
administration of test substance should be the same as intended for humans. Five
animals/sex/dose groups should be used. At least three dose levels, plus “solvent” and
“positive” control should be tested. Positive control may include cyclophosphamide.
Dosing should be done on day one followed by intraperitoneal colchicine administration at
22 hours. Animals should be sacrificed two hours after colchicine administration. Bone
marrow from both the femora should be taken out, flushed with hypotonic saline (20
minutes), pelletted and resuspended in Carnoy’s fluid. Once again, the cells should be
pelletted and dropped on clean glass slides with a Pasteur pipette. Giemsa staining should
be done and increased number of aberrations in metaphase chromosomes (minimum 100)
should be used as the evaluation criteria.
(1.7) Carcinogenicity- Carcinogenicity studies should be performed for all drugs that are
expected to be clinically used for more than six months as well as for drugs used frequently
in an intermittent manner in the treatment of chronic or recurrent conditions.
Carcinogenicity studies are also to be performed for drugs if there is concern about their
carcinogenic potential emanating from previous demonstration of carcinogenic potential in
the product class that is considered relevant to humans or where structure-activity
relationship suggests carcinogenic risk or when there is evidence of preneoplastic lesions in
repeated dose toxicity studies or when long-term tissue retention of parent compound or
metabolites results in local tissue reactions or other pathophysiological responses. For
pharmaceuticals developed to treat certain serious diseases, Central Licencing Authority
may allow carcinogenicity testing to be conducted after marketing permission has been
granted. In instances where the life-expectancy in the indicated population is short (i.e.,
less than 2 - 3 years) no long-term carcinogenicity studies may be required. In cases where
the therapeutic agent for cancer is generally successful and life is significantly prolonged
there may be later concerns regarding secondary cancers. When such drugs are intended for
adjuvant therapy in tumour free patients or for prolonged use in non-cancer indications,
carcinogenicity studies may be needed. Completed rodent carcinogenicity studies are not
needed in advance of the conduct of large scale clinical study/research, unless there is
special concern for the patient population.

Carcinogenicity studies should be done in a rodent species (preferably rat). Mouse may be
employed only with proper scientific justification. The selected strain of animals should
not have a very high or very low incidence of spontaneous tumors. At least three dose
levels should be used. The highest dose should be sub-lethal, and it should not reduce the
life span of animals by more than 10% of expected normal. The lowest dose should be
comparable to the intended human therapeutic dose or a multiple of it, e.g. 2.5x; to make
allowance for the sensitivity of the species. The intermediate dose to be placed
logarithmically between the other two doses. An untreated control and (if indicated) a
vehicle control group should be included. The drug should be administered seven days a
week for a fraction of the life span comparable to the fraction of human life span over
which the drug is likely to be used therapeutically. Generally, the period of dosing should
be 24 months for rats and 18 months for mice.
Observations should include macroscopic changes observed at autopsy and detailed
histopathology of organs and tissues. Additional tests for carcinogenicity (short-term

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bioassays, neonatal mouse assay or tests employing transgenic animals) may also be done
depending on their applicability on a case to case basis.

Note: Each dose group and concurrent control group not intended to be sacrificed early
should contain at least 50 animals of each sex. A high dose satellite group for evaluation of
pathology other than neoplasia should contain 20 animals of each sex while the satellite
control group should contain10animals of each sex. Observation parameters should include
signs of intoxication, effect on body weight, food intake, clinical chemistry parameters,
hematology parameters, urine analysis, organ weights, gross pathology and detailed
histopathology. Comprehensive descriptions of benign and malignant tumour development,
time of their detection, site, dimensions, histological typing etc. should be given.

(1.8) Animal toxicity requirements for clinical study/research and marketing of a new
drug:

Systemic Toxicity Studies

Duration of proposed Human Phase(s)

Route of for which study is Long term toxicity
human
administration proposed to be requirements
administration
conducted
Single dose or several
doses in one day, up I, II, III 2 species; 2 weeks
to 1 week
>1 week but upto 2
weeks I, II, III 2 species; 2weeks

Marketing
Upto 2 weeks 2 species; 4weeks
permission
2 species; equal to duration of
I, II, III human exposure
>2 weeks but upto 4
Oral or weeks Marketing
2 species; 12 weeks
Parenteral or permission
Transdermal 2 species; equal to duration of
I, II, III human exposure
> 4 weeks but upto 12
weeks Marketing
2 species; 24 weeks
permission
2 species; equal to duration of
I, II, III human exposure
> 12 weeks but upto
24 weeks Marketing 2 species; Rodent 24 weeks,
permission non- rodent 36 weeks

I, II, III 2 species; Rodent 24 weeks,

> 24 weeks non- rodent 36weeks
Marketing 2 species; Rodent 24 weeks,
permission non-rodent 36 weeks

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 Up to 2 weeks I, II, III 2 species; I month (Exposure
time 3h/d, 5d/week)
Inhalation
(general 2 species; 12 weeks (Exposure
Up to 4 weeks I, II, III
Anaesthetics, time 6h/d, 5d/week)
aerosols)
2 sp; 24 weeks (Exposure time
>14 weeks I, II, III
6h/d, 5d/week)
Local Toxicity Studies
I, II 1 species; 4 weeks
Up to 2 weeks
Dermal III 2 species; 4 weeks
> 2 weeks I, II, III 2 species; 12 weeks
I, II 1 species; 4 weeks
Ocular or Optic Up to 2 weeks
III 2 species; 4 weeks
or Nasal
> 2 weeks I, II, III 2 species; 12 weeks
I, II 1 species; 4weeks
Vaginal or Rectal Up to 2 weeks III 2 species; 4 weeks
> 2 weeks I, II, III 2 species; 12 weeks

Special Toxicity Studies

Male Fertility Study: Phase III in male volunteers or patients
Female Reproduction and Development Toxicity Studies:
Segment II studies in 2 species; Phase II, III involving female patients of childbearing age.
Segment I study; Phase III involving female patients of child-bearing age.
Segment III study; Phase III for drugs to be given to pregnant or nursing mothers for long periods or
where there are indications of possible adverse effects on foetal development.
Allergenicity or Hypersensitivity:
Phase I, II, III - when there is a cause of concern or for parenteral drugs (including dermal application)
Photo-allergy or dermal photo-toxicity:
Phase I, II, III - if the drug or a metabolite is related to an agent causing photosensitivity or the nature
of action suggests such a potential.
Genotoxicity:
In-vitro studies – Phase I
Both in-vitro and in-vivo – Phase II, III
Carcinogenicity:
Phase III – when there is a cause for concern, or when the drug is to be used for more than 6 months.

Abbreviations: d -day; h-hour; I, II, III - Phase of clinical study/research.

Note:
(1) Animal toxicity data generated in other countries may be accepted and may not be
asked to be repeated or duplicated in India on a case to case basis depending upon the
quality of data and the credentials of the laboratory where such data has been generated.
(2) Requirements for fixed dose combinations are given in clause 4 of this Schedule.

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(1.9) Number of animals required for repeated-dose toxicity studies:

14 to 28 days 84 to 182 days

Non-rodent Non-rodent (Dog

Group Rodent (Rat) (Dog or Rodent (Rat)
or Monkey)
Monkey)
Male Female Male Female Male Female Male Female
Control 6 to 10 6 to 10 2 to 3 2 to 3 15 to 30 15 to 30 4 to 6 4 to 6
Low dose 6 to 10 6 to 10 2 to 3 2 to 3 15 to 30 15 to 30 4 to 6 4 to 6
Intermediate
dose 6 to 10 6 to 10 2 to 3 2 to 3 15 to 30 15 to 30 4 to 6 4 to 6
High dose 6 to 10 6 to 10 2 to 3 2 to 3 15 to 30 15 to 30 4 to 6 4 to 6

(1.10) Laboratory parameters to be included in toxicity studies:

Haematological parameters
Haemoglobin Total Red Blood Cell Haematocrit Reticulocyte
count
Total White Blood Differential White Platelet count Terminal Bone Marrow
Cell count Blood Cell Count Examination

Erythrocyte General Blood Picture: A Special mention of abnormal and immature cells
sedimentation rate should be made
(ESR) (Non-
rodents only)

Coagulation parameters (Non-rodents only): Bleeding Time, coagulation Time, prothrombin time,
Activated partial Thromboplastin Time
Urinalysis Parameters
Colour Appearance Specific Gravity 24 hours urinary
output

Reaction(pH) Albumin Sugar Acetone

Bile pigments Urobilinogen Occult Blood

Microscopic examination of urinary sediment

Blood Biochemical parameters
Glucose Cholesterol Triglycerides High density
lipoproteins (HDL)
cholesterol (Non-
rodents only)
Low density Bilirubin Serum glutamic pyruvic Serum glutamic
lipoproteins (LDL) transaminase (SGPT) oxaloacetic
(Alanine aminotransferase transaminase (SGOT)
(ALT)

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 Cholesterol (Non-rodents only) Aspartate aminotransferase (AST)
Alkaline Phosphatase GGT (Non-rodents Blood urea Nitrogen Creatinine
(ALP) only)

Total proteins Albumin Globulin (Calculated Sodium

values)
Potassium Phosphorus Calcium

Gross and Microscopic Pathology

Brain*: Cerebrum, (Spinal cord) Eye (Middle Ear)
Cerebellum, Midbrain

Thyroid (Parathyroid) Spleen Thymus

Adrenal* (Pancreas) (Trachea) Lung*
Heart* Aorta Oesophagus Stomach
Duodenum Jejunum Terminal ileum Colon
(Rectum) Liver* Kidney* Urinary bladder
Epididymis Testis* Ovary Uterus*
Skin Mammary gland Mesenteric lymph node Skeletal muscle

* Organs marked with an asterisk should be weighed.

( ) Organs listed in parenthesis should be examined if indicated by the nature of the drug
or observed effects.

Non-clinical toxicity testing and safety evaluation data of an Investigational New Drug
(IND) needed for the conduct of different phases of clinical study/research.

Note: Refer clause 2 of Second Schedule for essential features of study designs of the
nonclinical toxicity studies listed below

For Phase I Clinical Study/research:

Systemic Toxicity studies: -

a. Single dose toxicity studies
b. Dose Ranging Studies
c. Repeat-dose systemic toxicity studies of appropriate duration to support the duration
of proposed human exposure.

 In-vitro genotoxicity tests, –Relevant local toxicity studies with proposed route of
clinical application (duration depending on proposed length of clinical exposure).
 Allergenicity or Hypersensitivity tests (when there is a cause for concern or for
parenteral drugs, including dermal application).
 Photo-allergy or dermal photo-toxicity test (if the drug or a metabolite is related to an
agent causing photosensitivity or the nature of action suggests such a potential).

For Phase II Clinical Study/research:

Provide a summary of all the non-clinical safety data (listed above) already submitted

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while obtaining the permissions for Phase I study/research, with appropriate references. In
case of an application for directly starting a Phase II study/research - complete details of
then on clinical safety data needed for obtaining the permission for Phase I study/research,
as per the list provided above must be submitted.
Repeat-dose systemic toxicity studies of appropriate duration to support the duration of
proposed human exposure.
In-vivo genotoxicity tests.
Segment II reproductive or developmental toxicity study (if female patients of childbearing
age are going to be involved).

For Phase III Clinical Study/research:

Provide a summary of all the non-clinical safety data (listed above) already submitted
while obtaining the permissions for Phase I and II study/research, with appropriate
references. In case of an application for directly initiating a Phase III study/research -
complete details of the non-clinical safety data needed from obtaining the permissions for
Phase I and II study/research, as per the list provided above must be provided. Repeat-dose
systemic toxicity studies of appropriate duration to support the duration of proposed human
exposure.

Reproductive or developmental toxicity studies

Segment I (if female patients of childbearing age are going to be involved), and Segment
III (for drugs to be given to pregnant or nursing mothers or where there are indications of
possible adverse effects on foetal development). Carcinogenicity studies (when there is a
cause for concern or when the drug is to be used for more than 6 months).

For Phase IV Clinical Study/research: Provide a summary of all the non-clinical safety
data (listed above) already submitted while obtaining the permissions for Phase I, II and III
study/research, with appropriate references. In case an application is made for initiating the
Phase IV study/research, complete details of the non-clinical safety data needed for
obtaining the permissions for Phase I, II and III study/research, as per the list provided
above must be submitted.

Application of Good Laboratory Practices (GLP) –

The animal studies be conducted in an accredited laboratory. Where the safety
pharmacology studies are part of toxicology studies, these studies should also be conducted
in an accredited laboratory.
The animal toxicology requirements as referred above should be viewed as general
guidance for drug developments. Animal toxicology studies may be planned, designed and
conducted as per the International Council of Harmonization (ICH) guidelines to promote
safe, ethical development and availability of new drugs with reduced use of animals in
accordance with the 3R (reduce/refine/replace) principles.

3. Animal Pharmacology

(1) General Principles.- Specific and general pharmacological studies should be

conducted to support use of therapeutics in humans. In the early stages of drug
development enough information may not be available to rationally select study design for
safety assessment. In such a situation, a general approach to safety pharmacology studies
can be applied. Safety pharmacology studies are studies that investigate potential
undesirable pharmacodynamic effects of a substance on physiological functions in relation

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to exposure within the therapeutic range or above.

1.1 Specific pharmacological actions,- Specific pharmacological actions are those which
demonstrate the therapeutic
potential for humans. The specific studies that should be conducted and their design will be
different based on the individual properties and intended uses of investigational drug.
Scientifically validated methods should be used. The use of new technologies and
methodologies in accordance with sound scientific principles should be preferred.

1.2 General pharmacological actions,-

1.2.1 Essential safety pharmacology.- Safety pharmacology studies need to be conducted to
investigate the potential undesirable pharmacodynamic effects of a substance on
physiological functions in relation to exposure within the therapeutic range and above.
These studies should be designed to identify undesirable pharmacodynamic properties of a
substance that may have relevance to its human safety; to evaluate adverse
pharmacodynamic or pathophysiological effects observed in toxicology or clinical studies;
and to investigate the mechanism of the adverse pharmacodynamic effects observed or
suspected. The aim of the essential safety pharmacology is to study the effects of the test
drug on vital functions. Vital organ systems such as cardiovascular, respiratory and central
nervous systems should be studied. Essential safety pharmacology studies may be excluded
or supplemented based on scientific rationale. Also, the exclusion of certain tests or
exploration(s) of certain organs, systems or functions should be scientifically justified.
1.2.1.1 Cardiovascular system: Effects of the investigational drug should be studied on
blood pressure, heart rate, and the electrocardiogram. If possible in vitro, in vivo and/or ex
vivo methods including electrophysiology should also be considered.
1.2.1.2 Central nervous system: Effects of the investigational drug should be studied on
motor activity, behavioural changes, coordination, sensory and motor reflex responses and
body temperature.
1.2.1.3 Respiratory system: Effects of the investigational drug on respiratory rate and other
functions such as tidal volume and haemoglobin oxygen saturation should be studied.

1.3 Follow-up and supplemental safety pharmacology studies.- In addition to the essential
safety pharmacological
studies, additional supplemental and follow-up safety pharmacology studies may need to
be conducted as appropriate. These depend on the pharmacological properties or chemical
class of the test substance, and the data generated from safety pharmacology studies,
clinical study/research, pharmacovigilance, experimental in vitro or in vivo studies, or from
literature reports.
1.3.1 Follow-up studies for essential safety pharmacology: Follow-up studies provide
additional information or a better und er s tand ing than tha t pr o vid ed b y the e s s ent ia l
sa f e ty pharmacology.
1.3.1.1 Cardiovascular system: These include ventricular contractility, vascular resistance
and the effects of chemical mediators, their agonists and antagonists on the cardiovascular
system.
1.3.1.2 Central nervous system: These include behaviour al s tudies , learning and memory,
electrophysiology studies, neurochemistry and ligand binding studies.
1.3.1.3 Respiratory system: These include airway resistance, compliance, pulmonary
arterial pressure, blood gases and blood pH.
1.3.2 Supplemental safety pharmacology studies: These studies are required to investigate
the possible adverse pharmacological effects that are not assessed in the essential safety

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pharmacological studies and are a cause for concern.
1.3.2.1 Urinary system: These include urine volume, specific gravity, osmolality, pH,
proteins, cytology and blood urea nitrogen, creatinine and plasma proteins estimation.
1.3.2.2 Autonomic nervous system: These include binding to receptors relevant for the
autonomic nervous system, and functional response to agonist or antagonist responses in
vivo or in vitro, and effects of direct stimulation of autonomic nerves and their effects on
cardiovascular responses.
1.3.2.3 Gastrointestinal system: These include studies on gastric secretion, gastric pH
measurement, gastric mucosal examination, bile secretion, gastric emptying time in vivo
and ileocaecal contraction in vitro.
1.3.2.4 Other organ systems: Effects of the investigational drug on organ systems not
investigated elsewhere should be assessed when there is a cause for concern. For example,
dependency potential, skeletal muscle, immune and endocrine functions may be
investigated.
1.4 Conditions under which safety pharmacology studies are not necessary: Safety
pharmacology studies are usually not required for locally applied agents e.g. dermal or
ocular, in cases when the pharmacology of the investigational drug is well known, and/or
when systemic absorption from the site of application is low. Safety pharmacology testing
is also not necessary, in the case of a new derivative having similar pharmacokinetics and
pharmacodynamics.
1.5 Timing of safety pharmacology studies in relation to clinical development :
1.5.1 Prior to first administration in humans: The effects of an investigational drug on the
vital functions listed in the essential safety pharmacology should be studied prior to first
administration in humans. Any follow-up or supplemental studies identified, should be
conducted if necessary, based on a cause for concern.
1.5.2 During clinical development: Additional investigations may be warranted to clarify
observed or suspected adverse effects in animals and humans during clinical development.
1.5.3 Before applying for marketing approval: Follow-up and supplemental safety
pharmacology studies should be assessed prior to approval unless not required, in which
case this should be justified. Available information from toxicology studies addressing
safety pharmacology endpoints or information from clinical studies can replace such
studies.
1.6 Application of Good Laboratory Practices (GLP): The animal studies be conducted in
an accredited laboratory. Where the safety pharmacology studies are part of toxicology
studies, these studies should also be conducted in an accredited laboratory.

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 Appendix IV - Conduct of Clinical Study/Research

1. Conduct of clinical study/research-

(i) Clinical study/research shall be conducted in accordance with the provisions of the
Act and these Rules and principles of Good Clinical Practice Guidelines.
(ii) Clinical study/research on a new drug shall be initiated only after the permission
has been granted by the Central Licencing Authority and the approval obtained
from the respective ethics committee.
(iii) The Central Licencing Authority shall be informed of the approval of the respective
ethics committee in accordance with these rules.
(iv) All study/research investigator should possess appropriate qualifications, training and
experience and should have access to such investigational and treatment facilities as
are relevant to the proposed study/research protocol. A qualified physician (or dentist,
when appropriate) who is an investigator or a sub-investigator for the study/research,
should be responsible for all study/research-related medical (or dental) decisions.
Laboratories used for generating data for clinical study/research should be compliant
with good laboratory practices.
(v) Protocol amendments, if become necessary before initiation or during the course of a
clinical study/research, all such amendments should be submitted to the Central
Licencing Authority in writing along with the approval by the ethics committee, if
available, which has granted the approval for the study.
(vi) No deviations from or changes to the protocol should be implemented without prior
written approval of the ethics committee and Central Licencing Authority except when
it is necessary to eliminate immediate hazards to the study/research
participant/subjector when change involves only logistic or administrative or minor
aspects of the study/research. All such exceptions must be immediately notified to the
ethics committee as well as to the Central Licencing Authority. Administrative or
logistic changes or minor amendments in the protocol should be notified to the Central
Licencing Authority within thirty days.
2. Informed Consent –

(a) In all study/research, a freely given, informed, written consent is required

to be obtained from each study participant. The Investigator must provide
information about the study verbally as well as using a patient information
sheet, in a language that is nontechnical and understandable by the study
participant.
(b) The participant's consent must be obtained in writing using an “Informed
Consent Form”. Both the patient information sheet as well as the informed
consent form should have been approved by the ethics committee and
furnished to the Central Licencing Authority. Any changes in the informed
consent documents should be approved by the ethics committee and
submitted to the Central Licencing Authority before such changes are
implemented.
(c) Where a participant/subjectis not able to give informed consent (e.g. an
unconscious person or a minor or those suffering from severe mental

112
 illness or disability), the same may be obtained from a legally acceptable
representative
Legally acceptable representative is a person who is able to give consent
for or authorise and intervention in the patient as provided by the law of
India).
(d) If the study/research participant, his or her legally acceptable
representative is unable to read or write an impartial witness should be
present during the entire informed consent process who must append his or
her signature to the consent form.
(e) In case of clinical study/research on paediatrics, the participants are
legally unable to provide written informed consent and are dependent on
their parent or legal guardian to assume responsibility for their
participation in clinical studies. In such case, -
(i) Written informed consent should be obtained from the parent or legal
guardian. However, all paediatric participants should be informed to the
fullest extent possible about the study in a language and in terms that they
are able to understand.
(ii) Where appropriate, paediatric participants should additionally assent to
enrol in the study. Mature minors and adolescents should personally sign
and date a separately designed written assent form.
(iii) Although a participant's wish to withdraw from a study must be respected,
there may be circumstances in therapeutic studies for serious or life-
threatening diseases in which, in the opinion of the Investigator and parent
or legal guardian, the welfare of a paediatric patient would be jeopardized
by his or her failing to participate in the study. In this situation, continued
parental or legal guardian consent should be sufficient to allow
participation in the study.
(f) A checklist of essential elements to be included in the study participant's
informed consent document as well as a format for the informed consent
form for study/research participant/subjectis given in Table 3of this
Schedule.
(g) An audio-video recording of the informed consent process in case of
vulnerable participants in clinical study/research of New Chemical Entity
or New Molecular Entity including procedure of providing information to
the participant/subjectand his understanding on such consent, shall be
maintained by the investigator for record:
Provided that in case of clinical study/research of anti-HIV and anti-
leprosy drugs, only audio recording of the informed consent process of
individual participant/subjectincluding the procedure of providing
information to the participant/subjectand his understanding on such
consent shall be maintained by the investigator for record.

3. Responsibilities -
(1) Sponsor- (i) The clinical study/research sponsor is responsible for
implementing and maintaining quality assurance systems to ensure that the

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 clinical study/research is conducted and data generated, documented and
reported in compliance with the protocol and Good Clinical Practices
Guidelines as well as with all applicable statutory provisions. Standard
standard operating procedures should be documented to ensure
compliance with Good Clinical Practices Guidelines and applicable
regulations.
(ii) Sponsors are required to submit a status report on the clinical
study/research to the Central Licencing Authority at the prescribed
periodicity.
(iii) In case of studies prematurely discontinued for any reason including lack
of commercial interest in pursuing the new drug application, a summary
report should be submitted within 3 months. The summary report should
provide a brief description of the study, the number of patients exposed to
the drug, dose and duration of exposure, details of adverse drug reactions,
if any, and the reason for discontinuation of the study or non-pursuit of the
new drug application;
(iv) Any report of the serious adverse event, after due analysis shall be
forwarded by the sponsor to the Central Licencing Authority, the
Chairperson of the ethics committee and the head of the institution where
the study/research has been conducted, within fourteen days of knowledge
of occurrence of the serious adverse event as specified in Table 5 of this
Schedule;
(v) In case of injury or death occurring to the study/research participant, the
sponsor (whether a pharmaceutical company or an institution) or his
representative or the investigator or the institution or centre where the
study was conducted, as the case may be, shall make payment for medical
management of the participant/subjectand also provide financial
compensation for the clinical study/research related injury or death in
accordance with the procedure as prescribed in Chapter VI of these rules
(vi) The sponsor (whether a pharmaceutical company or an Institution) or his
representative, whosoever had obtained permission from the Central
Licencing Authority for conduct of the clinical study/research, shall submit
details of compensation provided or paid for clinical study/research related
injury or death, to the Central Licencing Authority thirty days of the
receipt of the order of the Central Licencing Authority.
(vii) The sponsor shall provide post-study/research access of the investigational
drug by giving the drug free of cost to the study/research
participant/subjectas per directions of the Central Licencing Authority in
special circumstances on the recommendations of the investigator and the
ethics committee and written consent of the patient in accordance with rule
27.
(2) Investigator- (i) The investigator shall be responsible for the conduct of
the study/research according to the protocol and the Good Clinical
Practices Guidelines and also for compliance as per the undertaking given
in Table 4. Standard standard operating procedures are required to be
documented by the investigators for the tasks performed by them.

114
 (i) During and following a participant’s participation in study/research, the
investigator should ensure that adequate medical care is provided to the
participant/subjectfor any adverse events.
(ii) Investigator shall report all serious adverse events to the Central Licencing
Authority, the sponsor or his representative, whosoever had obtained
permission from the Central Licencing Authority for conduct of the
clinical study/research, and the ethics committee that accorded approval to
the study protocol, within twenty-four hours of their occurrence.
(iv) In case, the investigator fails to report any serious adverse event within the
stipulated period, he shall have to furnish the reason for the delay to the
satisfaction of the Central Licencing Authority along with the report of the
serious adverse event. The report of the serious adverse event, after due
analysis, shall be forwarded by the investigator to the Central Licencing
Authority, the Chairperson of the ethics committee and the Head of the
institution where the study/research has been conducted within fourteen
days of the occurrence of the serious adverse event.
(v) The investigator shall provide information to the study/research
participant/subjectthrough informed consent process as provided in Table
3about the essential elements of the clinical study/research and the
participant's right to claim compensation in case of study/research related
injury or death. He shall also inform the participant/subjecthis or her
nominee of their rights to contact the sponsor or his representative
whosoever had obtained permission from the Central Licencing Authority
for conduct of the clinical study/research for the purpose of making claims
in the case of study/research related injury or death.
(3) Ethics committee-
(i) It is the responsibility of the ethics committee that reviews and accords its
approval to a study/research protocol to safeguard the rights, safety and
well-being of all study/research participants.
(ii) The ethics committee should exercise particular care to protect the rights,
safety and well-being of all vulnerable participants participating in the
study, e.g., members of a group with hierarchical structure (e.g. prisoners
armed forces personnel, staff and students of medical, nursing and
pharmacy academic institutions), patients with incurable diseases,
unemployed or impoverished persons, patients in emergency situation,
ethnic minority groups, homeless persons, nomads, refugees, minors or
other incapable of personally giving consent.
„
(iii) Ethics committee should get documented standard standard operating
procedures ' and should maintain a record of its proceedings.
(iv) Ethics committee should make, at appropriate intervals, an ongoing review
of the study/research for which they have reviewed the protocol. Such a
review may be based on the periodic study progress reports furnished by
the investigators or monitoring and internal audit reports furnished by the
sponsor or visiting the study sites.
(v) In case an ethics committee revokes its approval accorded to a
study/research protocol, it must record the reasons for doing so and at once

115
 communicate such a decision to the Investigator as well as to the Central
Licencing Authority.
(vi) In case of serious adverse event occurring to the study/research participant,
the ethics committee shall forward its report or order on the event, after
due analysis, along with its opinion on the financial compensation, if any,
to be paid by the sponsor or his representative or institution or centre, as
the case may be, in accordance with Chapter VI of these rules.

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 Appendix V Information To Be Submitted By An Applicant And Format

TABLE 1: INFORMATION TO BE SUBMITTED BY AN APPLICANT FOR

GRANT OF REGISTRATION OF ETHICS COMMITTEE AND FORMAT FOR
ACCORDING TO APPROVAL

(A) Information required to be submitted by the applicant for registration of ethics

committee:
(a) Name of the ethics committee.
(b) Authority under which the ethics committee has been constituted,
membership requirements, the term of reference, conditions of appointment
and the quorum required.
(c) The procedure for resignation, replacement or removal of members.
(d) Address of the office of the ethics committee.
(e) Name, address, qualification, organisational title, telephone number, fax
number, email, mailing address and brief profile of the Chairperson.
(f) Names, qualifications, organisational title, telephone number, fax number, e-
mail and mailing address of the members of the ethics committee. The
information shall also include member's specialty (primary, scientific or
non-scientific), member's affiliation with institutions and patient group
representation, if any.
(g) Details of the supporting staff.
(h) The standard standard operating procedures to be followed by the committee
in general.
(i) Standard standard operating procedures to be followed by the committee for
vulnerable population Policy regarding training for new and existing
committee members along with standard standard operating procedures .
(j) Policy to monitor or prevent the conflict of interest along with standard
standard operating procedures .
(k) If the committee has been audited or inspected before, give details.

(B) Format for according to approval to clinical study/research protocol by the ethics
committee

TO Dr.

Dear Dr.

The Ethics committee or independent ethics committee (state name of the

committee, as appropriate) reviewed and discussed your application to conduct the

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 clinical study/research entitled “……...”on…….(date).

The following documents were reviewed:

(a) Study/research protocol (including protocol amendments),
dated……….version No.(s) …………
(b) Patient information sheet and informed consent form (including updates,
if any) in English or vernacular language.
(c) Investigator's brochure, dated........................................................................ ,
Version no……… Proposed methods for patient accrual including
advertisements etc. proposed to be used for the purpose.
(d) Principal investigator's current Curriculum Vitae.
(e) Insurance policy or compensation for participation and for serious adverse
events occurring during the study participation.
(f) Investigator's agreement with the sponsor.
(g) Investigator's undertaking (Table 4).

The following members of the ethics committee were present at the meeting held on
(date, time, place).
… ................. Chairperson of the ethics committee;
… ..................Member-Secretary of the ethics committee;
… ..................Name of each member with designation;
We approve the study/research to be conducted in its presented form.
The ethics committee to be informed about the progress of the study, any Serious
Adverse Events (SAE) occurring in the course of the study, any changes in the
protocol and patient information or informed consent and to be provided with a copy
of the final report.

Yours sincerely,

Member Secretary, Ethics Committee

TABLE 2: CONTENTS OF THE PROPOSED PROTOCOL FOR CONDUCTING

CLINICAL STUDY/RESEARCH

Title Page
(a) Full title of the clinical study,
(b) Protocol, Study number, and protocol version number with date.
(c) The Investigational New Drug (IND) name/number of the investigational
drug.
(d) Complete name and address of the Sponsor and contract research

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 organization if any.
(e) List of the investigators who are conducting the study, their
respective institutional affiliations and site locations
(f) Name of clinical laboratories and other departments and/or facilities
participating in the study. Table of Contents

1. Background and introduction:

(a) Preclinical experience
(b) Clinical experience
Previous clinical work with the new drug should be reviewed here and a description
of how the current protocol extends existing data should be provided. If this is an
entirely new indication, how this drug was considered for this should be discussed.
Relevant information regarding pharmacological, toxicological and other biological
properties of the drug/biologic/medical device, and previous efficacy and safety
experience should be described.
2. Study rationale: This section should describe a brief summary of the background
information relevant to the study design and protocol methodology. The reasons for
performing this study in the particular population included by the protocol should be
provided.
3. Study objective (primary as well as secondary) and their logical relation to the study
design.
4. Study design–
(a) Overview of the study design: Including a description of the type of study
(i.e., double-blind, multicentre, placebo controlled, etc.), a detail of the
specific treatment groups and number of study Participants in each group
and investigative site, Participant/subjectnumber assignment, and the type,
sequence and duration of study periods.
(b) Flow chart of the study
(c) A brief description of the methods and procedures to be used during the
study.
(d) Discussion of study design: This discussion details the rationale for the
design chosen for this study.
5. Study population: the number of participants required to be enrolled in the study at
the investigative site and by all sites along with a brief description of the nature of
the participant/subjectpopulation required is also mentioned.
6. Participant/subjecteligibility
(a) Inclusion criteria
(b) Exclusion criteria
7. Study assessments – plan, procedures and methods to be described in detail.
8. Study conduct stating the types of study activities that would be included in this
section would be: medical history, type of physical examination, blood or urine
testing, electrocardiogram (ECG), diagnostic testing such as pulmonary function

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 tests, symptom measurement, dispensation and retrieval of medication,
Participant/subjectcohort assignment, adverse event review, etc.
Each visit should be described separately as Visit 1, Visit 2, etc.
Discontinued participants: Describes the circumstances for
Participant/subjectwithdrawal, dropouts, or other reasons for discontinuation of
Participants. State how drop outs would be managed and if they would be replaced
describe the method of handling of protocol waivers, if any. The person who
approves all such waivers should be identified and the criteria used for specific
waivers should be provided.
Describes how protocol violations will be treated, including conditions where the
study will be terminated for noncompliance with the protocol.
9. Study treatment-
(a) Dosing schedule (dose, frequency, and duration of the experimental
treatment) Describe the administration of placebos and/or dummy
medications if they are part of the treatment plan. If applicable, concomitant
drug(s), their doses, frequency, and duration of concomitant treatment
should be stated.
(b) Study drug supplies and administration: A statement about who is going to
provide the study medication and that the investigational drug formulation
has been manufactured following all regulations Details of the product
stability, storage requirements and dispensing requirements should be
provided.
(c) Dose modification for study drug toxicity: Rules for changing the dose or
stopping the study drug should be provided.
(d) Possible drug interactions
(e) Concomitant therapy: The drugs that are permitted during the study and the
conditions under which they may be used are detailed here. Describe the
drugs that a Participant/subjectis not allowed to use during parts of or the
entire study. If any washout periods for prohibited medications are needed
prior to enrolment, these should be described here.
(f) Blinding procedures: A detailed description of the blinding procedure if the
study employs a blind on the Investigator and/or the Participant
(g) Un-blinding procedures: If the study is blinded, the circumstances in which
un-blinding may be done and the mechanism to be used for un-blinding
should be given
10. Adverse Events:
Description of expected adverse events should be given. Procedures used to evaluate
an adverse event should be described.
11. Ethical considerations: Give the summary of:
(a) Risk/benefit assessment:
(b) Ethics committee review and communications
(c) Informed consent process
(d) Statement of participant/subjectconfidentiality including ownership of data

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 and coding procedures.
12. Study monitoring and supervision:
A description of study monitoring policies and procedures should be provided along
with the proposed frequency of site monitoring visits, and who is expected to
perform monitoring.
Case Record Form (CRF) completion requirements, including who gets which
copies of the forms and any specific required in filling out the forms Case Record
Form correction requirements, including who is authorized to make corrections on
the Case Record Form and how queries about study data are handled and how errors,
if any, are to be corrected should be stated.
Investigator study files, including what needs to be stored following study
completion should be described.
13. Investigational Product Management:
(a) Give investigational product description and packaging (stating all
ingredients and the formulation of the investigational drug and any
placebos used in the study)
(b) The precise dosing required during the study
(c) Method of packaging, labelling, and blinding of study substances
(d) Method of assigning treatments to participants and the
participant/subjectidentification code numbering system

(e) Storage conditions for study substances

(f) Investigational product accountability: Describe instructions for the receipt,
storage, dispensation, and return of the investigational products to ensure a
complete accounting of all investigational products received, dispensed, and
returned or destroyed.
(g) Describe policy and procedure for handling unused investigational products.
14. Data Analysis: Provide details of the statistical approach to be followed including
sample size, how the sample size was determined, including assumptions made in
making this determination, efficacy endpoints (primary as well as secondary) and
safety endpoints.
Statistical analysis: Give complete details of how the results will be analysed and
reported along with the description of statistical tests to be used to analyse the
primary and secondary endpoints defined above. Describe the level of significance,
statistical tests to be used, and the methods used for missing data; method of
evaluation of the data for treatment failures, non-compliance, and
Participant/subjectwithdrawals; rationale and conditions for any interim analysis if
planned.
Describe statistical considerations for Pharmacokinetic (PK) analysis, if applicable.
15. Undertaking by the Investigator (see Table 4)
16. Appendices: Provide a study synopsis, copies of the informed consent documents
(patient information sheet, informed consent form etc.); Case Record Form (CRF)
and other data collection forms; a summary of relevant pre- clinical safety
information and any other documents referenced in the clinical protocol.

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 TABLE 3 INFORMED CONSENT
1. Checklist of informed consent documents for clinical study/research participant, –

1.1 Essential elements:

(i) Statement that the study involves research and explanation of the purpose of
the research.
(ii) Expected duration of the participation of participant.
(iii) Description of the procedures to be followed, including all invasive
procedures.
(iv) Description of any reasonably foreseeable risks or discomforts to the
Participant.
(v) Description of any benefits to the Participant/subjector others reasonably
expected from research. If no benefit is expected
Participant/subjectshould be made aware of this.
(vi) Disclosure of specific appropriate alternative procedures or therapies
available to the Participant.
(vii) Statement describing the extent to which confidentiality of records
identifying the Participant/subjectwill be maintained and who will have
access to Participant's medical records.
(viii) Study/research treatment schedule and the probability for random
assignment to each treatment (for randomized study/research).
(ix) Statement describing the financial compensation and the medical
management as under:
(a) In case of an injury occurring to the participant/subjectduring the clinical
study/research, free medical management shall be given as long as
required or till such time it is established that the injury is not related to
the clinical study/research, whichever is earlier.
(b) In the event of a study/research related injury or death, the sponsor or his
representative or the investigator or centre, as the case may be, in
accordance with the rule 39, as the case may be, shall provide financial
compensation for the injury or death.
(x) An explanation about whom to contact for study/research related queries,
rights of Participants and in the event of any injury.
(xi) The anticipated prorated payment, if any, to the participant/subjectfor
participating in the study/research.
(xii) Responsibilities of participant/subjecton participation in the study/research.
(xiii) Statement that participation is voluntary, that the participant/subjectcan
withdraw from the study at any time and that refusal to participate will not
involve any penalty or loss of benefits to which the participant/subjectis
otherwise entitled.
(xiv) Statement that there is a possibility of failure of investigational product
to provide intended therapeutic effect.
(xv) Statement that in the case of placebo-controlled study/research, the placebo

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 administered to the participants shall not have any therapeutic effect.
(xvi) Any other pertinent information.
1.2 Additional elements, which may be required:

(a) Statement of foreseeable circumstances under which the participation of the

participant/subjectmay be terminated by the Investigator without his or her
consent.
(b) Additional costs to the participant/subjectthat may result from participation
in the study.
(c) The consequences of a Participant's decision to withdraw from the
research and procedures for orderly termination of participation by
Participant.
(d) (d) Statement that the Participant/subjector Participant's representative will
be notified in a timely manner if significant new findings develop during the
course of the research which may affect the Participant's willingness to
continue participation will be provided.
(e). A statement that the particular treatment or procedure may involve risks to
the Participant/subject(or to the embryo or foetus, if the
Participant/subjectis or may become pregnant), which are currently
unforeseeable.
(f) Approximate number of Participants enrolled in the study.
2. Format of informed consent form for Participants participating in a clinical
study/research – Informed Consent form to participate in a clinical study/research

Study Title:
Study Number:
Participant's Initials: Participant's Name:
Date of Birth/Age:
Address of the Participant/subject Qualification
Occupation: Student or Self-Employed or Service or Housewife or Others
(Please click as appropriate) . Annual Income of the participant:
Name and address of the nominees and his relation to the participant/subject(for
the purpose of compensation in case of study/research related death).

Place
Initial
box
(Participa
nt)

(i) I confirm that I have read and understood the information [ ]

Sheet dated for the above study and have had the opportunity
to ask questions.
(ii) I understand that my participation in the study is voluntary and [ ]
that I am free to withdraw at any time, without giving any reason,

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 without my medical care or legal rights being affected.
(iii) I understand that the Sponsor of the clinical study/research, others
working on the Sponsor's behalf, the Ethics Committee
and the regulatory authorities will not need my permission to look at
my health records both in respect of the current study and any further
research that may be conducted in relation to it, even if I withdraw
from the study/research.
I agree to this access. However, I understand that my identity will
not be revealed in any information released to third parties or
published. [ ]
(iv) I agree not to restrict the use of any data or results that arise from this
study provided such a use is only for scientific purposes [ ]
(v) I agree to take part in the above study. [ ]

Signature (or Thumb impression) of the Participant/Legally Acceptable

Representative:

Date: / /
Signatory’s Name:
Signature of the Investigator: Date: / /

Study Investigator’s Name:

Signature of the Witness Date: / /

Name of the Witness:

Copy of the Patient Information Sheet and duly filled Informed Consent Form
shall be handed over to the participant/subjecthis or her attendant.

TABLE 3 UNDERTAKING BY THE INVESTIGATOR

1. Full name, address and title of the Principal Investigator (or Investigators when there is
no Principal Investigator).
2. Name and address of the medical college, hospital or other facility where the clinical
study/research will be conducted: Education, training & experience that qualify the
Investigator for the clinical study/research (Attach details including Medical Council
registration number, or any other statements of qualifications)
3. Name and address of all clinical laboratory facilities to be used in the study.
4. Name and address of the Ethics Committee that is 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

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 investigations.
6. Protocol Title and Study number (if any) of the clinical study/research to be conducted
by the Investigator.
7. Commitments:
(i) I have reviewed the clinical protocol and agree that it contains all the
necessary information to conduct the study. I will not begin the study until
all necessary ethics committee and regulatory approvals have been
obtained.
(ii) I agree to conduct the study in accordance with the current protocol. I will
not implement any deviation from or changes of the protocol without
agreement by the Sponsor and prior review and documented approval or
favourable opinion from the ethics committee of the amendment, except
where necessary to eliminate an immediate hazard to the study/research
participant/subjector when the changes involved are only logistical or
administrative in nature.
(iii) I agree to personally conduct or supervise the clinical study/research at my
site.
(iv) I agree to inform all study/research participant, that the drugs are being
used for investigational purposes and I will ensure that the requirements
relating to obtaining informed consent and ethics committee review and
approval specified in the New Drugs and Clinical Trials Rules, 2019 and
Good Clinical Practices guidelines are met.
(v) I agree to report to the Sponsor all adverse experiences that occur in the
course of the investigation(s) in accordance with the regulatory
requirements and Good Clinical Practices guidelines.
(vi) I have read and understood the information in the Investigator's brochure,
including the potential risks and side effects of the drug.
(vii) I agree to ensure that all associates, colleagues and employees assisting in
the conduct of the study are suitably qualified and experienced and they
have been informed about their obligations in meeting their commitments
in the study/research.
(viii) I agree to maintain adequate and accurate records and to make those
records available for audit or inspection by the Sponsor, ethics committee,
Central Licencing Authority or their authorised representatives, in
accordance with regulatory provisions and the Good Clinical Practices
guidelines. I will fully cooperate with any study related audit conducted by
regulatory officials or authorised representatives of the Sponsor.
(ix) I agree to promptly report to the ethics committee all changes in the
clinical study/research activities and all unanticipated problems involving
risks to human participants or others.
(x) I agree to inform all serious adverse events to the Central Licencing
Authority, sponsor as well as the ethics committee within twenty-four
hours of their occurrence. In case, of failure to do so, I shall furnish the
reason for the delay to the satisfaction of the Central Licencing Authority
along with the report of the serious adverse event.

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 (xi) The report of the serious adverse event, after due analysis, shall also be
forwarded by me to the Central Licencing Authority, the Chairperson of
the ethics committee and the Head of the institution where the
study/research has been conducted within fourteen days in accordance with
the regulatory requirements.
(xii) I will maintain confidentiality of the identification of all participating
participants and assure security and confidentiality of study data.
(xiii) I agree to comply with all other requirements, guidelines and statutory
obligations as applicable to clinical Investigators participating in clinical
study/research.
8. Signature of Investigator with date.

TABLE 4: DATA ELEMENTS FOR REPORTING SERIOUS ADVERSE

EVENTS OCCURRING IN A CLINICAL STUDY/RESEARCH OR
BIOAVAILABILITY OR BIOEQUIVALENCE STUDY

1. Patient Details:
Initials and other relevant identifier (hospital or out-patient
department (OPD) record number etc)* Gender
Age or date of birth
Weight
Height
Suspected Drug(s): Generic name of the drug*
Indication(s) for which suspect
drug was prescribed or tested.
Dosage form and strength.
Daily dose and regimen
(specify units - e.g., mg, ml,
mg/kg). Route of
administration.
Starting date and time of day.
Stopping date and time, or duration of treatment
2. Other Treatment(s):
Provide the same information for concomitant drugs (including non-
prescription or Over the Counter OTC drugs) and non-drug therapies, as
for the suspected drug(s).
3. Details of Serious Adverse Event :
Full description of the event including body site and severity, as well as
the criterion (or criteria) for considering the report as serious. In addition
to a description of the reported signs and symptoms, whenever possible,
describe a specific diagnosis for the event*
Start date (and time) of onset of event. Stop date (and time) or duration of
event. Dechallenge and rechallenge information.
Setting (e.g., hospital, out-patient clinic, home, nursing home).

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4. Outcome
Information on recovery and any sequelae; results of specific tests or
treatment that may have been conducted.
For a fatal outcome, cause of death and a comment on its possible
relationship to the suspected event; Any post-mortem findings.
Other information: anything relevant to facilitate assessment of the case,
such as medical history including allergy, drug or alcohol abuse; family
history; findings from special investigations etc.
Details about the Investigator* Name and Address
Telephone number Profession (specialty)
Date of reporting the event to Central Licencing Authority:
Date of reporting the event to ethics committee overseeing the site:
Signature of the Investigator or Sponsor
Note: Information marked * must be provided.

TABLE 5: STRUCTURE, CONTENT AND FORMAT FOR CLINICAL

STUDY/RESEARCH REPORT

1. Title Page: This page should contain information about the title of the
study, the protocol code, name of the investigational product tested,
development Phase, indication studied, a brief description of the
study/research design, the start and end date of patient accrual and the
names of the Sponsor and the participating Institutes (Investigators).
2. Study Synopsis (1 to 2 pages): A brief overview of the study from the
protocol development to the study/research closure should be given here.
This section will only summarise the important conclusions derived from
the study.
3. Statement of compliance with the Good Clinical Practices Guidelines.
4. List of abbreviations and definitions
5. Table of contents
6. Ethics Committee: This section should document that the study was
conducted in accordance with the ethical principles of Declaration of
Helsinki. A detailed description of the Ethics Committee constitution and
dates of approvals of study/research documents for each of the
participating sites should be provided. A declaration should state that
Ethics Committee (EC) notifications as per Good Clinical Practice
Guidelines and Ethical Guidelines for Biomedical Research on Human
Participants, issued by Indian Council of Medical Research have been
followed.
7. Study Team: Briefly describe the administrative structure of the study
(Investigators, site staff, Sponsor or designates, Central laboratory etc.).
8. Introduction: A brief description of the product development rationale should be given
here.

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9. Study Objective: A statement describing the overall purpose of the
study and the primary and secondary objectives to be achieved should
be mentioned here.
10. Investigational Plan: This section should describe the overall
study/research design, the Participant/subjectselection criteria, the
treatment procedures, blinding or randomisation techniques if any,
allowed or disallowed concomitant treatment, the efficacy and safety
criteria assessed, the data quality assurance procedures and the statistical
methods planned for the analysis of the data obtained.
11. Study/research Participants: A clear accounting of all study/research
Participants who entered the study will be given here. Mention should also
be made of all cases that were dropouts or protocol deviations. Enumerate
the patients screened, randomised, and prematurely discontinued. State
reasons for premature discontinuation of therapy in each applicable case.
12. Efficacy evaluation: The results of evaluation of all the efficacy variables
will be described in this section with appropriate tabular and graphical
representation. A brief description of the demographic characteristics of
the study/research patients should also be provided along with a listing of
patients and observations excluded from efficacy analysis.
13. Safety Evaluation: This section should include the complete list
13.1 all serious adverse events, whether expected or unexpected and

13.2 unexpected adverse events whether serious or not (compiled from

data received as per Table 5 of this Schedule).
The comparison of adverse events across study groups may be presented in
a tabular or graphical form. This section should also give a brief narrative
of all important events considered related to the investigational product.
14 Discussion and overall Conclusion: Discussion of the important
conclusions derived from the study/research and scope for further
development.
15. List of References:
16. Appendices: List of Appendices to the Clinical Study Report
(a) Protocol and amendments

(b) Specimen of Case Record Form

(c) Investigators’ names with contact addresses, phone, e-mail etc.

(d) Patient data listings

(e) List of study/research participants treated with investigational product

(f) Discontinued participants

(g) Protocol deviations

(h) Case Record Forms of cases involving death and life threatening adverse event
cases
(i) Publications from the study/research

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 (j) Important publications referenced in the study
(k) Audit certificate, if available

(l) Investigator’ certificate that he/she has read the report and that the
report accurately describes the conduct and the results of the study.

TABLE 6 INVESTIGATOR'S BROCHURE

The Investigator's Brochure should contain the version number, release date along with
the following sections, each with literature references where appropriate:
1 Table of Contents
2 Summary: A brief summary (preferably not exceeding two pages) should be
given, highlighting the significant physical, chemical, pharmaceutical,
pharmacological, toxicological, pharmacokinetic, metabolic, and clinical
information available that is relevant to the stage of clinical development of the
investigational product.
3 Introduction: A brief introductory statement should be provided that contains the
chemical name (and generic and trade name when approved) of the
investigational product, all active ingredients, the investigational product
pharmacological class and its expected position within this class (e.g.
advantages), the rationale for performing research with the investigational
product, and the anticipated prophylactic, therapeutic, or diagnostic indication.
Finally, the introductory statement should provide the general approach to be
followed in evaluating the investigational product.
4 Physical, Chemical, and Pharmaceutical Properties and Formulation: A
description should be provided of the investigational product substance
(including the chemical or structural formula), and a brief summary should be
given of the relevant physical, chemical, and pharmaceutical properties. To
permit appropriate safety measures to be taken in the course of the
study/research, a description of the formulation to be used, including excipients,
should be provided and justified if clinically relevant. Instructions for the storage
and handling of the dosage form should also be given. Any structural similarities
to other known compounds should be mentioned.
5 Nonclinical Studies
5.1 Introduction: The results of all relevant nonclinical pharmacology,
toxicology, pharmacokinetic, and investigational product metabolism
studies should be provided in summary form. This summary should
address the methodology used, the results, and a discussion of the
relevance of the findings to the investigated therapeutic and the possible
unfavourable and unintended effects in human. The information provided
may include the following, as appropriate, if known or available:

 Species tested

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  Number and sex of animals in each group
 Unit dose (e.g., milligram/kilogram (mg/kg))
 Dose interval
 Route of administration
 Duration of dosing
 Information on systemic distribution
 Duration of post-exposure follow-up
 Results, including the following aspects:
− Nature and frequency of pharmacological or toxic effects
− Severity or intensity of pharmacological or toxic effects
− Time to onset of effects
− Reversibility of effects
− Duration of effects
− Dose response
Tabular format or listings should be used whenever possible to enhance the clarity of
the presentation. The following sections should discuss the most important findings
from the studies, including the dose response of observed effects, the relevance to
humans, and any aspects to be studied in humans. If applicable, the effective and
nontoxic dose findings in the same animal species should be compared (i.e., the
therapeutic index should be discussed). The relevance of this information to the
proposed human dosing should be addressed. Whenever possible, comparisons should
be made in terms of blood/tissue levels rather than on a mg/kg basis.
(a) Nonclinical Pharmacology: A summary of the pharmacological aspects of
the investigational product and, where appropriate, its significant
metabolites studied in animals, should be included. Such a summary
should incorporate studies that assess potential therapeutic activity (e.g.
efficacy models, receptor binding, and specificity) as well as those that
assess safety (e.g., special studies to assess pharmacological actions other
than the intended therapeutic effect(s)).
(b) Pharmacokinetics and Product Metabolism in Animals: A summary of the
pharmacokinetics and biological transformation and disposition of the
investigational product in all species studied should be given. The
discussion of the findings should address the absorption and the local and
systemic bioavailability of the investigational product and its metabolites,
and their relationship to the pharmacological and toxicological findings in
animal species.
(c) Toxicology: A summary of the toxicological effects found in relevant
studies conducted in different animal species should be described under
the following headings where appropriate:
− Single dose
− Repeated dose

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 − Carcinogenicity
− Special studies (e.g. irritancy and sensitization)
− Reproductive toxicity
− Genotoxicity (mutagenicity)
6 Effects in Humans:
(a) A thorough discussion of the known effects of the investigational products
in humans should be provided, including information on
pharmacokinetics, metabolism, pharmacodynamics, dose response,
safety, efficacy, and other pharmacological activities. Where possible, a
summary of each completed clinical study/research should be provided.
Information should also be provided regarding results of any use of the
investigational products other than from in clinical study/research, such as
from experience during marketing.
(b) Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the investigational
products should be presented, including the following, if available:
− Pharmacokinetics (including metabolism, as appropriate, and
absorption, plasma protein binding, distribution, and elimination).
− Bioavailability of the investigational product (absolute, where
possible, or relative) using a reference dosage form.
− Population subgroups (e.g., gender, age, and impaired organ
function).
− Interactions (e.g., product-product interactions and effects of food).
− Other pharmacokinetic data (e.g., results of population studies
performed within clinical study/research(s).
(c) Safety and Efficacy: A summary of information should be provided about
the investigational product's or products' (including metabolites, where
appropriate) safety, pharmacodynamics, efficacy, and dose response that
were obtained from preceding study/research in humans (healthy
volunteers or patients). The implications of this information should be
discussed. In cases where a number of clinical study/research have
been completed, the use of summaries of safety and efficacy across
multiple study/research by indications in subgroups may provide a clear
presentation of the data. Tabular summaries of adverse drug reactions for
all the clinical study/research (including those for all the studied
indications) would be useful. Important differences in adverse drug
reaction patterns/incidences across indications or subgroups should be
discussed. The Investigators Brochure IB should provide a description of
the possible risks and adverse drug reactions to be anticipated on the basis
of prior experiences with the product under investigation and with related
products. A description should also be provided of the precautions or
special monitoring to be done as part of the investigational use of the
products.
(d) Marketing Experience: The Investigator's Brochure should identify

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 countries where the investigational product has been marketed or
approved. Any significant information arising from the marketed use
should be summarised (e.g., formulations, dosages, routes of
administration, and adverse product reactions). The Investigator's
Brochure should also identify all the countries where the investigational
product did not receive approval or registration for marketing or was
withdrawn from marketing or registration.
7 Summary of Data and Guidance for the Investigator: This section should provide
an overall discussion of the nonclinical and clinical data and should summarise
the information from various sources on different aspects of the investigational
products, wherever possible. In this way, the investigator can be provided with
the most informative interpretation of the available data and with an assessment
of the implications of the information for future clinical study/research. Where
appropriate, the published reports on related products should be discussed. This
could help the investigator to anticipate adverse drug reactions or other problems
in clinical study/research. The overall aim of this section is to provide the
investigator with a clear understanding of the possible risks and adverse
reactions, and of the specific tests, observations, and precautions that may be
needed for a clinical study/research. This understanding should be based on the
available physical, chemical, pharmaceutical, pharmacological, toxicological,
and clinical information on the investigational products. Guidance should also be
provided to the clinical investigator on the recognition and treatment of possible
overdose and adverse drug a reaction that is based on previous human experience
and on the pharmacology of the investigational product.

TABLE 7 PRESCRIBING INFORMATION

1. Generic Name
2. Qualitative and quantitative composition
3. Dosage form and strength
4. Clinical particulars
4.1 Therapeutic indication
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Drugs interactions
4.6 Use in special populations (such as pregnant women, lactating
women, paediatric patients, geriatric patients etc.)
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Mechanism of Action
5.2 Pharmacodynamic properties
5.3 Pharmacokinetic properties
6. Nonclinical properties

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 6.1 Animal Toxicology or Pharmacology
7. Description
8. Pharmaceutical particulars
8.1 Incompatibilities
8.2 Shelf-life
8.3 Packaging information
8.4 Storage and handing instructions
9. Patient Counselling Information
10. Details of manufacturer
11. Details of permission or licence number with date
12. Date of revision

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 APPENDIX VI: Format For Submission Of Preclinical And Clinical Data

FOR r-DNA BASED VACCINES, DIAGNOSTICS AND OTHER BIOLOGICALS

(Reproduced from Guidelines for Generating Preclinical and Clinical Data for r-DNA
based vaccines, diagnostics and other biologicals issued by Department of Biotechnology,
Ministry of Science and Technology, Govt. of India)

*For details to generate these data, please consult the document entitled “Guidelines for
generating preclinical and clinical data for r-DNA based vaccines, diagnostics and other
biologicals”.

A: SPECIFICATION AND CHARACTERIZATION INFORMATION ON r-DNA

VACCINES AND BIOLOGICAL PRODUCTS

1. Description in details of the method of r-DNA products:

(a) host cells,

(b) gene construct,

(c) vector construction including a description of the source and

function of the component parts of the vectors,

(d) source and diagram of the plasmid(s) used,

(e) all intermediate cloning procedures, and

(f) transfection methods.

2. Description of the method of sequence verification (such as restriction enzyme

mapping, PCR etc.)

3. Description on Identity-Physical, Chemical, Immunological and Biological

wherever applicable

(a) Description on recombinant DNA products:

(1) Primary structure (Amino acid sequences)

(2) Secondary structure (disulfide linkages etc.)

134
 (3) Post-translation modification (glycosylation etc.)

(b) Monoclonal antibodies (if applicable):

- identity by rigorous immunochemical and

physicochemical characterization.

4. Potency

(a) Production of specific antigen in transfected cell line,

(b) Immune response in mice,

(c) Hypersensitivity (Guinea pig maximization test), and

(d) Permissible limits of potency.

5. General Safety Test

6. Data on sterility tests as per Indian Pharmacopia guidelines

7. Data on purity of recombinant product

(a) Limits of purity,

(b) Characterization of minor impurities like RNA, protein and genomic DNA,

(c) Permissible limits of moisture, if lyophilized, and

(d) Pyrogenicity

8. Description of constituent materials like preservatives etc

9. Data on stability of finished formulation as per IP (Indian pharmacopia) guidelines

B : DATA ON PRECLINICAL TESTING

1. Biological activity/ pharmacodynamics in vitro and in appropriate animal models.

2. Safety Pharmacology (Functional indices of toxicity).
3. Toxicology and pharmacokinetics (Absorption, Distribution, Metabolism,
Excretion- ADME)
4. Immunogenicity/Immunotoxicity
5. Reproductive and developmental toxicity
6. Genotoxicity studies
7. Carcinogenicity studies

135
C: RECOMBINANT IMMUNODIAGNOSTIC REAGENTS

1. Specification and characterization of r-DNA diagnostic products (Please

provide information as per column1-9 under Section A of this format).
2. The data on the sensitivity / specificity / predictive positive value/ predictive
negative value / overall diagnostic accuracy of recombinant product in
diagnostic assay.
3. Data on (1) “in-house” validation and (2) independent validation.
4. Data using indigenous / internationally available panel of sera / clinical materials.

D: CLINICAL STUDY/RESEARCH

1. Phase I: Human/Clinical Pharmacology Immunogenic Potency

(a) Details on level of specific antibodies including its kinetics in healthy
participants.

(b) Details on cytokine profiles in healthy participants.

(c) Details on T-cell responses in healthy participants.

(d) Data on auto-antibodies and immune complexes in healthy participants.

(e) Details on haematological and clinical chemistry.

2. Phase II: Exploratory Clinical Study/research- Preventive/Therapeutic Efficacy

(Data to be generated in participants residing in endemic/ non-endemic areas)

(a) Protective / therapeutic potentials of r-DNA vaccines.

(b) Details of the haematological data.

(c) Details on the clinical chemistry.

(d) Data on experiments on minimum protective / therapeutic dose vis-à-vis

immune response (both T&B cells).

3. Phase III: Confirmatory Study/research

(a) Preventive / therapeutic effects.

(b) Immunological / clinical chemistry parameters in some participants

belonging to different ethnic and socio-economic groups.

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 APPENDIX V: Essential documents for the conduct of a clinical study/research

Essential Documents are those documents which individually and collectively permit evaluation
of the conduct of a study/research and the quality of the data produced. These documents serve to
demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good
Clinical Practice and with all applicable regulatory requirements.
Essential Documents also serve a number of other important purposes. Filing essential documents
at the investigator/institution and sponsor sites in a timely manner can greatly assist in the
successful management of a study/research by the investigator, sponsor and monitor. These
documents are also the ones which are usually audited by the sponsor's independent audit
function and inspected by the regulatory authority(ies) as part of the process to confirm the
validity of the study/research conduct and the integrity of data collected.
The minimum list of essential documents which has been developed follows. The various
documents are grouped in three sections according to the stage of the study/research during which
they will normally be generated: 1) before the clinical phase of the study/research commences, 2)
during the clinical conduct of the study/research, and 3) after completion or termination of the
study/research. A description is given of the purpose of each document, and whether it should be
filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine
some of the documents, provided the individual elements are readily identifiable.
Study/research master files should be established at the beginning of the study/research, both at
the investigator/institution’s site and at the sponsor's office. A final close-out of a study/research
can only be done when the monitor has reviewed both investigator/institution and sponsor files
and confirmed that all necessary documents are in the appropriate files.
Any or all of the documents addressed in this guideline may be participant/subjectto, and should
be available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).

ADDENDUM

The sponsor and investigator/institution should maintain a record of the location(s) of their
respective essential documents including source documents. The storage system used during the
study/research and for archiving (irrespective of the type of media used) should provide for
document identification, version history, search, and retrieval.
Essential documents for the study/research should be supplemented or may be reduced where
justified (in advance of study/research initiation) based on the importance and relevance of the
specific documents to the study/research.
The sponsor should ensure that the investigator has control of and continuous access to the CRF
data reported to the sponsor. The sponsor should not have exclusive control of those data.
When a copy is used to replace an original document (e.g., source documents, CRF), the copy
should fulfill the requirements for certified copies.

The investigator/institution should have control of all essential documents and records generated
by the investigator/institution before, during, and after the study/research.

1.1 Before the study/research commences

137
During this planning stage the following documents should be generated and should be on file
before the study/research formally start

Located in Files of
Title of Document Purpose Investigator
Sponsor
/Institution
8.2.1 INVESTIGATOR’S To document that relevant and X X
BROCHURE current scientific information
about the investigational
product has been provided to
the investigator
8.2.2 SIGNED PROTOCOL To document investigator and X X
AND AMENDMENTS, sponsor agreement to the
IF ANY, AND protocol/amendment(s) and
SAMPLE CASE CRF
REPORT FORM
(CRF)
8.2.3 INFORMATION To document the informed X X
GIVEN TO consent
STUDY/RESEARCH
PARTICIPANT
INFORMED
CONSENT FORM
(Including all
applicable
translations)
- ANY OTHER To document that participants X X
WRITTEN will be given appropriate
INFORMATION written information (content
and wording) to support their
ability to give fully informed
consent
- ADVERTISEMENT To document that recruitment X
FOR PARTICIPANT measures are appropriate and
RECRUITMENT (if not coercive
used)
8.2.4 FINANCIAL To document the financial X X
ASPECTS OF THE agreement between the
STUDY/RESEARCH investigator/institution and the
sponsor for the study/research
Title of Document Purpose Located in Files of
Investigator
Sponsor
/Institution
8.2.5 INSURANCE To document that X X
STATEMENT compensation to participant(s)
(where required) for study/research- related
injury will be available

138
8.2.6 SIGNED To document agreements
AGREEMENT
BETWEEN
INVOLVED
PARTIES, e.g.:
X X
- investigator/instituti
X X (where
on and sponsor
required)
- investigator/instituti
X X
on and CRO
X
- sponsor and CRO
- investigator/instituti
on and authority(ies)
(where required)
8.2.7 DATED, To document that the X X
DOCUMENTED study/research has been
APPROVAL/FAVOU participant/subjectto EC review
RABLE OPINION OF and given approval/favourable
INSTITUTIONAL opinion. To identify the version
REVIEW BOARD number and date of the
(IRB) document(s)
/INDEPENDENT
ETHICS
COMMITTEE (EC)
OF THE
FOLLOWING:
- protocol and any
amendments
- CRF (if applicable)
- informed consent
form(s)
- any other written
information to be
provided to the
participant(s)
- advertisement for
participant/subjectrecru
itment (if used)
- participant/subjectcom
pensation (if any)
- any other documents
given approval/
favourable opinion

139
 Located in Files of
Title of Document Purpose Investigator
Sponsor
/Institution
8.2.8 INSTITUTIONAL REVIEW To document that the EC is X X
BOARD/INDEPENDENT constituted in agreement with (where
ETHICS COMMITTEE GCP required)
COMPOSITION
8.2.9 REGULATORY To document appropriate X X
AUTHORITY(IES) authorisation/approval/notifica (where (where
AUTHORISATION/APPROVA tion by the regulatory required) required)
L/ NOTIFICATION OF authority(ies) has been
PROTOCOL obtained prior to initiation of
(where required) the study/research in
compliance with the
applicable regulatory
requirement(s)
8.2.10 CURRICULUM VITAE To document qualifications X X
AND/OR OTHER RELEVANT and eligibility to conduct
DOCUMENTS EVIDENCING study/research and/or provide
QUALIFICATIONS OF medical supervision of
INVESTIGATOR(S) AND participants
SUB-INVESTIGATOR(S)
8.2.11 NORMAL To document normal values X X
VALUE(S)/RANGE(S) FOR and/or ranges of the tests
MEDICAL/
LABORATORY/TECHNICAL
PROCEDURE(S) AND/OR
TEST(S) INCLUDED IN THE
PROTOCOL
8.2.12 MEDICAL/LABORATORY/TEC To document competence of X X
HNICAL PROCEDURES facility to perform required (where
/TESTS test(s), and support reliability required)
- certification or of results
- accreditation or
- established quality control
and/or external quality
assessment or
- other validation (where required)

140
 Located in Files of
Title of Document Purpose Investigator
Sponsor
/Institution
8.2.13 SAMPLE OF LABEL(S) To document compliance with X
ATTACHED TO applicable labelling regulations and
INVESTIGATIONAL appropriateness of instructions
PRODUCT provided to the participants
CONTAINER(S)
8.2.14 INSTRUCTIONS To document instructions needed to X X
FOR HANDLING OF ensure proper storage, packaging,
INVESTIGATIONA dispensing and disposition of
L PRODUCT(S) AND investigational products and
STUDY/RESEARCH study/research-related materials
-RELATED
MATERIALS
(if not included in protocol or
Investigator’s
Brochure)
8.2.15 SHIPPING To document shipment dates, batch X X
RECORDS FOR numbers and method of shipment of
INVESTIGATIONA investigational product(s) and
L PRODUCT(S) AND study/research-related materials.
STUDY/RESEARCH Allows tracking of product batch,
-RELATED review of shipping conditions, and
MATERIALS accountability
8.2.16 CERTIFICATE(S) OF To document identity, purity, and X
ANALYSIS OF strength of investigational product(s)
INVESTIGATIONAL to be used in the study/research
PRODUCT(S) SHIPPED
8.2.17 DECODING PROCEDURES To document how, in case of an X X
FOR BLINDED emergency, identity of (third
STUDY/RESEARCH blinded investigational product can be party if
revealed without breaking the blind for applicable)
the remaining participants' treatment
8.2.18 MASTER To document method for randomisation X
RANDOMISATION LIST of study/research population (third
party if
applicable)
8.2.19 PRE-STUDY/RESEARCH To document that the site is suitable for X
MONITORING REPORT the study/research (may be combined
with 8.2.20)
8.2.20 STUDY/RESEARCH To document that study/research X X
INITIATION MONITORING procedures were reviewed with the
REPORT investigator and the investigator’s
study/research staff ( may be combined
with 8.2.19)

141
1.2 During the Clinical Conduct of the Study/research

In addition to having on file the above documents, the following should be added to the
files during the study/research as evidence that all new relevant information is documented
as it becomes available

Located in Files of
Title of Document Purpose Investigator
Spons
/Institution
or
8.3.1 INVESTIGATOR’S BROCHURE To document that investigator is X X
UPDATES informed in a timely
manner of relevant information
as it becomes available
8.3.2 ANY REVISION TO: To document revisions of X X
- protocol/amendment(s) and CRF these study/research related
documents that take effect
- informed consent form
during study/research
- any other written
information provided to
participants
- advertisement for
participant/subjectrecruitment
(if used)
8.3.3 DATED, DOCUMENTED To document that the X X
APPROVAL/FAVOURABLE amendment(s) and/or
OPINION OF INSTITUTIONAL revision(s) have been
REVIEW BOARD (IRB) participant/subjectto EC
/INDEPENDENT ETHICS review and were given
COMMITTEE (EC) OF THE approval/favourable opinion.
FOLLOWING: To identify the version number
- protocol amendment(s) and date of the document(s).
- revision(s) of:
informed consent form
any other written information to be
provided to the participant
advertisement for
participant/subjectrecruit
ment (if used)
- any other documents given
approval/favourable
opinion
- continuing review of study/research
(where required)
Located in Files of

142
 Title of Document Purpose Investigator
Spon
/Institution
sor
8.3.4 REGULATORY To document compliance with X X
AUTHORITY(IES) applicable regulatory (where
AUTHORISATIONS/APPROVAL requirements required)
S/NOTIFICAT IONS WHERE
REQUIRED FOR:
- protocol amendment(s) and other
documents
8.3.5 CURRICULUM VITAE FOR (see 8.2.10) X X
NEW INVESTIGATOR(S)
AND/OR SUB-
INVESTIGATOR(S)
8.3.6 UPDATES TO NORMAL To document normal values and X X
VALUE(S)/RANGE(S) FOR ranges that are revised during the
MEDICAL/ LABORATORY/ study/research (see 8.2.11)
TECHNICAL
PROCEDURE(S)/TEST(S)
INCLUDED IN THE PROTOCOL
8.3.7 UPDATES OF To document that tests remain X X
MEDICAL/LABORATORY/ adequate throughout the (where
TECHNICAL study/research period (see required)
PROCEDURES/TESTS 8.2.12)
- certification or
- accreditation or
- established quality control
and/or external quality
assessment or
- other validation (where required)
8.3.8 DOCUMENTATION OF (see 8.2.15.) X X
INVESTIGATIONAL
PRODUCT(S) AND
STUDY/RESEARCH-RELATED
MATERIALS SHIPMENT
8.3.9 CERTIFICATE(S) OF ANALYSIS (see 8.2.16) X
FOR NEW BATCHES OF
INVESTIGATIONAL
PRODUCTS

143
 Located in Files of
Title of Document Purpose Investigator
Sponsor
/Institution
8.3.10 MONITORING To document site visits by, and findings X
VISIT REPORTS of, the monitor
8.3.11 RELEVANT To document any agreements or X X
COMMUNICATIO significant discussions regarding
NS OTHER THAN study/research administration, protocol
SITE VISITS violations, study/research conduct,
- letters adverse event (AE) reporting
- meeting notes
- notes of telephone
calls
8.3.12 SIGNED To document that consent is obtained in X
INFORMED accordance with GCP and protocol and
CONSENT FORMS dated prior to participation of each
participant/subjectin study/research. Also
to document direct access permission (see
8.2.3)
8.3.13 SOURCE To document the existence of the X
DOCUMENTS participant/subjectand substantiate
integrity of study/research data
collected. To include original documents
related to the study/research, to medical
treatment, and
history of participant
8.3.14 SIGNED, To document that the investigator or X X
DATED authorised member (copy) (original)
AND of the investigator’s staff confirms the
COMPLET observations recorded
ED CASE
REPORT
FORMS
(CRF)
8.3.15 DOCUMENTATIO To document all changes/additions or X X
N OF CRF corrections made to (copy) (original)
CORRECTIONS CRF after initial data were recorded
8.3.16 NOTIFICATION Notification by originating investigator X X
BY ORIGINATING to sponsor of serious adverse events and
INVESTIGATOR related reports in accordance with 4.11
TO SPONSOR OF
SERIOUS
ADVERSE
EVENTS AND
RELATED
REPORTS

144
 Located in Files of
Title of Document Purpose Investigator
Sponsor
/Institution
8.3.17 NOTIFICATION BY Notification by sponsor and/or X X
SPONSOR AND/OR investigator, where applicable, to (where
INVESTIGATOR, WHERE regulatory authorities and require
APPLICABLE, TO IRB(s)/EC(s) of unexpected d)
REGULATORY serious adverse drug reactions in
AUTHORITY(IES) AND accordance with 5.17 and 4.11.1
IRB(S)/EC(S) OF and of other safety information in
UNEXPECTED SERIOUS accordance with 5.16.2 and 4.11.2
ADVERSE DRUG
REACTIONS AND OF
OTHER
SAFETY INFORMATION
8.3.18 NOTIFICATION BY Notification by sponsor to X X
SPONSOR TO investigators of safety
INVESTIGATORS OF information in accordance with
SAFETY INFORMATION 5.16.2
8.3.19 INTERIM OR ANNUAL Interim or annual reports X X
REPORTS TO EC AND provided to EC in accordance (where
AUTHORITY(IES) with 4.10 and to authority(ies) in required)
accordance
with 5.17.3
8.3.20 PARTICIPANT/SUBJECTS To document identification of X X
CREENING LOG participants who entered pre- (where
study/research screening required)
8.3.21 PARTICIPANT/SUBJECTI To document that X
DENTIFICATION CODE investigator/institution keeps a
LIST confidential list of names of all
participants allocated to
study/research numbers on
enrolling in the study/research.
Allows
investigator/institution to reveal
identity of any participant
8.3.22 PARTICIPANT/SUBJECTE To document chronological X
NROLMENT LOG enrolment of participants by
study/research number
8.3.23 INVESTIGATIONAL To document that investigational X X
PRODUCTS product(s) have been
ACCOUNTABILITY AT used according to the protocol
THE SITE
8.3.24 SIGNATURE SHEET To document signatures and X X
initials of all persons
authorised to make entries and/or
corrections on CRFs
145
8.3.25 RECORD OF RETAINED To document location and X X
BODY FLUIDS/ identification of retained
TISSUE SAMPLES (IF samples if assays need to be
ANY) repeated

146
1.3 After Completion or Termination of the Study/research

After completion or termination of the study/research, all of the documents identified in sections 8.2 and 8.3
should be in the file together with the following
Located in Files of
Title of Document Purpose Investigator
Sponsor
/Institution
8.4.1 INVESTIGATIONAL To document that the X X
PRODUCT(S) investigational product(s) have
ACCOUNTABILITY been used according to the
AT SITE protocol. To documents the
final accounting of
investigational product(s)
received at the site, dispensed to
participants, returned by the
participants, and
returned to sponsor
8.4.2 DOCUMENTATION To document destruction of X X
OF unused investigational (if destroyed
INVESTIGATIONAL products by sponsor or at site at site)
PRODUCT
DESTRUCTION
8.4.3 COMPLETED To permit identification of all X
PARTICIPANT/SUBJ participants enrolled in the
ECTIDENTIFICATIO study/research in case follow-
N CODE LIST up is required. List should be
kept in a
confidential manner and for
agreed upon time
8.4.4 AUDIT To document that audit was X
CERTIFICATE (if performed
available)
8.4.5 FINAL To document that all activities X
STUDY/RESEARCH required for study/research
CLOSE-OUT close-out are completed, and
MONITORING copies of essential documents
REPORT are held
in the appropriate files
8.4.6 TREATMENT Returned to sponsor to document X
ALLOCATION AND any decoding that may
DECODING have occurred
DOCUMENTATION

147
8.4.7 FINAL REPORT BY To document completion of the X
INVESTIGATOR TO study/research
EC WHERE
REQUIRED, AND
WHERE
APPLICABLE, TO
THE REGULATORY
AUTHORITY(IES)
8.4.8 CLINICAL STUDY To document results and X X
REPORT interpretation of study/research (if applicable)

148
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 Particularly vulnerable tribal groups: Ministry of Tribal Affairs.
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 Clinical Trials Registry -ICMR India st of references
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149
 ICMR guideline on The Ethical Conduct of Controlled Human infection studies In India
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ASU), Department of Ayush, Ministry of Health and Family welfare
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 ICMR GCP guidelines for tribals
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 ICMR guideline on euthanasia
 ICMR guideline on publication policy
 ICMR guideline on systemic review and meta- analysis
 OECD guidelines on clinical toxicity studies

150