Good Clinical Practices For Clinical Research In India
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*Good Clinical Practices For Clinical Research In I**ndia*
*FOREWORD*
Clinical research is the key to the discovery of latest diagnostic
methods and to develop modern drugs for treatment of diseases. Good
Clinical Practices (GCP) is an ethical and scientific quality standard
for designing, conducting and recording trials that involve the
participation of human subjects. Compliance with this standard provides
assurance to public that the rights, safety and well being of trial
subjects are protected, consistent with the principles enshrined in the
Declaration of Helsinki and ensures that clinical trial data are credible.
It has been widely recognized that India offers unique opportunities for
conducting clinical trials in view of the large patient pool, well-
trained and enthusiastic investigators and premiere medical institutes
available in the country along with considerable low per patient trial
cost, as compared to developed countries.
A need was, however, felt to develop our own Indian Guidelines to ensure
uniform quality of clinical research throughout the country and to
generate data for registration for new drugs before use in the Indian
population. An Expert Committee set up by Central Drugs Standard Control
Organisation (CDSCO) in consultation with clinical expert has formulated
this GCP guideline for generation of clinical data on drugs.
The Drug Technical Advisory Board (DTAB), the highest technical body
under D&C, Act, has endorsed adoption of this GCP guideline for
streamlining the clinical studies in India.
I am confident that this guideline will be immensely useful to research
institutions, investigators, institutional ethics committees and
regulators in providing desired direction. The guideline would also be
helpful to companies who may want to locate their clinical programme in
the country.
Place: New
Delhi
Dr. S.P. Agarwal,
Director General of Health Services
and Chairman, DTAB
*Contents*
Introduction
1. Definitions
2. Pre-requisites for the study
2.1. Investigational Pharmaceutical Product
2.2. Pre-Clinical supporting data
2.3. Protocol
2.3.1. Relevant components of Protocol
2.3.1.1. General Information
2.3.1.2. Objectives and Justification
2.3.1.3. Ethical Considerations
2.3.1.4. Study design
2.3.1.5. Inclusion, Exclusion & Withdrawal of Subjects
2.3.1.6. Handling of the Product(s)
2.3.1.7. Assessment of Efficacy
2.3.1.8. Assessment of Safety
2.3.1.9. Statistics
2.3.1.10. Data handling and management
2.3.1.11. Quality control and quality assurance
2.3.1.12. Finance and Insurance
2.3.1.13. Publication policy
2.3.1.14. Evaluation
2.3.2. Supplementaries and appendices:
2.4. Ethical & Safety Considerations
2.4.1. Ethical Principles
2.4.2. Ethics Committee
2.4.2.1. Basic Responsibilities
2.4.2.2. Composition
2.4.2.3. Terms of Reference
2.4.2.4. Review Procedures
2.4.2.5. Submission of Application
2.4.2.6. Decision Making Process
2.4.2.7. Interim Review
2.4.2.8. Record Keeping
2.4.2.9. Special Considerations
2.4.3. Informed Consent Process
2.4.3.1. Informed Consent of Subject
2.4.3.2. Essential information for prospective research subjects
2.4.3.3. Informed Consent in Non-Therapeutic Study
2.4.4. Essential Information on Confidentiality for Prospective
Research Subjects
2.4.5. Compensation for Participation
2.4.6. Selection of Special Groups As Research Subject
2.4.6.1. Pregnant or nursing women
2.4.6.2. Children
2.4.6.3. Vulnerable groups
2.4.7. Compensation for Accidental Injury
2.4.7.1. Obligation of the sponsor to pay
3. Responsibilities
3.1. Sponsor
3.1.1. Investigator and Institution Selection
3.1.2. Contract
3.1.3. SOP
3.1.4. Allocation of duties and responsibilities
3.1.5. Study management, data handling and record keeping
3.1.6. Compensation for Participation
3.1.7. Confirmation of review by the Ethics Committee
3.1.8. Information on Investigational Products
3.1.9. Supply, storage and handling of Pharmaceutical Products
3.1.10 Safety Information
3.1.11 Adverse Drug Reaction Reporting
3.1.12 Study Reports
3.1.13 Monitoring
3.1.14 Audit
3.1.15 Multicentre Studies
3.1.16 Premature Termination or Suspension of a Study
3.1.17 Role of Foreign Sponsor
3.2. The Monitor
3.2.1. Qualifications
3.2.2. Responsibilities
3.3. Investigator
3.3.1. Qualifications
3.3.2. Medical Care of the Study Subjects
3.3.3. Monitoring and Auditing of records
3.3.4. Communication with Ethic Committee
3.3.5. Compliance with the Protocol
3.3.6. Investigational Product(s)
3.3.7. Selection and recruitment of Study Subjects
3.3.8. Records/Reports
4. Record Keeping and Data Handling
4.1. Documentation
4.2. Corrections
4.3. Electronic Data Processing
4.4. Validation of Electronic Data Processing Systems
4.5. Language
4.6. Responsibility of Investigator
4.7. Responsibilities of Sponsor and Monitor
5. Quality Assurance
6. Statistics
6.1. Role of Biostatistician
6.2. Study design
6.2.1. Randomisation and Blinding
6.3. Statistical Analysis
7. Special Concerns
7.1. Clinical Trials of Vaccines
7.1.1. Phases of Vaccine Trials
7.1.2. Guidelines
7.2. Clinical Trials of contraceptives
7.3. Clinical Trials with Surgical Procedures / Medical devices.
7.3.1. Definitions
7.3.2. Guidelines
7.4. Clinical Trials for Diagnostic agents – Use of
radioactive materials and X-rays
7.4.1. Guidelines
7.5. Clinical Trials of Herbal Remedies and Medicinal Plants
7.5.1. Categories of Herbal Product
7.5.2. Guidelines
Appendices
Appendix I: Declaration of Helsinki
Appendix II: Schedule Y
Appendix III: Format for submission of Pre-clinical and clinical data
for r-DNA based vaccines, diagnostics and other biologicals.
Appendix IV: Investigator’s Brochure
Appendix V: Essential Documents
*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 a Physician’s ethical and scientific responsibilities such
as obtaining informed consent or disclosing risk while involved in
biomedical 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 subjects.
The fundamental tenet of GCP is that in research on man, the interest of
science and society should never take precedence over considerations
related to the well being of the study subject. 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 of human subjects and authenticity
of biomedical data generated.
These guidelines have been evolved with consideration of WHO, ICH, USFDA
and European GCP guidelines as well as the Ethical Guidelines for
Biomedical research on Human Subjects 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*
Act
Wherever relevant, the Act means Drugs & Cosmetics Act 1940 (23 of 1940)
and the Rules made thereunder.
*/Adverse Event (AE)/*
Any untoward medical occurrence (including a symptom / disease or an
abnormal laboratory finding) during treatment with a pharmaceutical
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: A noxious and
unintended response at doses normally used or tested in humans
(b) In case of new unregistered pharmaceutical products (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 trials, an untoward medical occurrence seemingly caused by
overdosing, abuse / dependence and interactions with other medicinal
products is also considered as an ADR.
Adverse drug reactions are type A (pharmacological) or type B
(idiosyncratic). Type A reactions represent an augmentation of the
pharmacological actions of a drug. They are dose-dependent and are,
therefore, readily reversible on reducing the dose or withdrawing the
drug. In contrast, type B adverse reactions are bizarre and cannot be
predicted from the known pharmacology of the drug.
Audit of a Trial
A systematic verification of the study, carried out by persons not
directly involved, such as:
(a) Study related activities to determine consistency with the /Protocol/
(b) Study data to ensure that there are no contradictions on/Source
Documents/. The audit should also compare data on the Source Documents
with the interim or final report. It should also aim to find out if
practices were employed in the development of data that would impair
their validity.
(c) Compliance with the adopted Standard Operating Procedures (/SOPs)/
*Blinding / Masking*
A method of “control experimentation†in which one or more parties
involved are not informed of the treatment being given. Single blind
refers to the study subject(s) being unaware, while Double blind refers
to the study subject(s) and/or investigator(s), monitor, data analyst(s)
are being unaware of the treatment assigned.
/Case Record Form (CRF)/
A document designed in consonance with the Protocol, to record data and
other information on each trial subject. 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.
*Clinical Trial (Clinical Study)*
A systematic study of pharmaceutical products on human subjects –
(whether patients or non-patient volunteers) – in order to discover or
verify the clinical, pharmacological (including pharmacodynamics /
pharmacokinetics), and / or adverse effects, with the object of
determining their safety and / or efficacy.
*/Human/Clinical Pharmacology trials (Phase I)/*
The objective of phase I of trials is to determine the maximum tolerated
dose in humans; pharmacodynamic effect, adverse reactions, if any, with
their nature and intensity; and pharmacokinetic behaviour of the drug as
far as possible. These studies are often carried out in healthy adult
volunteers using clinical, physiological and biochemical observations.
At least 2 subjects should be used on each dose.
Phase I trials are usually carried out by investigators trained in
clinical pharmacology and having the necessary facilities to closely
observe and monitor the subjects. These may be carried out at one or two
centres.
*/Exploratory trials (Phase II)/*
In phase II trials a limited number of patients are studied carefully to
determine possible therapeutic uses, effective dose range and further
evaluation of safety and pharmacokinetics. Normally 10-12 patients
should be studied at each dose level. These studies are usually limited
to 3-4 centres and carried out by clinicians specialized on the
concerned therapeutic areas and having adequate facilities to perform
the necessary investigations for efficacy and safety.
*/Confirmatory trials (Phase III)/*
The purpose of these trials is to obtain sufficient evidence about the
efficacy and safety of the drug in a larger number of patients,
generally in comparison with a standard drug and/or a placebo as
appropriate. These trials may be carried out by clinicians in the
concerned therapeutic areas, having facilities appropriate to the
protocol. If the drug is already approved/marketed in other countries,
phase III data should generally be obtained on at least 100 patients
distributed over 3-4 centres primarily to confirm the efficacy and
safety of the drug, in Indian patients when used as recommended in the
product monograph for the claims made.
Data on ADRs observed during clinical use of the drug should be reported
along with a report on its efficacy in the prescribed format. The
selection of clinicians for such monitoring and supply of drug to them
will need approval of the licensing authority under Rule 21 of the Act.
*/Phase IV/*
Studies performed after marketing of the pharmaceutical product. Trials
in phase IV are carried out on the basis of the product characteristics
on which the marketing authorization was granted and are normally in the
form of post-marketing surveillance, assessment of therapeutic value,
treatment strategies used and safety profile. Phase IV studies should
use the same scientific and ethical standards as applied in
pre-marketing studies.
After a product has been placed on the market, clinical trials designed
to explore new indications, new methods of administration or new
combinations, etc. are normally considered as trials for new
pharmaceutical products.
/Comparator Product/
A pharmaceutical product (including placebo) used as a reference in a
clinical trial.
*Confidentiality*
Maintenance of privacy of study subjects 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.
/Co-Investigator/
A person legally qualified to be an investigator, to whom the
Investigator delegates a part of his responsibilities.
/Co-ordinating Investigator/
See Principal Investigator
*/Clinical Research Organisation (CRO)/*
An organisation to which the sponsor may transfer or delegate some or
all of the tasks, duties and / or obligations regarding a Clinical
Study. All such contractual transfers of obligations should be defined
in writing. A CRO is a scientific body – commercial, academic or other.
*/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 “Contractâ€.
*/Documentation/*
All records (including written documents, electronic, magnetic or
optical records, 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
*/Escape Treatment/*
A supplementary treatment, usually given to alleviate pain in
placebo-controlled trials, to relieve the trial subject of the symptoms
caused by the investigated disease in a study.
*/Essential Documents/*
The Documents that permit evaluation of the conduct of a study and the
quality of the data generated. /See Appendix V./
*/Ethics Committee/*
An independent review board or committee 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 subjects involved in a study. The independent
review provides public reassurance by objectively, independently and
impartially reviewing and approving the “Protocolâ€, the suitability of
the investigator(s), facilities, methods and material to be used for
obtaining and documenting “Informed Consent†of the study subjects and
adequacy of confidentiality safeguards.
*/Final Report/*
A complete and comprehensive description of the study after its
completion. It includes description of experimental and statistical
methods and materials, presentation and evaluation of the results,
statistical analyses and a 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 trials 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 subjects 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/*
An impartial independent witness who will not be influenced in any way
by those who are involved in the Clinical Trial, who assists at the
informed consent process and documents the freely given oral consent by
signing and dating the written confirmation of this consent.*/ /*
*/Informed Consent /*
Voluntary written assent of a subject’s willingness to participate in a
particular study and in its documentation. The confirmation is sought
only after information about the trial including an explanation of its
status as research, its objectives, potential benefits, risks and
inconveniences, alternative treatment that may be available and of the
subject’s rights and responsibilities has been provided to the potential
subject.
*/Inspection/*
An official review/ examination conducted by regulatory authority(ies)
of the documents, facilities, records and any other resources that are
deemed by the authority(ies) to be related to the study. The inspection
may be carried out at the site of the trial, at the sponsor’s / or CRO’s
facilities in order to verify adherence to GCP as set out in these
documents.
*/Institution/*
Any public or private medical facility where a clinical study is conducted.
*/Investigator/*
A person responsible for the conduct of the study at the trial site.
Investigator is responsible for the rights, health and welfare of the
study subjects. 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/,
/Sub-investigator/.
*/Investigational 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.
*/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 trial. There should be adequate data to
justify the nature, scale and duration of the proposed trial and to
evaluate the potential safety and need for special precautions. If new
substantially relevant data is generated during the trial, the
information in the Investigator’s Brochure must be updated. /See
Appendix IV./*/ /*
*/Monitor/*
A person appointed by the Sponsor or Contract Research Organisation
(CRO) for monitoring and reporting the progress of the trial and for
verification of data. The monitor ensures that the trial is conducted,
recorded and reported in accordance with the Protocol, Standard
Operating Procedures (SOPs), Good Clinical Practice (GCP) and the
applicable regulatory requirements.
*/Multi-Centric Study/*
A clinical trial conducted according to one single protocol in which the
trial is taking place at different investigational sites, therefore
carried out by more than one investigator.
*/Non-Clinical Study/*
Biomedical studies that are not performed on human subjects.
*/Non-Therapeutic Study/*
A study in which there is no anticipated direct clinical benefit to the
Subject(s). Such studies, unless an exception is justified, should be
conducted in patient(s) having a disease or condition for which the
Investigational Product is intended. Subject(s) in these studies should
be particularly closely monitored and should be withdrawn if they appear
to be unduly distressed.
*/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.
*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)/*
Systems and processes established to ensure that the trial is performed
and the data are generated in compliance with GCP. QA is validated
through in-process Quality Control and in and post-process auditing of
clinical trial process as well as data.
*/Quality Control (QC)/*
The operational techniques and activities undertaken within the system
of QA to verify that the requirements for quality of the trial related
activities have been fulfilled. QC activities concern everybody
involved with planning, conducting, monitoring, evaluating, data
handling and reporting.
The objective of QC is to avoid exposure of study subjects to
unnecessary risks and to avoid false conclusions being drawn from
unreliable data.
*Randomisation*
The process of assigning study subjects to either the treatment or the
control group. Randomisation gives all subjects the same chance of
being in either group in order 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 Trials
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 the trial. Also see
/Source Data./
*/ /*
*/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.
Schedule
Unless repugnant to the context, the Schedule means Schedule Y to the
Drugs & Cosmetics Rules. (Reproduced here at Appendix II)
*/Source Data/*
Original documents (or their verified and certified copies) necessary
for evaluation of the Clinical Trial. These documents may include Study
Subjects’ files, recordings from automated instruments, tracings, X-Ray
and other films, laboratory notes, photographic negatives, magnetic
media, hospital records, clinical and office charts, Subjects’ diaries,
evaluation check-lists, and pharmacy dispensing records.
*/Sponsor/*
An individual or a company or an institution that takes the
responsibility for the initiation, management and / or financing of a
Clinical Study. An Investigator who independently initiates and takes
full responsibility for a trial automatically assumes the role of a Sponsor.
*/Study Product/*
Any /Pharmaceutical Product/ or /Comparator Product /used in a clinical
study.
Sub-Investigator
See */Co-Investigator/*
*/Subject Files / Patient Files/*
A file containing demographic and medical information about a study
subject. It includes hospital files, consultation records or special
subject files 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 Subject (Subject) /*
An individual participating in a clinical trial as a recipient of the
/Investigational Product/.
A /Study Subject/ may be a healthy person volunteering in a trial 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 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.
/*Subj*//*/*e*/ct Identification Code*/
A unique identification number / code assigned by the Investigator to
each Study Subject to protect the Subject’s identity. Subject
Identification Code is used in lieu of the Subject’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.
*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.**
* *
* *
* *
* *
* *
* *
* *
* *
* *
* *
* *
*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 subjects
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
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 subject participation 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 subjects 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 subjects’ compliance
*/ 2.3.1.5. Inclusion,
Exclusion and Withdrawal of Subjects/*
a. Subject inclusion criteria: specifications of the subjects
(patients / healthy volunteers) including age, gender, ethnic groups,
prognostic factors, diagnostic admission criteria etc. should be clearly
mentioned where relevant.
b. Subject exclusion criteria, including an exhaustive statement on
criteria for pre-admission exclusions
c. Subject withdrawal criteria (i.e. terminating investigational
product treatment / study treatment) and procedures specifying – when
and how to withdraw subjects from the treatment, type and timing of the
data to be collected from withdrawn subjects, whether and how subjects
are to be replaced and the follow-up on the withdrawn subjects
d. Statistical justification for the number of Subjects to be
included in the Study
*/ 2.3.1.6. Handling of the
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.)
c. The label should necessarily contain the following information:
the words - “For Clinical Studies onlyâ€, the name or a code number of
the study, name and contact numbers of the investigator, name of the
institution, subject’s identification code.
*/ 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 subjects 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 subjects needed to achieve the study objective,
and statistical considerations on which the proposed number of subjects
is based
c. Detailed break-up of the number of subjects planned to be
enrolled at each 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 subjects to be included in the final analyses
(e.g. all randomized subjects / all dosed subjects / all eligible
subjects / evaluable subjects
*/ 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 / documentsâ€.
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 subjects.
*/ 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 subjects, refunding expenses of the
subjects, 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) / manufacturer involved, institution and the
investigator(s) in case such information is not stated explicitly
d. Study Subjects 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 subjects 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 Subjects and the mode of providing it
b. Instructions to staff
c. Descriptions of special procedures
*/2.4. Ethical & Safety Considerations/*
*/2.4.1. Ethical Principles/*
All research involving human subjects should be conducted in
accordance with the ethical principles contained in the current revision
of Declaration of Helsinki (see Appendix 1) and should respect three
basic principles, namely justice, respect for persons, beneficence (to
maximize benefits and to minimize harms and wrongs) and non malaficence
(to do no harm) as defined by “Ethical Guidelines for Biomedical
Research on Human Subjects†issued by the Indian Council of Medical
Research and any other laws and regulations of the country, which ensure
a greater protection for subjects.
The following principles are to be followed:
a.*Principles of essentiality* whereby, the research entailing the use
of human subjects is considered to be absolutely essential after a due
consideration of all alternatives in the light of the existing knowledge
in the proposed area of research and after the proposed research has
been duly vetted and considered by an appropriate and responsible body
of persons who are external to the particular research and who, after
careful consideration, come to the conclusion that the said research is
necessary for the advancement of knowledge and for the benefit of all
members of the human species and for the ecological and environmental
well being of the planet.
b.*Principles of voluntariness, informed consent and community agreement
*whereby, Study Subjects are fully apprised of the Study and the impact
and risk of such Study on the Study Subjects and others; and whereby the
research subjects retain the right to abstain from further participation
in the research irrespective of any legal or other obligation that may
have been entered into by them or by someone on their behalf, subject to
only minimal restitutive obligations of any advance consideration
received and outstanding.
c.*Principles of non-exploitation* whereby as a general rule, research
subjects are remunerated for their involvement in the research or
experiment; and, irrespective of the social and economic condition or
status, or literacy or educational levels attained by the research
subjects kept fully apprised of all the dangers arising in and out of
the research so that they can appreciate all the physical and
psychological risks as well as moral implications of the research
whether to themselves or others, including those yet to be born.
d.*Principles of privacy and confidentiality* whereby, the identity and
records of the human subjects of the research or experiment are as far
as possible kept confidential; and that no details about identity of
said human subjects, which would result in the disclosure of their
identity, are disclosed without valid scientific and legal reasons which
may be essential for the purposes of therapeutics or other
interventions, without the specific consent in writing of the human
subject concerned, or someone authorised on their behalf; and after
ensuring that the said human subject does not suffer from any form of
hardship, discrimination or stigmatisation as a consequence of having
participated in the research or experiment.
e.*Principles of precaution and risk minimisation* whereby due care and
caution is taken at all stages of the research and experiment (from its
inception as a research idea, its subsequent research design, the
conduct of the research or experiment and its applicative use) to ensure
that the research subject and those affected by it are put to the
minimum risk, suffer from no irreversible adverse effects and,
generally, benefit from and by the research or experiment.
f.*Principles of professional competence* whereby, the research is
conducted at all times by competent and qualified persons, who act with
total integrity and impartiality and who have been made aware of, and
mindful of, the ethical considerations to be borne in mind in respect of
such Study.
f. *Principles of accountability and transparency*whereby, the
research or experiment will be conducted in a fair, honest, impartial
and transparent manner, after full disclosure is made by those
associated with the Study of each aspect of their interest in the Study,
and any conflict of interest that may exist; and whereby, subject to the
principles of privacy and confidentiality and the rights of the
researcher, full and complete records of the research inclusive of data
and notes are retained for such reasonable period as may be prescribed
or considered necessary for the purposes of post-research monitoring,
evaluation of the research, conducting further research (whether by the
initial researcher or otherwise) and in order to make such records
available for scrutiny by the appropriate legal and administrative
authority, if necessary.
h.*Principles of the maximisation of the public interest and of
distributive justice *whereby, the research or experiment and its
subsequent applicative use are conducted and used to benefit all human
kind and not just those who are socially better off but also the least
advantaged; and in particular, the research subject themselves.
i.*Principles of institutional arrangements* whereby, there shall be a
duty on all persons connected with the research to ensure that all the
procedures required to be complied with and all institutional
arrangements required to be made in respect of the research and its
subsequent use or application are duly made in a bonafide and
transparent manner; and to take all appropriate steps to ensure that
research reports, materials and data connected with the research are
duly preserved and archived.
j.*Principles of public domain* whereby, the research and any further
research, experimentation or evaluation in response to, and emanating
from such research is brought into the public domain so that its results
are generally made known through scientific and other publications
subject to such rights as are available to the researcher and those
associated with the research under the law in force at that time.
k.*Principles of totality of responsibility* whereby the professional
and moral responsibility, for the due observance of all the principles,
guidelines or prescriptions laid down generally or in respect of the
research or experiment in question, devolves on all those directly or
indirectly connected with the research or experiment including the
researchers, those responsible for funding or contributing to the
funding of the research, the institution or institutions where the
research is conducted and the various persons, groups or undertakings
who sponsor, use or derive benefit from the research, market the product
(if any) or prescribe its use so that, inter alia, the effect of the
research or experiment is duly monitored and constantly subject to
review and remedial action at all stages of the research and experiment
and its future use.
l.*Principles of compliance *whereby, there is a general and positive
duty on all persons, conducting, associated or connected with any
research entailing the use of a human subject to ensure that both the
letter and the spirit of these guidelines, as well as any other norms,
directions and guidelines which have been specifically laid down or
prescribed and which are applicable for that area of research or
experimentation, are scrupulously observed and duly complied with.
*/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 /Subjects/ and
obtaining their /Informed Consent/ including adequacy of the information
being provided to the Subjects. 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
programmes 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 IEC 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 IECs 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 IEC 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/*
a.IEC should be multidisciplinary and multi-sectorial in composition.
Independence and competence are the two hallmarks of an IEC.
b.The number of persons in an ethical committee
be kept fairly small (5-7 members). It is generally accepted that a
minimum of five persons is required to compose a quorum. There is no
specific recommendation for a widely acceptable maximum number of
persons but it should be kept in mind that too large a Committee will
make it difficult in reaching consensus opinion. 12 to 15 is the maximum
recommended number
c.The Chairperson of the Committee should preferably be from outside the
Institution and not head of the same Institution to maintain the
independence of the Committee. The Member Secretary who generally
belongs to the same Institution should conduct the business of the
Committee. Other members should be a mix of medical/non-medical,
scientific and non-scientific persons including lay public to reflect
the differed viewpoints. The composition may be as follows :-
1. Chairperson
2. 1-2 basic medical scientists (preferably one pharmacologists).
3. 1-2 clinicians from various Institutes
4. One legal expert or retired judge
5. One social scientist / representative of non-governmental
voluntary agency
6. One philosopher / ethicist / theologian
7. One lay person from the community
8. Member Secretary
d.The ethical committee at any institution can have as its members,
individuals from other institutions or communities if required. There
should be adequate representation of age, gender, community; etc. in the
Committee to safeguard the interests and welfare of all sections of the
community/society. Members should be aware of local, social and cultural
norms, as this is the most important social control mechanism. If
required subject experts could be invited to offer their views.
*/2.4.2.3.Terms of Reference/*
The IEC 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 operating procedures available with each member.
*/2.4.2.4. Review Procedures/*
The Ethics Committee should review every research proposal on human
subjects. 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 subjects 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 proposals.*
*/2.4.2.5. Submission of Application/*
The researcher should submit an appropriate application to the IEC 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 subjects in the light of existing knowledge.
2. Recent curriculum vitae of the Investigators indicating
qualification and experience.
3. Subject recruitment procedures.
4. Inclusion and exclusion criteria for entry of subjects 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 trial.
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 trials.
17.Details of Funding agency / Sponsors and fund allocation for the
proposed work.
*/ /*
*/ /*
*/2.4.2.6. Decision Making Process/*
The IEC 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.
1. 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.
2. A member must voluntarily withdraw from the IEC 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.
3. If one of the members has her/his own proposal for review, then
the member should not participate when the project is discussed.
4. A negative decision should always be supported by clearly
defined reasons.
5. An IEC may decide to reverse its positive decision on a study in
the event of receiving information that may adversely affect the
benefit/risk ratio.
6. The discontinuation of a trial should be ordered if the IEC
finds that the goals of the trial have already been achieved midway or
unequivocal results are obtained.
7. In case of premature termination of study, notification should
include the reasons for termination along with the summary of results
conducted till date.
8. The following circumstances require the matter to be brought to
the attention of IEC :
a. any amendment to the protocol form the originally approved
protocol with proper justification;
b. serious and unexpected adverse events and remedial steps taken
to tackle them;
c. any new information that may influence the conduct of the study.
9. 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.
10.Subject experts may be invited to offer their views, but should not
take part in the decision making process. However, her/his opinion must
be recorded.
11.Meetings are to be minuted which should be approved and signed by the
Chairperson.
* *
*/2.4.2.7. Interim Review/*
The IEC 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 IEC;
ii) research study of a minor nature such as examination of case
records etc.;
iii) an urgent proposal of national interest.
*/2.4.2.8. Record Keeping/*
All documentation and communication of an IEC 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 IEC;
ii. the curriculum vitae of all IEC members;
iii. standing operating procedures of the IEC;
iv. national and international guidelines;
v. copies of the Protocol, data collection formats, CRFs,
investigational brochures etc. submitted for review;
vi. all correspondence with IEC members and investigators regarding
application, decision and follow up;
vii. agenda of all IEC meetings;
viii.minutes of all IEC 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.
*/2.4.2.9.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 IEC to take note of. Examples of such instances are research
involving children, pregnant and lactating women, vulnerable subjects
and those with diminished autonomy besides issues pertaining to
commercialisation of research and international collaboration. The
observations and suggestions of IEC should be given in writing in
unambiguous terms in such instances.
*/2.4.3. Informed Consent Process/*
*/2.4.3.1./**Informed Consent of Subject :*
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 Subjects 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 Subject(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 Subjects and / or their
legal representatives or guardians in a language and at a level of
complexity that is understandable to the Subject(s) in both written and
oral form, whenever possible.
Subjects, 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 Subject to 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 Subject’s participation in the Study the written Informed
Consent form should be signed and personally dated by
1. (i) The Subject /or /(ii) if the Subject is incapable of giving
an Informed Consent for example children, unconscious or suffering from
severe mental illness or disability, by the Subject’s legal
representative or guardian /or/ (iii) if the Subject and 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 Subject or the Subject’s
legal representative or the guardian, and that informed consent was
freely given by the Subject or the Subject’s legal representative or the
guardian.
The Subject’s legal representative or guardian (if the subject is
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
Subject. The agreement of a legal representative or the guardian that
participation will promote the welfare and inte