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 “Contract”.
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
“Protocol”, 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.
Subject
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 only”, 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 / 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
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 interest of the Subject should 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 subjects : 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 subject participation;
iii.
the benefits that might reasonably be expected as an outcome of
research to the subject or to others;
iv.
any alternative procedures or courses of treatment that might be
as advantageous to the subject as the procedure or treatment to which
she/he is being subjected;
v.
any foreseeable risk or discomfort to the subject resulting 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 subjects 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
subject would 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 their agreement to volunteer may be unduly influenced
by the Investigator.
2.4.3.3.
Informed Consent in Non-Therapeutic Study :
In
case of a Non-Therapeutic Study the consent must always be given by the
subject. Non-Therapeutic
Studies may be conducted in subjects with consent of a legal
representative or guardian provided all of the following conditions are
fulfilled:
1.
The objective of the Study can not be met by means of a trial in
Subject(s) who can personally give the informed consent
2.
The foreseeable risks to the Subject(s) are low
3.
Ethics Committee’s written approval is expressly sought on the
inclusion of such Subject(s)
2.4.4. Essential
Information on Confidentiality for Prospective Research Subjects
Safeguarding
confidentiality - The
investigator must safeguard the confidentiality of research data, which
might lead to the identification of the individual subjects. Data of
individual subjects 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.
2.4.5.
Compensation for Participation
Subjects
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 subjects to consent to participate in research
against their better judgement (inducement). All payments, reimbursement
and medical services to be provided to research subjects should be
approved by the IEC. 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 subject is withdrawn from research for medical reasons
related to the study the subject should get the benefit for full
participation;
iii.
when a 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.
2.4.6.
Selection of Special Groups As Research Subject
2.4.6.1.
Pregnant or nursing women :
Pregnant
or nursing women should in no circumstances be the subject of 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 subjects of any clinical trial
except such trials 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 subjects.
a.
The justification of participation of these women in clinical
trials 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
trials are, to test the efficacy and safety of a drug for reducing
perinatal transmission of HIV infection from mother to child, trials 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
subjects for such research as per The Medical Termination of Pregnancy
Act, GOI, 1971.
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 Prenatal Diagnostic Techniques
(Regulation and Prevention of Misuse) Act, GOI, 1994 and not for sex
determination of the foetus.
2.4.6.2.
Children:
Before
undertaking trial 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 trials 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 subject must be justified
in relation to anticipated risks involved in the study and anticipated
benefits to society;
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
subject as any available alternative interventions;
i.
the risk presented by interventions not intended to benefit the
individual child subject is low when compared to the importance of the
knowledge that is to be gained.
2.4.6.3.
Vulnerable groups :
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;
b.
persons who are economically or socially disadvantaged should not
be used to benefit those who are better off than them;
c.
rights and welfare of mentally challenged and mentally
differently able persons who are incapable of giving informed consent or
those with behavioral disorders must be protected.
d.
Adequate justification is required for the involvement of
subjects such as prisoners, students, subordinates, employees, service
personnel etc. who have reduced autonomy as research subjects.
2.4.7.
Compensation for Accidental Injury
Research
subjects who suffer physical injury as a result of their participation
in the Clinical Trial are entitled to financial or other assistance to
compensate them equitably for any temporary or permanent impairment or
disability subject to confirmation from IEC In case of death, their
dependents are entitled to material compensation.
2.4.7.1.
Obligation of the sponsor to pay :
The
sponsor whether a pharmaceutical company, a government, or an
institution, should agree, before the research begins, to provide
compensation for any serious
sphysical or mental injury for which subjects are entitled to
compensation or agree to provide insurance coverage for an unforeseen
injury whenever possible.
Responsibilities
3.1.
Sponsor:
3.1.1.
Investigator and Institution 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 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.
Before
entering an agreement with an Investigator(s) / 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.
Sponsor should provide sufficient time to review the Protocol and
the information provided in the Investigator’s Brochure.
3.1.2.
Contract
The
Sponsor should enter into a formal and legal agreement / contract with
the Investigator(s) / Institution(s) 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
d.
To retain the study related essential documents until the Sponsor
informs the Investigator(s) / Institution(s) in writing that these
documents are no longer needed
The
agreement should define the relationship between the investigator and
the sponsor in matters such as financial support, fees, honorarium,
payments in kind etc.
3.1.3.
SOP
The Sponsor should
establish detailed Standard Operating Procedures (SOP’s).
The Sponsor and the Investigator(s) should sign a copy of the
Protocol and the SOPs or an alternative document to confirm their
agreement.
3.1.4.
Allocation of duties and responsibilities:
Prior to initiating
a Study the Sponsor should define and allocate all Study related duties
and responsibilities to the respective identified person(s) /
organisation(s).
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:
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.
Quality Assurance and Quality Control systems with written SOPs
to ensure that the Study is conducted and data are generated, documented
(recorded), and reported – in compliance with the Protocol, GCP and
the applicable regulatory requirement(s)
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 three years after the completion of the study or submission of the
data to the regulatory authority(ies) whichever is later.
The
Sponsor may consider establishing an Independent Data Monitoring
Committee (IDMC) to assess the progress of the Study. This includes the
safety data and the critical efficacy endpoints at various intervals,
and to recommend to the Sponsor whether to continue, modify, or stop a
Study. The IDMC should have written operating procedures and should
maintain written records of all its meetings.
3.1.6.
Compensation for Participation
Subjects
may be paid compensation for participation in accordance with the
guidelines listed in 2.4.5.
3.1.7.
Confirmation of review by the Ethics Committee
The
Sponsor shall obtain from the Investigator(s) and / or the Institutions
a.
The particulars about the members of the Investigator’s /
Institution’s Ethics Committee including their names, addresses,
qualifications and experience
b.
An undertaking that the Ethics Committee is organised and
operates according to the GCP and the applicable laws and regulations
c.
Documented approval / favourable opinion of the Ethics Committee
before the initiation of the Study
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.
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) 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.
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, besides stating them on the Product labels where ever 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 Ethics Committee and Regulatory 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 Subjects and
c.
return of unused Product to the Sponsor (or its alternative
disposal procedure).
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.
3.1.10.
Safety Information:
Sponsor
is responsible for the ongoing safety evaluation of the Product.
The Sponsor should promptly notify all concerned of findings that
could adversely affect the safety of the Subjects, 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 subjects.
3.1.11.
Adverse Drug Reaction Reporting:
The
Sponsor should provide ADR / AE reporting forms to the Investigator(s) /
Institution(s). The Sponsor should expedite the reporting to all
concerned (including the Ethics Committee and the regulatory
authorities) of all serious and/or unexpected adverse drug reactions.
3.1.12.
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 GCP
guidelines 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.
3.1.13.
Monitoring
Although
an extensively written guidance can assure appropriate conduct of the
study, the sponsor should ensure that the studies are adequately
monitored. The
determination of the extent and the nature of monitoring should be based
on considerations such as objective, purpose, design, complexity,
blinding, size and endpoints of the study.
The sponsor must appoint adequately trained monitors or CRO to
supervise an ongoing study.
3.1.14.
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, 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.
3.1.15.
Multicentre Studies
Since
multicentre studies are conducted simultaneously by several
investigators at different institutions following the same protocol, the
sponsor should make special administrative arrangements for their
conduct. These administrative arrangements should provide adequate
assurance that the study will be planned and conducted according to GCPs.
The
various tasks that may need special consideration include responsibility
for commencement and overall performance of the study, supervision of
the data, monitoring of the ADRs / AEs and various other policy matters.
The functions, responsibilities and mandate of any special committee(s)
set up or person(s) should be described in the study protocol, along
with the procedure for their nomination.
A
co-ordinating committee may be set up or a co-ordinator appointed with
responsibility for the control of practical performance and progress of
the study and maintaining contact with the regulatory authorities and
the ethics committee(s).
Ideally,
the studies should begin and end simultaneously at all institutions.
The
sponsor should make arrangements to facilitate the communication between
investigators at various sites. All
investigators and other specialists should be given the training to
follow the same protocol and systems. The sponsor should obtain written
acceptance of the protocol and its annexes from each of the investigator
and institution involved.
The
CRFs should be so designed as to record the required data at all
multicentre sites. For
those investigators who are collecting additional data, supplemental
CRFs should be provided to record the additional data.
Before
initiation of multi-centre studies the sponsor should carefully define
and document the following:
a.
ethics committee(s), and the number of ethics committees to be
consulted
b.
role and responsibilities of the co-ordinating investigators
c.
role and responsibilities of the CRO
d.
randomisation procedure
e.
standardisation and validation of methods of evaluation and
analyses of laboratory and diagnostic data at various centres
f.
structure and function of a centralised data management set-up
3.1.16.
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), the ethics committee and the regulatory authorities
accordingly. The
notification should document the reason(s) for the termination or
suspension by the sponsor or by the investigator / institution.
3.1.17.
Role
of Foreign Sponsor
If the sponsor is a
foreign company, organisation or person(s) – it shall appoint a local
representative or CRO 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 CRO 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 CRO should be specified in writing.
Any Study related duties, functions or responsibilities not
specifically transferred to and assumed by a CRO or a local
representative shall be deemed to have been retained by the Sponsor. The
sponsor should utilise the services of qualified individuals e.g.
bio-statisticians, clinical pharmacologists, and physicians, as
appropriate, throughout all stages of the study process, from designing
the protocol and CRFs and planning the analyses to analysing and
preparing interim and final clinical study reports.
3.2.
The Monitor:
The
monitor is the principal communication link between the sponsor and the
investigator and is appointed by the sponsor.
3.2.1.
Qualifications
The
monitor should have adequate medical, pharmaceutical and / or scientific
qualifications and clinical trial experience.
Monitor should be fully aware of all the aspects of the product
under investigation and the protocol (including its annexes and
amendments).
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. Monitor should also
confirm that the investigator(s) shall be available throughout the study
period.
(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
2.
the investigational product(s) are supplied only to subjects who
are eligible to receive it and at the specified dose(s) and time(s)
3.
the subjects are provided with the necessary instructions on
proper handling of the product(s)
4.
the receipt, use, return and disposal of the 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
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
SOPs
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
(d)
The monitor should promptly inform the sponsor and the ethics
committee in case any unwarranted deviation from the protocol or any
transgression of the principles embodied in GCP is noted.
(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.
(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 subjects is likely to be available during the study.
(g)
The monitor should observe and report the subject recruitment
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.
(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
1.
the data required by the protocol are reported accurately on the
CRFs and are consistent with the source documents
2.
any dose and / or therapy modifications are well documented for
each of the study subjects
3.
adverse events, concomitant medications and inter-current
illnesses are promptly reported on the CRFs in accordance with the
protocol and the SOPs
4.
visits that the subjects fail to make, tests that are not
conducted and examinations that are not performed are clearly reported
as such on the CRFs
5.
all withdrawals and drop-outs of enrolled subjects 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 report with the
sponsor should be documented by the sponsor’s designated
representative.
(n)
The monitor should confirm that the prescribed procedures for
storage, handling, dispensing and return of investigational product are
being followed and their compliance is being documented in a form as in
the SOPs.
3.3.
Investigator
3.3.1.
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 Medical Council of India (MCI).
The investigator should provide a copy of the curriculum vitae and / or
other relevant documents requested by the sponsor, the ethics committee,
the CRO or the regulatory authorities. He / she should clearly
understand the time and other resource demands the study is likely to
make and ensure they can be made available throughout the duration of
the study. The investigator
should also ensure that other studies do not divert essential subjects
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 GCPs, SOPs and the
applicable regulatory requirements.
3.3.2.
Medical care of the study subjects
A qualified Medical
Practitioner (or a Dentist, when appropriate) who is an Investigator or
a Co-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 subject for
any adverse events including clinically significant laboratory values
related to the study. Investigator
should inform the subject when medical care is needed for inter-current
illness(es) of which the investigator becomes aware.
Investigator should also inform the subject’s other attending
physician(s) about the subject’s participation in the study if the
subject has another attending physician(s) and if the subject agrees to
such other physician(s). Subsequent
to the completion of the study or dropping out of the subject(s) the
investigator should ensure that medical care and relevant follow-up
procedures are maintained as needed by the medical condition of the
subject and the study and the interventions made.
Although
a subject is 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 subject’s rights.
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,
subject recruitment procedures (e.g. advertisements) and any written /
verbal information to be provided to the subjects.
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 subjects
2.
changes that increase the risk to subject(s) and / or affecting
significantly the conduct of the study
3.
all adverse drug reactions and adverse events that are serious
and / or unexpected
4.
new information that may adversely affect safety of the subjects
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 may implement a deviation from, or change of protocol to
eliminate an immediate hazard(s) to study subjects without prior ethics
committee approval / favourable opinion. 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 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.
The Investigator should follow the study randomisation procedure,
if any, and should ensure that the randomisation code is broken only in
accordance with the Protocol. If
the study is blinded, the Investigator should promptly document and
explain to the Sponsor any premature un-blinding e.g. accidental
un-blinding, un-blinding due to serious adverse event) of the
Investigational Product(s).
3.3.6.
Investigational
Product(s)
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 subject, 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 subjects.
Investigator should maintain records that describe that the
subjects 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.
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 subject and should check at intervals appropriate for
the study that each subject is following the instructions properly.
The person who carries them out should document such periodic
checks.
3.3.7.
Selection and recruitment of study subjects:
The
investigator is responsible for ensuring the unbiased selection of an
adequate number of suitable subjects according to the protocol.
It may be necessary to secure the co-operation of other
physicians in order to obtain a sufficient number of subjects.
In order to assess the probability of an adequate recruitment
rate for subjects for the study it may be useful to determine
prospectively or review retrospectively the availability of the
subjects. Investigator
should check whether the subject(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 Subjects allocated to each study.
This list facilitates the investigator / institution to reveal
identity of the subject(s) in case of need and also serve as a proof of
Subject’s existence. The
investigator / institution shall also maintain a Subjects’ screening
log to document identification of Subjects who enter pre-study
screening. A
Subject’s enrolment log shall also be maintained to document
chronological enrolment of Subjects in a particular Study.
The
Investigator is responsible for giving adequate information to subjects
about the trial 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 -
1.
Communicate to prospective subjects all the information necessary
for informed consent. There should not be any restriction on subject's
right to ask any questions related to the study as any restriction on
this undermines the validity of informed consent.
2.
Exclude the possibility of unjustified deception, undue influence
and intimidation. Deception of the subject is not permissible However,
sometimes information can be withheld till the completion of study, if
such information would jeopardize the validity of research.
3.
Seek consent only after the prospective subject is adequately
informed. Investigator should not give any unjustifiable subject's
decision to participate in the study.
4.
As a general rule obtain from each prospective subject a signed
form as an evidence of informed consent (written informed consent)
preferably witnessed by a person not related to the trial, and in case
of incompetence to do so, a legal guardian or other duly authorised
representative.
5.
Renew the informed consent of each subject, if there are material
changes in the conditions or procedures of the research or new
information becomes available during the ongoing trial.
6.
Not use intimidation in any form which invalidates informed
consent. The investigator must assure prospective subjects 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 Subject, the Investigator should
supply subjects with, and encourage them to carry with them, information
about their participation in the trial and information about contact
persons who can assist in an emergency situation.
3.3.8.
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.
Any
change or correction to the CRF should be dated, signed and explained
(if 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.
Progress
Reports
The
investigator should submit the written summaries of the study status at
the periodicity specified in the protocol to the person(s) /
organisation(s) to whom the investigator is reporting.
All reportings made by the investigator should identify the
subjects by unique code numbers assigned to the study subjects rather
than by the subjects’ 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 Subjects, the Ethics Committee as well as the
Regulatory Authorities. The investigators should also ensure appropriate
therapy and follow-up for the subjects.
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 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
study can be closed only when the Investigator (or the Monitor or CRO
– if this responsibility has been delegated to them) has reviewed both
Investigator / Institution and Sponsor files and confirm that all
necessary documents are in the appropriate files.
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 and the ethics committee.
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.
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 trial subject(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.
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 and the
system should be validated. 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
trial 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.
4.5.
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 Subjects, paramedical staff, Monitors etc.)
4.6.
Responsibilities of the Investigator
Investigator
should ensure that the observations and findings are recorded correctly
and completely in the CRFs and signed by the responsible person(s)
designated in the Protocol.
Laboratory
values with normal reference ranges should always be recorded on a CRF
or enclosed with the CRF. Values
outside the clinically accepted reference range or values that differ
importantly from previous values must be evaluated and commented upon by
the Investigator. Data
other than that requested by the Protocol may appear on the CRF clearly
marked as the additional findings and their significance described by
the investigator. Units of
measurement must always be stated and transformation of units must
always be indicated and documented.
In
the medical records of the patient(s) it should be clearly indicated
that the individual is participating in a clinical trial.
4.8.
Responsibilities of the Sponsor and the Monitor
The
sponsor must ensure that electronic data processing system conforms to
the certain documented requirements for completeness, accuracy,
reliability and consistent intended performance (i.e. validation).
The Sponsor must maintain SOPs for using these systems.
The Monitor should take adequate measures to ensure that no data
is overlooked. If the
computer system automatically assigns any missing values – the fact
should be clearly documented.
Sponsor
should safeguard the blinding, if any, particularly during data entry
and processing. The Sponsor
should use an explicit Subject identification code that allows
identification of all the data reported for each Subject.
Ownership of the data and any transfer of the ownership of data
should be documented and intimated to the concerned party(ies).
Quality
Assurance
The Sponsor
is responsible for the implementation of a system of Quality Assurance
in order to ensure that the Study is performed and the data is
generated, recorded and reported in compliance with the Protocol, GCP
and other applicable requirements.
Documented Standard Operating Procedures are a prerequisite for
quality assurance.
All
observations and findings 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
specified and justified.
Statistically
controlled sampling may be an acceptable method of data verification in
each Study. Quality control
must be applied to each stage of data handling to ensure that all data
are reliable and have processed correctly.
Sponsor’s
audits should be conducted by persons independent of those responsible
for the Study. Investigational sites, facilities, all data and
documentation should be available for inspection and audit by the
Sponsor’s auditor as well as by the Regulatory Authority(ies).
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 Subjects 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 “a priori” 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 trial 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 subjects 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
subjects, 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 Subject’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 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.
SPECIAL
CONCERNS
7.1
Clinical Trials of Vaccines
7.1.1
Phases of Vaccine Trials
The
guidelines to conduct the clinical trial on investigational vaccines are
similar to those governing a clinical trial. The phase of these trials
differ from drug trials 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 subjects. For example, immunogenicity to hepatitis vaccine
should not be determined in high-risk subjects.
Phase
II:
This refers to the initial trials examining effectiveness (immunogenicity)
in a limited number of volunteers. Vaccines can be prophylactic and
therapeutic in nature. While prophylactic vaccines are given to normal
subjects, 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
·
The
sponsor and investigator should be aware of the approval process(es)
involved in conducting clinical trials of vaccines. They should
familiarize themselves with the guidelines provided by Drug Controller
General (India), Department of Biotechnology (DBT) and Ministry of
Environment and Genetic Engineering Approval Committee (GEAC) in the
case of vaccines produced by recombinant DNA technology.
See Appendix III.
·
Some
vaccines that contain active or live-attenuated microorganisms can
possibly possess a small risk of producing that particular infection.
The subjects to be vaccinated should be informed of the same.
·
The
subjects in control groups or when subjected to ineffective vaccines run
a risk of contracting the disease.
·
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 strictly followed.
·
Trials
should be conducted by investigator with the requisite experience and
having necessary infrastructure for the laboratory evaluation of
seroconversion.
·
Protocols
for such trials should include appropriate criteria for selection of
subjects, plan of frequency of administration of the test vaccine in
comparison with the reference vaccine. It should accompany detailed
validation of testing method to detect the antibody titter levels.
·
It
should specify methodology to be adopted for prevention of centrifuged
serum for the purpose of testing.
·
The
investigator should be provided with Quality Control data of the
experimental batch of the vaccine made for the purpose of clinical
trials.
·
The
sponsor should provide the Independent Ethics Committee approval of the
nodal body (ies) to carry out clinical trials with the vaccine.
·
The
generic version of new vaccines already introduced in the other markets
after step up clinical trials including extensive Phase III trials
should be compared with the reference vaccine with regard to
seroconversion in a comparative manner in a significant sample size.
·
Post
Marketing Surveillance (PMS) should be required following seroconversion
studies. PMS data should be generated in a significant sample size
sensitive to detect side effects and address other safety issues.
·
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 Trials of Contraceptives
·
All
procedures for clinical trials are applicable. Subjects should be
clearly informed about the alternative available.
·
In
women where implant has been used as a contraceptive for trial, a proper
follow up for removal of the implant should be done, whether the trial
is over or the subject has withdrawn from the trial.
·
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 trials with surgical procedures/ medical devices
Of late, biomedical technology has made considerable progress in
the conceptualisation and designing of bio-equipments. Several medical
devices and critical care equipments have been developed and many more
are in various stages of development. However, only through good
manufacturing practices (GMP) can the end products reach the stage of
utilization by society. Most of these products are only evaluated by
Central Excise testing for taxation purposes, which discourages
entrepreneurs to venture in this area with quality products especially
when they do not come under the strict purview of the existing
regulatory bodies like ISI, BSI and Drug Controller General. This is
evidenced by the very low number of patents or propriety medical
equipments manufactured and produced in the country. As the capacity of
the country in this area is improving day by day the need for a
regulatory mechanism/ authority is increasingly obvious. The concept of
regulations governing investigations involving biomedical devices is
therefore relatively new in India. At present, except for needles and
syringes these are not covered by the Drugs and Cosmetics Act, 1940. The
Chief Executive of the Society of Biomedical Technology (SBMT) set up
under the Defence Research Development Organisation (DRDO) has drafted a
proposal for the setting up of a regulatory, tentatively named as the
Indian Medical Devices Regulatory Authority (IMDRA). Until the
guidelines are formulated and implemented by this regulatory Authority
clinical trials with biomedical devices should be approved on case to
case basis by committees constituted for the specific purpose.
7.3.1.
Definitions:
Medical
devices: A
medical device is defined as an inert diagnostic of therapeutic article
that does not achieve any of its principal intended purposes through
chemical action, within or on the body unlike the medicated devices
which contain pharmacologically active substances which are treated as
drugs. Such devices include diagnostic test kits, crutches, electrodes,
pacemakers, arterial grafts, intra-ocular lenses, orthopaedic pins and
other orthopaedic accessories.
Depending
upon risks involved the devices could be classified as follows:
a.
Non critical devices: An investigational device that does not
present significant risk to the patients’
e.g. Thermometer, B.P. apparatus.
b.
Critical devices: An investigational device that presents a
potential risk to the health, safety, welfare of the subject- for
example, pacemakers, implants, internal catheters.
All
the general principles of clinical trials described for clinical trials
should also be considered for trials of medical devices. As for the
drugs, safety evaluation and pre-market efficacy of devices for 1-3
years with data on adverse reactions should be obtained before
pre-market certification. The duration of the trial and extent of use
may be decided in case to case basis by the appropriate authorities.
However, the following important factors that are unique to medical
devices should be taken into consideration while evaluating the related
research projects.
7.3.2.
Guidelines
o
Safety
data of the medical device in animals should be obtained and likely
risks posed by the device should be considered.
o
A
clinical trial of medical devices is different from drug trials, as
former can not be done in healthy volunteers. Hence phase I of drug
trial is not necessary for trial on devices.
o
Medical
devices used within the body may have greater risk potential than those
used on or outside the body, for example, orthopaedic pins Vs crutches.
o
Medical
device not used regularly have less risk potential than those used
regularly, for example, contact lens Vs intraocular lenses.
o
Safety
procedures to introduce a medical device in the patient should also be
followed as the procedure itself may cause harm to the patient.
o
Informed
consent procedures should be followed as in drug trials. The patient
information sheet should contain information on following procedures to
be adopted if the patient decides to withdraw from the trial.
7.4.
Clinical trials 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 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
subjects 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 subjects 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 subject about 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 trials of Herbal Remedies and Medicinal Plants
For
the herbal remedies and medicinal plants that are to be clinically
evaluated for use in the Allopathic System and which may later be used
in allopathic hospitals, the procedures laid down by the office of the
DCG (I) 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 trials described earlier pertain also to herbal remedies.
However, when clinical trials of herbal drugs used in recognized Indian
systems of Medicine and Homoeopathy are to be undertaken in Allopathic
Hospitals, associations of physicians from the concerned system as
co-investigators/ collaborators/ members of the expert group is
desirable for designing and evaluating the Study.
7.5.1.
Categories of Herbal Products
The herbal products can belong to any of the three categories
given below:
a.
A lot is known about the use of a plant or its extract in the
ancient Ayurveda, Siddha or Unani literature or the plant may actually
be regularly used by physicians of the traditional systems of medicine
for a number of years. The substance is being clinically evaluated for
same indication for which it is being used or as has been described in
the 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 ancient
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 GMP 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 trial 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 trial
is subsequently planned based on results of phase II study.
·
Clinical
trials 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, subject, inducements for
participation, information to be provided to the subject, withdrawal
from study and research involving children or persons with diminished
autonomy, all apply to trials on plant drugs also. These trials have
also got to be approved by the appropriate scientific and ethical
committees of the concerned Institutes. However, it is essential that
such clinical trials be carried out only when a competent Ayurvedic,
Siddha or Unani physician is a co-investigator in such a clinical trial.
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 commercialisation
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.
APPENDICES
Appendix
I:
WORLD
MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical
Principles for Medical Research Involving Human Subjects
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, Somerset West, Republic of South Africa,
October 1996
and the
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
A.
INTRODUCTION
1.
The World Medical Association has developed the Declaration of
Helsinki as a statement of ethical principles to provide guidance to
physicians and other participants in medical research involving human
subjects. Medical research involving human subjects includes research on
identifiable human material or identifiable data.
2.
It is the duty of the physician to promote and safeguard the
health of the people. The physician's knowledge and conscience are
dedicated to the fulfilment of this duty.
3.
The Declaration of Geneva of the World Medical Association 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 only in the patient's
interest when providing medical care which might have the effect of
weakening the physical and mental condition of the patient."
4.
Medical progress is based on research, which ultimately must rest
in part on experimentation involving human subjects.
5.
In medical research on human subjects, considerations related to
the well-being of the human subject should take precedence over the
interests of science and society.
6.
The primary purpose of medical research involving human subjects
is to improve prophylactic, diagnostic and therapeutic procedures and
the understanding of the aetiology and pathogenesis of disease. Even the
best proven prophylactic, diagnostic, and therapeutic methods must
continuously be challenged through research for their effectiveness,
efficiency, accessibility and quality.
7.
In current medical practice and in medical research, most
prophylactic, diagnostic and therapeutic procedures involve risks and
burdens.
8.
Medical research is subject to ethical standards that promote
respect for all human beings and protect their health and rights. Some
research populations are vulnerable and need special protection. The
particular needs of the economically and medically disadvantaged must be
recognised. Special attention is also required for those who cannot give
or refuse consent for themselves, for those who may be subject to giving
consent under duress, for those who will not benefit personally from the
research and for those for whom the research is combined with care.
9.
Research Investigators should be aware of the ethical, legal and
regulatory requirements for research on human subjects in their own
countries as well as applicable international requirements. No national
ethical, legal or regulatory requirement should be allowed to reduce or
eliminate any of the protections for human subjects set forth in this
Declaration.
B.
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
10.
It is the duty of the physician in medical research to protect
the life, health, privacy, and dignity of the human subject.
11.
Medical research involving human subjects must conform to
generally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and on adequate laboratory and, where appropriate, animal
experimentation.
12.
Appropriate caution must be exercised in the conduct of research
which may affect the environment, and the welfare of animals used for
research must be respected.
13.
The design and performance of each experimental procedure
involving human subjects should be clearly formulated in an experimental
protocol. This protocol should be submitted for consideration, comment,
guidance, and where appropriate, approval to a specially appointed
ethical review committee, which must be independent of the investigator,
the sponsor or any other kind of undue influence. This independent
committee should be in conformity with the laws and regulations of the
country in which the research experiment is performed. The committee has
the right to monitor ongoing trials. The researcher has the obligation
to provide monitoring information to the committee, especially any
serious adverse events. The researcher should also submit to the
committee, for review, information regarding funding, sponsors,
institutional affiliations, other potential conflicts of interest and
incentives for subjects.
14.
The research protocol should always contain a statement of the
ethical considerations involved and should indicate that there is
compliance with the principles enunciated in this Declaration.
15.
Medical research involving human subjects should be conducted
only by scientifically qualified persons and under the supervision of a
clinically competent medical person. The responsibility for the human
subject must always rest with a medically qualified person and never
rest on the subject of the research, even though the subject has given
consent.
16.
Every medical research project involving human subjects should be
preceded by careful assessment of predictable risks and burdens in
comparison with foreseeable benefits to the subject or to others. This
does not preclude the participation of healthy volunteers in medical
research. The design of all studies should be publicly available.
17.
Physicians should abstain from engaging in research projects
involving human subjects unless they are confident that the risks
involved have been adequately assessed and can be satisfactorily
managed. Physicians should cease any investigation if the risks are
found to outweigh the potential benefits or if there is conclusive proof
of positive and beneficial results.
18.
Medical research involving human subjects should only be
conducted if the importance of the objective outweighs the inherent
risks and burdens to the subject. This is especially important when the
human subjects are healthy volunteers.
19.
Medical research is only justified if there is a reasonable
likelihood that the populations in which the research is carried out
stand to benefit from the results of the research.
20.
The subjects must be volunteers and informed participants in the
research project.
21.
The right of research subjects to safeguard their integrity must
always be respected. Every precaution should be taken to respect the
privacy of the subject, the confidentiality of the patient's information
and to minimize the impact of the study on the subject's physical and
mental integrity and on the personality of the subject.
22.
In any research on human beings, each potential subject must be
adequately informed of the aims, methods, sources of funding, any
possible conflicts of interest, institutional affiliations of the
researcher, the anticipated benefits and potential risks of the study
and the discomfort it may entail. The subject should be informed of the
right to abstain from participation in the study or to withdraw consent
to participate at any time without reprisal. After ensuring that the
subject has understood the information, the physician should then obtain
the subject's freely given informed consent, preferably in writing. If
the consent cannot be obtained in writing, the non-written consent must
be formally documented and witnessed.
23.
When obtaining informed consent for the research project the
physician should be particularly cautious if the subject is in a
dependent relationship with the physician or may consent under duress.
In that case the informed consent should be obtained by a well-informed
physician who is not engaged in the investigation and who is completely
independent of this relationship.
24.
For a research subject who is legally incompetent, physically or
mentally incapable of giving consent or is a legally incompetent minor,
the investigator must obtain informed consent from the legally
authorised representative in accordance with applicable law. These
groups should not be included in research unless the research is
necessary to promote the health of the population represented and this
research cannot instead be performed on legally competent persons.
25.
When a subject deemed legally incompetent, such as a minor child,
is able to give assent to decisions about participation in research, the
investigator must obtain that assent in addition to the consent of the
legally authorised representative.
26.
Research on individuals from whom it is not possible to obtain
consent, including proxy or advance consent, should be done only if the
physical/mental condition that prevents obtaining informed consent is a
necessary characteristic of the research population. The specific
reasons for involving research subjects with a condition that renders
them unable to give informed consent should be stated in the
experimental protocol for consideration and approval of the review
committee. The protocol should state that consent to remain in the
research should be obtained as soon as possible from the individual or a
legally authorised surrogate.
27.
Both authors and publishers have ethical obligations. In
publication of the results of research, the investigators are obliged to
preserve the accuracy of the results. Negative as well as positive
results should be published or otherwise publicly available. Sources of
funding, institutional affiliations and any possible conflicts of
interest should be declared in the publication. Reports of
experimentation not in accordance with the principles laid down in this
Declaration should not be accepted for publication.
C.
ADDITIONAL PRINCIPLES FOR
MEDICAL RESEARCH COMBINED WITH MEDICAL CARE
28.
The physician may combine medical research with medical care,
only to the extent that the research is justified by its potential
prophylactic, diagnostic or therapeutic value. When medical research is
combined with medical care, additional standards apply to protect the
patients who are research subjects.
29.
The benefits, risks, burdens and effectiveness of a new method
should be tested against those of the best current prophylactic,
diagnostic, and therapeutic methods. This does not exclude the use of
placebo, or no treatment, in studies where no proven prophylactic,
diagnostic or therapeutic method exists.
30.
At the conclusion of the study, every patient entered into the
study should be assured of access to the best proven prophylactic,
diagnostic and therapeutic methods identified by the study.
31.
The physician should fully inform the patient which aspects of
the care are related to the research. The refusal of a patient to
participate in a study must never interfere with the patient-physician
relationship.
32.
In the treatment of a patient, where proven prophylactic,
diagnostic and therapeutic methods do not exist or have been
ineffective, the physician, with informed consent from the patient, must
be free to use unproven or new prophylactic, diagnostic and therapeutic
measures, if in the physician's judgement it offers hope of saving life,
re-establishing health or alleviating suffering. Where possible, these
measures should be made the object of research, designed to evaluate
their safety and efficacy. In all cases, new information should be
recorded and, where appropriate, published. The other relevant
guidelines of this Declaration should be followed.
Appendix
II:
Schedule
y
Requirements
and guidelines on clinical trials for import and manufacture of new drug
- Clinical
Trials
- Nature
of trials:
The clinical trials required to be carried out in the country
before a new drug is approved for marketing depend on the status
of the drug in other countries. If the drug is already
approved/marketed, phase III trials as required under item 7 of
Appendix I (to Sch. Y) usually are required. If the drug is not
approved/ marketed, trials are generally allowed to be initiated
at one phase earlier to the phase of trials in other countries.
For new drug substances
discovered in other countries phase I trials are not usually allowed to
be initiated in India unless phase I data as required under Item 5 of
the said Appendix from other countries are available. However, such
trials may be permitted even in the absence of phase I data from other
countries if the drug is of special relevance to the health problem of
India.
For new drug substances
discovered in India, clinical trials are required to be carried out in
India right from phase I as required from Item 5 of the said Appendix,
through phase III as required under Item 7 of the said Appendix,
permission to carry out these trials is generally given in stages,
considering the data emerging from earlier phase.
- Permission
for trials: Permission
to initiate clinical trials with a new drug may be obtained by
applying in Form 12 for a test license (TL) to import or
manufacture the drug under the Rules. Data appropriate for the
various phases of clinical trials to be carried out should
accompany the application as per format given in Appendix I (Items
I-4). In addition, the protocol for proposed trials, case report
forms to be used, and the names of investigators and institutions
should also be submitted for approval. The investigators selected
should possess appropriate qualifications and experience and
should have such investigational facilities as are germane to the
proposed trials protocol.
Permission to carry out
clinical trials with a new drug is issued along with a test license in
Form 11.
It
is desirable that protocols for clinical trials be reviewed and approved
by the institution’s ethical committee. Since such committees at
present do not exist in all institutions, the approval granted to a
protocol by the ethical committee of one institution will be applicable
to the use of that protocol in other institutions, which do not have an
ethical committee. In case none of the trial centres/institutions has an
ethical committee the acceptance of the protocol by the investigator and
its approval by the Drugs Controller (India) or any officer as
authorized by him to do so will be adequate to initiate the trials.
For
new drugs having potential for use in children, permission for clinical
trials in the paediatric age group is normally given after phase III
trials as required under item 7 of the said Appendix, in adults are
completed. However, if the drug is of value primarily in a disease of
children, early trials in the paediatric age group may be allowed.
- Responsibilities
of Sponsor/Investigator:
Sponsors are required to submit to the Licensing Authority as
given under Rule 21 an annual status report on each clinical
trial, namely, ongoing, completed, or terminated. In case a trial
is terminated, reason for this should be stated. Any unusual,
unexpected, or serious adverse drug reaction (ADR) detected during
a trial should be promptly communicated by the sponsor to the
Licensing Authority under Rule 21 and the other investigators.
In
all trials an informed, written consent is required to be obtained from
each volunteer/patient in the prescribed form (See Appendix V), which
must be signed, by the patient/volunteer and the chief investigator.
- Chemical
and Pharmaceutical Information
Most
of the data under this heading (See Appendix I to Sch. Y, Item 2) are
required with the application for marketing permission. When the
application is for clinical trials only, information covered in item 2.1
to 2.3 of Appendix I will usually suffice.
- Animal
Toxicology
- Acute
toxicity:
Acute toxicity studies (See Appendix I – Sch. Y - Item 4.2)
should be carried out in at least two species, usually mice and
rats using the same route as intended for humans. In addition, at
least two more route should be used to ensure systemic absorption
of the drug, this route may depend on the nature of the drug.
Mortality should be looked for up to 72 hours after parenteral
administration and up to 7 days after oral administration.
Symptoms, signs and mode of death should be reported, with
appropriate macroscopic and microscopic findings where necessary.
LD 50s should be reported preferably with 95 percent confidence
limits, if LD 50s cannot be determined, reasons for this should be
stated.
- Long-term
toxicity: Long-term toxicity studies
(see Appendix I – Sch. Y, Item 1.3) should be carried out in at
least two mammalian species, of which one should be a non-rodent.
The duration of study will depend on whether the application is
for marketing permission or for clinical trial, and in the later
case, on the phases of trials (see Appendix III). If a species is
known to metabolize the drug in the same way as humans, it should
be preferred.
In
long-term toxicity studies the drug should be administered 7 days a week
by the route intended for clinical use in humans. The number of animals
required for these studies, i.e. the minimum number on which data should
be available, is shown in Appendix IV to Sch. Y.
A
control group of animals, given the vehicle alone, should always 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, eg: 2.5x to
make allowance for the sensitivity of the species; the intermediate dose
should cause some symptoms, but not gross toxicity or death, and may be
placed logarithmically between the other two doses.
The
variables to be monitored and recorded in long-term toxicity studies
include behavioral, physiological, biochemical and microscopic
observations.
- Reproduction
studies: Reproduction
studies (see Appendix I – Sch. Y, item 4.4) need to be carried
out only if the new drug is proposed to be studied or used in
women of childbearing age. Two species should generally be used,
one of them being non-rodent if possible.
(a)Fertility
studies:
The drug should be administered to both males and females, beginning a
sufficient number of days before mating. In females the medication
should be continued after mating and the pregnant one should be treated
throughout pregnancy. The highest dose used should not affect general
health or growth of the animals. The route of administration should be
the same as for therapeutic use in humans. The control and the treated
group should be of similar size and large enough to give at least 20
pregnant animals in the control group of rodents and at least 8 pregnant
animals in the control group of non-rodents. Observations should include
total examination of the litters from both the groups, including
spontaneous abortions, if any.
(b)Teratogenicity
studies:
The drugs should be administered throughout the period of organogenesis,
using three dose levels. One of the doses should cause minimum maternal
toxicity and one should be the proposed dose for clinical use in humans
or multiple of it. The route of administration should be the same as for
human therapeutic use. The control and the treated groups should consist
of at least 20 pregnant females in case of non-rodents, on each dose
used. Observations should include the number of implantation sites,
resorptions if any; and the number of fetuses with their sexes, weights
and malformations if any.
(c)
Perinatal studies: The
drug should be administered throughout the last third of pregnancy and
then through lactation and weaning. The control of each treated group
should have at least 12 pregnant females and the dose which causes low
foetal loss should be continued throughout lactation weaning. Animals
should be sacrificed and observations should include macroscopic autopsy
and where necessary, histopathology.
4.Local
toxicity:
These studies (see Appendix I, Sch. Y, Item 4.5) are required when the
new drug Is proposed to be used typically in humans. The drug should be
applied to an appropriate site to determine local effects in a suitable
species such as guinea pigs or rabbits, if the drug is absorbed from the
site of applications, appropriate systemic toxicity studies will be
required.
5.Mutagenicity and
Carcinogenicity : These
studies (see Appendix I, Sch. Y Item 4,6) are required to be carried out
if the drug or its metabolite is related to a known carcinogen or when
the nature and action of the drug is such as to suggest a carcinogenic/mutagenic
potential. For
carcinogenicity studies, at least two species should be used. These
species should not have high incidence of spontaneous tumors and should
preferably be known to metabolize the drug in the same manner as humans.
At least three does levels should be used; the highest does
should be sub-lethal but cause observable toxicity; the lowest does
should be comparable to the intended human therapeutic does or a
multiple of it, eg: 2.5x; to make allowance for the sensitivity of the
species; the intermediate does to be placed logarithmically between the
other two doses. A control
group should always be included. The
drug should be administered 7 days a week or a fraction of the life span
comparable to the fraction of human life span over which the drug is
likely to be used therapeutically.
Observations should include macroscopic changes observed at
autopsy and detailed histopathology.
4.
Animal Pharmacology
Specific
pharmacological actions (see Appendix I to Sch. Y, Item 3.2) are those
with therapeutic-potential for humans.
These should be described according to the animal models and
species used. Wherever
possible, dose-response relationships and ED 50s should be given. Special
studies to elucidate mode of action may also be described.
General pharmacological action (see Appendix I to Sch. Y, Item
3.3) are effects on other organs and systems, especially cardiovascular,
respiratory and central nervous systems.
Pharmacokinetic data help relate drug effect to plasma
concentration and should be given to the extent available.
5.
Human/Clinical Pharmacology trials (Phase I)
The objective of phase I of trials (see Appendix I, Sch. Y, Item
5) is to determine the maximum tolerated dose in humans; pharmacodynamic
effects, adverse reactions, if any, with their nature and intensity; and
pharmacokinetic behaviors or the drug as far as possible.
These studies are carried out in healthy adult males, 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 centers.
6.
Exploratory trials (Phase II)
In phase II trial (see Appendix I to Sch. Y, Item 6) 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 centers and carried out
by clinicians specialized on the concerned therapeutic areas and having
adequate facilities to perform the necessary investigations for efficacy
and safety.
7.
Confirmatory trials (Phase III)
The purpose of these trials (see
Appendix I to Sch. Y, Item 7) 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.
If the drug is a new drug substance discovered in India and not
marketed in any other country, phase III data should be obtained on at
least 500 patients distributed over 10-15 centers.
In addition, data on adverse drug reactions observed during
clinical use of the drug as recommended and to provide a report on its
efficacy and adverse drug reactions in the treated patients.
The selection of clinicians for such monitoring and supply of
drug to them will need approval of the licensing authority under Rule-21
of Drugs & Cosmetics Rules.
8.
Special Studies
(A)
These include studies on solid oral dosage forms, such as,
bioavailability and dissolution studies.
These are required to be submitted on the formulations
manufactured in the country. (See
Appendix I, Items 8.1 and 8.2)
(B) These
include studies to explore additional aspects of the drug, eg: use in
elderly patients or patients with renal failure, secondary or ancillary
effects, interactions, etc. (See Appendix I to Sch. Y, Item 8.1 and
8.2).
9.
Submission of Reports (Appendix II to Schedule Y)
The
reports of completed clinical trials shall be submitted by the applicant
duly signed by the investigator within a stipulated period of time.
The applicant should do so even if he is no longer interested to
market the drug in the country unless there are sufficient reasons for
not doing so.
10.
Regulatory status in other counties
It
is important to state if any restrictions have been placed on the use of
the drug in any other country, eg: dosage limits, exclusion of certain
age groups, warnings about adverse drug reaction, etc. (See Appendix I,
Sch. Y, Item 9.2)
Likewise,
if the drug has been withdrawn from any country especially by a
regulatory directive such information should e furnished along with
reasons and their relevance, if any, to India (See Appendix I, Item
9.1(d)).
11.
Marketing Information
The
product monograph should comprise the full prescribing information
necessary to enable a physician to use the drug properly.
It should include description, actions, indications, dosage
precaution, drug interactions, warnings and adverse reactions.
The
drafts of label and carton texts should comply with provisions of Rules
96 and 97 of the said rules.
Appendix I
to Schedule Y
Data
required to be submitted with application for permission to market a new
drug
1.
Introduction
A brief
description of the drug and the therapeutic class to which it belongs.
2.
Chemical and pharmaceutical information
1.
Chemical name; code name or number, if any; non-proprietary or
generic name, if any; physio-chemical proportion.
2.
Dosage form and its composition.
3.
Specifications of active and inactive ingredients.
4.
Tests for identification of the active ingredient and method of
its assay.
5.
Outline of the method of manufacture of the active ingredient.
6.
Stability data.
3.
Animal pharmacology
1.
Summary.
2.
Specific pharmacological actions.
3.
General pharmacological actions.
4.
Pharmacokinetics, absorptions, distribution, metabolism,
excretion.
4.
Animal toxicology (See Appendix III and IV to Sch. Y)
1.
Summary
2.
Acute toxicity
3.
Long term toxicity
4.
Reproduction studies
5.
Local toxicity
6.
Mutagenicity and carcinogenicity
5.
Human/clinical pharmacology (Phase I)
1.
Summary.
2.
Specific pharmacological actions.
3.
General pharmacological actions.
4.
Pharmacokinetics, absorptions, distribution, metabolism,
excretion.
6.
Exploratory clinical trials (Phase II)
1.
Summary
2.
Investigator wise reports.
7.
Confirmatory clinical trials (Phase III)
- Summary
- Investigator
wise reports.
8.
Special studies
- Summary
- Bioavailability
and dissolution studies.
- Investigator
wise reports.
9.
Regulatory status in other countries
- Countries
where
(a)
Marketed
(b)
Approved
(c)
Under trial, with phase
(d)
Withdrawn, if any, with reasons
- Restrictions
on use, if any, in countries where marketed/approved.
- Free
sale certificate from country of origin.
10.
Marketing information
- proposed
product monograph
- Drafts
of labels and cartons
- Sample
of pure drug substance, with testing protocol
Notes
I: All items may not be
applicable to all drugs, for explanation, see text of Schedule Y.
II:
For requirements of data to be submitted with application for clinical
trials see text of Schedule Y, Section I and also Appendices II and III
to Sch. Y.
APPENDIX I
to Schedule YI
Format
for submission of Clinical Trial Reports
….Title
of the trial
….Name
of the investigator and institution
….Objectives
of the trial
….Design
of study: open, single-blind or double-blind, non-comparative or
comparative; parallel group or crossover.
….Number
of patients, with criteria for selection and exclusion; whether written
informed consent, was obtained.
….Treatments
given: drugs and dosage forms: regimens; method of allocations of
patients to the treatments; method of verifying compliance, if any.
….Observations
made before, during and at the end of the treatment, for efficacy and
safety , with methods used.
….Results:
exclusions and dropouts, if any, with reasons; description of patients
with initial comparability of groups where appropriate; clinical and
laboratory observations on efficacy and safety; adverse drug reactions.
….Discussions
of results: relevance to objectives, correlation with other reports
data, if any; guidance for further study, if necessary.
….Summary
and conclusion.
APPENDIX III
to Schedule Y
Animal
toxicity requirements for clinical trials and marketing of a new drug
|
Route
of
administration
|
Duration
of
Human
administration
|
Phase
|
Long
term toxicity requirements
|
|
Single
dose or several doses in one
Day
|
I-III,
MP
|
2sp;
2 wk
|
|
Oral
or Parenteral or Transdermal
|
Up
to 2 wk
|
I,
II
III,
MP
|
2sp;
Up to 4 wk
2sp:
Up to 3 mo
|
|
|
Up
to 3 wk
|
I,
II
III
MP
|
2sp;
4 wk
2sp;
3 mo
2sp;
up to 6 mo
|
|
|
Over
3 mo
|
I,II
III,
MP
|
2sp;
3 mo
2sp;
6 mo
|
|
Inhalation
(general anaesthetics)
|
I:III,
MP
|
4sp;
5d (3h/d)
|
|
Aerosol
|
Repeated
or Chronic use
|
III
MP
|
I:II
1-2 sp; 3h/exp.
1-2
sp; Up to 6wk, (2 exp/d)
1-2
sp; 24wk (2 exp/d)
|
|
Dermal
|
Short
term or Long term application
|
I,II
III:MP
|
1
sp; single 24th exp;
then
2 wk observation
1
sp; **
|
|
Ocular
or Otic or Nasal
|
Single
or Multiple application
|
I:II
III
MP
|
Irrigation
test; graded doses
1
sp; 3 wk; daily applications as in clinical use.
1
sp; **
|
|
Vaginal
or Rectal
|
Single
or Multiple application
|
I,
II,
III,
MP
|
1
sp; **
|
**
Number and/or duration of application commensurate with duration of use
Abbreviations:
sp- species; wk- week; d- day; h- hour; mo- month; MP – Marketing
Permission; exp- exposure I, II, III – Phases of clinical trial (see
Appendix I, item No. 5-8).
Note
: (1) Animal toxicity data available from other countries are acceptable
and do not need to be repeated/duplicated in India. (2) Requirements for
fixed dose combinations are given in Appendix VI.
APPENDIX IV to Schedule Y
Number of animals for long term
toxicity studies
| 2-6
Weeks
|
7-26
Weeks
|
| Group
|
Rodents
(rats)
|
Non-Rodents
(dogs)
|
Rodents
(rats)
|
Non-Rodents
(dogs)
|
|
|
M
|
F
|
M
|
F
|
M
|
F
|
M
|
F
|
| Control
|
6-10
|
6-10
|
2-3
|
2-3
|
15-30
|
15-30
|
4-6
|
4-6
|
| Low
dose
|
6-10
|
6-10
|
2-3
|
2-3
|
15-30
|
15-30
|
4-6
|
4-6
|
| Interme-diate
dose
|
6-10
|
6-10
|
2-3
|
2-3
|
15-30
|
15-30
|
4-6
|
4-6
|
| High
dose
|
6-10
|
6-10
|
2-3
|
2-3
|
15-30
|
15-30
|
4-6
|
4-6
|
APPENDIX V to Schedule Y
Patient consent form for
participation in a Phase I Clinical Trial
This
clinical trial involves the study of a new
……………………….….. agent
in volunteers/patients suffering from ………………………..
The
drug which will be administered to volunteers/patients has been found to
be safe in animal toxicity tests and other experimental data. The
volunteers/patients will be required to undergo, if necessary, all
routine examinations including taking of X-ray, ECG, EEG etc. at
intervals. The volunteers/patients may be asked to collect stool and
urine, and there may be need to draw blood or any other body fluid on
several occasions to test the effects of concentrations of the drugs.
The volunteers/patients are free to withdraw from the trial at any
stage.
Authorisation
I have read/been briefed on the above project summary and I
voluntarily agree to
participate in the project. I understand that participation in this
study may or may not benefit me. Its general purpose, potential
benefits, possible hazards, and inconveniences have been explained to my
satisfaction. I hereby give my consent for this treatment.
Signature
or thumb impression
Name
of the volunteer/patient
Date:
Signature of Chief Investigator
Patient consent form for
participation in Phase II and Phase III Clinical Trial
I
………………………………… exercising my free power of
choice, hereby give my consent to be included as a subject in the
clinical trial of a new drug, namely …………………………. for
the treatment of ……………………….. . I understand that I may
be treated with this drug for the diseases. I am suffering from
………………………….. . I have been informed to my
satisfaction, by the attending physician the purpose of the clinical
trial and the nature of drug treatment and follow up including the
laboratory investigation to monitor and safeguard my body function.
I
am also aware of my right to opt out of the trial at any time during the
course of the trial without having to give the reasons for doing so.
Signature
of the patient
Date:
Signature
of the attending physician
APPENDIX VI to Schedule Y
Data
requirements of Fixed Dose Combinations
Fixed
Dose combinations (FDC) fall into four groups and their data
requirements accordingly
(a)
The first group of FDC includes those in which one or more of the
active ingredients is a new drug. Such FDC are treated in the same way
as any other new drug , both the clinical trials and for marketing
permission (see Rule 122-E, Item (a)).
(b)
The second group of FDC includes those in which active
ingredients already approved/marketed individually are combined for the
first time, for a particular claim and where the ingredients are likely
to have significant interaction of a pharmacodynamic or pharmacokinetic
nature (see Rule 122-E, item (c)). For permission to carry out clinical
trials with such FDC, a summary of available pharmacological,
toxicological and clinical data on the individual ingredients should be
submitted, along with the rationale for combining them in the proposed
ratio. In addition, acute toxicity data (LD 50) and pharmacological data
should be submitted on the individual ingredient as well as their
combinations in the proposed ratio. If clinical trials have been carried
out with the FDC in other countries, reports of such trials should be
submitted. If the FDC is marketed abroad, the regulatory status in other
countries should be stated. (See Appendix I, Item 9).
For
marketing permission, the reports of clinical trials carried out with
the FDC in India should be submitted. The nature of trials depending on
the claims to be made and the data already available.
(c)
The third group of FDC includes those which are already marketed,
but in which it is proposed either to change the ratio of active
ingredients or to make a new therapeutic claim.
(d)
The fourth group of FDC includes those whose individual active
ingredients have been widely used in particular indication for years,
there concomitant use is often necessary and no claim is proposed to be
made other than convenience, and a stable acceptable dosage form and the
ingredients are unlikely to have significant interaction of a
pharmacodynamic or pharmacokinetic nature.
No
additional animals or human data are generally required for these FDC,
and marketing permission may be granted if the FDC has an acceptable
rationale.
APPENDIX
III
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
- 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.).
- 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.)
(3)
Post-translation modification (glycosylation etc.)
(b)
Monoclonal antibodies (if applicable) :
-
identity by rigorous immunochemical and physicochemical
characterization.
- 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.
- General
Safety Test.
- Data
on sterility tests as per Indian Pharmacopia guidelines.
- 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
- Description
of constituent materials like preservatives etc.
- Data
on stability of finished formulation as per IP (Indian pharmacopia)
guidelines.
B
: DATA ON PRECLINICAL TESTING
- Biological
activity/ pharmacodynamics in
vitro and in appropriate
animal models.
- Safety
Pharmacology (Functional indices of toxicity).
- Toxicology
and pharmacokinetics (Absorption, Distribution, Metabolism,
Excretion- ADME)
- Immunogenicity/Immunotoxicity
- Reproductive
and developmental toxicity
- Genotoxicity
studies
- Carcinogenicity
studies
C:
RECOMBINANT IMMUNODIAGNOSTIC REAGENTS
- Specification
and characterization of r-DNA diagnostic products (Please provide
information as per column1-9
under Section A of this format).
- The
data on the sensitivity / specificity / predictive positive value/
predictive negative value / overall diagnostic accuracy of
recombinant product in diagnostic assay.
- Data
on (1) “in-house” validation and (2) independent validation.
- Data
using indigenous / internationally available panel of sera /
clinical materials.
D: CLINICAL
TRIALS
- Phase
I : Human/Clinical Pharmacology Immunogenic Potency
(a)
Details on level of specific antibodies including its kinetics in
healthy subjects.
(b)
Details on cytokine profiles in healthy subjects.
(c)
Details on T-cell responses in healthy subjects.
(d)
Data on auto-antibodies and immune complexes in healthy subjects.
(e)
Details on haematological and clinical chemistry.
- Phase
II: Exploratory Clinical Trials- Preventive/Therapeutic Efficacy
(Data to be generated in subjects 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).
- Phase
III: Confirmatory Trials
(a)
Preventive / therapeutic effects.
(b)
Immunological / clinical chemistry parameters in some subjects
belonging to different ethnic and socio-economic groups.
APPENDIX IV
INVESTIGATOR’S
BROCHURE (IB)
Introduction
The
Investigator’s Brochure is a compilation of the clinical and
non-clinical data on the Investigational Product(s) that are relevant to
a study of the product(s). It provides the investigator(s) and others
involved in the study with the information on the rationale to
facilitate compliance with the key features of the protocol, such as the
dose, dose frequency/interval, methods of administration and safety
monitoring procedures. The IB also provides background material to
support the clinical management of the study subjects. The information
contained in the IB should be in a concise, simple, objective, balanced,
and non-promotional form to enable an understanding unbiased
risk-benefit assessment of the appropriateness of the proposed trial.
For this reason, a medically qualified person should generally
participate in the editing of an IB, but the contents of the IB should
be approved by the disciplines that generated the described data. The IB
should be revised whenever necessary in compliance with the sponsor’s
written procedures, the stage of development and the generation of
relevant new information. However, any relevant new information that is
considered important should be communicated to the Investigator(s),
Ethics Committee and the Regulatory Authorities immediately, even before
it can be methodically included in the IB.
Contents
of the Investigator’s Brochure
The IB
should include Sponsor’s name, the reference number allocated to the
study, the identity of each investigational product (ie. research
number, chemical or approved generic name, and trade name(s) where
legally permissible and desired by the sponsor).
The IB should bear an edition number and date.
Besides, wherever applicable it also bears a reference to the
number and date of the edition it supersedes.
The Sponsor
may wish to include a statement instructing the readers to treat the IB
as a confidential document for the sole purpose of the Study for which
it has been prepared.
The IB
should contain the following sections, each with literature references
where appropriate:
1
Table of Contents
2
Introduction: This section includes information relevant to the
stage of clinical development including the significant physical
properties , chemical properties, pharmaceutical, pharmacological
(pharmacological class, advantages over other substances in that class
and rationale for performing the proposed study), toxicological,
pharmacokinetic, metabolic, and clinical information (anticipated
prophylactic/ therapeutic or diagnostic indication(s)) of all active
ingredients. The
introductory statement should necessarily provide the general approach
to be followed in evaluating the Investigational Product.
3 Physical,
Chemical, and Pharmaceutical Properties and Formulation parameters: A
description should be provided of the Investigational Product
substance(s), including the chemical and / or structural formula(e), and
a brief summary of the relevant physical, chemical and pharmaceutical
properties. Any structural similarities to other known compounds should
be mentioned. Information
should also be provided on the excipients.
Appropriate
storage and dosage handling instructions should also be given.
4
Non-clinical Studies: Information provided should include data relating
to non-clinical pharmacology, pharmacokinetics, metabolism profile in
animals and toxicology. The
results of all relevant non-clinical pharmacology, toxicology,
pharmacokinetic, and the Investigational Product metabolism studies
should be provided in summary form, stating the methodology used, the
results, and a discussion of the relevance of the findings to the
investigated therapeutic effects besides the possible unfavourable
effects in humans.
The
information provided may include the following, as appropriate, if
known/available:
·
Species used
·
Number and sex of animals in each group
·
Unit dose (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
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 non-toxic 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)
Non-clinical Pharmacological (Pharmacodymanics)
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 (eg. 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
- Carcinogenicity
- Special studies (eg. irritancy and sensitisation)
-Reproductive
toxicity
-
Genotoxicity (mutagenicity)
5
Effects in Humans:
A thorough
discussion of the known effects of the investigational product(s) in
humans should be provided, including information on pharmacokinetics,
metabolism, pharmacodynamics, dose response, safety, efficacy, and other
pharmacological activities. Brief summaries of other clinical studies
conducted on the same product should be provided if available.
(a)
Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the
investigational
product(s)
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, and/or
relative) using a reference dosage form.
Population
subgroups (eg. gender, age, and impaired organ function).
Interactions
(eg. Product-product interactions and effects of food).
Other
pharmacokinetic data (eg. results of population studies performed within
clinical trial(s).
(b)
Safety and Efficacy
Information
should be provided about the Investigational Product(s)’ (including
their metabolites, where appropriate) safety pharmacodynamics, efficacy
and dose response(s) that were obtained from preceding trials in humans
(healthy volunteers and/or patients). The implications of the
information should be discussed. In cases where a number of clinical
studies have been completed, the use of summaries of safety and efficacy
across multiple trials by indications in subgroups may provide a clear
presentation of the data. Tabular summaries of adverse drug reactions
for all the clinical trials (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 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 product(s).
(c)
Regulatory & Post-marketing Experiences
The IB
should identify countries where the investigational product has been
marketed or approved. Any significant information arising from the
marketed use should be summarised (eg. formulations, dosages, routes of
administration, and adverse product reactions). The IB should also
identify all the countries where the investigational product did not
receive approval/registration for marketing or was withdrawn from
marketing/registration.
6
Summary of Data and Guidance for the Investigator
7
Bibliography
This section
should provide an overall discussion of the non-clinical and clinical
data, and should summarise the information from various sources on
different aspects of the investigational product(s), wherever possible.
Available published reports on related products should be discussed.
The
information given in this section should provide the investigator with a
clear understanding of the possible risks and adverse reactions.
Guidance
should also be provided on the recognition and treatment of possible
overdose and adverse drug reactions.
APPENDIX
V
ESSENTIAL
DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
Essential
Documents are those documents which individually and collectively allow
the evaluation of the conduct of a study and the quality of the data
generated. These documents demonstrate the compliance (or otherwise) of
the Investigator, Sponsor and Monitor with the Good Clinical Practice
and with other applicable regulatory requirements.
Essential
Documents are needed for Sponsor’s independent audit function and
inspection by the Regulatory Authority.
The various
Essential Documents needed for different stages of the study are
classified under three groups:
1.
before the clinical phase of the study commences,
2.
during the clinical conduct of the study, and
3.
after completion or termination of the study.
The
documents may be combined but their individual elements should be
readily identifiable.
Master files
containing all documents pertaining to the study should be created at
the beginning of the study, at the Investigator / Institution site,
Sponsor’s office, Ethics committee’s office and the CRO’s office.
| Legend
:
I
- Investigator
/ Institute,
S - Sponsor,
C - CRO,
E -
IEC,
·
- Yes,
°
- Not applicable
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
|
|
I
|
S
|
C
|
E
|
| Before
the Clinical Phase of the Trial Commences
During
this planning stage the following documents should be generated
and should be on file before the trial formally starts.
|
|
1
|
Investigator’s
brochure
|
To
document that relevant and current scientific information about
the investigational product has been provided to the
investigator
|
·
|
·
|
·
|
·
|
|
2
|
Signed
protocol and
amendments, if any, and sample case
report form(CRF)
|
To
document investigator and sponsor agreement to the protocol/amendment(s)
and CRF
|
·
|
·
|
·
|
·
|
|
3
|
Information
given to trial subject
-
informed consent form (including all applicable translations)
|
To
document the informed consent
|
·
|
·
|
·
|
·
|
|
4
|
-
Any other written information
|
To
document that subjects will be given appropriate information
(content and wording) to support their ability to give fully
informed consent
|
·
|
·
|
·
|
·
|
|
5
|
-
Advertisement for subject
recruitment
(if used)
|
To
document that recruitment measures are appropriate and not
coercive
|
·
|
·
|
·
|
·
|
|
6
|
Financial
aspects of the trial
|
To
document the financial agreement between the
investigator/institution and the sponsor for the trial
|
·
|
·
|
·
|
·
|
|
7
|
Insurance
statement
(where
required)
|
To
document that compensation to subject(s) for trial-related
injury will be available
|
·
|
·
|
·
|
·
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
|
I
|
S
|
C
|
E
|
|
8
|
Dated,
documented approval / favourable opinion of independent ethics
committee (IEC) of the following:
-
protocol and any amendments
-
CRF (if applicable)
-
informed consent form(s)
-
any other written information
to be provided to the subject(s)
-
advertisement for
subject recruitment
(if used)
-
Subject compensation
(if any)
-
any other documents
given approval / favourable opinion
|
To
document that the trial has been subject to IEC review and given
approval / favourable opinion.
To
identify the version number and date of the document(s)
|
·
|
·
|
·
|
·
|
|
9
|
Independent
ethics committee composition
|
To
document that the IEC is constituted in agreement with GCP
|
·
|
·
|
·
|
·
|
|
10
|
Regulatory
authority(ies) authorisation / approval / notification of
protocol (where required)
|
To
document appropriate authorisation / approval / notification by
the regulatory authority(ies) has been obtained prior to
initiation of the trial in compliance with the applicable
regulatory requirement(s)
|
·
|
·
|
·
|
·
|
|
11
|
Curriculum
vitae and/or other relevant documents evidencing qualifications
of Investigator(s) and Co-Investigator / Sub-Investigator(s)
|
To
document qualifications and eligibility to conduct trial and/or
provide medical supervision of subjects
|
·
|
·
|
·
|
·
|
|
12
|
Normal
value(s) / range(s) for medical / laboratory / technical
procedure(s) and/or test(s) included in the protocol
|
To
document normal values and/or ranges of the tests
|
·
|
·
|
·
|
°
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
|
I
|
S
|
C
|
E
|
|
13
|
Sample
of label(s) attached to investigational product container(s)
|
To
document compliance with applicable labelling regulations and
appropriateness of instructions provided to the subjects
|
·
|
·
|
·
|
°
|
|
14
|
Instructions
for handling of investigational product(s) and trial-related
materials
(if
not included in protocol or Investigator’s Brochure)
|
To
document instructions needed to ensure proper storage,
packaging, dispensing and disposition of investigational
products and trial-related materials
|
·
|
·
|
·
|
°
|
|
15
|
Shipping
records for investigational product(s) and trial-related
materials
|
To
document shipment dates, batch numbers and method of shipment of
investigational product(s) and trial-related materials. Allows
tracking of product batch, review of shipping conditions, and
accountability
|
·
|
·
|
·
|
°
|
|
16
|
Certificate(s)
of analysis of investigational product(s) shipped
|
To
document identity, purity, and strength of investigational
product(s) to be used in the trial
|
°
|
·
|
·
|
°
|
|
|
Decoding
procedures for blinded trials
|
To
document how, in case of an emergency, identity of blinded
investigational product can be revealed without breaking the
blind for the remaining subject’s treatment
|
·
|
·
|
·
|
°
|
|
17
|
Master
randomisation list
|
To
document method for randomisation of trial population
|
°
|
·
|
·
|
°
|
|
18
|
Pre-trial
monitoring report
|
To
document that the site is suitable for trial (may be combined
with Trial initiation monitoring report)
|
°
|
·
|
·
|
°
|
|
19
|
Trial
initiation monitoring report
|
To
document that the trial procedures were reviewed with the
investigator and the investigator’s trial staff
(may
be combined with Pre-trial monitoring report)
|
·
|
·
|
·
|
°
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
I
|
S
|
C
|
E
|
| During
the Clinical Conduct of the Trial
In
addition to having on file the above documents, the following
should be added to the files during the trial as evidence that
all new relevant information is documented as it becomes
available
|
|
20
|
Investigator’s
brochure updates
|
To
document that investigator is informed in a timely manner of
relevant information as it becomes available
|
·
|
·
|
·
|
·
|
|
21
|
Any
revision to:
-
protocol amendment(s) and CRF
-
informed consent form
-
any other written information provided to subjects
-
advertisement for subject recruitment(if used)
|
To
document revisions of these trial related documents that take
effect during trial
|
·
|
·
|
·
|
·
|
|
22
|
Dated,
documented approval / favourable opinion of Independent ethics
committee (IEC) of the following:
-
protocol amendment(s)
-
revision(s) of:
- informed consent
form
- any other written
information
provided
to subject
- advertisement for
subject
recruitment(if used)
-
any other documents given approval / favourable opinion
-
continuing review of trial
(where required)
|
To
document that the trial has been subject to IEC review and given
approval / favourable opinion.
To
identify the version number and date of the document(s).
|
·
|
·
|
·
|
·
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
I
|
S
|
C
|
E
|
|
23
|
Regulatory
authority(ies) authorisations / approvals / notifications where
required for:
-
protocol amendment(s) and other documents
|
To
document compliance with applicable regulatory requirements
|
·
|
·
|
·
|
·
|
|
24
|
Curriculum
vitae for new investigator(s) and / or sub- investigator(s)
|
To
document qualifications and eligibility to conduct trial and/or
provide medical supervision of subjects
|
·
|
·
|
·
|
·
|
|
25
|
Updates
to normal value(s) / range(s) for medical / laboratory /
technical procedure(s) / test(s) included in the protocol
|
To
document normal values and ranges that are revised during the
trial
|
·
|
·
|
·
|
°
|
|
26
|
Medical
/ laboratory / technical procedures / tests
-
certification or
-
accreditation or
-
established quality control and / or external quality assessment
or
-
other validation
(where required)
|
To
document that tests remain adequate throughout the trial period
|
·
|
·
|
·
|
°
|
|
27
|
Documentation
of investigational product(s) and trial-related material
shipment
|
To
document shipment dates, batch numbers and method of shipment of
investigational product(s) and trial-related materials. Allows
tracking of product batch, review of shipping conditions, and
accountability
|
·
|
·
|
·
|
°
|
|
28
|
Certificate(s)
of analysis for new batches of investigational products
|
To
document identity, purity, and strength of investigational
product(s) to be used in the trial
|
°
|
·
|
·
|
°
|
|
29
|
Monitoring
visit reports
|
To
document site visits by, and findings of, the monitor
|
°
|
·
|
·
|
°
|
|
30
|
Relevant
communications other than site visits
-
letters
-
meeting notes
- notes
of telephone calls
|
To
document any agreements or significant discussions regarding
trial administration, protocol violations, trial conduct,
adverse event (AE) reporting
|
·
|
°
|
·
|
°
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
I
|
S
|
C
|
E
|
|
31
|
Signed
informed consent forms
|
To
document that consent is obtained in accordance with GCP and
protocol and dated prior to participation of each subject in
trial. Also to document direct access permission
|
·
|
·
|
·
|
°
|
|
(Original)
|
(Copy)
|
(Copy)
|
|
|
32
|
Source
documents
|
To
document the existence of the subject and substantiate integrity
of trial data collected. To include original documents related
to the trials, to medical treatment, and history of subject
|
·
|
·
|
·
|
°
|
|
(Original)
|
(Copy)
|
(Copy)
|
|
33
|
Signed,
dated and completed case report forms (CRF)
|
To
document the existence of the subject and substantiate integrity
of trial data collected. To include original documents related
to the trial, to medical treatment, and history of subject
|
·
|
·
|
·
|
°
|
|
(Copy)
|
(Copy)
|
(Copy)
|
|
34
|
Documentation
of CRF corrections
|
To
document all changes / additions or corrections made to CRF
after initial data were recorded
|
·
|
·
|
·
|
°
|
|
(Original)
|
(Copy)
|
(Copy)
|
|
35
|
Notification
by originating investigator to sponsor of serious adverse events
and related reports
|
Notification
by originating investigator to sponsor of serious adverse events
and related reports
|
·
|
·
|
·
|
·
|
|
36
|
Notification
by sponsor
and/or
investigator, where applicable, to regulatory authority(ies) and
IEC(s) of unexpected serious adverse drug reactions and of other
safety information
|
Notification
by sponsor and/or investigator, where applicable, to regulatory
authorities and IEC(s) of unexpected serious adverse drug
reactions and of other safety information
|
·
|
·
|
·
|
·
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
I
|
S
|
C
|
E
|
|
37
|
Notification
by sponsor to investigators of safety information
|
Notification
by sponsor to investigators of safety information
|
·
|
·
|
·
|
·
|
|
38
|
Interim
or annual reports to IEC and authority(ies)
|
Interim
or annual reports provided to IEC and to authority(ies)
|
·
|
·
|
·
|
·
|
|
39
|
Subject
screening log
|
To
document identification of subjects who entered pre-trial
screening
|
·
|
·
|
·
|
°
|
|
(Where
required)
|
(Where
required)
|
|
40
|
Subject
identification code list
|
To
document that investigator / Institution keeps a confidential
list of names of all subjects allocated to trial numbers on
enrolling in the trial. Allows investigator/ Institution to
reveal identity of any subject
|
·
|
·
|
·
|
°
|
|
41
|
Subject
enrolment log
|
To
document chronological enrolment of subjects by trial number
|
·
|
·
|
·
|
°
|
|
42
|
Investigational
products accountability at the site
|
To
document that investigational product(s) have been used
according to the protocol
|
·
|
·
|
·
|
°
|
|
43
|
Signature
sheet
|
To
document signatures and initials of all persons authorised to
make entries and / or corrections on CRFs
|
·
|
·
|
·
|
°
|
|
44
|
Record
of retained body fluids/ tissue samples
(if
any)
|
To
document location and identification of retained samples if
assays need to be repeated
|
·
|
·
|
·
|
°
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
|
I
|
S
|
C
|
E
|
| After
Completion or Termination of the Trial
After
completion or termination of the trial, all of the documents
identified should be in the file together with the following
|
|
45
|
Investigational
product(s) accountability at site
|
To
document that the investigational product(s) have been used
according to the protocol. To documents the final accounting of
investigational
product(s) received at the site, dispensed to subjects, return
by the subjects, and returned to sponsors
|
·
|
·
|
·
|
°
|
|
46
|
Documentation
of investigational product destruction
|
To
document destruction of unused investigational products by
sponsor or at site
|
·
|
·
|
·
|
°
|
|
(if
destroyed at site)
|
|
47
|
Completed
subject identification code list
|
To
permit identification of all subjects enrolled in the trial in
case follow-up is required. List should be kept in a
confidential manner and for agreed upon time
|
·
|
·
|
·
|
°
|
|
48
|
Audit
certificate
(if
available)
|
To
document that audit was performed
|
°
|
·
|
·
|
°
|
|
49
|
Final
trial close-out monitoring report
|
To
document that all activities required for trial close-out are
completed, and copies of essential documents are held in the
appropriate files
|
°
|
·
|
·
|
°
|
|
50
|
Treatment
allocation and decoding documentation
|
Returned
to sponsor to document any decoding that may have occurred
|
°
|
·
|
·
|
°
|
|
Title
of the document
|
Purpose
|
Located
in files of
|
| I
|
S
|
C
|
E
|
|
51
|
Final
report by investigator to IEC where required, and where
applicable, to the regulatory authority(ies)
|
To
document completion of the trial
|
·
|
·
|
·
|
·
|
|
52
|
Clinical
study report
|
To
document results and interpretation of trial
|
·
|
·
|
·
|
·
|