STATEMENT OF SPECIFIC PRINCIPLES FOR
CLINICAL EVALUATION OF DRUGS/DIAGNOSTICS/VACCINES/HERBALREMEDIES ETC.
Human studies designed to evaluate the safety, effectiveness, or
usefulness of an intervention include research on therapeutics,
diagnostic procedures and preventive measures including vaccines. The
type of experimental procedures that a patient is submitted to has
become more complex and varied as the complexities of medical research
have increased. It is clearly accepted that it is essential to carry
out research on human subjects to discover better medical and
therapeutic modalities for the benefit of mankind. It is equally clear
that such research on normal subjects and patients is associated with
some degree of risk to the individual concerned. The guidelines have
been framed to carry out the evaluation of drugs, vaccines, devices
and other diagnostic materials on human subjects including herbal
remedies, in accordance with basic ethical principles. These
guidelines are important for the protection of research subjects
against any avoidable risk and to guide the researchers in the
preparation of research proposals/protocols.
For the evaluation of proposed research intervention the framework of
guidelines is as follows:
A. General Ethical Principles
B. Special Ethical concerns related to
- Drug Trials
- Vaccine Trials
- Medical Devices
- Diagnostic agents - with special reference to use of Radioactive
Materials and X-rays
- Trials with Herbal remedies.
A. GENERAL ETHICAL PRINCIPLES
All the research involving human subjects should be conducted in
accordance with three basic ethical principles, namely respect for
person/subject, beneficience and justice. The guidelines laid down are
directed at application of these basic principles to research
involving human subjects.
An investigator is the person responsible for the clinical trial and
for the rights, health and welfare of the subjects recruited for the
study. He/she should have qualification and competence in clinical
trial research methods for proper conduct of the trial and should be
aware of and comply with the legal and ethical requirements of the
study protocol
1. Informed Consent of Subject:
1.1 Individual Informed Consent
For all biomedical research involving human subjects, the
investigator must obtain the informed consent of the prospective
subject or, in the case of an individual who is not capable of giving
informed consent, the consent of a legal guardian.
- Informed consent is based on the principle that competent
individuals are entitled to choose freely whether to participate in
research or not. Informed consent protects the individual's freedom
of choice and respect for individual's autonomy.
- When research design involves no more than minimal risk (for
example, where the research involves only collecting data from
subject's records) the ethical review committee may waive some or
all elements of informed consent.
1.2 Essential information for prospective research subjects
Before taking the informed consent of subject, the investigator
must provide the individual with the following information in the
language he or she is able to understand -
- the aims and methods of the research,
- the expected duration of the subject participation,
- the benefits that might reasonably be expected as an outcome of
research to the subject or to others,
- any risk to the subject, associated with study,
- maintenence of confidentiality of records,
- responsibility of investigators,
- provision of free treatment for research related injury,
- compensation of subjects for disability or death resulting from
such injury, and
- freedom of individual to participate and to withdraw from
research any time without penalty or loss of benefits to which the
subject would otherwise be entitled.
1.3 Obligations of investigators regarding informed consent The
investigator has
duty to:
- communicate with prospective subject all the information
necessary for informed consent. There should not be any restriction
on subject's right to ask any questions related to study, and any
restriction on this undermines the validity of informed consent.
- 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.
- seek consent only after prospective subject is adequately
informed. Investigator should not give any unjustifiable assurances
to prospective subject, which may influence the subject's decision
to participate in the study.
- 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 with trial, and in case
of incompetence, a legal guardian or other duly authorised
representative should do so.
- renew the informed consent of each subject if there are material
changes in the conditions or procedures of the research along the
trial.
- Intimidation in any form 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.
1.4 Inducement to participate
Subjects may be paid for the inconvenience and time spent, 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 Ethical Committee.
- 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.
- When a subject is withdrawn from research for medical reasons
related to the study the subject should get the benefit for full
participation. When a subject withdraws for any other reasons,
he/she should be paid in proportion to the amount of participation.
2. Selection of Research Subjects:
2.1 Equitable distribution of burdens and benefits
Effort may be made that individuals or communities invited for
research should be selected in such a way that the burdens and
benefits of the research should be equally distributed. Special
justification is required for inviting vulnerable subjects, whose
rights and welfare must be protected.
Vulnerable subjects:- Equitable distribution of the burdens and
benefits of research participation is generally more difficult when
the intended subjects include vulnerable individuals or groups. These
subjects are children, persons with mental or behavioural disorders,
who are incapable of giving informed consent and prisoners, students,
subordinates service personnel etc. who have reduced autonomy.
Adequate justification of their involvement as research subjects is
required.
The quality of the consent of certain social groups requires careful
consideration, as their agreement to volunteer may be unduly
influenced by the Investigator.
2.2 Selection of pregnant or nursing women as research
subjects:-
As a general rule, pregnant and nursing (breast feeding) women
should not be subjects of any clinical trials except such trials which
are designed to protect or advance the health of pregnant or nursing
women or fetuses or nursing infants, and for which drugs can be tested
only in pregnant women.
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, trials of therapies 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.
Research related to termination of pregnancy:- Pregnant women
who desire to undergo Medical Termination of Pregnancy (MTP) could be
made subjects for research relating to termination of pregnancy, as
per The Medical Termination of Pregnancy Act, 1971.
Research related to pre-natal diagnostic techniques:- In
pregnant women research on prenatal diagnostic techniques should be
limited to detect the fetal abnormalities. Such research should take
the consideration of The Prenatal Diagnostic Techniques (Regulation
and Prevention of Misuse) Act, 1994.
2.3 Research involving children
Before undertaking children as subjects for clinical trial, the
investigator must ensure that
- children will not be involved in research that might be carried
out equally well with adults,
- the purpose of the research is to obtain knowledge relevant to
health needs of children. For a new drug usually the study in
children should always be 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,
- a parent or legal guardian of each child has given proxy consent
on behalf of the child,
- the consent of the child should be obtained to the extent of the
child's capabilities such as in the case of mature minors,
adolescents etc.,
- research involving children should be conducted in settings in
which the child and parent can obtain adequate medical and
psychological support,
- 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.
The risks of interventions that are not intended to be of direct
benefit to the child subject must be justified in relation to
anticipated benefits to society.
3. Confidentiality of Data:
3.1 Safeguarding confidentiality
The investigator should safeguard the confidentiality of research
data, which might lead to the identification of 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 industrial
sponsor of research or in cases of certain communicable diseases to
health authority. Therefore, the limitations in maintaining the
confidentiality of data should be anticipated and assessed.
4. Compensation of Research Subjects from Accidental Injury:
4.1 Right of subjects to compensation
Research subjects who suffer physical injury as a result of their
participation are entitled to financial or other assistance to
compensate them equitably for any temporary or permanent impairment or
disability. In case of death, their dependents are entitled to
material compensation.
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 physical
injury for which subjects are entitled to compensation.
5. Ethical Review Committee:
All trials involving human subjects must be submitted for scientific
review and approval of ethical review committee of institute before
starting such research.
All the medical colleges and research institutions/centres involved
in clinical research should form scientific and ethical committees
which may be either combined or be two independent committees. The
scientific evaluation will assess the technical excellence of the
proposed clinical trial.
5.1 Composition of the Ethical Committee
The ethical committee should be able to provide complete and
adequate review of the research proposals submitted to them. The
committee should be headed by a chairman, who should not be head of
the same institution. Other members should be - one pharmacologist
preferably clinical pharmacologist if available, one pathologist, two
clinicans, one or more members of non-clinical departments, one person
having knolwedge of law (preferably a Judge or Lawyer) and a social
scientist or philosopher. The member secretary should be from the
Institute concerned.
The number of persons in an ethical committee be kept fairly small
(5-7 members). The ethical committee at any institution should not
hesitate to have as its members, individuals from other institutions
or communities if required. If the Investigator is a member of the
Institutional Ethical Committee, he/she should not be present when
his/her own project is discussed.
5.2 Basic responsibilities
The ethical committee should meet periodically (at least twice a
year) and review all research proposals and their progress reports.
Ethical approval through circulation of research proposal among
members should not be resorted to. The basic responsibilities of
ethical committee are -
- to verify the safety, integrity and human rights of the subjects
participating in the trials.
- to verify that all proposed interventions, and particularly the
administration of drugs and vaccines or use of medical devices under
development, have been assessed by a competent expert body as
acceptably safe to be undertaken in human subjects; and
- to ensure that all other ethical and scientific concerns arising
from a protocol are satisfactorily resolved both in principle and in
practice.
5.3 Assessment of research proposal
The ethical committee should review every research proposal on
human subjects. It should observe that the research proposal is
scientifically sound, the possible risks to the subjects are justified
by the expected benefits, informed consent is satisfactory and
procedures for selection of subjects are equitable and properly
documented.
The protocol should include -
- clear research objectives and rationale for undertaking the
investigation in human subjects in light of the existing knowledge,
- precise description of methodology of the proposed research,
including intended dosages of drugs and planned duration of
treatment,
- a description of plans to withdraw or withhold standard therapies
in the course of research,
- the plans for statistical analysis of the study,
- inclusion and exlusion criteria for admission of subjects in the
study,
- procedure for seeking and obtaining informed consent,
- safety of proposed intervention and any drug or vaccine to be
tested, including results of relevant laboratory and animal
research, and
- for research carrying more than minimal risk, if any, an account
of plans to provide medical therapy for such risk or injury should
be included.
- storage and maintenance of all data collected during the trial.
The role of ethical committee is not only to permit the initiation
of research but also to review research during the course of study.
When there is anticipation of likely injury or detection of adverse
events during the course of study the termination of study should be
recommended.
6. Externally Sponsored Research:
The externally sponsored research entails two ethical
obligations:-
- The external sponsoring agency should submit the research
proposal according to the standards applied by ethical committee of
sponsoring agency/country with due approval.
- The ethical committee of host Institution/country should satisfy
themselves that the proposed research meets their own ethical
requirement before sanctioning approval. The decision of the host
Institution where the study will be conducted is ultimate.
