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

1. Drug Trials
2. Vaccine Trials
3. Medical Devices
4. Diagnostic agents - with special reference to use of Radioactive Materials and X-rays
5. 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.