Islamic Center of Southern California

International Ethical Guidelines for Biomedical Research Involving Human Subjects

Guideline 2

Ethical Review Committees

All proposals to conduct research involving human subjects must be submitted to one or more scientific review and ethical review committees for review of their scientific merit and ethical acceptability. The review committees must be independent of the research team, and any direct financial or other material benefit they may derive from the research should not be contingent on the outcome of their review. The investigator must obtain their approval or clearance before undertaking the research. The ethical review committee should conduct further reviews as necessary in the course of the research, including monitoring of the progress of the study.

Commentary on Guideline 2

Ethical review committees may function at the institutional, local, regional, or national level, and in some cases at the international level. The regulatory or other governmental authorities concerned should promote uniform standards across committees within a country, and, under all systems, sponsors of research and institutions in which the investigators are employed should allocate sufficient resources to the review process. Ethical review committees may receive money for the activity of reviewing protocols, but under no circumstances may payment be offered or accepted for a review committee's approval or clearance of a protocol.

Scientific Review. According to the Declaration of Helsinki (Paragraph 11), medical research involving humans must conform to generally accepted scientific principles, and be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, where indicated, animal experimentation. Scientific review must consider, inter alia, the study design, including the provisions for avoiding or minimizing risk and for monitoring safety. Committees competent to review and approve scientific aspects of research proposals must be multidisciplinary.

Ethical Review. The ethical review committee is responsible for safeguarding the rights, safety, and well-being of the research subjects. Scientific review and ethical review cannot be separated: scientifically unsound research involving humans as subjects is ipso facto unethical in that it may expose them to risk or inconvenience to no purpose; even if there is no risk of injury, the wasting of subjects' and researchers' time in unproductive activities represents loss of a valuable resource. Normally, therefore, an ethical review committee considers both the scientific and the ethical aspects of proposed research. It must either carry out a proper scientific review or verify that a competent expert body has determined that the research is scientifically sound. Also, it considers provisions for the monitoring of data and safety.

If the ethical review committee finds a research proposal scientifically sound, or verifies that a competent expert body has found it so, it should then consider whether any known or possible risks to the subjects are justified by the expected benefits, direct or indirect, and whether the proposed research methods will minimize harm and maximize benefit. (See Guideline 8: Benefits and Risks of Study Participation.) If the proposal is sound and the balance of risks to anticipated benefits is reasonable, the committee should then determine whether the procedures proposed for obtaining informed consent are satisfactory and those proposed for the selection of subjects are equitable.

Ethical Review of Emergency Compassionate Use of an Investigational Therapy. In some countries, drug regulatory authorities require that the so-called compassionate or humanitarian use of an investigational treatment be reviewed by an ethical review committee as though it were research. Exceptionally, a physician may undertake the compassionate use of an investigational therapy before obtaining the approval or clearance of an ethical review committee, provided three criteria are met: a patient needs emergency treatment, there is some evidence of possible effectiveness of the investigational treatment, and there is no other treatment available that is known to be equally effective or superior. Informed consent should be obtained according to the legal requirements and cultural standards of the community in which the intervention is carried out. Within one week the physician must report to the ethical review committee the details of the case and the action taken, and an independent health-care professional must confirm in writing to the ethical review committee the treating physician's judgment that the use of the investigational intervention was justified according to the three specified criteria. (See also Guideline 13 Commentary section: Other Vulnerable Groups.)

National (Centralized) or Local Review. Ethical review committees may be created under the aegis of national or local health administrations, national (or centralized) medical research councils, or other nationally representative bodies. In a highly centralized administration a national, or centralized, review committee may be constituted for both the scientific and the ethical review of research protocols. In countries where medical research is not centrally administered, ethical review is more effectively and conveniently undertaken at a local or regional level. The authority of a local ethical review committee may be confined to a single institution or may extend to all institutions in which biomedical research is carried out within a defined geographical area. The basic responsibilities of ethical review committees are:

to determine that all proposed interventions, particularly the administration of drugs and vaccines, or the use of medical devices or procedures under development, are acceptably safe to be undertaken in humans or to verify that another competent expert body has done so;

to determine that the proposed research is scientifically sound or to verify that another competent expert body has done so;

to ensure that all other ethical concerns arising from a protocol are satisfactorily resolved both in principle and in practice;

to consider the qualifications of the investigators, including education in the principles of research practice, and the conditions of the research site with a view to ensuring the safe conduct of the trial; and

to keep records of decisions and to take measures to follow up on the conduct of ongoing research projects.

Committee Membership. National or local ethical review committees should be so composed as to be able to provide complete and adequate review of the research proposals submitted to them. It is generally presumed that their membership should include physicians, scientists, and other professionals such as nurses, lawyers, ethicists, and clergy, as well as lay persons qualified to represent the cultural and moral values of the community and to ensure that the rights of the research subjects will be respected. They should include both men and women. When uneducated or illiterate persons form the focus of a study they should also be considered for membership or invited to be represented and have their views expressed.

A number of members should be replaced periodically with the aim of blending the advantages of experience with those of fresh perspectives.

A national or local ethical review committee responsible for reviewing and approving proposals for externally sponsored research should have among its members or consultants persons who are thoroughly familiar with the customs and traditions of the population or community concerned and sensitive to issues of human dignity.

Committees that often review research proposals directed at specific diseases or impairments, such as HIV/AIDS or paraplegia, should invite or hear the views of individuals or bodies representing patients with such diseases or impairments, so that there views may be submitted or verbally expressed. Similarly, for research involving such subjects as children, students, elderly persons, or employees, committees should invite or hear the views of their representatives or advocates.

To maintain the review committee's independence from the investigators and sponsors and to avoid conflict of interest, any member with a special or particular, direct or indirect, interest in a proposal should not take part in its assessment if that interest could subvert the member's objective judgment. Members of ethical review committees should be held to the same standard of disclosure as scientific and medical research staff with regard to financial or other interests that could be construed as conflicts of interest. A practical way of avoiding such conflict of interest is for the committee to insist on a declaration of possible conflict of interest by any of its members. A member who makes such a declaration should then withdraw, if to do so is clearly the appropriate action to take, either at the member's own discretion or at the request of the other members. Before withdrawing, the member should be permitted to offer comments on the protocol or to respond to questions of other members.

Multi-Center Research. Some research projects are designed to be conducted in a number of centers in different communities or countries. Generally, to ensure that the results will be valid, the study must be conducted in an identical way at each center. Such studies include clinical trials, research designed for the evaluation of health service programs, and various kinds of epidemiological research. For such studies, local ethical or scientific review committees are not normally authorized to change doses of drugs, to change inclusion or exclusion criteria, or to make other similar modifications. They should be fully empowered to prevent a study that they believe to be unethical. Moreover, changes that local review committees believe are necessary to protect the research subjects should be documented and reported to the research institution or sponsor responsible for the whole research program for consideration and due action, to ensure that all other subjects can be protected and that the research will be valid across sites.

To ensure the validity of multi-center research, any change in the protocol should be made at every collaborating center or institution, or, failing this, explicit inter-center comparability procedures must be introduced; changes made at some but not all will defeat the purpose of multi-center research. For some multi-center studies, scientific and ethical review may be facilitated by agreement among the centers to accept the conclusions of a single review committee; its members could include a representative of the ethical review committee at each of the centers at which the research is to be conducted, as well as individuals competent to conduct scientific review. In other circumstances, a centralized review may be complemented by local review relating to the local participating investigators and institutions. The central committee could review the study from a scientific and ethical standpoint, and the local committees could verify the practicability of the study in their communities, including the infrastructures, the state of training, and ethical considerations of local significance.

In a large multi-center trial, individual investigators will not have authority to act independently, with regard to data analysis or to preparation and publication of manuscripts, for instance. Such a trial usually has a set of committees which operate under the direction of a steering committee and are responsible for such functions and decisions. The function of the ethical review committee in such cases is to review the relevant plans with the aim of avoiding abuses.

Sanctions. Ethical review committees generally have no authority to impose sanctions on researchers who violate ethical standards in the conduct of research involving humans. They may, however, withdraw ethical approval of a research project if judged necessary. They should be required to monitor the implementation of an approved protocol and its progression, and to report to institutional or governmental authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that they have approved or in the conduct of the studies. Failure to submit a protocol to the committee should be considered a clear and serious violation of ethical standards.

Sanctions imposed by governmental, institutional, professional, or other authorities possessing disciplinary power should be employed as a last resort. Preferred methods of control include cultivation of an atmosphere of mutual trust, and education and support to promote in researchers and in sponsors the capacity for ethical conduct of research.

Should sanctions become necessary, they should be directed at the non-compliant researchers or sponsors. They may include fines or suspension of eligibility to receive research funding, to use investigational interventions, or to practice medicine. Unless there are persuasive reasons to do otherwise, editors should refuse to publish the results of research conducted unethically, and retract any articles that are subsequently found to contain falsified or fabricated data or to have been based on unethical research. Drug regulatory authorities should consider refusal to accept unethically obtained data submitted in support of an application for authorization to market a product. Such sanctions, however, may deprive of benefit not only the errant researcher or sponsor but also that segment of society intended to benefit from the research; such possible consequences merit careful consideration.

Potential Conflicts of Interest Related to Project Support. Increasingly, biomedical studies receive funding from commercial firms. Such sponsors have good reasons to support research methods that are ethically and scientifically acceptable, but cases have arisen in which the conditions of funding could have introduced bias. It may happen that investigators have little or no input into trial design, limited access to the raw data, or limited participation in data interpretation, or that the results of a clinical trial may not be published if they are unfavorable to the sponsor's product. This risk of bias may also be associated with other sources of support, such as government or foundations. As the persons directly responsible for their work, investigators should not enter into agreements that interfere unduly with their access to the data or their ability to analyze the data independently, to prepare manuscripts, or to publish them. Investigators must also disclose potential or apparent conflicts of interest on their part to the ethical review committee or to other institutional committees designed to evaluate and manage such conflicts. Ethical review committees should therefore ensure that these conditions are met. See also Multi-Center Research, above.

The Islamic Point of View Concerning Guideline 2

Ethical Review Committees

From a jurisprudence point of view, it should be established, before research which involves human subject gets under way, that the conditions and controls set in guideline 1 are met. This should be done by one or more specialized scientific review committee, independent of the research team and funding sponsors, and by an Islamic jurisprudence (fiqh) committee that bases its legal decision on the data it receives from specialized scientific review committees. Nor should the determination of material and non-material reward obtained by a committee be contingent on the outcome of its review. An investigator should obtain the approval, or clearance, of such committees before he undertakes his research.

In the case of non-compliance by researchers and/or sponsors with the scientific and jurisprudence criteria stated in the commentary on guidelines 1 and 2, institutional or government authorities should undertake to impose disciplinary sanction on violators.

The review by specialized scientific and jurisprudence committee(s) to determine whether conducting the research is permissible, and the subsequent clearance or approval, has its basis in the unanimously-endorsed basic rule of Islamic Law which stipulates that "a responsible adult is not to embark on any undertaking before he finds out how it is regarded by God." 20

As to the point that such specialized committee(s) should be independent of the research team and sponsors, this should be guided by the regulations of testimony and arbitration, one of the conditions of which is to be undertaken by a neutral party who has no direct or indirect purpose or interest in the matter on which he testifies.

The rule that material and non-material rewards for the committees should not be contingent on the outcome of the review is based on the need to guarantee that their decisions are objective and free from suspicion, which is also a basic rule in regards to testimonies.

As for the sanctions imposed by institutional or government authorities in cases of non-compliance with and violation of criteria, they are required by Islamic Law, for legal decisions against individuals should be proportionate to the damage they cause. This is for the protection of an individual, i.e. a study subject, against the aggressive violation of his human dignity and his inviolable, personal concerns.

Such punishments should be discretionary, i.e. determined by the proper authorities, and should be deterrent.

20. Al-Kittaani, Al-Taraateeb Al-Idariyah, II: 16; Al-Ghazaali, Ihyaa 'Uloom Al-Deen, II: 59 & 84. Islamic Center of Southern California