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1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects


Prepared by the Council for International Organizations of Medical Sciences (CIOMS) in Collaboration with the World Health Organization (WHO)


(Introductory sections, as well as Annexes, Appendices and Acknowledgments are omitted here)

Informed Consent of Subjects

Guideline 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 proxy consent of a properly authorized representative.

Commentary on Guideline 1

General considerations. Informed consent is consent given by a competent individual who has received the necessary information; who has adequately understood the information; and who, after considering the information, has arrived at a decision without having been subjected to coercion, undue influence or inducement, or intimidation.

Informed consent is based on the principle that competent individuals are entitled to choose freely whether to participate in research. Informed consent protects the individual's freedom of choice and respects the individual's autonomy.

In itself, informed consent is an imperfect safeguard for the individual, and it must always be complemented by independent ethical review of research proposals. Moreover, many individuals, including young children, many adults with severe mental or behavioural disorders, and many persons who are totally unfamiliar with modern medical concepts, are limited in their capacity to give adequate informed consent. Because their consent could imply passive and uncomprehending participation, investigators must on no account presume that consent given by such vulnerable individuals is valid, without the prior approval of an independent ethical-review body. When an individual is incapable of making an informed decision whether to participate in research, the investigator must obtain the proxy consent of the individual's legal guardian or other duly authorized representative.

When the research design involves no more than minimal risk - that is, risk that is no more likely and not greater than that attached to routine medical or psychological examination - and it is not practicable to obtain informed consent from each subject (for example, where the research involves only excerpting data from subjects' records) the ethical review committee may waive some or all of the elements of informed consent. Investigators should never initiate research involving human subjects without obtaining each subject's informed consent, unless they have received explicit approval to do so from an ethical review committee.

Guideline 2: Essential information for prospective research subjects

Before requesting an individual's consent to participate in research, the investigator must provide the individual with the following information, in language that he or she is capable of understanding:

• that each individual is invited to participate as a subject in research, and the aims and methods of the research;
• the expected duration of the subjectÕs participation;
• the benefits that might reasonably be expected to result to the subject or to others as an outcome of the research;
• any foreseeable risks or discomfort to the subject, associated with participation in the research;
• any alternative procedures or courses of treatment that might be as advantageous to the subject as the procedure or treatment being tested;
• the extent to which confidentiality of records in which the subject is identified will be maintained;
• the extent of the investigator's responsibility, if any, to provide medical services to the subject;
• that therapy will be provided free of charge for specified types of research-related injury;
• whether the subject or the subjectÕs family or dependants will be compensated for disability or death resulting from such injury; and
• that the individual is free to refuse to participate and will be free to withdraw from the research at any time without penalty or loss of benefits to which he or she would otherwise be entitled.

Commentary on Guideline 2

Process. Obtaining informed consent is a process that is begun when initial contact is made with a prospective subject and continues throughout the course of the study. By informing the subjects, by repetition and explanation, by answering subjects' questions as they arise, and by assuring that each procedure is understood by each subject, the research team not only elicits the informed consent of subjects but also manifests deep respect for the dignity of the subjects.

Language. Informing the subject must not be simply a ritual recitation of the contents of a form. Rather, the investigator must convey the information in words that suit the individual's level of understanding. The investigator must bear in mind that ability to understand the information necessary to give informed consent depends on the individual's maturity, intelligence, education and rationality.

Comprehension. The investigator must then ensure that the prospective subject has adequately understood the information. This obligation is the more serious as risk to the subject increases. In some instances the investigator might administer an oral or a written test to check whether the information has been adequately understood.

Benefits. In research designed to evaluate vaccines, drugs or other products, subjects should be told whether and how the product will be made available to them if it proves to be safe and effective. They should be told whether they will have continuing access to the product between the end of their participation in the research and the time of approval of the product for general distribution, and whether they will receive it free of charge or will be expected to pay for it.

Risks. In the case of complex research projects it may be neither feasible nor desirable to inform prospective subjects fully about every possible risk. However, they must be informed of all risks that a reasonable person would consider material to making a decision about whether to participate. An investigator's judgment about what risks are to be considered material should be reviewed and approved by the ethical review committee (see Guideline 3). Subjects who desire additional information should be afforded an opportunity to ask questions.

The investigator's responsibility for medical care. If the investigator is a physician, the subject must be told clearly whether the investigator will act only as an investigator or as both an investigator and a physician to the subject. However, an investigator who agrees to act as physician investigator undertakes all of the legal and ethical responsibilities of the subject's primary-care physician. In such a case, if the subject withdraws from the research owing to complications related to the research or in the exercise of the right to withdraw without loss of benefit, the physician has an obligation to continue to provide medical care to the subject, or to see that the subject receives the necessary care in the community or district health-care system, or to offer assistance in finding another physician.

If the investigator is to act only as an investigator, the subject must be advised to seek any necessary medical care, outside the context of the
research.

Other considerations. For further details of the obligation to provide economic compensation in the event of death or disability resulting from specified types of research-related injury, see Guideline 13. For further discussion of confidentiality, see Guideline 12.

Guideline 3: Obligations of investigators regarding informed consent

The investigator has a duty to:

• communicate to the prospective subject all the information necessary for adequately informed consent;
• give the prospective subject full opportunity and encouragement to ask questions;
• exclude the possibility of unjustified deception, undue influence and intimidation;
• seek consent only after the prospective subject has adequate knowledge of the relevant facts and of the consequences of participation, and has had sufficient opportunity to consider whether to participate;
• as a general rule, obtain from each prospective subject a signed form as evidence of informed consent; and
• renew the informed consent of each subject if there are material changes in the conditions or procedures of the research.

Commentary on Guideline 3

Necessary information. The standards for communicating information as set forth in Guidelines 2 and 3 should be regarded as minimum. Other types of information that should be conveyed include the reasons for selecting prospective subjects (ordinarily because they either have certain diseases or have no apparent disease) and certain features of the research design (for example, randomization, double-blind, case control), stated in language that the subjects can understand. Additional types of information that should be conveyed in some circumstances are suggested below in the commentaries on several other guidelines. In general the standard for communicating information is that any and all information that a reasonable person would consider material to reaching a decision about whether to consent should be communicated. Investigators and ethical review committees should determine together what should be communicated in connection with particular studies.

Opportunity to ask questions. The investigator must be prepared to answer all of the subject's questions relating to the proposed research. Any restriction of the subject's ability to ask questions and receive answers before or during the research undermines the validity of the informed consent.

Deception. Sometimes, to ensure valid research, subjects are deliberately misled. In biomedical research, deception mostly takes the form of withholding information about the purpose of procedures; for example, subjects in clinical trials are often not told the purpose of tests performed to monitor their compliance with the protocol, in case that if they knew their compliance was being monitored they would modify their behaviour and thus invalidate the results. In most such cases the prospective subjects are asked to consent to remain uninformed of the purpose of some procedures until the research is completed; in other cases, because a request for permission to withhold some information would jeopardize the validity of the research, prospective subjects are not made aware that some information has been withheld until the research is completed.

Telling lies to subjects is a tactic not commonly employed in biomedical research. However, social and behavioural scientists may deliberately misinform subjects to study their attitudes and behaviour; for example, scientists have pretended to be patients to study the behaviour of health-care professionals and patients in their natural settings.

Deception of the subject is not permissible in research projects that carry more than minimal risk of harm to the subject. When deception is indispensable to the methods of an experiment, the investigator must demonstrate to an ethical review committee that no other research method would suffice; that significant advances could result from the research; and that nothing has been withheld that, if divulged, would cause a reasonable person to refuse to participate. The ethical review committee with the investigator should determine whether and how deceived subjects should be informed of the deception upon completion of the research. Such informing, commonly called "debriefing", ordinarily entails explaining the reasons for the deception. A subject who disapproves of having been deceived is ordinarily offered an opportunity to refuse to allow the investigator to use information obtained from studying the subject.

Undue influence. The investigator should seek to exclude any undue influence on the subject. However, the borderline between justifiable persuasion and undue influence is imprecise. The investigator should not give the prospective subject any unjustifiable assurances about the benefits, risks or inconveniences of the research. An example of undue influence would be to induce a close relative or a community leader to influence a prospective subject's decision or to threaten to withhold health services. See also Guideline 4.

Intimidation. Intimidation in any form invalidates informed consent. Prospective subjects who are patients often depend upon the investigator for medical care, and the investigator has a certain credibility in their eyes. If the research protocol has a therapeutic component, the investigator's influence over them may be considerable. They may fear, for example, that refusal to participate would damage their relationship with the investigator. The investigator must assure prospective subjects that their decision on whether to participate will not affect the therapeutic relationship or any other benefits to which they are entitled.

Documentation of consent. Consent may be indicated in a number of ways. The subject may imply consent by his or her voluntary actions, express consent orally, or sign a consent form. As a general rule, the subject should sign a consent form, or, in the case of incompetence, a legal guardian or other duly authorized representative should do so. The ethical review committee may approve the waiving of the requirement of a signed consent form if the research carries no more than minimal risk and if the procedures to be used are only those for which signed consent forms are not customarily required outside the research context. Such waivers may also be approved when existence of a signed consent form would be an unjustified threat to the subjects' confidentiality. In some cases, particularly when the information is complicated, it is advisable to give subjects information sheets to retain; these may resemble consent forms in all respects except that subjects are not required to sign them.

Continuing consent. The initial consent should be renewed when material changes occur in the conditions or the procedures of the research. For example, new information may have come to light, either from the study or from outside the study, about the risks or benefits of therapies being tested or about alternatives to the therapies. Subjects should be given such information. In many clinical trials, data are not disclosed to subjects and investigators until the study is concluded. This is ethically acceptable if the data are monitored by a committee responsible for data and safety monitoring (see Guideline 14, page 40) and an ethical review committee has approved their non-disclosure.

Guideline 4: Inducement to participate

Subjects may be paid for 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, the payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in the research against their better judgment ("undue inducement"). All payments, reimbursements and medical services to he provided to research subjects should be approved by an ethical review committee.

Commentary on Guideline 4

Acceptable recompense. Research subjects may have their transport and other expenses reimbursed and receive a modest allowance for inconvenience due to their participation in the research. Also, investigators may provide them with medical services and the use of facilities, and perform procedures and tests free of charge, provided these are done in connection with the research.

Unacceptable recompense. Payments in money or in kind to research subjects should not be so large as to persuade them to take undue risks or volunteer against their better judgment. Payments or rewards that undermine a person's capacity to exercise free choice invalidate consent. It may be difficult to distinguish between suitable recompense and undue influence to participate in research. An unemployed person or a student may view promised recompense differently from an employed person. Someone without access to medical care may be unduly influenced to participate in research simply to receive such care. Therefore, monetary and in-kind recompense must be evaluated in the light of the traditions of the particular culture and population in which they are offered, to determine whether they constitute undue influence. The ethical review committee will ordinarily be the best judge of what constitutes reasonable material recompense in particular circumstances.

Incompetent persons. Incompetent persons may be vulnerable to exploitation for financial gain by guardians. A guardian asked to give proxy consent on behalf of an incompetent person should be offered no remuneration except a refund of out-of-pocket expenses.

Withdrawal from study. When a subject withdraws from research for reasons related to the study, or is withdrawn on health grounds, the investigator should pay the subject as if full participation had taken place. When a subject withdraws for any other reason, the investigator should pay in proportion to the amount of participation. An investigator who must remove a subject from the study for wilful noncompliance is entitled to withhold part or all of the payment.

Guideline 5: Research involving children

Before undertaking research involving children, the investigator must ensure that:

• children will not be involved in research that might equally well be carried out with adults;
• the purpose of the research is to obtain knowledge relevant to the health needs of children;
• a parent or legal guardian of each child has given proxy consent;
• the consent of each child has been obtained to the extent of the child's capabilities;
• the child's refusal to participate in research must always be respected unless according to the research protocol the child would receive therapy for which there is no medically acceptable alternative;
• the risk presented by interventions not intended to benefit the individual child-subject is low and commensurate with the importance of the knowledge to be gained; and
• 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.

Commentary on Guideline 5

Justification of the involvement of children. The participation of children is indispensable for research into diseases of childhood and conditions to which children are particularly susceptible. The aims of the research should be relevant to the health needs of children.

Consent of the child. The willing cooperation of the child should be sought, after the child has been informed to the extent that the child's maturity and intelligence permit. The age at which a child becomes legally competent to give consent differs substantially from one jurisdiction to another; in some countries the "age of consent" established in their different provinces, states or other political subdivisions varies considerably. Often children who have not yet reached the legally established age of consent can understand the implications of informed consent and go through the necessary procedures; they can therefore knowingly agree to serve as research subjects. Such knowing agreement is insufficient to permit participation in research unless it is supplemented by the proxy consent of a parent, legal guardian or other duly authorized representative.

Older children who are capable of informed consent should be selected before younger children or infants, unless there are important scientific reasons related to age for involving younger children first. An objection by a child to taking part in research should always be respected even if the parent gives proxy consent, unless according to the research protocol the child would receive therapy for which there is no medically acceptable alternative; in such a case parents or guardians may properly be authorized to override the objections of the child, particularly if the child is very young or immature.

Proxy consent of a parent or guardian. The investigator must obtain the proxy consent of the parent or guardian in accordance with local laws or established procedures. It may be assumed that children over the age of 13 years are usually capable of giving informed consent, but their consent must be complemented by the proxy consent of a parent or guardian, unless this is not required by local law.

Observation of research by parent. A parent or guardian who gives proxy consent for a child to participate in research should be given the opportunity to observe the research as it proceeds, so as to be able to withdraw the child from the research if the parent or guardian decides it is in the child's best interests to do so.

Psychological and medical support. Research involving children should be conducted in settings in which the child and the parent can obtain adequate medical and psychological support. As an additional protection for children, an investigator may, when possible, obtain the advice of a child's family physician or other health-care provider on matters concerning the child's involvement in the research.

Justification of risks. Interventions intended to provide direct diagnostic, therapeutic or preventive benefit for the individual child-subject must be justified by the expectation that they will be at least as advantageous to the individual child-subject, considering both risks and benefits, as any available alternative. Risks are to be justified in relation to anticipated benefits to the child.

The risk 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 (generalizable knowledge). In general, the risk from such interventions should be minimal - that is, no more likely and not greater than the risk attached to routine medical or psychological examination of such children. When an ethical review committee is persuaded that the object of the research is sufficiently important, slight increases above minimal risk may be permitted.

Guideline 6. Research involving persons with mental or behavioural disorders

Before undertaking research involving individuals who by reason of mental or behavioural disorders are not capable of giving adequately informed consent, the investigator must ensure that:

• such persons will not be subjects of research that might equally well be carried out on persons in full possession of their mental faculties;
• the purpose of the research is to obtain knowledge relevant to the particular health needs of persons with mental or behavioural disorders;
• the consent of each subject has been obtained to the extent of that subjectÕs capabilities, and a prospective subject's refusal to participate in non-clinical research is always respected;
• in the case of incompetent subjects, informed consent is obtained from the legal guardian or other duly authorized person;
• the degree of risk attached to interventions that are not intended to benefit the individual subject is low and commensurate with the importance of the knowledge to be gained; and
• interventions that are intended to provide therapeutic benefit are likely to be at least as advantageous to the individual subject as any alternative.

Commentary on Guideline 6

General considerations. Although the two populations differ in many respects, the ethical considerations discussed earlier in the case of children apply by and large to persons who are unable to give adequately informed consent by reason of mental or behavioural disorders. They should never be subjects of research that might equally well be carried out on adults in full possession of their mental faculties, but they are clearly the only subjects suitable for a large part of research into the origins and treatment of certain severe mental or behavioural disorders.

Consent of the individual. People with mental or behavioural disorders may not be capable of giving adequately informed consent. The willing cooperation of such prospective subjects should be sought to the extent that their mental state permits, and any objection on their part to taking part in any non-clinical research should always be respected. When an investigational intervention is intended to be of therapeutic benefit to a subject, the subject's objection should be respected unless there is no reasonable medical alternative and local law permits overriding the objection.

Proxy consent of the guardian. The Declaration of Helsinki states "In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent... permission from the responsible relative replaces that of the subject in accordance with national legislation" (Article 1. 1 1).
The agreement of an immediate family member - whether spouse, parent, adult offspring or sibling - should be sought, but is sometimes of doubtful value, especially as families sometimes regard persons with mental or behavioural disorders as an unwelcome burden. In the case of an individual who has been committed to an institution by a court order, it may be necessary to seek legal authorization for involving the person in research.

Serious illness in persons who are unable to give adequately informed consent because of mental or behavioural disorders. Such persons who have, or are at risk of, serious illnesses such as HIV infection, cancer or hepatitis should not be deprived of the possible benefits of investigational drugs, vaccines or devices that show promise of therapeutic or preventive benefit, particularly when no superior or equivalent therapy or prevention is available. Their entitlement to access to such therapy or prevention is justified ethically on the same grounds as is such entitlement for other vulnerable groups (see Guideline 10). Persons who are unable to give adequately informed consent by reason of mental or behavioural disorders are, in general, not suitable subjects for formal clinical trials except those designed to be responsive to their particular health needs. Direct HIV infection of the brain may result in mental impairment; in the case of patients with such impairment, formal clinical trials of drugs, vaccines and other interventions designed to treat or prevent the impairment may be approved by an ethical review committee.

Anticipated incapacity to give informed consent. When it can be reasonably predicted that a competent person will lose the capacity to make valid decisions about medical care, as in the case of early manifestations of cognitive impairment due to HIV infection or Alzheimer's disease, such a person may be asked to designate the conditions, if any, in which he or she would consent to becoming a research subject while unable to communicate, and to designate a person who will consent on his or her behalf in accordance with the subject's previously expressed wishes.

Guideline 7. Research involving prisoners

Prisoners with serious illness or at risk of serious illness should not arbitrarily be denied access to investigational drugs, vaccines or other agents that show promise of therapeutic or preventive benefit.

Commentary on Guideline 7

General considerations. Guideline 7 is not intended as an endorsement of involving prisoners as research subjects. The involvement of volunteer prisoners in biomedical research is permitted in very few countries, and even in those is controversial. Advocates of allowing prisoners to participate in research argue that they are particularly suitable in that they are living in a standard physical and psychological environment; that unlike fully-employed or mobile populations they have time to participate in long-term experiments; and that they regard such participation as relief from the tedium of prison life, evidence of their social worth, and a chance to earn a small income.

Opponents claim that the consent of prisoners cannot be valid in that it is influenced by the hope of rewards and other expectations, such as earlier parole.

Although none of the international declarations bars prisoners from serving as subjects of biomedical research, the contradictory though persuasive arguments preclude an internationally agreed recommendation. However, where the practice is permitted, there should be provision for the independent monitoring of the research projects.

Prisoners and serious illness. Prisoners suffering from or at risk of serious illnesses such as HIV infection, cancer or hepatitis should not be deprived of the possible benefits of investigational drugs, vaccines or devices, particularly when no superior or equivalent products are available. Their entitlement to access to such therapy and prevention is justified ethically on the same grounds as is that of other vulnerable groups (see Guideline 1 0). However, as no diseases afflict prisoners only, one cannot sustain arguments analogous to those supporting the suitability of children and of persons with mental or behavioural disorders as subjects in formal clinical trials.

Guideline 8: Research involving subjects in underdeveloped
communities

Before undertaking research involving subjects in underdeveloped communities, whether in developed or developing countries, the investigator must ensure that:

• persons in underdeveloped communities will not ordinarily be involved in research that could be carried out reasonably well in developed communities;
• the research is responsive to the health needs and the priorities of the community in which it is to be carried out;
• every effort will be made to secure the ethical imperative that the consent of individual subjects be informed ; and
• the proposals for the research have been reviewed and approved by an ethical review committee that has among its members or consultants persons who are thoroughly familiar with the customs and traditions of the community.

Commentary on Guideline 8

General considerations. Diseases that rarely or never occur in economically developed countries or communities exact a heavy toll of illness, disability or death in some communities that are socially and economically at risk of being exploited for research purposes. Research into the prevention and treatment of such diseases is needed and, in general, must be carried out in large part in the countries and communities at risk.

The ethical implications of research involving human subjects are identical in principle wherever the work is undertaken; they relate to respect for the dignity of each individual subject as well as to respect for communities, and protection of the rights and welfare of human subjects. Assessment of inherent risks is a pre-eminent concern. However, a number of subsidiary considerations apply particularly to research undertaken in underdeveloped communities of either developing or developed countries, by investigators and sponsors from developed countries or from developed institutions of developing countries.

Individuals and families in such communities are liable to exploitation for various reasons. Some of them may be relatively incapable of informed consent because they are illiterate, unfamiliar with the concepts of medicine held by the investigators, or living in communities in which the procedures typical of informed-consent discussions are unfamiliar or alien to the ethos of the community. Certain investigators may wish to take advantage of the lack in most developing countries of well-developed regulations or ethical review committees, which could have the effect of delaying access to research subjects; others may find it less expensive to conduct in developing countries research designed to develop drugs and other products for the markets of developed countries.

Guideline 8 is written on the presumption that research in developing countries or underdeveloped communities will generally be conducted by investigators and sponsored by agencies from developed countries or from developed communities of developing countries. Such investigators or sponsors may encounter practices that would be considered immoral in their own countries. This should be anticipated and the range of acceptable responses by the sponsors and investigators should be detailed in the protocol submitted to an ethical committee for review and approval.

Investigators must respect the ethical standards of their own countries and the cultural expectations of the societies in which research is undertaken, unless this implies a violation of a transcending moral rule. Investigators risk harming their reputation by pursuing work that host countries find acceptable but their own countries find offensive. Similarly, they may transgress the cultural values of the host countries by uncritically conforming to the expectations of their own.

Nature of the research. To guard against exploitation of individuals and families in socially and economically exploitable communities, sponsors and investigators who wish to conduct in such communities research that could be carried out reasonably well in developed communities must satisfy their national or local ethical review committees, and in the case of externally sponsored research the appropriate ethical review committee in the host country, that the research would not be exploitative. The reason for choosing an underdeveloped community should be made explicit.

The research conducted in underdeveloped communities should be responsive to the health needs and priorities of those communities. It should not exhaust resources which the community usually devotes to the health care of its members. If any product is to be developed, such as a new therapeutic agent, clear understanding should be reached among investigators, sponsors, representatives of the collaborating countries, and community leaders about what the community is to expect and what can or cannot be provided during and at the close of the research. Such understanding must be reached before the research is begun, to ensure that the research is truly responsive to the priorities of the community.

As a general rule, the sponsoring agency should ensure that, at the completion of successful testing, any product developed will be made reasonably available to inhabitants of the underdeveloped community in which the research was carried out; exceptions to this general requirement should be justified, and agreed to by all concerned parties before the research is begun.

Phase 1 drug studies and Phase 1 and 11 vaccine studies (Annex 2) should be conducted only in developed communities of the country of the sponsor. In general, Phase 111 vaccine trials and Phase 11 and 111 drug trials should be conducted simultaneously in the host community and the sponsoring country; they may be omitted in the sponsoring country on condition only that the drug or vaccine is designed to treat or prevent a disease or other condition that rarely or never occurs in the sponsoring country.

Informed consent. All reasonable efforts should be made to obtain the informed consent of each prospective subject according to the standards specified in Guidelines 1 to 3, to ensure that the rights of prospective subjects are respected. For example, when because of communication difficulties investigators cannot make prospective subjects sufficiently aware of the implications of participation to give adequately informed consent, the decision of each prospective subject on whether to consent should be elicited through a reliable intermediary such as a trusted community leader. In some cases other mechanisms, approved by an ethical review committee, may be more suitable. However consent is obtained, all prospective subjects must be clearly told that their participation is entirely voluntary, and that they are free to refuse to participate or to withdraw their participation at any time without loss of any entitlement. The investigator is required to ensure that each prospective subject is clearly told everything that would be conveyed if the study were to be conducted in a developed community and, further, to ensure that earnest attempts are made to enable the prospective subject to understand this information; otherwise, assurance of freedom to refuse or withdraw from participation would be meaningless.

All plans to use the above standard for informing, providing assistance with understanding, and assuring freedom to refuse or withdraw must be approved by an ethical review committee and supplemented with other means of assuring that the rights of prospective subjects are respected.

Ethical review. The ability to judge the ethical acceptability of various aspects of a research proposal requires a thorough understanding of a community's customs and traditions. The ethical review committee must have as either members or consultants persons with such understanding, so that the committee may evaluate proposed means of obtaining informed consent and otherwise respecting the rights of prospective subjects. Such persons should be able, for example, to identify appropriate members of the community to serve as intermediaries between investigators and subjects, to decide whether material benefits or inducements may be regarded as appropriate in the light of a community's gift-exchange traditions, and to provide safeguards for data and personal information that subjects consider to be private or sensitive.

HIV/AIDS considerations. HIV infection and AIDS are endemic in many of the world's countries and communities, both developed and developing. Some features of HIV/AIDS justify the involvement of people from underdeveloped communities in epidemiological research relevant to the HIV/AIDS pandemic as well as in research designed to test candidate drugs and vaccines for the treatment and prevention of HIV infection and AIDS. These include, but are not limited to, evidence that modes of transmission of the infection, and the natural history of the disease, may differ substantially among communities. Moreover, strains of HIV are different in various regions of the world, and the current scientific understanding is that different strains may respond differently to vaccines or drugs. If research were conducted only in developed countries and communities, developing countries could be deprived of many of the benefits of such research. Therefore, participation in HIV/AIDS research of inhabitants of appropriately selected underdeveloped communities should be encouraged, provided their rights and welfare are adequately safeguarded as set forth in Guideline 8.

Guideline 9: Informed consent in epidemiological studies

For several types of epidemiological research individual informed consent is either impracticable or inadvisable. In such cases the ethical review committee should determine whether it is ethically acceptable to proceed without individual informed consent and whether the investigator's plans to protect the safety and respect the privacy of research subjects and to maintain the confidentiality of the data are adequate.

Commentary on Guideline 9

General considerations. For epidemiological studies it is normal for investigators to secure the agreement and cooperation of the national or local authority responsible for public health in the population to be studied. In the case of a community in which collective decision-making is customary it is also advisable to seek the agreement of the community, usually through its chosen representatives.

Informed consent. Epidemiological studies that require the examination of documents, such as medical records, or of anonymous "leftover" samples of blood, urine, saliva or tissue specimens may be conducted without the consent of the individuals concerned, as long as their right to confidentiality is assured by the study methods.

When the focus of a study is an entire community rather than individual human subjects - for example, to test the use of an additive in a community's water supply, or a new health care procedure or method, or a new method of control of disease vectors such as mosquitoes or rats - individual consent or an individual's refusal to be exposed to the intervention would be meaningless unless the individual were willing to leave the community. However, individuals may refuse to submit to such procedures as questionnaires or blood tests designed to obtain data for evaluating the intervention.

When epidemiological studies entail personal contact between investigators and individual subjects, the general requirements for informed consent are directly applicable. When they involve individuals primarily as members of population groups, it may be acceptable not to obtain the informed consent of each individual. In the case of population groups with social structures, common customs, and an acknowledged leadership, the investigator will need to secure the cooperation and obtain the agreement of the group's leadership. In the case of groups defined solely in demographic or statistical terms, with neither leaders nor representatives, the investigator must satisfy an ethical review committee that the safety of the research subjects and the confidentiality of the data will be strictly safeguarded.

Consent is not required for the use of publicly available information, but the investigator should know that countries and communities differ with regard to what information about individuals is considered public. Investigators who use such information should avoid disclosure of personally sensitive information.

In the case of studies of certain forms of social behaviour, an ethical review committee may determine that it would be inadvisable to seek individual informed consent because to do so would frustrate the purpose of a study; for example, prospective subjects on being informed of the behaviour to be studied would change the behaviour. The review committee must be satisfied that there will be adequate safeguards of confidentiality and that the importance of the objectives of the research is in proportion to the risks to the subjects.

Investigators who propose to carry out epidemiological studies should consult International Guidelines for Ethical Review of Epidemiological Studies (CIOMS, 1991).

Selection of Research Subjects

Guideline 10: Equitable distribution of burdens and benefits

Individuals or communities to be invited to be subjects of research should be selected in such a way that the burdens and benefits of the research will be equitably distributed. Special justification is required for inviting vulnerable individuals and, if they are selected, the means of protecting their rights and welfare must be particularly strictly applied.

Commentary on Guideline 10

General considerations. In general, the equitable distribution of the burdens and the benefits of participation in research raises no serious problems when the intended subjects do not include vulnerable individuals or communities. Occasionally, when research is designed to evaluate therapeutic agents widely perceived to offer substantial advantages over those generally available, it may be appropriate to publicize widely the opportunity to participate in the research or to establish outreach programs for individuals or groups who have no ready access to information about research programs.

Equitable distribution of the burdens and benefits of research participation is generally more difficult when the intended subjects include vulnerable individuals or groups. Classes of individuals traditionally considered vulnerable are those with limited capacity or freedom to consent. They are the subject of specific guidelines in this publication and include children, persons who because of mental or behavioural disorders are incapable of giving informed consent, and prisoners. Ethical justification of their involvement usually requires that investigators satisfy ethical review committees that:

• the research could not be carried out reasonably well with less vulnerable subjects;
• the research is intended to obtain knowledge that will lead to improved diagnosis, prevention or treatment of diseases or other health problems characteristic of or unique to the vulnerable class, either the actual subjects or other similarly situated members of the vulnerable class;
• research subjects and other members of the vulnerable class from which subjects are recruited will ordinarily be assured reasonable access to any diagnostic, preventive or therapeutic products that will become available as a consequence of the research;
• the risks attached to research that is not intended to benefit individual subjects will be minimal, unless an ethical review committee authorizes a slight increase above minimal risk (see Guideline 5); and
• when the prospective subjects are either incompetent or otherwise substantially unable to give informed consent, their agreement will be supplemented by the proxy consent of their legal guardians or other duly authorized representatives.

Other vulnerable social groups. The quality of the consent of prospective subjects who are junior or subordinate members of a hierarchical group requires careful consideration, as their agreement to volunteer may be unduly influenced by the expectation, whether justified or not, of preferential treatment or by fear of disapproval or retaliation if they refuse. Examples of such groups are medical and nursing students, subordinate hospital and laboratory personnel, employees of pharmaceutical companies, and members of the armed forces or police.

Because they work in close proximity to investigators or disciplinary superiors, they tend to be called upon more often than others to serve as research subjects, and this could result in inequitable distribution of the burdens and benefits of research.

Other groups or classes may also be considered vulnerable. They include residents of nursing homes, people receiving welfare benefits or social assistance and other poor people and the unemployed, patients in emergency rooms, some ethnic and racial minority groups, homeless persons, nomads, refugees, and patients with incurable disease. To the extent that these and other classes of people have attributes resembling those of classes identified as vulnerable, the need for special protection of their rights and welfare should be considered.

Persons with HIV infection or at risk of contracting HIV infection. Persons in this category are not vulnerable in the sense of having limited capacity to consent. However, certain features of HIV infection and of the AIDS pandemic have prompted reconsideration of some aspects of the ethics of research involving human subjects; as a result, various countries have developed policies and practices designed to be responsive to the special problems presented by HIV infection; some of these problems are discussed in the following paragraphs. Although this commentary concerns problems associated with HIV infection, the basic principles apply equally to problems associated with other more or less similar conditions.

Drugs and other therapies that have not yet been licensed for general availability because studies designed to establish their safety and efficacy remain to be completed are sometimes made available to persons with HIV infection. This is compatible with the Declaration of Helsinki, Article 11.1, which states "...the physician must be free to use a new diagnostic or therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing health or alleviating suffering."

Drugs and other therapies that are made available, because they show promise of therapeutic benefit, to persons not considered vulnerable should be made equally available to members of vulnerable populations, particularly when no superior or equivalent approaches to therapy are available; children, pregnant or nursing women, persons with mental disorders who are not capable of giving informed consent, and prisoners are entitled to equal access to the benefits of such investigational agents unless there is good reason, such as a medical contraindication, not to afford such access.

When women take investigational drugs for HIV infection, special precautions are often needed. Women who are not pregnant when they begin to take such drugs should be counselled about reliable contraception. In developed countries, nursing mothers who ask to be treated with investigational drugs for HIV infection should be advised that they must discontinue breast-feeding while taking such drugs, unless there is clear evidence that the drug does not appear in milk. In each case in which an investigational drug is administered to a pregnant or nursing woman, there should be careful monitoring and reporting of the effects, if any, on the fetus or child.

Although it is generally required that research be conducted on less vulnerable populations before involving more vulnerable populations, some exceptions are justified. In general, children are not suitable subjects for Phase 1 drug trials or for Phase I or 11 vaccine trials, but in some cases such trials may be permissible after clinical trials in adults have shown some degree of therapeutic effect. For example, a Phase 11 vaccine trial seeking evidence of immunogenicity in infants may be justified in the case of a vaccine that has shown evidence of preventing or slowing progression from asymptomatic HIV infection to disease in adults. Additional examples are provided in the commentaries on Guidelines 6 and 8.

The life-threatening and infectious nature of HIV/AIDS does not justify any suspension of the rights of research subjects to informed consent, voluntary participation in or withdrawal from the study, or protection of confidentiality. In the case of research protocols that provide for diagnostic tests for HIV infection, the procedures for obtaining informed consent should be supplemented by counselling in which each subject is informed about AIDS and HIV infection, advised to avoid risky behaviour, and advised of the risk of social discrimination against individuals who are thought to be HIV-infected or at risk of such infection. In the case of patients with HIV disease or persons becoming aware of being HIV-infected, research teams should provide them with necessary services or refer them for follow-up.

Participation in drug and vaccine trials in the field of HIV infection and AIDS may impose on the research subjects significant associated risks of social discrimination or harm; such risks merit consideration equal to that given to the adverse medical consequences of the drugs and vaccines. Efforts must be made to reduce their likelihood and severity. For example, participants in vaccine trials must be enabled to demonstrate that their HIV seropositivity is due to their having been vaccinated rather than to natural infection. This may be accomplished by providing subjects with documents attesting to their participation in vaccine trials, or by maintaining a confidential register of trial participants, from which information can be made available to outside agencies at a participant's request.

Guideline 11: Selection of pregnant or nursing (breastfeeding) women as research subjects

Pregnant or nursing women should in no circumstances be the subjects of non-clinical 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 pregnancy or lactation. As a general rule, pregnant or nursing women should not be subjects of any clinical trials except such trials as are designed to protect or advance the health of pregnant or nursing women or fetuses or nursing infants, and for which women who are not pregnant or nursing would not be suitable subjects.

Commentary on Guideline 11

General considerations. In general, pregnant and nursing women are not suitable subjects of formal clinical trials other than those designed to respond to the health needs of such women or their fetuses or nursing infants. Examples of such trials would be a trial designed to test the safety and efficacy of a drug for reducing perinatal transmission of HIV infection from mother to child, a trial of a device for detecting fetal abnormalities, or trials of therapies for conditions associated with or aggravated by pregnancy, such as nausea and vomiting, hypertension or diabetes. The justification for their participation in such clinical trials would be that they should not be deprived arbitrarily of the opportunity to benefit from investigational drugs, vaccines or other agents that promise therapeutic or preventive benefit. In all cases risks to women subjects, fetuses and infants should be minimized, as far as sound research design permits.

A woman may decide to discontinue nursing to become eligible to participate in clinical research, but this is not to be encouraged, particularly in developing countries, where cessation of breast-feeding may be harmful to the nursing child and also increase the risk of another pregnancy.

Selection of women as research subjects. Women in most societies have been discriminated against with regard to their involvement in research. Women who are biologically capable of becoming pregnant have been customarily excluded from formal clinical trials of drugs, vaccines, and devices owing to concern about undetermined risks to the fetus. Consequently, relatively little is known about the safety and efficacy of most drugs, vaccines, or devices for such women, and this lack of knowledge can be dangerous. For example, thalidomide caused much more extensive damage than it would have if its first administration to such women had been in the context of a formal, carefully-monitored clinical trial. 

A general policy of excluding from such clinical trials women biologically capable of becoming pregnant is unjust in that it deprives women as a class of persons of the benefits of the new knowledge derived from the trials. Further, it is an affront to their right of self-determination. The exclusion of such women can be justified only on such grounds as evidence or suspicion that a particular drug or vaccine is mutagenic or teratogenic. Nevertheless, although women of childbearing age should be given the opportunity to participate in research, they should be helped to understand that the research could include risks to the fetus.

Premenopausal women have also been excluded from participation in many research activities, including non-clinical studies, that do not entail administration of drugs or vaccines, in case the physiological changes associated with various phases of the menstrual cycle would complicate interpretation of research data. Consequently, much less is known of women's than of men's normal physiological processes. This, too, is unjust in that it deprives women as a class of persons of the benefits of such knowledge.

Informed consent. Obtaining the informed consent of women, including those who are pregnant or nursing, usually presents no special problems. In some cultures, however, women's rights to exercise self-determination and thus give valid informed consent are not acknowledged. In such cases, women should not normally be involved in research for which societies that recognize these rights require informed consent. Nevertheless, women who have serious illnesses or who are at risk of developing such illnesses should not be deprived of opportunities to receive investigational therapies when there are no better alternatives, even though they may not consent for themselves. Efforts must be made to let such women know of these opportunities and to invite them to decide whether they wish to accept the investigational therapy, even though the formal consent must be obtained from another person, usually a man. Such invitations may best be extended by women who understand the culture sufficiently well to discern whether prospective recipients of investigational therapies genuinely wish to accept or reject the therapy.

Research related to termination of pregnancy. No recommendation is made regarding the acceptability of research relating to the termination of pregnancy, or undertaken in anticipation of termination of pregnancy. The acceptability of such research depends on religious belief, cultural traditions and national legislation. 

Confidentiality of Data

Guideline 12: Safeguarding confidentiality

The investigator must establish secure safeguards of the confidentiality of research data. Subjects should be told of the limits to the investigators' ability to safeguard confidentiality and of the anticipated consequences of breaches of confidentiality.

Commentary on Guideline 12

General considerations. The Declaration of Helsinki, Article 1.6, states: "The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject." The customary approach to showing respect for privacy is by obtaining prior informed consent to releases of research data and minimizing the possibility of a breach of confidentiality. If the requirement of individual informed consent is to be waived by an ethical review committee, alternative measures should be taken. Such measures are discussed in International Guidelines for Ethical Review of Epidemiological Studies (CIOMS, 1991).

Confidentiality between physician and patient. Patients in therapeutic relationships with their physicians have the right to expect that all information will be held in strict confidence and disclosed only to those who need, or have a legal right to, the information, such as nurses and technicians, to treat the patients. A treating physician should not disclose any identifying data about patients to an investigator unless the patients have first given their consent to such disclosure.

Physicians and other health care professionals record the details of their observations and interventions in medical and other records. Epidemiologists and other investigators often make use of such records. In studies of medical records it is usually impracticable to obtain the informed consent of each identifiable patient. Accordingly, an ethical review committee may waive the requirement for informed consent. In institutions in which records may be used for research purposes without the informed consent of identifiable patients, it is advisable to notify patients generally of such practices; notification is usually by means of a statement in patient-information brochures.

In the case of research limited to subjects' medical records, access must be approved by an ethical review committee and must be supervised by a person who is fully aware of the confidentiality requirements.

Confidentiality between investigator and subject. Research relating to individuals and groups may involve the collection and storage of data that, if disclosed to third parties, could cause harm or distress. Investigators should arrange to protect the confidentiality of such data by, for example, omitting information that might lead to the identification of individual subjects, limiting access to the data, or other means.

Prospective subjects should be informed of limits to the investigators' ability to ensure strict confidentiality and of the foreseeable adverse social consequences of limitations or breaches of confidentiality. In some cases investigators are required to communicate data from records to a national drug registration authority or to an industrial sponsor of the research. Some jurisdictions require the reporting of, for instance, certain communicable diseases to public health authorities or evidence of child abuse or neglect to appropriate agencies. These and similar limits to the ability to maintain confidentiality should be anticipated and disclosed to prospective subjects.

Compensation of Research Subjects for Accidental Injury

Guideline 13: Right of subjects to compensation

Research subjects who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability. In the case of death, their dependants are entitled to material compensation. The right to compensation may not be waived.

Commentary on Guideline 13

Accidental injury. Accidental injury due to procedures performed exclusively to accomplish the purposes of research rarely results in death or in permanent or temporary impairment or disability. Death, impairment or disability is much more likely to result from investigational diagnostic, preventive or therapeutic interventions. In general, however, death or serious injury is less likely to result from investigational therapies administered in the context of properly designed, conducted and sanctioned studies than from similar standard therapies in routine medical practice. Usually, human research subjects are in exceptionally favourable circumstances in that they are under close and continuing observation by qualified investigators alert to detecting the earliest signs of untoward reactions. Such favourable conditions are less likely in medical practice.

Equitable compensation. Compensation is owed to subjects who sustain significant physical injury from procedures performed solely to accomplish the purposes of research. Justice requires that every subject of biomedical research be automatically entitled to fair compensation for any such injury. Compensation is generally not owed to research subjects who suffer expected or foreseen adverse reactions from investigational therapies or other procedures performed to diagnose or prevent disease. Such reactions are not different in kind from those that occur in medical practice.

When, as in the early stages of drug testing, it is unclear whether a procedure is performed primarily for research or for therapeutic purposes, the ethical review committee should determine in advance the injuries for which subjects will be compensated and those for which they will not; prospective subjects should be informed of the review committee's decisions, as part of the informed consent process.

Subjects should not be required to waive their rights to compensation or to show negligence or lack of a reasonable degree of skill on the part of the investigator in order to claim compensation. The informed consent process or form should contain no words that would absolve an investigator from responsibility in the case of accidental injury, or that would imply that subjects would waive their legal rights, including the right to seek compensation for injury.

In some societies the right to compensation for accidental injury is not acknowledged. Therefore, when giving their informed consent to participate, research subjects should be told whether there is provision for compensation in case of physical injury, and the circumstances in which they or their dependants would receive it.

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. Sponsors are advised to obtain adequate insurance against risks to cover compensation, independent of proof of fault.

Review Procedures

Guideline 14: Constitution and responsibilities of ethical review committees

All proposals to conduct research involving human subjects must be submitted for review and approval to one or more independent ethical and scientific review committees. The investigator must obtain such approval of the proposal to conduct research before the research is begun.

Commentary on Guideline 14

General considerations. The provisions for review of research involving human subjects are influenced by political institutions, the organization of medical practice and research, and the degree of autonomy accorded to medical investigators. Whatever the circumstances, however, society has a dual responsibility to ensure that: 
- all drugs, devices and vaccines under investigation in human subjects meet adequate standards of safety; and
- the provisions of the Declaration of Helsinki are applied in all biomedical research involving human subjects.

Assessment of safety. Authority to assess the safety and quality of medicines and vaccines intended for use in humans is most effectively vested in a multidisciplinary advisory committee. In many cases such committees will function best if they operate at the national level; in other instances they are most effective at regional or local level. Clinicians, clinical pharmacologists, pharmacologists, microbiologists, epidemiologists, statisticians and other experts have important contributions to offer to such assessment. Many countries lack the resources to assess technical data independently according to procedures and standards now required in the more developed countries. Improvement in this respect depends, in the short term, on more efficient exchange of information internationally.

Ethical review committees. Scientific review and ethical review cannot be clearly separated: scientifically unsound research on human subjects is ipso facto unethical in that it may expose subjects to risk or inconvenience to no purpose. Normally, therefore, ethical review committees consider both the scientific and the ethical aspects of proposed research.

Scientific review. The Declaration of Helsinki, Article 1.1, states that "biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature."

Committees competent to review and approve scientific aspects of clinical trials must be multidisciplinary, much like those specified earlier for assessment of safety. In many cases such committees operate most effectively at the national level. A national scientific review committee offers several advantages over local committees. First, consolidating the necessary expertise in one group allows members to deepen their knowledge in the field, thereby improving the quality and utility of the review. Second, a national committee's awareness of all proposals for research in the country facilitates the performance of another essential function, the selection of those protocols most likely to achieve the nation's health research objectives.

If an ethical review committee considers a research proposal scientifically sound, or verifies that a competent expert body has found it so, it will then consider whether any known or possible risks to the subjects are justified by the expected benefits (and whether the methods of carrying out the research will minimize harm and maximize benefit) and, if so, whether the procedures proposed for obtaining informed consent are satisfactory and those proposed for selection of subjects are equitable.

Risks and benefits. The Declaration of Helsinki forbids the imposition of unwarranted risks on human research subjects. Article 1.4 requires that "the importance of the objective is in proportion to the inherent risk to the subject." The need for means of preventing or treating HIV infection or AIDS, for example, is obvious justification of research aimed at developing such treatment or prevention. However, it may not be possible to justify clinical testing of all investigational substances. Clinical testing must be preceded by sufficient laboratory experiments, including, when appropriate, animal testing, to demonstrate a reasonable probability of success without undue risk. Such preliminary testing is implied by the Declaration of Helsinki, Article 1.7, which requires forgoing research involving human subjects unless "the hazards involved are believed to be predictable", and by Article 1.5, which requires that clinical testing "be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others."

Ideally, when benefits are intended for society but not for the subject, the subjects should be individuals who are fully capable of informed consent and who understand and accept the risks. Thus, unless there is specially strong justification, Phases 1 and 11 of vaccine testing and Phase 1 of drug testing should not involve subjects with limited capacity to consent or who are otherwise vulnerable. The requirement of the Declaration of Helsinki, Article 111.2, that "subjects should be volunteers-either healthy persons or patients for whom the experimental design is not related to the patient's illness" is not to be disregarded lightly.

In Phases 11 and 111 of drug testing and Phase 111 of vaccine testing, when benefits are intended for the subjects and they are reasonably likely to be realized, it is permissible to involve members of vulnerable groups and persons with limited capacity to consent. However, as required by the Declaration of Helsinki, Article II.3, "every patient - including those of a control group, if any - should be assured of the best proven diagnostic and therapeutic method." Therefore, if there is already an approved and accepted drug for the condition that a candidate drug is designed to treat, placebo for controls usually cannot be justified.

Ethical justification to begin a randomized clinical trial also meets the requirements of Article 11. 3. The therapies (or other interventions) to be compared must be regarded as equally advantageous to the prospective subjects: there should be no scientific evidence to establish the superiority of one over another. Moreover, no other intervention must be known to be superior to those being compared in the clinical trial, unless eligibility to participate is limited to persons who have been unsuccessfully treated with the other superior intervention or to persons who are aware of the other intervention and its superiority and have chosen not to accept it.

For each randomized clinical trial there should be a data and safety monitoring committee, responsible for monitoring the data obtained in the course of a study and for making recommendations to the sponsors and investigators about modifying or terminating the study, or about amending the informed-consent process or form. Such recommendations are made in response to the committee's detection of adverse events of which the nature, frequency or magnitude had not been anticipated by the investigators or sponsors as they planned the study, or of evidence that one of the therapies or preventive measures being tested in the clinical trial is superior to another. During the planning stage of a clinical trial, stopping-rules should be established to guide the data and safety monitoring committee in determining when it should recommend termination of the study.

National or local review. Review committees may be created under the aegis of national or local health administrations, national medical research councils or other nationally-representative bodies. In a highly centralized administration, a national review committee may be constituted for both the scientific and the ethical review of research protocols. In countries where medical research is not centrally directed, protocols are more effectively and conveniently reviewed from the ethical standpoint at a local or regional level. The competence of a local committee may be confined exclusively to a single research institution or may extend to all human-subject biomedical research undertaken within a defined geographical area. The basic responsibilities of local ethical review committees are twofold:

• 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 concerns arising from a protocol are satisfactorily resolved both in principle and in practice.

Committee membership. Local review committees should be so composed as to be able to provide complete and adequate review of the research activities referred to them. They 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. The membership should include both men and women. Committees that often review research directed at specific diseases or impairments, such as AIDS or paraplegia, should consider the advantages of including as members or consultants patients with such diseases or impairments. Similarly, committees that review research involving such vulnerable groups as children, students, aged persons or employees should consider the advantages of including representatives of, or advocates for, such groups. Membership should be rotated periodically with the aim of blending the advantages of experience with those of openness to cultural and scientific evolution. Independence from the investigators and avoidance of conflict of interest are maintained by excluding from the assessment of a proposal any member with a direct interest in the proposal.

Need for particularly stringent review requirements. The requirements of review committees should be particularly stringent in the case of proposed research involving children, pregnant and nursing women, persons with mental or behavioural disorders, communities unfamiliar with modern clinical concepts, and other vulnerable social groups, and in the case of invasive non-clinical research. In considering such proposals the review committee should be especially attentive in determining that selection of research subjects is both equitable (designed to distribute fairly the burdens and benefits of research) and likely to minimize risk to subjects.

Multicentre research. Some research projects are designed to be conducted in a number of sites 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 of the different sites. Such studies include multicentre clinical trials, evaluation of health service programs, and various kinds of epidemiological research. In such studies local ethical review committees must either accept or reject the protocol in its entirety; they must not impose requirements to change doses of drugs, to change inclusion or exclusion criteria, or to make other similar modifications. In some such studies, scientific and ethical review may be facilitated by agreement among institutions to accept the results of review by a single review committee, whose members would include representatives of ethical review committees at each of the places in which the research is to be conducted.

Sanctions. Ethical review committees generally have no authority to impose sanctions on investigators who violate ethical standards in the conduct of research involving human subjects. However, they should be required to report to institutional or governmental authorities any serious or continuing noncompliance with ethical standards as they are reflected in protocols that they have approved. Failure to submit a protocol to the committee should be considered a violation of ethical standards.

Sanctions imposed by institutional, governmental, 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 investigators and in sponsors the capacity for ethical conduct of research. 

Should sanctions become necessary, they should be directed at the noncompliant investigators or sponsors. They may include fines or suspension of eligibility to receive research funding, to use investigational therapies, or to practise medicine. Refusal to publish the results of research conducted unethically, as prescribed in the Declaration of Helsinki, Article 1.8, may be considered, as may refusal to accept unethically obtained data submitted in support of an application for drug registration. However, these sanctions deprive of benefit not only the errant investigator or sponsor but also that segment of society intended to benefit from the research; such possible consequences merit careful consideration.

Publications of reports of the results of research involving human subjects should include, when appropriate, a statement that the research was conducted in accordance with these guidelines. Departures, if any, from these guidelines should be explained and justified in the report submitted for publication.

Information to be provided by investigators. Whatever the procedure adopted for ethical review, such review should be based on a detailed protocol comprising:

• a clear statement of the research objectives, having regard to the
  present state of knowledge, and a justification for undertaking the investigation in human subjects;
• a precise description of all proposed interventions, including intended dosages of drugs and planned duration of treatment;
• a description of plans to withdraw or withhold standard therapies in the course of the research;
• a description of the plans for statistical analysis of the study, which includes a calculation of the statistical power of the study, specifies the criteria for terminating the study, and demonstrates that the proper number of subjects will be recruited;
• the criteria determining admission and withdrawal of individual subjects, including full details of the procedure for seeking and obtaining informed consent;
• an account of any economic or other inducements to participate, such as offers of cash payments, gifts, or free services or facilities, and of any financial obligations assumed by the subjects, such as payment for medical services; and
• for research carrying more than minimal risk of physical injury, an account of plans, if any, to provide medical therapy for such injury and to provide compensation for research-related disability or death.

Information should also be included to establish:

• the safety of each proposed intervention and of any drug or vaccine to be tested, including the results of relevant laboratory and animal research;
• the anticipated benefits and the risks of participation;
• the means proposed to obtain individual informed consent or, when a prospective subject is not capable of informed consent, satisfactory assurance that proxy consent will be obtained from a duly authorized person and that the rights and welfare of each subject will be adequately protected;
• the identification of the organization that is sponsoring the research and a detailed account of the sponsor's financial commitments to the research institution, investigators, research subjects and, when appropriate, the community;
• plans to inform subjects about harms and benefits during the study, and of the results of the study at its conclusion;
• an explanation of who will be involved in the research, their age, sex and circumstances, and, if any classes are excluded, the justification for the exclusion;
• justification for involving as research subjects persons with limited
  capacity to consent or members of vulnerable social groups;
• evidence that the investigator is qualified and experienced and is assured of adequate facilities for the safe and efficient conduct of the research;
• provisions that will be made for protecting the confidentiality of data; and,
• the nature of any other ethical considerations involved, together with an indication that the principles of the Declaration of Helsinki will be implemented.

Externally Sponsored Research

Guideline 15: Obligations of sponsoring and host countries

Externally sponsored research entails two ethical obligations:

• An external sponsoring agency should submit the research protocol to ethical and scientific review according to the standards of the country of the sponsoring agency, and the ethical standards applied should he no less exacting than they would be in the case of research carried out in that country.
  
  
• After scientific and ethical approval in the country of the sponsoring agency, the appropriate authorities of the host country, including a national or local ethical review committee or its equivalent, should satisfy themselves that the proposed research meets their own ethical requirements.

Commentary on Guideline 15

Definition. The term "externally sponsored research" refers to research undertaken in a host country but sponsored, financed, and sometimes wholly or partly carried out by an external international or national agency, with the collaboration or agreement of the appropriate authorities, institutions and personnel of the host country.

Ethical and scientific review. Committees in both the country of the sponsoring agency and the host country have responsibility for conducting both scientific and ethical review, as well as the authority to withhold approval of research proposals that fail to meet their scientific or ethical standards. Special responsibilities may be assigned to review committees in the two countries when a sponsor or investigator in a developed country proposes to carry out research in a developing country. When the external sponsor is an international agency the research protocol must be reviewed according to its own independent ethical review procedures and standards.

Committees in the external sponsoring country or international agency have a special responsibility to determine whether the scientific methods are sound and suitable for the aims of the research, whether the drugs, vaccines or devices to be studied meet adequate standards of safety, whether there is sound justification for conducting the research in the host country rather than in the country of the external sponsoring agency, and that the proposed research does not in principle violate the ethical standards of the external sponsoring country or international organization.

Committees in the host country have the special responsibility to determine whether the goals of the research are responsive to the health needs and priorities of the host country. Moreover, because of their better understanding of the culture in which the research is proposed to be carried out, they have special responsibility for assuring the equitable selection of subjects and the acceptability of plans to obtain informed consent, to respect privacy, to maintain confidentiality, and to offer benefits that will not be considered excessive inducements to consent.

In short, ethical review in the external sponsoring country may be limited to ensuring compliance with broadly stated ethical standards, on the understanding that ethical review committees in the host country will have greater competence in reviewing the detailed plans for compliance in view of their better understanding of the cultural and moral values of the population in which the research is proposed to be conducted.

Research designed to develop therapeutic, diagnostic or preventive products. When externally sponsored research is initiated and financed by an industrial sponsor such as a pharmaceutical company, it is in the interest of the host country to require that the research proposal be submitted with the comments of a responsible authority of the initiating country, such as a health administration, research council, or academy of medicine or science.

Externally sponsored research designed to develop a therapeutic, diagnostic or preventive product must be responsive to the health needs of the host country. It should be conducted only in host countries in which the disease or other condition for which the product is indicated is an important problem. As a general rule, the sponsoring agency should agree in advance of the research that any product developed through such research will be made reasonably available to the inhabitants of the host community or country at the completion of successful testing. Exceptions to this general requirement should be justified and agreed to by all concerned parties before the research begins. Consideration should be given to whether the sponsoring agency should agree to maintain in the host country, after the research has been completed, health services and facilities established for purposes of the study.

Obligations of external sponsors. An important secondary objective of externally sponsored collaborative research is to help develop the host country's capacity to carry out similar research projects independently, including their ethical review. Accordingly, external sponsors are expected to employ and, if necessary, train local individuals to function as investigators, research assistants, or data managers or in other similar capacities. When indicated, sponsors should also provide facilities and personnel to make necessary health-care services available to the population from which research subjects are recruited. Although sponsors are not obliged to provide health-care facilities or personnel beyond that which is necessary for the conduct of the research, to do so is morally praiseworthy. However, sponsors have an obligation to ensure that subjects who suffer injury as a consequence of research interventions obtain medical treatment free of charge, and that compensation is provided for death or disability occurring as a consequence of such injury (see Guideline 13 for a statement of the scope and limits of such obligations). Also, sponsors and investigators should refer for health care services subjects or prospective subjects who are found to have diseases unrelated to the research, and should advise prospective subjects who are rejected as research subjects because they do not meet health criteria for admission to the investigation to seek medical care. Sponsors are expected to ensure that research subjects and the communities from which they are recruited are not made worse off as a result of the research (apart from justifiable risks of research interventions) - for example, by the diversion of scarce local resources to research activities. Sponsors may disclose to the proper authorities in the host country information that relates to the health of the country or community, discovered in the course of a study.

External sponsors are expected to provide, as necessary, reasonable amounts of financial, educational and other assistance to enable the host country to develop its own capacity for independent ethical review of research proposals and to form independent and competent scientific and ethical review committees. To avoid conflict of interest, and to assure the independence of committees, such assistance should not be provided directly to the committees; rather funds should be made available to the host-country government or to the host research-institution.

Obligations of sponsors will vary with the circumstances of particular studies and the needs of host countries. The sponsors' obligations in particular studies should be clarified before research is begun. The research protocol should specify what, if any, resources, facilities, assistance and other goods or services will be made available, during and after the research, to the community from which the subjects are drawn and to the host country. The details of these arrangements should be agreed by the sponsor, officials of the host country, other interested parties, and, when relevant, the community from which subjects are to be drawn. The ethical review committee in the host country should determine whether any or all of these details should be made a part of the consent process.

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