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Research, Multinational

RESEARCH, MULTINATIONAL

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The term multinational research refers to biomedical, epidemiological, or social science research that involves investigators and subjects from more than one nation. The type of multinational research that has raised the most ethical concerns is that in which the investigators or sponsors are from an industrialized country and the research is conducted in a developing country (the "host" country). Two chief ethical concerns have dominated this type of research in the past. The first concern is that research subjects in the host country might be vulnerable by virtue of their low educational level or lack of familiarity with modern scientific concepts and, therefore, open to exploitation in some manner. The second concern is that the cultural norms and practices in the industrialized and host countries may differ, leading to the question of which to adhere to when such norms and practices conflict.

More recently, a third ethical concern has become prominent: the level of care and treatment provided to research subjects during a clinical trial. Should it be identical to what subjects in the industrialized, sponsoring country would receive in a similar trial? Or can a lower level of care be justified based on affordability and a less well-developed infrastructure in resource-poor countries? These latter questions have been prompted primarily by HIV/AIDS research conducted in countries in Africa and Asia. A fourth concern has also risen to prominence in recent years: What, if anything, is owed to trial participants, to the community, or to the host country as a whole when a biomedical research project results in a successful product?

Two trends bring concern about biomedical research ethics in a multinational context to the fore. The first is a vast increase in the number of studies conducted in developing countries and sponsored by the pharmaceutical industry or by governmental agencies of industrialized countries (Brennan; U.S. Department of Health and Human Services). The second trend is the growing gap in the burden of disease between industrialized and developing countries, a result in part of the AIDS epidemic but also stemming from the lack of affordable treatments for diseases such as malaria and tuberculosis in resource-poor countries (Michaud, Murray, and Bloom).

Although the chief ethical concerns of the past continue to require vigilance in the ethical review and conduct of multinational research, the two more recent concerns have generated considerable controversy. A clinical trial conducted in Thailand and other developing countries, aimed at finding an affordable and appropriate treatment to prevent the transmission of HIV/AIDS from pregnant women to their infants, led to fierce debates in leading medical and bioethics journals (Angell; Lurie and Wolfe; Varmus and Satcher; Annas and Grodin, 1998; Crouch and Arras; Lie; Schüklenk). The controversy went beyond the debates in academic journals, leading eventually to a prolonged process to revise two of the leading international ethical guidelines for research: the World Medical Association's Declaration of Helsinki and the International Ethical Guidelines for Biomedical Research Involving Human Subjects, prepared by the Council for International Organizations of Medical Sciences (CIOMS) in conjunction with the World Health Organization.

International Research Guidelines and Recommendations

The first international code of ethics for research involving human subjects, the Nuremberg Code, was drafted in 1947 at the Nuremberg Doctors' Trial in response to the atrocities committed by physicians in Nazi Germany in experiments they conducted on inmates of concentration camps (Annas and Grodin, 1992). The purpose of the code was both to acknowledge the importance of research involving human beings and to provide a set of universally applicable rules for protecting human subjects of research from violations of their rights and welfare. The first principle of the Nuremberg Code is: "The voluntary consent of the human subject is absolutely essential." This requires that the subject "be able to exercise free power of choice, without … any element of force, fraud, deceit, duress … or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision." Other principles in the Nuremberg Code require that the proposed research be meaningful and essential, that it be based on prior animal experiments, and that it "avoid all unnecessary physical and mental suffering and injury."

The Declaration of Helsinki, first promulgated by the World Medical Association (WMA) in 1964, with relatively minor revisions in 1975, 1983, 1989, and 1996, adapted and expanded the principles of the Nuremberg Code to apply more readily to clinical research in the medical setting. Until the revision in 2000, the Declaration of Helsinki did not address the special features of research sponsored by industrialized countries and carried out in developing countries. However, the controversy that surrounded the trial to test an affordable drug to prevent maternal-to-child transmission of HIV/AIDS produced a subsequent, related controversy over a provision in the Declaration of Helsinki itself.

Critics of the HIV/AIDS trial in developing countries argued that the trial design was unethical because some of the pregnant women were given a placebo, an inactive substance, thereby withholding from them a treatment proven to be effective in reducing the transmission of HIV/AIDS in the United States. These critics also contended that the trial violated the following provision in the Declaration of Helsinki: "In any medical study, every patient—including those of a control group, if any—should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists" (WMA, II, 3). Whereas critics of the placebo-controlled trials cited the Declaration of Helsinki in support of their contention that the trials were unethical (Lurie and Wolfe), defenders of the trials argued that the Declaration of Helsinki was in need of revision (Levine).

The WMA embarked on a process to revise the declaration, a process that took place over a two-year period and was itself fraught with controversy. In an effort to make the process transparent and democratic, the WMA posted a draft of the revised version on its web site and invited comments. As a consequence of many comments that found the draft unsatisfactory primarily because it weakened the provision requiring that a control group be given "the best proven diagnostic and therapeutic method," the WMA appointed a new drafting committee whose members reinstated the original requirement in slightly different words: "The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists" (WMA, paragraph 29).

The newly revised draft was posted on the WMA web site, once again with an invitation for comments. In October 2000 the WMA adopted the second revised version at its meeting in Edinburgh, Scotland. But that did not end the controversy. A substantial number of influential spokespersons from the research community, the pharmaceutical industry, and U.S. federal agencies that sponsor research objected that adherence to this provision would prevent important research from going forward that could benefit developing countries. In an attempt to compromise between these opposing factions, the WMA issued the following clarification in 2001:

The WMA is concerned that paragraph 29 of the revised Declaration of Helsinki (October 2000) has led to diverse interpretations and possible confusion. It hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

  • Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
  • Where a prophylactic, diagnostic, or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.…

This clarification did not lay the controversy to rest. Defenders of placebo-controlled trials conducted in developing countries would cite what they consider "compelling and scientifically sound methodological reasons" for using placebo controls. Critics of such trials would then question whether the reasons provided were scientifically compelling and would propose instead a trial design comparing the experimental treatment with a treatment currently and widely used in the industrialized country sponsoring the research. The debate appears intractable, with each side comprising researchers, bioethicists, governmental spokespersons, and others from both developing and industrialized countries.

The same controversial clinical trials that prompted revision of the Declaration of Helsinki created a need to undertake a review and revision of the CIOMS International Ethical Guidelines, which were first published in 1993. In part because the CIOMS guidelines were promulgated with the purpose of applying the standards of the Declaration of Helsinki in developing countries, but also because the rapidly increasing amount of multinational research called for a reassessment of the 1993 guidelines, a multistage process was undertaken for the CIOMS revisions.

Predictably, the same debate that arose among defenders and opponents of placebo-controlled trials in the revision of the Declaration of Helsinki surfaced among drafters, members of an appointed steering committee, and commentators who responded to a posting of drafts on the CIOMS web site. The controversial guideline that emerged from this process departs significantly from the strict requirement in the Declaration of Helsinki; it permits clinical trials "in which the comparator is other than the best current intervention, such as placebo or no treatment or a local remedy" (CIOMS, Guideline 11). The justification for withholding the best current intervention is that it "cannot be used as comparator because its use as comparator would not yield scientifically reliable results that would be relevant to the health needs of the study population" (CIOMS, Guideline 11). Critics of this position argue that it is unethical to use placebos when doing so can lead to serious or irreversible harm to subjects in the control group.

Other studies of multinational research were launched at about the same time. The U.S. National Bioethics Advisory Commission (NBAC) launched an international project and in 2001 issued a final report, Ethical and Policy Issues in International Research. This report contains a recommendation on the same controversial point:

Researchers and sponsors should design clinical trials that provide members of any control group with an established effective treatment, whether or not such treatment is available in the host country. Any study that would not provide the control group with an established effective treatment should include a justification for using an alternative design. Ethics review committees must assess the justification provided, including the risks to participants, and the overall ethical acceptability of the research design. (NBAC, Recommendation 2.2)

This recommendation sets up a strong presumption to provide an "established effective treatment" to the control group. But it also contains an escape hatch, allowing the proposal of an alternative trial design, which must be approved by an ethics review committee.

The Nuffield Council on Bioethics in the United Kingdom issued a report on multinational research one year after publication of the NBAC report. The Nuffield report's recommendation on level of care provided to a control group is also less stringent than the requirements in the 2000 Declaration of Helsinki:

Wherever appropriate, participants in the control group should be offered a universal standard of care for the disease being studied. Where it is not appropriate to offer a universal standard of care, the minimum standard of care that should be offered to the control group is the best intervention available for that disease as part of the national public health system. (Nuffield Council, paragraph 7.29)

This unresolved controversy about what should be provided to a control group gives rise to a series of philosophical questions about ethical guidelines: When reasonable people disagree on key provisions, what should be done? Should the controversy be resolved in favor of the position held by the majority? Should it be resolved in favor of the more influential party to the dispute? Or should there be no guideline at all on points of major contention among reasonable persons of good will? On the one hand, if a published ethical guideline is systematically violated, it leads to disrespect for or cynicism about the guidelines as a whole. This is the contention of critics of the paragraph in the Declaration of Helsinki requiring that a control group receive "the best current treatment." On the other hand, if a guideline is published and held by some to be exploitative of research subjects in developing countries, it creates a general skepticism concerning the ethical conduct of multinational research. This is the view of defenders of the paragraph requiring the "best current treatment" for the control group in studies in developing countries.

Understanding the Controversy

Opponents on both sides of this controversy are committed to finding appropriate and affordable diagnostic, prophylactic, and therapeutic methods for populations in developing countries. Both sides believe that to be ethical, research must be responsive to the health needs of the population where the research is conducted. That is where their agreement ends.

The chief difference between the two sides from an ethical perspective concerns the obligation to research subjects enrolled in a clinical trial. A study with the identical design of the maternal-to-child transmission study carried out in Thailand could not have been conducted in the United States for both moral and practical reasons. Morally, women outside the trial in the United States had access to an effective treatment, so they would be made worse off if they participated in the trial. Practically, many would obtain the effective treatment from other sources, undermining the study. In contrast, women in the trials in developing countries had limited or no access to a preventive treatment for their infants outside the trial, so those in the placebo group would not be made worse off by participating in the trial. Defenders of the placebo controls contended that women in the control group received the "standard of care" in their country. Critics argued that they could have been provided with the effective treatment, which could then have been compared to the experimental treatment.

As the Thai studies demonstrate, what appears to be a straightforward debate about obligations to research subjects in a clinical trial turns in part into a debate over research methodology. Defenders of the placebo-controlled trials argue that the research question to be addressed is: "In cases where there is no standard treatment whatsoever, is the experimental treatment better than nothing?" To answer that question, the only appropriate research design is one that uses a placebo control. Moreover, some test placebo against standard treatments in the United States because they can make the case that the treatment may not be any better than placebo and it is important to find that out. Critics of these placebo-controlled trials argue that a different research question is meaningful and could be addressed: "Is the experimental drug as good, or almost as good, as the best current treatment used in the United States?" The first group argues that an answer to the latter question is not responsive to the needs of the developing country. The second group replies that given a large enough number of subjects, the use of appropriate statistical tools, and a research design comparing the experimental and the proven treatments, a research question relevant to the developing country can be formulated and answered.

Thus a resolution to this ethical controversy turns, in part, on a methodological issue in the design and conduct of clinical trials. Because researchers and methodologists can be found on both sides of the debate, there is little hope that this type of controversy can be resolved by rational means unless the risks of harm are low.

Providing Posttrial Benefits in Developing Countries

The 2000 version of the Declaration of Helsinki added two new provisions that were not included in the revision issued only four years earlier. These new paragraphs reflect the widely acknowledged fact that much past research conducted in developing countries failed to produce subsequent benefits to the populations of the countries in which the research was carried out; the benefits of biomedical research typically accrued to the populations in industrialized countries. This imbalance violates the principle of distributive justice, which calls for an equitable distribution of the benefits and burdens of research. Paragraph 19 of the declaration addresses this point: "Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research." And paragraph 30 states: "At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study."

Both of these newly added provisions are a response to criticisms that have been leveled against past research sponsored by industrialized countries or industry in which any resulting benefits of the research have accrued to the sponsoring country but not to the population from which the research subjects were drawn. Paragraph 19 of the 2000 declaration seeks to ensure that research is not carried out on inhabitants of developing countries solely for the benefit of inhabitants of wealthy, industrialized countries. Paragraph 30 seeks to ensure that the sponsoring country or industry does not simply pull out when the study is concluded, abandoning research subjects who still need a treatment that has been demonstrated to be effective.

Although these situations might very well occur when research is conducted wholly within an industrialized country, the lack of access to affordable treatments outside a research study is much more prevalent in resource-poor countries. This has been especially true of medications to treat HIV/AIDS. By the year 2000, virtually all pregnant women in the United States had access to effective treatments to prevent HIV transmission to their infants, but those treatments remained out of reach for most inhabitants of most developing countries (Joint United Nations Programme on HIV/AIDS, 2002). Effective treatments to prevent progression of HIV infection into symptomatic AIDS is also available to large numbers of people in industrialized countries, but here again, only a small minority of people in developing countries can afford the cost of these drugs, which remain too expensive for purchase by the ministries of health, as well. (Brazil has been an exception, as the government made a commitment to provide treatments for HIV/AIDS to its entire infected population.)

The requirement that research be responsive to the health needs of the population of the country in which the research is conducted has been a feature of the CIOMS guidelines, which were promulgated specifically with developing countries in mind. The 2002 revision of the guidelines reiterates a requirement in the 1993 version that the research be responsive to the health needs and priorities of the community in which it is carried out. The 2002 revision goes considerably further than the 1993 version by elevating a key provision to the status of a guideline instead of being relegated to the commentary under a guideline:

Guideline 10: Research in populations and communities with limited resources

Before undertaking research in a population or community with limited resources, the sponsor and the investigator must make every effort to ensure that:

  • the research is responsive to the health needs and the priorities of the population or community in which it is to be carried out; and
  • any intervention or product developed, or knowledge generated, will be made reasonably available for the benefit of that population or community.

Although the term reasonably available has been criticized as being too vague, the guideline nevertheless establishes a presumption for sponsoring countries or industry to seek to ensure access to successful products developed in the course of research conducted in developing countries. The reports of both the NBAC and the Nuffield Council on Bioethics address this issue, but their recommendations permit a failure to ensure access if researchers provide sufficient justification to a research ethics committee.

Preventing Exploitation

The ongoing controversy over what should be provided to a control group and the acceptability of placebo controls, along with the question of posttrial obligations to research subjects, the community, and the country in which the research takes place, have overtaken the main ethical concerns of the past regarding multinational research. Yet those past concerns have not disappeared. The need to prevent exploitation of research subjects is an ethical requirement everywhere, but it becomes more problematic in settings where subjects are illiterate or semiliterate, and where they are unfamiliar with the concepts of modern science as well as the purpose and conduct of biomedical research. Two mechanisms exist to aid in protecting research subjects from violations of their rights and welfare: prior ethical review of research protocols by an independent committee; and an adequate process for obtaining voluntary, informed consent from individual subjects. Problem exist with regard to the effectiveness of both of these mechanisms in developing countries.

PRIOR ETHICAL REVIEW. The first and most obvious shortcoming is the absence of ethical review committees in many developing countries and in the institutions within those countries (such committees are termed institutional review boards [IRBs] in the United States, research ethics boards [REBs] in Canada, and other names elsewhere). Even where such committees exist, they may be newly established and therefore inexperienced. Even committees that are not recently established may lack adequate education and training for their members. Or they may be staffed with researchers or institutional officials who have a conflict of interest regarding the research to be reviewed. In the poorest countries, institutions lack the resources to make photocopies of the protocols to be reviewed by all the members, and time spent on committee work means loss of income from clinical work for which they would otherwise be paid.

Recent guidelines and reports acknowledge these shortcomings and propose that they be remedied through efforts to build capacity for local or national ethical review in developing countries. For example, a guidance document issued by the Joint United Nations Programme on HIV/AIDS (UNAIDS) contains the following point, titled "Capacity building": "Strategies should be implemented to build capacity in host countries and communities so that they can practise meaningful self-determination in vaccine development, can ensure the scientific and ethical conduct of vaccine development, and can function as equal partners with sponsors and others in a collaborative process" (UNAIDS, p. 15). Although the guideline specifically addresses vaccine research, a similar point appears in many other documents.

The revised version of the CIOMS guidelines issued in 2002 elevates to the level of a guideline the obligation of sponsors of research to engage in building capacity for ethical review (in the 1993 CIOMS guidelines, the obligation appeared under a commentary):

Guideline 20: Strengthening capacity for ethical and scientific review and biomedical research

Many countries lack the capacity to assess or ensure the scientific quality or ethical acceptability of biomedical research proposed or carried out in their jurisdictions. In externally sponsored collaborative research, sponsors and investigators have an ethical obligation to ensure that biomedical research projects for which they are responsible in such countries contribute effectively to national or local capacity to design and conduct biomedical research, and to provide scientific and ethical review and monitoring of such research.

The obligation of sponsoring countries and agencies to build capacity for ethical review of research is included as a recommendation in both the NBAC and Nuffield reports. The NBAC report states:

Recommendation 5.7: Where applicable, U.S. sponsors and researchers should assist in building the capacity of ethics review committees in developing countries to conduct scientific and ethical review of international collaborative research.

INFORMED CONSENT. The second mechanism designed to prevent exploitation of research subjects is the requirement for voluntary, informed consent from each prospective research subject. All ethical guidelines for research include this requirement, which can pose special problems in multi-national research in countries in which customs, traditions, and even the concept of a person vary considerably from those that predominate in the North America and Europe. In some developing countries a substantial portion of the population is illiterate or semiliterate. It is clear that the practice of requiring written, signed consent documents when the research subjects are illiterate is inappropriate. For semiliterate subjects, a written consent document may be appropriate, especially because family members whom the subject may wish to involve in the consent process may be literate.

It is important to distinguish between the requirement that a written document be provided to a prospective subject and the requirement that the subject sign the document. In some countries, the meaning of signing a document is quite different from what it is in North America or Western Europe. Even when the need for individual, informed consent is fully accepted, if the country has a history of oppressive regimes, or if people are fearful, based on their experience, that a signed document might be used against them in some manner, it is appropriate for the research ethics committee to waive the requirement of a signature on a consent document (NBAC).

One challenge for researchers who conduct clinical trials in developing countries is how to deal with practices that depart from the requirements of informed consent in the United States and other industrialized countries. These practices include withholding diagnoses from patients who become research subjects (Sugarman et al.; Kass and Hyder) and not disclosing key elements that comply with the substantive ethical standard of informed consent, such as the use of placebo controls, the process of randomizing subjects into different groups in a clinical trial, and the expected efficacy (or lack of efficacy) of a method being tested (Sugarman et al.). Even if the custom of routinely withholding complete information from patients with certain diseases might be defended in ordinary medical practice, it poses a severe challenge to the need to adhere strictly to the ethical standard of disclosure required for research involving human subjects. Potential subjects cannot make an informed decision to participate without knowing that they may not receive a proven treatment that will benefit them. To enroll individuals who are not provided with these key items of information deviates from the substantive ethical standard of disclosure required for adequate informed consent.

A different problem arises when research subjects are unacquainted with the concepts and methods of modern science or biomedical research. These problems are addressed in NBAC's 2001 report, Ethical and Policy Issues in International Research, which contains several recommendations on informed consent. Recommendation 3.2 urges researchers to seek creative ways of presenting information, for example, by means of analogies readily understood by the population:

Researchers should develop culturally appropriate ways to disclose information that is necessary for adherence to the substantive ethical standard of informed consent, with particular attention to disclosures relating to diagnosis and risk, research design, and possible post-trial benefits. Researchers should describe in their protocols and justify to the ethics review committee(s) the procedures they plan to use for disclosing such information to participants. (NBAC, p. 40)

It is not sufficient simply to present the information. An important component of the process is determining whether the prospective subjects adequately understand what they have been told. To this end, NBAC has two recommendations:

Recommendation 3.4: Researchers should develop procedures to ensure that potential participants do, in fact, understand the information provided in the consent process and should describe those procedures in their research protocols.

and

Recommendation 3.5: Researchers should consult with community representatives to develop innovative and effective means to communicate all necessary information in a manner that is understandable to potential participants. When community representatives will not be involved, the protocol presented to the ethics review committee should justify why such involvement is not possible or relevant. (NBAC, p. 42)

Some have considered it problematic in cross-cultural contexts to require that informed consent be obtained from each individual recruited as a research subject. This has been described as "philosophically and practically difficult" (Christakis and Levine, p. 1783). The problem is characterized as one in which some cultures lack the individualistic concept of a person to which the Western world adheres, so the question of how to apply the respect for persons principle becomes problematic. Debate on this point is illustrated in the following two positions.

The first holds that researchers should adhere to local customs and traditions regarding individual informed consent, and that it is ethical imperialism to insist on Western requirements in other cultures (Newton). The second maintains the opposite view that individual informed consent is a requirement that should not be eliminated or altered: "We see no convincing arguments for a general policy of dispensing with, or substantially modifying, the researcher's obligation to obtain first-person consent in biomedical research conducted in Africa" (IJsselmuiden and Faden, p. 883).

The Nuffield Council on Bioethics report addresses the tension between respect for culture and respect for persons:

[W]e cannot avoid the responsibility of taking a view when the two aspects of respect—respect for culture and respect for persons—come into conflict with one another. We are of the view that the fundamental principle of respect for persons requires that participants who have the capacity to consent to research should never be subjected to research without such consent. (Nuffield Council, paragraph 6.22)

Those who would subordinate the respect for persons principle to other considerations have not identified a competing ethical principle that deserves a higher ranking. The unstated assumption that respect for cultural tradition may outrank respect for persons construes respect for cultural tradition as an ethical principle on a par with the following three widely acknowledged principles: respect for persons, beneficence, and justice (National Commission). Although an ethical obligation to be culturally sensitive should be honored, a limit is reached when a cultural practice violates an internationally accepted principle of research ethics.

A different sort of problem arises when it is necessary to obtain permission from a community leader or tribal chief in order to enter the community to embark on research. That requirement has to be respected, but it is no different, in principle, from the need in Western culture to obtain permission from the head of a workplace or a school principal to enter the premises to conduct research. Permission from a tribal chief or village leader may be required but should not serve as a substitute for individual informed consent obtained from each potential subject. The NBAC report contains the following recommendation:

Where culture or custom requires that permission of a community representative be granted before researchers may approach potential research participants, researchers should be sensitive to such local requirements. However, in no case may permission from a community representative or council replace the requirement of a competent individual's voluntary informed consent. (NBAC, p. 43)

Considerably more problematic is the need to obtain individual informed consent from women in cultures in which the husband or father of an adult woman normally grants permission for her participation in activities outside the home. NBAC's recommendation on this point calls for a presumption to treat men and woman equally in the informed-consent process but allows for a loophole:

Researchers should use the same procedures in the informed-consent process for women and men. However, ethics review committees may accept a consent process in which a woman's individual consent to participate in research is supplemented by permission from a man if all of the following conditions are met:

a. it would be impossible to conduct the research without obtaining such supplemental permission; and

b. failure to conduct this research could deny its potential benefits to women in the host country; and

c. measures to respect the woman's autonomy to consent to research are undertaken to the greatest extent possible.

In no case may a competent adult woman be enrolled in research solely upon the consent of another person; her individual consent is always required. (NBAC, p. 45)

Here, as in other recommendations, NBAC leaves the ultimate decision on controversial matters to the discretion of the ethics review committee. The Nuffield Council's recommendation on this point is also somewhat flexible.

Unlike the NBAC and Nuffield recommendations, the CIOMS 2002 guidelines do not permit a departure from the need to obtain individual informed consent from the woman only. The commentary under Guideline 16 states:

[O]nly the informed consent of the woman herself is required for her participation. In no case should the permission of a spouse or partner replace the requirement of individual informed consent. If women wish to consult with their husbands or partners or seek voluntarily to obtain their permission before deciding to enroll in research, that is not only ethically permissible but in some contexts highly desirable. A strict requirement of authorization of spouse or partner, however, violates the substantive principle of respect for persons.

In this, as in other areas of multinational research, what some people take to be ethical imperialism, others consider proper adherence to universally applicable ethical standards.

INDUCEMENTS. In avoiding exploitation when research is conducted in developing countries, there are two important considerations: whether inducements are offered for participation and whether such inducements are undue, that is, so attractive as to diminish voluntariness on the part of subjects who are invited to enroll. When medical treatment is an inevitable part or accompaniment of clinical research, this may provide a strong inducement to enrollment for people without access to medical care. The Nuffield Council report noted that this need not amount to exploitation. The report stated, however, that "when participants are ill and do not have alternative ways of receiving treatment, the possibility for exploitation is greater" (Nuffield Council, paragraph6.29). The report urged that special care should be taken in determining the type and amount of additional healthcare that may be offered to participants as an inducement.

The NBAC report addresses this concern, distinguishing between, on the one hand, an inducement that may exist because participants receive beneficial clinical care and, on the other hand, the different circumstance that arises out of the "therapeutic misconception"—the belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data for the purpose of contributing to scientific knowledge. This misconception is widespread even among research subjects in industrialized countries and may be considerably greater in developing countries where people are unfamiliar with scientific research and view medical researchers as healers in whom they place great trust. The NBAC report recommends the following: "Researchers working in developing countries should indicate in their research protocols how they would minimize the likelihood that potential participants will believe mistakenly that the purpose of the research is solely to administer treatment rather than to contribute to scientific knowledge" (NBAC, p. 48).

Guideline 7 of the 2002 CIOMS document permits both monetary payments to subjects as an inducement to participate in research and the provision of free medical services. CIOMS cautions that the monetary payments should not be so great or the medical services so extensive that they induce people to participate against their better judgment. Any payments or provision of medical services should be approved by an ethical review committee.

Crossing National Boundaries: Ethical Standards and Procedural Variations

Different views exist regarding how conflicts between Western cultural conceptions and norms and those of non-Western cultures should be resolved. This raises the question of how ethical standards should be arrived at and whose standards should be adopted. The 1993 CIOMS guidelines included in Guideline 15 a provision intended to prevent exploitation, titled "Obligations of sponsoring and host countries" in externally sponsored research. This guideline required scientific and ethical review of proposed research "according to the standards of the country of the sponsoring agency, and the ethical standards applied should be no less exacting than they would be in the case of research carried out in that country." This provision prompted the criticism that the guidelines reflected a "Western bias" because of "the assumption that the circumstances … in the developed world are the norm. Thus, the developed world is envisioned as more advanced, not only technologically but also morally" (Christakis and Levine, p. 1781).

This criticism is not shared by the many developing countries that by 2002 had enacted laws or adopted ethical guidelines governing research (NBAC). Most provisions in these regulations and guidelines replicate the CIOMS guidelines and the Declaration of Helsinki. All require that informed consent be obtained from each individual research subject, yet, as outlined in these regulations and guidelines, certain procedures for obtaining consent may diverge from the requirement for written, signed informed-consent forms that is included in the U.S. regulations.

Guidelines issued by the Medical Research Council of South Africa in 1993 include two rules regarding informed consent: (1) research subjects should know that they are taking part in research; and (2) research involving subjects should be carried out only with their consent. Yet these guidelines also say: "It can be proper for research involving less than minimal risk and which is easily comprehended to proceed on the basis of oral consent given after an oral description of what is involved." Similarly, the guidelines issued in 2000 by the Indian Council of Medical Research require that informed consent be obtained from each individual subject. But the guidelines also say that the nature and form of the consent may depend on a number of different factors.

The NBAC international report (2001) makes a useful distinction between substantive and procedural ethical requirement in research. Substantive ethical requirements are those embodied in the fundamental principles of bioethics stated in the Belmont Report: respect for persons, beneficence, and justice (National Commission). These substantive requirements are the ones that constitute ethical standards, and they should be applied universally. Examples are the requirement to obtain informed consent individually from each adult participant and the need to disclose complete information about the research maneuvers to be performed and the expected risks of those interventions. Procedural requirements, on the other hand, may vary according to cultural and other differences in multinational research. Examples include the requirement that informed-consent documents be signed, and the composition of ethical review committees and their rules of procedure. Attention to the distinction between substantive and procedural ethical requirements shows that the same ethical standards can be applied across national borders, while permitting differences in specific procedures in order to respect cultural variations.

Ethical codes and international guidelines are not likely to resolve all questions or conflicts that may arise in proposing, reviewing, and conducting multinational research. Any differences in judgments made by two or more committees that review a research protocol will have to be negotiated. On some points, codes and guidelines may be insufficiently specific. In other respects, provisions in codes or guidelines that address the same point may vary in minor or even major respects. An example of an unresolved conflict is the difference in existing guidelines and recommendations on the use of placebo controls and the level of care and treatment to be provided to research subjects during and after a clinical trial. As long as unresolved differences remain among parties committed to conducting such research according to the highest ethical standards, it is open to question whether ethical codes or guidelines should attempt to settle the conflict by imposing an unequivocal rule.

nicholas a. christakis

robert j. levine (1995)

revised by ruth macklin

SEE ALSO: AIDS: Healthcare and Research Issues; Anthropology and Bioethics; Epidemics; Human Rights; Informed Consent: Consent Issues in Human Research; International Health; Patenting Organisms and Basic Research; Pharmaceutical Industry; Placebo; Research, Human: Historical Aspects; Research Policy; Scientific Publishing

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INTERNET RESOURCES

Council for International Organizations of Medical Sciences (CIOMS), in collaboration with the World Health Organization. 2002. International Ethical Guidelines for Biomedical Research Involving Human Subjects, revised edition. Available from <http://www.cioms.ch>.

Indian Council of Medical Research. 2000. Ethical Guidelines for Biomedical Research on Human Subjects. Available from <http://icmr.nic.in/ethical.pdf>.

Joint United Nations Programme on HIV/AIDS (UNAIDS). 2000. Ethical Considerations in HIV Preventive Vaccine Research: UNAIDS Guidance Document. Available from <http://www.unaids.org/publications/documents/vaccines/>.

Nuffield Council on Bioethics. 2002. "The Ethics of Research Related to Healthcare in Developing Countries." Available from <http://www.nuffieldbioethics.org/developingcountries/>.

South Africa. Medical Research Council. 1993. "Guidelines on Ethics for Medical Research," revised edition. Available from <http://www.mrc.ac.za/ethics/consent.htm>.

U.S. Department of Health and Human Services. Office of Inspector General. 2001. "The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects." Available from <http://oig.hhs.gov/oei/>.

U.S. National Bioethics Advisory Commission (NBAC). 2001. Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. Available from <http://bioethics.georgetown.edu/nbac/pubs.html>.

World Medical Association (WMA). 2000. "Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects." Available from <http://www.wma.net/e/policy/17-c_e.html>.

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