The requirement  for  freely  given  and  informed consent to participate in research reflects important substantive ethical principles, including respect for persons, human dignity, and autonomy. However, it is possible to respect persons and their dignity or autonomy and affirm the requirement to obtain voluntary informed consent and at the same time allow for the modification of the procedures that are involved in obtaining consent, such as those stipulated in the Federal Policy for the Protection of Human Subjects, known as the Common Rule (45 CFR 46.117(c)).²

    Despite the ethical centrality of voluntary informed consent and its underlying principles, problems of inter-pretation and application exist for researchers and ethics review committees in both developed and developing countries. Some problems regarding informed consent are particularly difficult when the host country has little experience with clinical trials and has markedly different cultural values and ethical commitments than the United States. It is important, therefore, for U.S. sponsors of international research to address pressing issues concerning  the  application  of  U.S.  research  regulations  for informed consent in settings with different cultures and customs.

   This chapter addresses a number of related topics, including the following:

• whether cultural factors create a barrier to complying with the substantive ethical standard of informed consent and whether it is permissible to depart from that standard if the research could not otherwise becarried out;
• how investigators obtain voluntary informed consent in settings in which the belief system of potential research participants does not explain health and disease using the concepts and terms of modern medical science and technology;
• how voluntary participation can be ensured in settings in which community leaders may exert pressure on the entire community to enroll in a proposed clinical trial;
• how cultural differences can be addressed between the United States and other countries that make it difficult or impossible for other countries to adhere to U.S. federal regulations stipulating specific procedures for obtaining voluntary informed consent; and
• the means by which the United States could modify its informed consent regulations to adapt to various cultural  circumstances  in  other  countries  without compromising  the  substantive  ethical  standard  of informed consent.

Although individual voluntary informed consent by competent adults is a widely accepted standard in most research environments, it is not universally embraced.

Nonetheless, the National Bioethics Advisory Commission (NBAC)  remains  convinced  that  U.S.  sponsors  ofresearch in developing countries should adhere to internationally agreed-upon ethical standards of voluntary informed consent for research, even in the face of cultural diversity. Obtaining adequately informed voluntary consent from individual research participants is a necessary requirement in preventing exploitation, and it should be possible to remain sensitive to cultural differences without departing from these standards.

    The justification for the need for obtaining informed voluntary consent is simple: The use of human beings as a means to the ends of others without their knowledge and freely granted permission constitutes exploitation and is therefore unethical. NBAC recognizes, however, that disagreement still exists about this claim. One commentator has argued that "[i]t is `ethical imperialism' at its worst to assume that the informed consent requirement,which does indeed serve one (only one) moral principlein the Western setting, is in itself such a universal ethicalstandard" (Newton 1990, 11). This same commentator contends that growing doubt surrounds the values of individualism and individual rights, so "the investigator might better stick to the research, and accept the local assessment as to adequate protection of individual rights" (Newton 1990, 11). 

   Two other commentators, Ijsselmuiden and Faden, take an opposing view: "Appeals to cultural sensitivity... are no substitute for careful moral analysis. 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"  (1992, 833).  They  add  that defenders of such a policy "have relied on limited and often dated anthropologic literature that does not reflect the rapid cultural changes brought about by colonialism and independence, warfare, and urbanization" (1992, 833).

   The  recommendations  developed  in  this  chapter focus on three traditional elements of informed consent (Faden and Beauchamp 1986): 1) disclosing information to  potential  research  participants  (see  Exhibit  3.1);  2) ascertaining their understanding of what has been disclosed; and 3) ensuring that their agreement to participate in research is voluntary. The basic elements of disclosure in the informed consent process as presented in the Federal Policy for the Protection of Human Subjects are listed in Exhibit 3.1. References in this chapter to the basic elements of disclosure in informed consent are to these eight requirements.

Various descriptions of the process and nature of informed consent can be found in the Common Rule (45 CFR 46.116 and  46.117),  Food  and  Drug  Administration  (FDA) regulations (21 CFR 56), the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS 1993), the International Conference on Harmonisation (ICH) ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice (GCP) (ICH 1996), and the World Medical Association's (WMA) Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (WMA 1964, as amended in 1996 and again in 2000). Principle 9 of the 1996 revision of the Declaration of Helsinki states that "[i]n any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the subject's freely given informed consent, preferably in writing" (WMA 1964, as amended in 1996). In the October 2000 revised Declaration of Helsinki, Principle 22 addresses the informed consent process, stating that:  

[I]n any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician National Bioethics Advisory Commission should then obtain the subject's freely given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed (WMA 1964, as amended in 2000).

   Substantive changes between the 1996 and 2000 revisions of the Declaration include 1) informing each potential subject about any possible conflicts of interest and the institutional affiliations of the researcher; 2) ensuring that research participants have understood the information presented to them; and 3) requiring that if the consent cannot be obtained in writing, the nonwritten consent must be formally documented and witnessed.

   For this report, NBAC adopts, as the clearest and most appropriate guides for discussion, the following definitions of informed consent and the substantive standard of informed consent: Informed consent is a process by which an individual voluntarily expresses his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the decision to participate. This definition is adopted from the ICH Guideline for Good Clinical Practice, GCP Guideline 1.28 (ICH 1996). An important feature of this definition is that it focuses on the process of obtaining consent rather than on the documentation of that process using, for example, a written, signed, and dated form. 

   In an ethically sound consent process, a member of the research team provides information to the potential participant, determines that the individual understands the information provided, and ensures that the individual voluntarily agrees to participate. Although consent traditionally has been documented by the signing of a consent form, other methods of documentation often are acceptable or even preferable, such as oral consent with a witness signature. In many settings, it is also required that the person obtaining the consent sign the consent form or other related documents and that a witness (or person  designated  by  the  participant)  attests  to  the process. It is always essential to make a distinction between the consent document and the consent process and to not allow the document itself to constitute the process.

   The phrase substantive standard of informed consent refers to the requirement to obtain voluntary informed consent  and  reflects  the  principle  that  competent individuals are entitled to choose freely whether to participate in research. This definition was adopted from  the  CIOMS  International  Ethical  Guidelines  for Biomedical Research Involving Human Subjects, Guideline 1, Commentary, para. 2 (CIOMS 1993, 13). In general, voluntary informed consent protects the individual's freedom of choice, respects his or her personhood, dignity, and autonomy, and reduces the chances of exploitation.

   Objections to this substantive ethical standard are rarely, if ever, voiced, even in parts of the world in which less cultural emphasis is placed on individual rights and freedom of choice than is common in Western and most developed countries. However, various objections often arise about the need for certain procedures for obtaining and  documenting  informed  consent,  including  those stipulated in U.S. research regulations and other documents, such as the ICH Guideline for Good Clinical Practice. As noted, it is important to distinguish substantive ethical principles and standards from the procedures that implement them. Although procedures are important, they often can be modified without compromising ethical principles or standards. Examples of procedural aspects of the informed consent process and its documentation include the following requirements: the informed consent documents should be in writing and signed by the research participant; the consent form should be signed by the person obtaining consent or by the principal investigator; and there should be a witness to the signing of consent forms. Other examples of procedures that are not always central to meeting the substantive ethical principles and standards of voluntary informed consent are involving family members in the consent process or obtaining  a  community  leader's  permission  before approaching individuals in the community. Although it is necessary—and not always easy—to determine which procedural  aspects  are  ethically  required  and  which might  be  altered  or  waived  altogether,  procedural requirements should be viewed as less fundamental than matters of substantive ethical standards or principles.

Recommendation 3.1: Research should not deviate from the substantive ethical standard of voluntary informed consent. Researchers should not propose, sponsors should not support, and ethics review committees should not approve research that deviates from this substantive ethical standard.

   In some parts of the world, it is still customary for physicians  to  withhold  certain  information  from patients.³ Clinicians often provide diagnoses (as well as prognoses)  of  cancer  or  other  serious  conditions  to family members, but they withhold such information from patients. As a result, the patient's consent to certain procedures, if sought, may not be fully informed. Jeremy Sugarman and his colleagues noted in their report to NBAC  that  "[i]n  one  country,  complete  information about medical diagnoses and prognoses are withheld routinely from patients with certain diseases, such as cancer. Consequently, valid informed consent (for either treatment or research participation) can be difficult or impossible."⁴

   Nancy Kass and Adnan Hyder describe a similar situation in their study for NBAC: "...in some developing country settings, a diagnosis of cancer would never be revealed directly to the patient but rather to members of the  patient's  family."⁵  Although  this  observation  was made in reference to clinical care, these cultural practices are relevant to research participants, who may have similar expectations. Similarly, different cultures have different attitudes toward the disclosure of risks in the clinical context, and some researchers believe that it is not always appropriate to disclose to patients the full ramifications of their situation.

   In  another  study  conducted  for  NBAC,  Nigerian researchers indicated that consent documents attached to certain  research  protocols  included  information  that potential participants might find extraneous, irrelevant, or culturally inappropriate. These researchers called particular attention to the emphasis placed on explaining the potential risks to study participants, noting that in the United States, there is much greater interest in communicating the possibility of harm to research participants than there is in Nigeria. One physician noted that, given Nigerian cultural norms, disclosing all possible risks would unnecessarily alarm potential research participants  associated  with  the  research.⁶  Based  on  such observations, some people believe that, at least in some cultures, it would be impossible to enroll research participants by adhering to the basic elements of disclosure as presented in 45 CFR 46.116(a).

    NBAC believes that cultural standards regarding the inappropriateness of providing diagnoses and prognoses to patients or research participants do not justify deviation from the substantive ethical standard of informed consent in research. Even if the custom of routinely withholding complete information about diagnoses and prognoses from patients with certain diseases could be defended in ordinary medical practice, it poses a severe challenge to the need to adhere to the substantive ethical standard of disclosure required for research involving human participants. Those who lack information about their diagnosis and prognosis cannot be expected to understand the purpose of the research, any potential direct benefits, the risks of not participating, or the alternatives to participation. Similarly, potential participants cannot make an informed decision to participate without knowing that they may not receive a proven treatment that could be beneficial. Enrolling individuals in research who are not given the opportunity to understand such important information represents a deviation from the substantive ethical standard of disclosure required for adequate informed consent and should not be permitted. Diversity in the practice of disclosing information in the clinical context does not alter the requirements for such disclosure in the research context.

   These matters must be studied in more detail to learn about how cultural variations affect the meaning and effectiveness of the consent process and the use of particular consent documents. It is critical that we find innovative  and  culturally  responsive  ways  to  disclose information to potential participants. NBAC heard testimony from U.S. and developing country researchers who have  succeeded  in  adhering  to  this  standard,⁷ even though doing so often takes more time and effort than researchers typically expend in the informed consent process. Even in cultures in which a diagnosis of serious illness is not normally revealed in the treatment context, researchers often can find ways to overcome this barrier to disclosure in the research setting.

   Although the Commission recognizes the challenges raised by these cultural differences in practicing medicine and obtaining consent, it does not believe that these challenges provide adequate justification for foregoing the requirement to make disclosures about alternative therapies  that  are  available  to  potential  participants should they choose not to enter a clinical trial.

Recommendation 3.2: 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 todiagnosis 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 fordisclosing such information to participants.

Recommendation 3.3: Ethics review committees should require that researchers include in theinformed consent process and consent documents information about what benefits, if any, will be available to research participants when their participation in the study in question has ended.

   In  some  cultures,  the  belief  system  of  potential research participants does not explain health and disease using the concepts and terms of modern medical science and technology. This is significant, because when people do not understand or accept scientific explanations of health and disease, the challenge of obtaining informed consent can be daunting.⁹ Patricia Marshall's report to NBAC quotes one physician as follows: "...[W]hat I worry about is whether we are really informing them. We are talking to a society that does not believe in the germtheory  of  disease  so  it's  difficult  to  explain."  The researcher provided an example of the pervasive belief that a person's death is a result of sorcery rather than a lethal infection.¹⁰ In noting that he had encountered a cultural belief that spirits cause epilepsy, Alfred Sommer, Dean of the Johns Hopkins University School of Hygiene  nd Public Health, told NBAC that "we do not want to fight a belief system. We simply say we have this pill. We believe it is safe. We think it may reduce the recurrence of the following thing. We would like you to take it."¹¹

   Despite this potential barrier to adequate understanding, if they are willing to devote the time and effort to do so, researchers often are able to devise creative measures for overcoming these barriers. An example appears in the Kass/Hyder report for NBAC: "...the concept of immunology, an immune response, that there's something in your blood that's going to attack bacteria and viruses which you also don't have a concept for....[H]ow much can someone really focus on the consent form when they have this whole new idea that there's this battle going on in their bloodstream?...When we go and translate, we try to use, for example, immune cells, we talk about people who guard houses...it's a particular kind of watchman. So you have a particular kind of watchman in your blood...."¹² Even in countries with very low literacy rates (e.g., 30 percent for men and 10 percent for women in Senegal), one group found that "widespread illiteracy is not a barrier to comprehension, especially since informed consent is more an interactive process than one that depends on reading" (Preziosi et al. 1997, 372). However, the authors of this study concluded that understanding abstract scientific concepts, such as double blinding and randomization, could be difficult.  To  help  explain  these  complex  issues, researchers used terms and concepts that were understandable to the community involved: "To illustrate the principle of randomization and the possibility that one of the vaccines might fail, the presenters used a familiar agricultural example: the evaluation of fertilizers or of seed varieties on randomized plots, a procedure familiar to farmers in the area" (Preziosi et al. 1997, 370).

   Another illustration emphasizes the importance of educating  individuals  and  the  community  about  the study  and  its  specific  purpose  and  procedures. Investigators  and  research  assistants  interviewed  by Marshall noted that education should begin at the community level. "You approach some person as a contact person...you often start with the local governance...we need to obtain permission from them and we need their help to get to community leaders...they need to work with community leaders...we spend time discussing [thestudy]...you have to explain [it] fully."¹³ Researchers may find, for example, that, in circumstances where they do not speak the local language, the use of intermediaries can be an effective means of ensuring adequate understanding among potential participants.

    In some countries, a process of community education acts as a precursor to the process of obtaining individual consent.  For  example,  one  study  reported  that  in Senegal, the field staff and physicians held meetings in each village to provide information about a study of a new pertussis vaccine and to obtain consensus about its use. A physician then provided additional information and sought individual informed consent at the monthly vaccination session. A clinical trial for vaccination against Haemophilus influenzae type b in The Gambia was preceded  by  an  intensive  publicity  campaign  involving radio, newspapers, and discussions with village leaders (Leach et al. 1999). When mothers attended the first child health clinic, they received an information sheet about the clinical trial to take home for discussion with their families. When a mother returned for the first vaccination, the trial worker explained the study again, and, if the mother gave oral consent, the trial worker signed the information sheet.

   Translation and back translation of a written consent form may be one way of ensuring that information is correctly disclosed; however, this may not always be effective. Jean Pape, a researcher from Haiti, who is also on the Cornell University faculty, described the complexity of this process.¹⁴ In preparing to begin HIV vaccine trials in Haiti, his research group needed approval from its own IRB in Haiti, as well as from the IRB at Vanderbilt University—one of the collaborators—and from the IRB at Cornell University Medical School. To be understandable to participants, the consent form had to be in the Creole language. Yet, the document also had to be in French, the language of the Haitian researchers. Because the consent form had to be reviewed by the Cornell IRB, a translation in English was also required. Pape said that the back translation of a consent form "does not guarantee that volunteers have really understood the objective of the study, the risks and advantages, and their voluntary  participation,"¹⁵  a  difficulty reported  in  another study in Nigeria.¹⁶

   NBAC also heard about the desirability of testing research participants to understand whether and how much they understood regarding the informed consent process.¹⁷ Pape described the process he regularly undertakes to ensure understanding. This process includes a person who counsels potential participants about all aspects of the project, helps to develop a test questionnaire that all potential participants must pass before being given the actual consent form, and is available to address participants' concerns and questions. The period before  obtaining  ethical  clearance  from  the  various review committees is used to counsel and inform potential volunteers, who should pass this test of understanding before receiving a simpler informed consent form.¹⁸ These mechanisms—the counseling sessions and test questionnaires—illustrate some of the ways in which informed consent can and should be a process that takes place over time and that is much more than the mere signing of a document that may be imperfectly comprehended. Despite the acknowledged difficulties of administering tests of understanding, NBAC supports the idea of incorporating these tests into research protocols.

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.

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.

   The need to obtain permission from a community leader before approaching individuals does not need to compromise the ethical standard requiring an individual's voluntary informed consent to participate in research. Gaining permission from a community leader is no different,  in  many  circumstances,  from  the  common requirement in this country of obtaining permission from a school principal before involving pupils in research, from a nursing home director before approaching individual residents, or from a workplace supervisor before initiating an experimental screening program. An ethical problem arises only when the community leader exerts pressure on the community in a way that compromises the voluntariness of individual consent. The reports commissioned by NBAC describe a number of situations in which community leaders have been involved in the informed consent process. (See Exhibit 3.2.)

   Nevertheless, recruitment procedures in some cultures involve community leaders whose authority does not allow individual members of the community to refuse to participate in research for which the leader has National Bioethics Advisory Commission granted permission. Also, in some settings, authoritarian governments may limit autonomous decisionmaking by their citizens, which may affect their participation inresearch.²⁷ The question then arises regarding whether there  are  some  countries  in  which  U.S.  researchers should not engage in international collaborative research. In NBAC's view, if a country's political system or a local situation makes it impossible for individuals' consent to be voluntary and that fact is known in advance, then, because U.S. researchers cannot adhere to the substantive ethical standard of informed consent, it would be inappropriate for them to choose such settings.

Recommendation 3.6: 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.

Recommendation 3.7: Researchers should strive to ensure that individuals agree to participate in research without coercion or undue inducements from community leaders or representatives.

   Researchers in other countries also have reported on their efforts to involve the family in the informed consent process in ways that do not undermine the standard of individual consent. Marshall reported, for example, that in Nigeria in areas where traditional cultural norms are strong, the permission of a woman's husband might be required before she can enroll in research. A Nigerian physician involved in a breast cancer study noted that cancer patients often need the approval of their husbands to participate in research. However, the physician also emphasized that in such cases, the woman's individual consent is still essential. Indeed, most investigators have developed strategies that accommodate and encourage discussion  regarding  study  participation  with  family members.²⁹

    NBAC recognizes that this situation does not apply in cases in which a family member lacks the capacity to give  informed consent. Indeed, there is consensus that having the capacity to decide is an important precondition (or threshold element) for informed consent (Beauchamp and Childress 1994; NBAC 1998).

   In many cases, family members may be approached before asking an individual directly to participate in a research project. However, seeking permission from family members without engaging the potential research participants at all clearly departs from the ethical standard of informed consent. On the other hand, potential participants might also choose to involve others, such as family members,  in  the  consent  process.  Indeed,  involving family or community members in the informed consent process need not diminish, and might even enhance, the individual's ability to make his or her choices and to give informed consent (or refusal).

   These examples show that it is often possible to obtain individual informed consent, which may require and indeed benefit from the involvement of family or community members, while at the same time preserving cultural norms. Such involvement ranges from providing written information sheets for potential participants to take home and discuss with family members to holding community meetings during which information is presented about the research and community consensus is obtained.  When  the  potential  participant  wishes  to involve family members in the consent discussion, the researcher should take appropriate steps to accommodate this desire.

Recommendation 3.8: When a potential research participant wishes to involve family members in the consent process, the researcher should take appropriate steps to accommodate this wish. In nocase, however, may a family member's permission replace the requirement of a competent individual's voluntary informed consent.

   Much research is directed at conditions that affect both women and men. Yet, it is important not to neglect research  on  diseases  or  conditions  that  affect  only women. In reality, without involving the husband in the consent procedures, it may be impossible to conduct some research on common and serious health problems that affect only women. In such cases, a likely consequence would be a lack of knowledge on which to base health care decisions for women in that country. The prospect of denying such a substantial benefit to all women in a particular culture or country calls for a narrow exception to the requirement that researchers use the same procedures in the consent process for women as for men, one that would allow for obtaining the permission of a man in addition to the woman's consent. 

Recommendation 3.9: 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.

   Other aspects of research design that may pose a problem of undue influence have received considerably less  attention.  As  the  CIOMS  Guidelines  document acknowledges: "It may be difficult to distinguish between suitable recompense and undue influence to participate in research....Someone without access to medical care may be unduly influenced to participate in research simply to receive such care" (CIOMS 1993, 19). This situation is likely to exist in developing countries in which large numbers of people have little or no access to medical care and treatment even for ordinary illnesses, a concern expressed to NBAC in testimony.³²

   It is necessary, then, to answer the threshold question of whether the very offer to participate in research constitutes an undue inducement to citizens of developing countries who have little or no access to medical care and treatment (Bernstein 1999). Even a placebo-controlled trial offers such individuals a 50 percent likelihood (in a two-arm trial) of receiving an intervention that, although unproven, may be beneficial. If the solution to this fundamental problem is to forgo research entirely in such places, it might make those populations worse off than they would be if research goes forward. This consideration requires the review of the ethical consequences of not conducting research and the determination of whether those  consequences  outweigh  the  ethical  problems alleged to exist in the conduct of the research. But the need to attempt such a balance can be avoided if a proper distinction can be made between acceptable inducements and those that constitute undue influence or coercion. 

   No hard-and-fast criterion can be stipulated for making this distinction. However, one approach would be to consider the possible motivations for participating in research, according to the following schema. People may,for example:

1. Act out of self-interest, when there is a potential benefit to them.
2. Act out of rational or enlightened self-interest, when there is potential benefit to others as well as to  themselves, and some risk to themselves.
3. Act out of pure altruism, when they expect no benefit to themselves but expect benefit to others, and accept some risk to themselves.
4. Refuse to act because of perceived high risk or great inconvenience, only agreeing to undergo the risk when offered considerable material reward.
5. Act out of fear of the consequences of refusing to participate.

   All  of  these  situations  apply  to  some  extent  in research. Situation (b) is the standard presupposition in Phase II or III clinical trials. Prospective participants weigh the risks and potential benefits, recognizing that there may be some risk to themselves but also some possible benefit and that the research as a whole may provide benefits  to  others.  Situation  (c)  is  the  standard  for research not designed to provide direct benefit to participants, but, for example, to determine the safety of drugs in Phase I studies, to discover basic physiological mechanisms, or to arrive at baseline data. Situation (d) captures the idea of undue inducement when people make a rational refusal based on perceived risk, but then agree to accept the risk only when provided with a considerable material reward. Situation (e), by definition, is the paradigm of coercion: In hierarchical groups, in coercive settings, or under threat, individuals agree to participate in research because they fear the consequences of refusal. In this situation, their participation is coerced, not voluntary. Situation (e), therefore, is ethically prohibited.

   In principle, there is no difference between the sort of motivation that prompts people anywhere to volunteer for research—situation (b)—and what may induce people in developing countries to agree to participate. The more difficult challenge lies in situation (d): Does the prospect of receiving medical care as a benefit during (or possibly after) the research prompt people in developing countries to undertake serious risks they would other wise refuse to accept? There can be no general answer to this question, which can be determined only on a case-by-case basis. In studies with the usual range of risks, the provision of medical care may be an inducement to participate, but there is little reason to believe it is an undue inducement. Recalling the definition of undue influence cited earlier—"an excessive, unwarranted,inappropriate or improper reward"—it is reasonable to conclude that providing medical care to research participants is warranted, appropriate, and proper.

   One might object that this definition is embedded in a document created in the United States—a wealthy, industrialized country—and therefore is irrelevant to resource-poor countries. The reply to this objection is twofold. First, poor people exist in every country, and participation in a clinical trial often is the only way that uninsured individuals in the United States can gain access to some medical care. Yet, no one could reasonably maintain that the poor or uninsured should be excluded from participation in research or that it would be ethically acceptable to deny them medical benefits that they could not otherwise obtain.

   Second, the problem may not lie in the idea that an offer to possibly receive medical care is an inducement, but rather in the difficulty of determining when such an offer—admittedly an inducement—becomes undue. Those who argue that participation in research constitutes an undue inducement for poor people in developing countries would have to maintain that offering high-quality medical care and treatment that participants would not otherwise receive is unwarranted and inappropriate. However, the provision of medical care or treatment that would not otherwise be available to research participants should not, in principle, be construed as an undue influence to participate. This conclusion is supported by developing country researchers surveyed by Kass and Hyder: 64 percent stated that  participants joined research projects in order to obtain benefits.³³  Many researchers interviewed in focus groups for this same study seemed to believe that this was acceptable, given the overall risk/benefit ratio of the research; some focus group respondents remarked that providing significant benefits essentially left potential participants with no reasonable choice except to participate, but they did not specifically refer to this as undue inducement.³⁴  NBAC concludes that although the potential benefits of participation in research may be an inducement for those in developing countries who lack access to medical care to participate in research, this does not sufficiently diminish the voluntariness of their decision in a way that would make their consent ethically invalid.

   Somewhat more problematic are clinical trials studying a new intervention in which members of a control group receive an established effective treatment that is unavailable outside the trial. Does provision of the established effective treatment constitute an undue inducement to participate? 

   This situation can be cast in the form of a dilemma. If providing treatment otherwise unavailable to members of a control group is an undue inducement and hence ethically unacceptable, then the only ethically acceptable research design in such situations would be that of a placebo control or some other substandard treatment that is available. However, as discussed in Chapter 2, placebo-controlled trials may be ethically unacceptable in cases in which the disease is life threatening or permanently disabling and established effective treatments exist for the condition. The dilemma arises because of the tension between the potential loss of full voluntariness on the part of participants and the probability of harm befalling those in the control arm who receive the placebo instead of an established effective treatment.

   As in any ethical dilemma, this one requires that moral considerations be weighed in order to determine which alternative is more acceptable. An appeal to certain ethical principles offers some insight. The well-accepted principle of nonmaleficence (Beauchamp and Childress 1994; National Commission 1979) requires that harm to participants be minimized;35however, it could never be used to justify coercion of research participants, which would entirely preclude their voluntary participation. NBAC concludes that in this situation, it is more acceptable to allow the possibility of somewhat diminished voluntariness  of  participation  than  to  risk  harm  to participants in the control arm, who are denied an established effective treatment. This is a position consistent  with  other  guidelines,  such  as  those  of  the Medical  Research  Council  of  the  United  Kingdom (MRC-UK 1999).

   The therapeutic misconception has been documented in a wide range of developing and developed countries. For example, in a study conducted in a clinic in Brazil,  all  of  the  women  who  were  interviewed  said  that  they entered the study because they "thought that the contraceptive being offered would be good for them" (Hardy et al. 1998). In some parts of the world, a different kind of complication arises from the language itself. One American respondent to the study conducted by Kass and Hyder stated the following: "In many African languages, there is no word for `research' or `science.'  The word used is generally the same as the word for `medicine.' There is no concept of an experiment, placebos, etc., and despite the best translation of the most simply worded consent form, many adult subjects still have no understanding of the difference between being a research subject and receiving medical treatment."³⁶ The researcher went on to say that "[t]his should not be a reason to exclude these people from research; in fact they are often the population who will benefit most from the research and the only population in whom the studies can be done, e.g., persons at risk of naturally acquired malaria or other tropical diseases."³⁷

   It is important to distinguish the confusion that arises from the therapeutic misconception from a related consideration.  In  the  research  setting,  participants  often receive  beneficial  clinical  care.  In  some  developing countries, the type and level of clinical care provided to research  participants  may  not  be  available  to  those individuals outside the research context. It is not a misconception to believe that participants probably will receive good clinical care during research. But it is a misconception to believe that the purpose of clinical trials is to administer treatment rather than to conduct research.  Researchers  should  make  clear  to  research  participants, in the initial consent process and throughout the study, which activities are elements of research and which are elements of clinical care.

Recommendation 3.10: 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 (see also Recommendation 3.2).

Recommendation 3.11: U.S. research regulations should be amended to permit ethics review committees to waive the requirements for written and signed consent documents in accordance with local cultural norms. Ethics review committees should grant such waivers only if the research protocol specifies how the researchers and others could verify that research participants have given their voluntary informed consent.

Recommendation 3.12: The National Institutes of Health, the Centers for Disease Control and Prevention, and other U.S. departments and  agencies should support research that addresses specifically the informed consent process in various cultural settings. In addition, those U.S. departments and agencies that conduct
international research should sponsor workshops and conferences during which international researchers can share their knowledge of the informed consent process.

   During the course of its deliberations, NBAC found that there is a great deal of support in developing countries for the requirement of voluntary, individual informed consent. The surveys conducted by Kass and Hyder lend considerable support to the view that both developed and developing country researchers view the requirement to obtain voluntary informed consent as a critical ethical standard. Adherence to this standard requires that researchers disclose relevant information, take steps to determine that potential participants understand what they have been told, and ensure that each individual's consent is voluntary. Nevertheless, for some customs and traditions, some of the specific procedures related to the process and documentation of informed consent as stipulated in the U.S. regulations must be modified. These procedures should be sufficiently flexible to be adapted for use in various developing countries. The requirements of written consent and the participant's signature, mark, or thumbprint on consent forms are procedures that ethics review committees should be allowed to waive when researchers provide adequate justification for such waivers. Every competent adult should be able to decide freely whether to participate in research, a position adopted in previous NBAC reports (NBAC 1998; NBAC 1999). Those who wish to cede that decision to another should be able to do so, but the initial choice is still theirs. Often, personal and local circumstances complicate this choice, and many obstacles remain to achieving an ideal process. Nevertheless, adherence to a country's customs and  traditions need not compromise the ethical standard of informed consent. In some circumstances, researchers should have greater flexibility in determining how they inform participants about the research and in the methods they use to document consent. In addition, potential participants may wish to involve family members in their decision to participate, and researchers may need to obtain a community leader's permission before approaching individuals in the recruitment process. NBAC believes that these recommendations represent only the first steps toward eventually reaching a point at which every competent individual, based on adequate information, can voluntarily make his or her own decision about participating in research.

2 We acknowledge that the principle of respect for persons also permits the foregoing of voluntary informed consent in certain situations, such as research involving those who lack the capacity to give consent, research involving only minimal risk, or emergency research. These areas pose their own unique issues, which will not be addressed in this report.

3 See Kass and Hyder; Marshall; and Sugarman et al. 

4 See Sugarman et al., 10.

5 From data collected by Kass, N., and L. Dawson, 1999, Preliminary Focus Group Report, 9. For Kass, N., and A. Hyder, "Attitudes and Experiences of U.S. and Developing Country Investigators Regarding U.S. Human Subjects Regulations."

6 See Marshall, 18.

7 Plowe, C., Testimony before NBAC. February 29, 2000. Herndon, Virginia; Pape, J.P., Testimony before NBAC. February 29, 2000. Herndon, Virginia.

8 See Sugarman et al., 17.

9 See Kass and Hyder.

10 See Marshall, 34.

11 Sommer, A., Testimony before NBAC. September 16, 1999.  Arlington, Virginia. Meeting transcript, 214.

12 See Kass and Hyder, 6.

13 See Marshall, 17.

14 Pape, J.P., Testimony before NBAC. February 29, 2000. Herndon, Virginia.

15 Ibid., 32.

16 See Marshall, 15.

17 Plowe, C., Testimony before NBAC. February 29, 2000. Herndon, Virginia. Meeting transcript, 151.

18 Pape, J.P., Testimony before NBAC. February 29, 2000. Herndon, Virginia.

19 See Kass and Hyder.

20 From data collected by Kass, N., and L. Dawson, 1999, Preliminary Focus Group Report. For Kass, N., and A. Hyder, "Attitudes and Experiences of U.S. and Developing Country Investigators Regarding U.S. Human Subjects Regulations."

21 See Kass and Hyder, 43.

22 From data collected by Kass, N., and L. Dawson, 1999, Preliminary Focus Group Report, 8. For Kass, N., and A. Hyder, "Attitudes and Experiences of U.S. and Developing Country Investigators Regarding U.S. Human Subjects Regulations."

23 See Marshall, 34.

24 Ibid., 22.

25 From data collected by Kass, N., and L. Dawson, 1999, Preliminary Focus Group Report, 1. For Kass, N., and A. Hyder, "Attitudes and Experiences of U.S. and Developing Country Investigators Regarding U.S. Human Subjects Regulations."

26 Plowe, C., Testimony before NBAC. February 29, 2000. Herndon, Virginia.

27 See Kass and Hyder, 43.

28 Sugarman and colleagues state that "investigators in one country repeatedly noted that patients who might be asked to enroll in a medical study would be skeptical of an investigator who did not involve the family in the decision making process."  See Sugarman et al., 9.

29 See Marshall, 28.

31 Loue, S., Testimony before NBAC. October 21, 1999. Washington, D.C.

32 Plowe, C., Testimony before NBAC. February 29, 2000. Herndon, Virginia. Meeting transcript, 106.

33 See Kass and Hyder, 56.

34 Ibid., 57.

35 This same principle is implicit in 45 CFR 46.111(a)(1), stating that in reviewing research, IRBs must determine that risks to subjects are minimized.

36 See Kass and Hyder, 41.

37 Ibid.

38 See Sugarman et al., 11.

39 Loue, S., Testimony before NBAC. October 21, 1999. Washington, D.C. Meeting transcript, 28 - 29, 40.

40 Pape, J.P., Testimony before NBAC. February 29, 2000. Herndon, Virginia. Meeting transcript, 32.

41 Malenga, G., Testimony before NBAC. February 29, 2000. Herndon, Virginia. Meeting transcript, 61.

42 See Marshall, 24.

43 Ibid., 26.

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