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Overview of Ethical Issues in Collecting Data in Developing Countries, with Special Reference to Longitudinal Designs Richard A. Cash and Tracy L. Rabin Program on Ethical Issues in International Health Research Department of Population and International Health Harvard School of Public Health This paper identifies major ethical issues in longitudinal health research and demographic and health data collection and analysis, specifically as they are related to research conducted in developing countries. A discussion of general ethical principles for health research and questions of community-based ethics is followed by a description of the benefits and risks of longitudinal health research, with special reference to the issues of informed consent, confidentiality, and researcher responsibilities to the host community. BASIC PRINCIPLES OF ETHICAL RESEARCH Discussions of biomedical ethics usually begin with the introduction of four basic principles: respect for persons, beneficence, nonmaleficence, and justice. This set of principles was first formalized in the Belmont Report, the final product of the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979). This commission was charged with identifying the basic ethical principles that should underlie the conduct of biomedical and behavioral research using human subjects and then developing guidelines to ensure that such research is conducted in accordance with the basic principles. Since the release of the Belmont Report, the import of these four principles has become recognized internationally. As a set of key considerations
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in the design and implementation of ethical research, however, they are by no means all-encompassing, and additional principles have been articulated in the literature. Contending that good scientific research is not necessarily ethical research, Emanuel et al. (2000) recently proposed a set of seven requirements to ensure that clinical research is ethical: (1) social or scientific value; (2) scientific validity; (3) fair subject selection; (4) favorable risk/benefit ratio; (5) independent review; (6) informed consent; and (7) respect for potential and enrolled subjects. Each of these principles also applies to community-based studies and data collection and requires that community needs and values be considered along with those of the individual. In September 2000, the Indian Council on Medical Research (ICMR) published Ethical Guidelines for Biomedical Research on Human Subjects, an excellent example of a high-quality developing country document (Indian Council on Medical Research, 2000). The ICMR proposed that 12 general principles be considered in designing research projects involving human subjects: (1) essentiality (of the research); (2) voluntariness, informed consent, and community agreement; (3) nonexploitation; (4) privacy and confidentiality; (5) precaution and risk minimization; (6) professional competence; (7) accountability and transparency; (8) maximization of the public interest and of distributive justice; (9) institutional arrangements; (10) public domain; (11) totality of responsibility; and (12) compliance. These sets of formally articulated ethical principles cover a wide spectrum, ranging from (but not limited to) the four broad principles of the Belmont Report to the more specific set of twelve principles provided by the ICMR. The variation in the items on these lists demonstrates that no single list of principles has authority over others, although some are cited more often. It is instructive to examine the application of these principles in the context of the different international guidelines that have been published over the past 40 years. INTERNATIONAL GUIDELINES Worldwide, several documents have been formulated to provide researchers with a standard set of directions for ensuring that the human subjects of their research are “adequately” protected.1 An early document, 1 Here “adequate” protection is equivalent to the level of human subject protection that is considered appropriate under the internationally recognized guidelines.
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the Nuremberg Code, emerged from the 1949 “Trials of War Criminals before the Nuremberg Military Tribunals” as a direct reaction to the crimes perpetrated by German doctors against human research subjects during the Nazi regime (U.S. Government Printing Office, 1949). This 10-point document deals primarily with the idea that acceptable consent to participate in research is an irrevocable requirement and can only be given voluntarily and by persons who “have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision” (U.S. Government Printing Office, 1949). Though the German doctors have been held up as the ultimate example of unethical treatment of human subjects, the Japanese Imperial Army’s Unit 731 was responsible for similar atrocities against the Chinese in World War II. Unlike the German doctors in the trials at Nuremberg, however, many of the Japanese perpetrators were released by the U.S. Army in exchange for their data. The World Medical Association, founded in 1947 as an independent confederation of medical associations worldwide, adopted the Declaration of Helsinki as its organizational policy on ethical principles for medical research involving human subjects in 1964 (World Medical Assembly, 1964 ). This document was, historically, the follow-up to the Nuremberg Code, although it was intended primarily to govern physician-researchers, not researchers in general. The Declaration of Helsinki is not itself a legally binding document, and it has undergone five revisions since it was first adopted. The most recent revision was adopted in October 2000 and is composed of 32 standalone clauses (World Medical Association, 2000). The Declaration has been used to inform World Health Organization (WHO) practices and national legislation in various countries. The Council for International Organizations of Medical Sciences (CIOMS) is an international, nongovernmental, not-for-profit organization that was jointly established by WHO and the United Nations Educational, Scientific, and Cultural Organization (UNESCO) in 1949. CIOMS has three main objectives: (1) facilitating and promoting international activities in the field of biomedical sciences; (2) maintaining collaborative relations with the United Nations and its specialized agencies; and (3) serving the scientific interests of the international biomedical community in general. In 1991, after two years of international discussion, CIOMS published the International Guidelines for Ethical Review of Epidemiological Studies (Council for International Organizations of Medical Sciences, 1991). These guidelines are designed to aid in the development of national poli-
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cies on the ethics of epidemiological research and practice and the ethical review of epidemiological studies. They are intended for all people (not just physicians) who face the ethical issues that arise in the course of epidemiological research, including scientific investigators, health policy-makers, and ethical review committee members. The International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences, 1993), originally published by CIOMS in 1993 and presently undergoing revisions, replaced a 1982 set of proposed guidelines that were intended to elucidate how to apply effectively the ethical principles set forth in the Declaration of Helsinki, with particular attention to research conducted in developing countries. The International Ethical Guidelines for Biomedical Research Involving Human Subjects are designed for use in developing national policies on ethical biomedical research and mechanisms for ethical review of research using human subjects. In addition to recognizing the importance of both clinical and nonclinical research, the preamble to the guidelines contains an extensive list of the various types of research that fall under the category of “research involving human subjects.” In April 2001, the U.S. National Bioethics Advisory Commission (NBAC) published a report entitled Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries—Volume I, Report and Recommendations of the National Bioethics Advisory Commission (U.S. National Bioethics Advisory Commission, 2001). The purpose of this document is to respond to ethical issues that arise over the course of research in developing countries that is subject to U.S. regulation. Although the recommendations contained in the report can be applied to many types of research, the scope of this document was mainly limited to issues related to clinical trials involving competent adult participants. DEFINING THE COMMUNITY AND COMMUNITY-BASED ETHICS As longitudinal research requires that human subjects be considered at both the community level and individual level, special conditions affect ethical concerns for the community. The community-level concerns include: how to obtain communal approval; potential benefits and risks to groups with varying literacy levels; use of incentives; the issue of providing feedback and results to the host community; and anonymity of communities. Until recently, these concerns had not been directly addressed in an
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official document, although several of the documents described earlier in this paper now contain guidelines that can be extended to community-based research. The International Guidelines for Ethical Review of Epidemiological Studies published by CIOMS acknowledges in Guideline 25 that there are often cultural differences between researchers and research subjects: Investigators must respect the ethical standards of their own countries and the cultural expectations of the societies in which epidemiological studies are undertaken, unless this implies a violation of a transcending moral rule. Investigators risk harming their reputation by pursuing work that host countries find acceptable but their own countries consider offensive. Similarly, they may transgress the cultural values of the host countries by uncritically conforming to the expectations of their own. (Council for International Organizations of Medical Sciences, 1991) This statement provides little actual guidance, however, about how these differences can be handled in an ethical fashion, other than making the claim that a set of (unidentified) “transcendent” moral rules exist. A community may be thought of as “a group of people understood as having a certain identity due to the sharing of common interests, a common set of values, a common disease or a shared geographical proximity” (Weijer and Emanuel, 2000). In demographic health research or evaluation projects, however, communities are much more narrowly defined. Focusing on one particular community or group of people serves to decrease the cost of the study and potentially increase the quality of the data collected over time (follow-up is easier). These are especially important considerations in areas that do not have reliable health or demographic data registration systems. Depending on the research topic or the results of the study, however, the focus on one community may lead to stigmatization or discrimination by its neighbors or within the larger society. The tension between defining a community for research purposes and minimizing the potential social harms associated with being identified with such a group is an important concern. In addition, individuals are usually members of several different communities simultaneously, depending on the definition of a community. Therefore, one community could benefit from the involvement of some of its members in a research project, whereas another community (of which some of those same individuals are members) could be affected in a negative way. To minimize the potential risks to host communities, some questions must be addressed before identifying a group. Is a particular population
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potentially overrepresented in a study, so that it might appear that the condition under investigation is more prevalent in that group? How are potential participants approached or selected? Can the findings be generalized to a larger community, and is it scientifically valid to do so? Coughlin notes: Epidemiological research does not take place in a social vacuum, and areas of ethical conflict may exist between the need to obtain scientifically accurate information about the health of population subgroups and the moral imperative to avoid harming populations that already suffer stigmatization and discrimination from the mainstream societies in which they live. (Coughlin, 1996) The type of community-based research conducted is an extension of concerns about the definition of a host community. The draft revision of the CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects offers two statements in response to this question. Guideline 6 states that the research should be “responsive to the health needs and the priorities of the population or community in which it is to be carried out” (Council for International Organizations of Medical Sciences, 2001). This is similar to Principle 19 in the most recent revision of the Declaration of Helsinki, which asserts that “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” (World Medical Assembly, 2000). These comments were added, it seems, to ensure that research in developing countries (especially that sponsored by institutions or industry from developed countries) not be conducted there simply because of lower costs or absent or slack regulations. The dilemma is how does one determine “reasonable likelihood”? Research should first address local needs. When initially tested in developing countries, the hepatitis B vaccine was priced way beyond their reach. Hepatitis B was, however, a local problem, and the price has now come down to a level that allows the vaccine to be used widely in many countries, especially in East and Southeast Asia. Given that the vaccine was initially unaffordable to the majority of Chinese citizens, should it not have been tested in China? This also raises the question of what to do if a government refuses to distribute an effective product within the national health care system, such as the South African government’s refusal to distribute nevirapine to HIV/AIDS patients. Does this mean that no studies involving that product can be conducted in that country? Should the researcher be held responsible for the government policy? As official govern-
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ment positions and policies are constantly changing, this hardly seems to be a sensible recommendation. There is also the matter of how involved host communities should be in setting the research agenda and to what degree community representatives should be involved in study design or in deciding how to use collected data. Recommendation 2.3 of the NBAC report Ethical and Policy Issues in International Research calls for the involvement of host community representatives in the entire development and implementation of research projects. If community representatives decline to be involved in the processes, investigators are required to justify this to their ethical review committee(s) (U.S. National Bioethics Advisory Commission, 2001). The rationale for recommending this level of community involvement is that these consultations will provide a greater insight into the relevance of the research question(s) to the host community and may better inform the development of the consent process. Increased community involvement marks a dramatic shift in the historically paternalistic attitudes of many researchers, serving to improve the relationship between investigators and the host community. ISSUES OF INFORMED CONSENT Informed consent is the primary ethical concern of many researchers and ethical review boards (ERBs). All international guidelines consider consent “informed” if the participant knows the purpose and nature of the study, the nature of his or her participation, and the potential risks and benefits involved. Implicit in this definition, however, is the belief that potential participants will understand the information they are given. Today, the practice of obtaining informed consent has become a matter of following more the letter than the spirit of the law. Perhaps the requirements should direct researchers to obtain “understood” consent—confirmation that participants understand what they are consenting to—rather than simply document that the conversation took place. At present, most guidelines deal specifically with obtaining consent from individuals (and express a strong preference for written proof of consent), because this method traditionally has been used by researchers in the developed world. When dealing with less educated populations (in both developed and developing countries), however, researchers may find it difficult to explain sufficiently the purpose, benefits, and potential risks of a study. Moreover, written consent forms are not always appropriate for
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illiterate populations or for particular social, political, or cultural traditions. The ICMR Ethical Guidelines for Biomedical Research on Human Subjects address these issues, acknowledging that many communities in India, because of an insufficient level of education, are less able to understand study procedures or implications than communities in more developed countries: When individuals are to be the subject of any epidemiological studies, the purpose and general objectives of the study has to be explained to them keeping in mind their level of understanding. . . . In the context of developing countries, obtaining informed consent has been considered many times as difficult/impractical/not meeting the purpose on various grounds such as incompetence to comprehend the meaning or relevance of the consent. . . . [H]owever, there is no alternative to obtaining individual’s informed consent but what should be the content of the informed consent is also a crucial issue. (Indian Council on Medical Research, 2000; emphasis in original) One of the contentious issues that has surfaced in some countries is whether it is ethically acceptable for a representative of the community to give consent for individual members of the community. This issue is addressed in Guideline 5 of the CIOMS International Guidelines for Ethical Review of Epidemiological Studies: When it is not possible to request informed consent from every individual to be studied, the agreement of a representative of a community or group may be sought, but the representative should be chosen according to the nature, traditions, and political philosophy of the community or group. . . . For communities in which collective decision-making is customary, communal leaders can express the collective will. However, the refusal of individuals to participate in a study has to be respected; a leader may express agreement on behalf of a community but an individual’s refusal of personal participation is binding. (Council for International Organizations of Medical Sciences, 1991) The consent of other parties is also involved in many other situations— that is, other than those requiring collective decision-making. For example, in some cultures women traditionally cannot provide their own consent, or a woman’s husband or father must grant his permission before she can consent to participate in research. Recognizing that these situations are generally one-sided (meaning that women generally are in the position of needing a man’s permission), NBAC Recommendation 3.9 states: 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
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are met: . . . it would be impossible to conduct the research without obtaining such supplemental permission; and…failure to conduct this research would deny its potential benefits to women in the host country; and . . . measures to respect the woman’s autonomy to consent in 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. (U.S. National Bioethics Advisory Commission, 2001) The three special conditions under which supplemental permission is acceptable are written with the intent of protecting researchers’ abilities to conduct research around issues that affect only women and to ensure that the women would not be denied benefits that can only result from such research (e.g., the information needed to list women’s health care needs by priority in that population). Dealing with informed consent in a longitudinal study also presents a number of other issues. For example, if the subjects are ”minors” (and the definition may well be culturally dependent) at the outset of the study and will become adults over the course of the follow-up period, does consent for participation have to be obtained twice? Should consent for a long-term longitudinal study that goes on for years ever have to be renegotiated and, if so, how often? How long after a study is completed should investigators be responsible for returning to the community to share data and make recommendations? Should a follow-up period be scheduled to maximize the benefits that might accrue from the delivery of health care in the community as compared with the potential risks to the individual? In addition, when dealing with biological specimens that have been collected and stored over a period of time are researchers required to seek additional consent from participants in order to conduct additional research on those materials? The NBAC report Research Involving Human Biological Materials: Ethical Issues and Policy Guidance provides an elaborate discussion of guidelines for collecting specimens for storage, testing, and later use (U.S. National Bioethics Advisory Commission, 1999). Questions about the appropriateness of obtaining re-consent for research are dealt with in the CIOMS draft revision of the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Addressing the planning and initial stages of research, the commentary on Guideline 9 states: All individuals enrolled as research subjects should be allowed to decide about potential uses of their biological materials for research. . . . Subjects
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should be told whether the specimens will be stored for future research, and, if so, for how long, and whether the nature of the future research is currently unknown, whether the materials will be shared with other researchers, and whether commercial products will be developed from the specimens. (Council for International Organizations of Medical Sciences, 2001) This passage suggests that participants would decide from the outset whether they consent to future research using their specimens or information. While this advance planning may prevent some problems for future research, it is not difficult to imagine a situation in which an ethical review committee does not accept (as “informed consent for future research”) the fact that participants were told at the outset that research might be conducted at some point in the future. The last three sentences of this commentary are particularly relevant to the use of medical records in research, requiring that [p]atients should be told about the possible research uses of their medical records and of biological specimens that are taken in the course of clinical care. In many cases it will suffice to notify patients that research involving such records or specimens is commonly performed without individual informed consent. In other cases, the research ethics committee may require individual informed consent. (Council for International Organizations of Medical Sciences, 2001) This section raises interesting questions about the role of local medical practitioners in research. For studies involving data from medical records, should all physicians have to explain to patients that their medical records may be used for research purposes, even if their anonymity is maintained? This is an important question, considering the potential for negative effects on health-care-seeking behavior. Is it even appropriate for physicians to be in the position of having to explain the concepts of “research” and “informed consent” to their patients? The notion of research does not exist or is very poorly understood in many cultures. Where records are unlinked or delinked and the risk to the individual is minimal or nonexistent, the local ethical review board should determine whether informed consent is required. The commentary on Guideline 10 of the CIOMS draft revision provides some guidance for questions of re-consent that may arise after the initial stages of the research: Medical records and biological specimens may be used for research without the consent of the patients/subjects only if an ethics review board has decided that the protocol poses minimal risk, that the rights or interests of the pa-
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tients will not be violated, and that the research is designed to answer an important question and could not practicably be conducted with specimens and records for which informed consent had been obtained. . . . Records and specimens of individuals who have specifically rejected such uses in the past may be used only in the case of public health emergencies. (Council for International Organizations of Medical Sciences, 2001) Thus, according to the CIOMS, the ultimate decision about whether re-consent is required should fall on the shoulders of the ethical review committee(s). This external check on researchers’ activities serves to satisfy the requirement in the Declaration of Helsinki that “[e]very precaution should be taken to respect the privacy of the subject and the confidentiality of the patient’s information” (World Medical Assembly, 2000). As part of the informed consent process, a form or script providing the necessary information about the study should be read by or read to the potential participants. What should be the scope of this consent document? If the document is too broad, researchers run the risk of including more information than potential participants need to be able to make an informed decision, or information that is too technically involved for participants to understand. But if the document is too limited, researchers run the risk of not including enough of the information potential participants need to be able to make an informed decision. Another problem is how to communicate the necessary information when the population of interest is illiterate. Finally, in light of the recent shift toward an increased emphasis on the informed consent process, how should the investigator determine whether the participant truly understands the potential risks, benefits, and procedures of the study? Researchers will likely approach such a question differently if understanding becomes the focus of the process. The NBAC report Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries provides a more detailed discussion of this issue (U.S. National Bioethics Advisory Commission, 2001). ISSUES OF CONFIDENTIALITY Personal information collected by researchers may be damaging to either individuals or a community if disclosed to a third party. Stigmatization, discrimination, and other social or physical harms may occur if participants in a study are identified as different in some way from a larger community. Investigators must be able to assure participants that all infor-
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mation collected will be protected and, where appropriate, will not be linked to an individual or a group or community. Depending on the research topic, participation in a study itself may have to be treated in a confidential manner (e.g., vaginal microbicide trials or tests of family planning methods). When information collected as part of a study is not linked to an individual or community (i.e., it is collected anonymously or without personal identifiers), breach of confidentiality is not a concern. Longitudinal research raises special issues, however, because it may be necessary to maintain a linkage between data and identifying variables for the purpose of collecting follow-up information. These data are termed “confidential”— information that is collected using either personal identifiers (and then is kept in a storage facility with strictly controlled access) or using unique identifiers that are associated with a key (also stored under secure conditions) to allow matching of individuals or groups with the identifiers. Because researchers working on longitudinal studies expect a certain number of participants to be “lost to follow-up” (and will try to minimize this number), consideration must be given early on to how to minimize this loss within the context of maintaining confidentiality. In addition, investigators need to consider issues of confidentiality along with the question of potential obligations to track participants down and notify them of any unanticipated study results that may have personal implications. Due to the risks involved in using data that have explicit personal identifiers, investigators should justify to the ERB the need for linked data and provide a detailed explanation of how confidentiality will be protected. Regardless, communities (and individuals) may want to remain anonymous if the disclosure of research findings could potentially harm the community. For example, a high prevalence of a particular disease in a community or occupational group, such as the prevalence of HIV/AIDS among commercial sex workers, may stigmatize the group. The CIOMS International Guidelines for Ethical Review of Epidemiological Studies address the issues related to “harmful publicity” in Guideline 22: Conflict may appear between, on the one hand, doing no harm and, on the other, telling the truth and openly disclosing scientific findings. Harm may be mitigated by interpreting data in a way that protects the interests of those at risk, and is at the same time consistent with scientific integrity. Investigators should, where possible, anticipate and avoid misinterpretation that might cause harm. (Council for International Organizations of Medical Sciences, 1991)
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These statements presume that investigators are in the best position to make judgments about the best way to prevent harm. As suggested in the NBAC report (U.S. National Bioethics Advisory Commission, 2001), however, there may be a role for community representatives at this stage of the research project, because they could provide important insight into how to minimize potential harms. In the interest of full disclosure of potential harms, the commentary on Guideline 19 of the draft revision of the International Ethical Guidelines for Biomedical Research Involving Human Subjects requires that information about the efforts that will be taken to ensure confidentiality be included in the informed consent process and, just as important, that prospective research participants “be informed of limits to the researchers’ ability to ensure strict confidentiality and of the foreseeable adverse social consequences of breaches of confidentiality” (Council for International Organizations of Medical Science, 2001). In light of these concerns, it is also important to raise questions about who should ultimately have the power to decide about the publication of certain data, and whether the host community should have a say in the matter (and, if yes, to what extent). Data sharing is important to the demographic community (and the general scientific community), producing tension between the desire to improve general knowledge of the long-term effects of various factors on individuals and populations and the desire of research subjects to have control over information about their private lives. This tension requires balancing two legitimate interests: transparency for the sake of science and concealment of information out of respect for subjects. Important questions stem from this conflict, including deciding who should have access to certain information and who should have the right to agree or disagree to have that information used for various purposes. The answers to these questions stem from the solution to the underlying question: What are the obligations of the data collectors to the persons who are registered in the database? The CIOMS International Guidelines for Ethical Review of Epidemiological Studies address the investigators’ responsibilities in Guideline 21: Investigators who find sensitive information that may put a group at risk of adverse criticism or treatment should be discreet in communication and the explanation of their findings. When the location or circumstances of a study are important to understanding the results the investigators must explain by what means they propose to protect the group from harm or disadvantage; such means include provisions for confidentiality and the use of language
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that does not imply moral criticism of subjects’ behavior. (Council for International Organizations of Medical Sciences, 1991) Although the clause requiring investigators to “explain” proposed means to protect against harm does not explicitly state the identity of the “explainee,” it would seem appropriate that the means of protection be explained to the host community (to reach a consensus on the importance of disclosure). It also might be appropriate to justify the disclosure of identifying information to an ethical review board. This step, however, is not common practice as part of preparing research results for publication and, if anticipated, could be better addressed in the initial application for ethical review committee approval. OBLIGATIONS TO RESEARCH PARTICIPANTS Individual participants in a study seldom receive many direct benefits or, in some cases, benefits may be difficult to quantify. In a phase I drug trial, for example, the potential benefits to the individual are few. For nonintervention studies, the community benefits may not be as tangible to each individual as the more traditional benefits (such as new jobs related to the research project, a new clinic, and information for subjects about their health status and health risks), or they may be time-limited (such as— during the study—additional health care and improved access to drugs or procedures that have a direct effect on health). More sustainable modes of compensation (such as strengthening health data management capacity or training local staff) may be more appropriate, however. Increased economic activity surrounding a research project, including the use and purchase of equipment, and the construction of new buildings, is also an important benefit. The draft revision of the CIOMS guidelines and the recently released NBAC report have given more attention to the responsibilities of the researcher to the community than other guidelines (Helsinki) or earlier CIOMS guidelines. They are concerned with what happens within the relationship between the researcher and the research subjects at the conclusion of the study: What should be provided to research participants and by whom? What, if anything, should be made available to others in the host community or country? Guideline 6 in the draft revision of the 1993 CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects states:
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Before undertaking research in a population or community with limited resources, the sponsor and the researcher must make every effort to ensure that . . . the research is responsive to the health needs and the priorities of the community in which it is to be carried out . . . and . . . any product developed will be made reasonably available to that population or community. (Council for International Organizations of Medical Sciences, 2001) What is meant by “reasonable” and “available”? Should the “population” only include those persons involved in the research, or should it also include the geographic region, a particular group of people, or the entire country? The commentary goes on to interpret the notion of responsiveness as more than simply confirming that a particular health problem is prevalent in a community. It calls for successful interventions developed during the research or any other beneficial research conclusions to be made available to the population. CIOMS recommends that these arrangements be negotiated before the research begins and that a variety of host community and country representatives be involved in this process. As for negotiating the post-project researcher-participant relationship, NBAC Recommendation 4.1 makes a similar suggestion: Researchers and sponsors in the clinical trials should make reasonable, good faith efforts before the initiation of a trial to secure, at its conclusion, continued access for all participants to needed experimental interventions that have been proven effective for the participants. . . . R]esearch protocols should typically describe the duration, extent, and financing of such continued access. When no arrangements have been negotiated, the researcher should justify to the ethics review committee why this is the case. (U.S. National Bioethics Advisory Commission, 2001) These requirements are less extreme than the controversial clause in the most recent version of the Declaration of Helsinki, which 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” (World Medical Assembly, 2000). If upheld, the mandate that investigators provide their participants with access to the best proven intervention—which often far exceeds the community standard of care and is likely to be unsustainable over the long term— may limit the types of research that can be conducted in the developing country context beyond the exploitative situations that the mandate is meant to prevent. Most research in developing countries is, after all, locally funded. As written, the guideline implies immediate access, though
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such success may not be possible or desirable. This recommendation seems reserved for developing countries. Why adopt this paternalistic approach? Why should local ERBs not make these decisions? Although most of the international guidelines focus on clinical studies, the principles expressed are relevant to longitudinal studies. If one thinks about collecting information, as opposed to testing interventions, the tie to the longitudinal studies becomes clear. But should all information be released to the individual participants or the host community? What if the release of information to certain groups puts other groups at increased risk of harm? For example, a study of sexual behavior may reveal unexpectedly high rates of extramarital affairs among the women. Would it be ethical for the information to be released to the men of the community if it puts the women at risk? Just because an intervention has proven to be effective in a developing country context does not mean it is appropriate to release it in the developed world or other communities in the developing world. A drug or vaccine should first be adequately studied in a setting similar to that in which it would be used. The surveillance systems of most poor countries are usually inadequate to detect all but the most obvious side effects of a drug or vaccine. Regardless of the specific type of research being conducted or the exact location, clearly greater attention should be paid to issues at the community level. Michael Bennish, director of the Africa Centre for Health and Population Studies (KwaZulu Natal, South Africa) states at the conclusion of a video case study dealing with questions of researcher responsibilities to the community: We certainly have relatively well-defined policies for ethical conduct of research as it affects an individual. There are far fewer guidelines, and certainly much less in the way of specifics, that deal with the obligation of a research program to communities at large. (John F. Kennedy School of Government Case Program, 1999) As a related issue, Guideline 22 of the draft revision of the International Ethical Guidelines for Biomedical Research Involving Human Subjects deals with the approval of externally sponsored research: An external sponsoring agency should submit the research protocol to ethical and scientific review in the country of the sponsoring agency and according to the standards of that country, and the ethical standards applied should be no less exacting than they would be for research carried out in that country. Appropriate authorities of the host country, including a national or local
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ethical review committee or its equivalent, should ensure that the proposed research meets their own ethical standards. (Council for International Organizations of Medical Sciences, 2001) This statement does not offer specific solutions to conflicts between ethical review authorities in the sponsoring and host countries. The guideline does specify, however, that the host country committees are responsible for determining whether the research objectives are responsive to the needs and priorities of the country, and charges ethical reviewers in the sponsoring countries with the task of ensuring compliance with broad ethical standards. This guideline suggests that it is unethical to conduct research in a particular country if the study in question would not receive the approval of the ethical review board of the sponsoring agency. The guideline is a version of a more extreme guideline that appeared in the 1993 draft of the document. It stated that investigators working in less developed communities “must ensure that … persons in underdeveloped communities will not ordinarily be involved in research that could be carried out reasonably well in developed communities” (Council for International Organizations of Medical Sciences, 1993). FUTURE DIRECTIONS Future ethical concerns will be influenced by factors that bear on the types of research questions that investigators will be able to ask, including rapid advancements in the fields of genomics and biotechnology. In addition, developing country governments and institutions will continue to make their voices heard as they become more equal partners in the international research community and as the need for formal training around ethical issues continues to grow. Genomics and Biotechnology Science and technology are advancing faster than the ability of the scientific community to handle the moral and ethical dilemmas produced by such advances. Longitudinal studies have faced some of these issues in genetics research and the storing of biologic specimens. Developing countries will exert more pressure to retain some degree of ownership of biologic specimens collected for research purposes, and they will increasingly focus on securing access to benefits that result from research projects conducted in their own communities. How much control should a nation-state or a
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community exercise over a study if the individual participants fully consent to their involvement? Are some of the guidelines that were intended to protect individual research subjects and host communities hindering the process of investigation (and at the expense of those the researchers are trying to assist)? Capacity for Ethical Review in Developing Countries U.S. guidelines insist that the institutions or countries in which research will take place have the capability to conduct their own independent ethical reviews. With the exception of a handful of ethical review boards in a small number of developing countries, not many meet the standards set forth in these guidelines. Few members of developing country ERBs have had any formal training in research ethics (not unlike IRB members in U.S. institutions), and in many of the ERBs the structure of the review process would not meet the criteria for conducting ethical review of research proposals in most U.S. universities. But this inequality is changing with the development of courses, workshops, and fellowships designed to provide short- and long-term training to researchers and ethical review board members from developing countries. Two such training programs are run through the Program on Ethical Issues in International Health Research at the Harvard School of Public Health, and the Bioethics Institute at the Johns Hopkins University. The UNDP (United Nations Development Programme)-UNFPA (United Nations Population Fund)-WHO-World Bank Special Programme of Research, Development, and Research Training in Human Reproduction, within the WHO Department of Reproductive Health and Research, began conducting capacity-building workshops in 1997 (Thailand) and is continuing to improve capacity in this area. The Joint United Nations Programme on HIV/AIDS (UNAIDS) also has conducted similar workshops in Brazil, India, and South Africa. Most recently, the UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases (TDR) developed programs to increase the capacity for conducting ethical reviews of research in Asian and Western Pacific countries through the Forum for Ethical Review Committees in Asia and the Western Pacific (FERCAP). Similar forums have been held in other regions. The TDR/WHO Operational Guidelines for Ethics Committees that Review Biomedical Research (UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases, 2000), designed to define the role and composition of an ethics committee, lay out the
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requirements for submitting an application for review and detail the review procedure and decision-making process. The guidelines were published in 2000 and have been translated into more than twelve languages. As these capacity-building efforts increase, developing country scientists are asking that some of the international guidelines be reviewed, giving greater consideration to the situation that exists in these countries. Indeed, many scientists, ERB members, and others have noted informally that much of the research in developing countries does not involve collaboration with Western scientists or companies, and that the international guidelines developed to protect the disadvantaged from foreign exploitation may in fact prevent scientists in developing countries from conducting some research that would, by most standards, be considered ethical in their country (personal communications with participants of research ethics workshops in Mexico, South Africa, India, Pakistan, and Nigeria). In addition, there is the issue of financial support for developing country ethical review boards. The Partners Human Research Committee, the institutional review board network of the Partners HealthCare System that is affiliated with Harvard University, employs more than 30 persons (not including volunteer committee members) and has a yearly budget in the millions of dollars. By contrast, ERBs in most developing country institutions do not have a budget or staff, and ERB members, many on low university salaries often supplemented by private medical practice, volunteer their time. Most developing country ethical review boards usually have a much smaller workload than U.S. institutional review boards, yet there are still costs associated with time, copying, and transport, among other things. One possible solution is for ERBs to charge a fee to review research proposals—either a flat fee or a percentage of the proposed budget. In addition, outside investigators could consider providing support for the general training of ERB members at collaborating institutions. With few exceptions, local ERBs will not have all the relevant expertise (i.e., biostatisticians, geneticists, and other experts) to evaluate each and every protocol and will have to seek guidance from elsewhere. Both field scientists and ethicists should be encouraged to support and use Web-based forums for the discussion of ethical dilemmas. One example is the Web site and Listserv administered and maintained by the Program on Ethical Issues in International Health Research at the Harvard School of Public Health (http://www.hsph.harvard.edu/bioethics). The Web site, which has been functioning since 1999, serves as a source of general information on the ethics of international health research and a discussion site for research
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ethics concerns. The Listserv has been operational since the spring of 2000, and the entire discussion (including dialogues on specific case studies and the revisions of the Declaration of Helsinki and the 1999 and 2001 NBAC reports) is archived on the Web site. To ensure the success of these resources and the advancement of good science, however, scientists and ethicists have to be open to sharing their expertise. Following the trends in scientific advancements, ethical issues in health research, especially those relevant to developing countries, will continue to change. Although differences in the recommendations presented in the international guidelines may at times be confusing to the individual investigator, they reflect the fluid nature of this international dialogue. It is important for researchers to remember that the ultimate goal of these guidelines is to improve, not encumber, both the ethical and scientific standards of health research. In the end, each institution will have to apply these guidelines within its local context. These discussions will strengthen the ethical reviews in developing countries and their position as contributors to the global dialogue on research ethics. REFERENCES Coughlin, S.S. 1996 Ethically optimized study designs in epidemiology. In Ethics and Epidemiology, S.S. Coughlin and T.L. Beauchamp, eds. New York: Oxford University Press. Council for International Organizations of Medical Sciences 1991 International Guidelines for Ethical Review of Epidemiological Studies. Geneva: CIOMS. 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS. 2001 Draft Revision of 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS. Available: http://www.cioms.ch [May 30, 2001]. Emanuel, E., D. Wendler, and C. Grady 2000 What makes clinical research ethical? JAMA 283(20):2701-2711. Indian Council on Medical Research 2000 Ethical Guidelines for Biomedical Research on Human Subjects. New Delhi: ICMR. John F. Kennedy School of Government Case Program 1999 Good Neighbors? The Africa Centre and the Local Community in Rural KwaZulu/Natal, South Africa . Videocassette.
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UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases (TDR) 2000 Operational Guidelines for Ethics Committees that Review Biomedical Research. Geneva: World Health Organization. U.S. Government Printing Office 1949 The Nuremberg Code. [Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law 10(2):181-182.] Washington, DC: U.S. Government Printing Office. Available: http://ohsr.od.nih.gov/nuremberg.php3 [June 15, 2001]. U.S. National Bioethics Advisory Commission 1999 Research Involving Human Biological Materials: Ethical Issues and Policy Guidance—Volume I, Report and Recommendations of the National Bioethics Advisory Commission. Available: http://bioethics.georgetown.edu/nbac/hbm.pdf [February 1, 2002]. 2001 Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries—Volume I, Report and Recommendations of the National Bioethics Advisory Commission. Available: http://bioethics.georgetown.edu/nbac/clinical/Vol1.pdf [February 2002]. U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979 The Belmont Report: Office of the Secretary. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Available: http://ohrp.osophs.dhhs.gov/humansubjects/guidance/Belmont.htm [May 7, 2001]. Weijer, C., and E.J. Emanuel 2000 Protecting communities in biomedical research. Science 289:1142-1144. World Medical Assembly 1964 World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. 1st ed. Helsinki: 18th World Medical Assembly . 2000 World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. 6th ed. Edinburgh: 52nd World Medical Assembly. Available: http://www.wma.net/e/policy/17-c_e.html [May 30, 2001].
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Representative terms from entire chapter: