ETHICAL ISSUES

SPECIAL FEATURE

ETHICAL ISSUES

Ethical Issues in International Collaborative Research on the Human Genome: The HGP and the HGDP BARTHA MARIA KNOPPERS,1 MARIE HIRTLE, AND SE´BASTIEN LORMEAU Public Law Research Centre (CRDP), Faculty of Law, Universite´ de Montre´al, Canada Received October 23, 1995; accepted March 5, 1996

The Human Genome Project (HGP) aims to identify the full set of genetic instructions contained inside human cells and to translate the complete text written in the language of the hereditary chemical deoxyribonucleic acid (DNA). The new information is expected to be the source book for biomedical science in the next century. The information obtained will aid in the understanding of the treatment and possible prevention of some of the more than 5000 genetic diseases as well as the many multifactorial diseases in which genetic predisposition plays an important role. The Human Genome Diversity Project (HGDP) (1–16) is an effort by anthropologists, geneticists, doctors, linguists, and other scholars from around the world to document the genetic variation of the human species worldwide. This scientific endeavour is designed to collect information on human genome variation so as to understand the genetic makeup of all of humanity and not just some of its parts. The information will also be used to learn about human biological history and the biological relationships among different human groups and may be useful in understanding the causes of and determining the treatment of particular human diseases. The Project aims to study the genetic richness of the entire human species and is largely still in its planning stages. Up to now, HGDP has focused on polymorphic neutral genetic variation as markers for diversity. It could also use disease-producing allelic variation and the corresponding genetic diversity at the relevant loci as descriptors of diversity and human evolution. Databases documenting locus-specific disease-producing allelic variation would serve not only the HGDP but also medical genetic concerns. While involving DNA sampling, the HGDP is not solely a ‘‘genetics’’ project. In some important respects, its greatest contribution may be anthropological, as it combines genetic information with other sources of knowledge about our species (9). The HGDP came under the auspices of the Human Genome Organization (HUGO) in January, 1994. 1

To whom correspondence should be addressed.

0888-7543/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.

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Consistent with respect for fundamental human rights as found in international law and in accordance with the ‘‘Nuremberg Code’’ (17) and the ‘‘Helsinki Declaration’’ (18), a 1988 international consensus on ethics of research involving human subjects maintained that ‘‘[r]apid progress in bioscience has created an urgent need for continuing developments of national standards of ethics in research with human subjects (44, p.60).’’ It is interesting to note that genetic research was not singled out for special concern. Similarly, the background document to the 1991 Council for International Organizations of Medical Sciences (CIOMS) ‘‘Guidelines for Ethical Review of Epidemiological Studies’’ (CIOMS Guidelines) highlights in one brief mention the fact that ‘‘[a]head lie entirely new challenges, such as those arising from the conjunction of molecular and population genetics’’ (20, p.9). The CIOMS Guidelines themselves are generic. It was only in 1993 that the first draft of the proposed UNESCO ‘‘Outline of a Declaration on the Protection of the Human Genome’’ maintained that ‘‘[t]he human genome is a fundamental component of the common heritage of humanity and needs to be protected in order to safeguard the integrity of the human species, as a value in itself, and the dignity and rights of each of its members’’ (27, article 1). This followed a flurry of international statements on ownership and possible patents with regards to human genes (21–24, 28, 30). The ‘‘Draft Convention of Human Rights and Dignity of Human Being with regard to the Application of Biology and Medicine (Draft Bioethics Convention)’’ of the Council of Europe does not address the issue of genomic research per se but does address the issue of noncommerciality (38). In the United States, a recently proposed ‘‘Genetic Privacy Act’’ holds that ‘‘[a]n individually identifiable DNA sample [be] the property of the sample source’’ (74, articles 104(a), 105(b)) (our emphasis). Such ‘‘property’’ terminology lends credence to the fear that genetically ‘‘interesting’’ individuals and selected populations—the ‘‘sample sources’’ in both the HGP and the HGDP—are but human versions of a natural resource and that such research may be potentially stigmatizing and ultimately discriminatory (7). A 1995 report of a UNESCO subcommittee on bioethics and human population genetics research recommended that the UNESCO International Bioethics Committee consider whether they should outline some principles of ethical guidance and give fuller explanation of practical measures and procedures for the HGDP (11, p.18). More recently, this same subcommittee advocated that UNESCO set up a separate ethics committee for population genetics generally, the issues surrounding sampling in the HGDP and HGP being the same (87, 88). Researchers both in the diversity project and in genetic research generally sample individuals and populations for either cultural or genetic purposes or both. Like the controversial issues surrounding international collaborative research, sample/data ownership, and patents in the HGP, the HGDP alliance of population genetics, of genetic epidemiology, and of cultural and anthropological studies requires further research on the ethical, legal, and social issues. The

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SPECIAL FEATURE HGDP has been aware of these issues (2). Its North American regional committee has drafted an extensive ‘‘Model Ethical Protocol for Collecting DNA Samples’’ that discusses in some detail many of the ethical issues raised by this kind of research (10). Nevertheless, the HGDP’s views should be subject to outside discussion and criticism. What is needed then is a ‘‘macroethical’’ framework for the HGP and the HGDP focusing on both communities and individuals (2). Currently, ethical oversight through review by ethics committees (however constituted) applies to human genetic research. In particular, the recruitment of vulnerable populations is subject to stringent review (20, 27, 29, 35). A recent study (79) on ethical, legal, and social issues (ELSI) in human genetics identified an emerging international consensus on the core principles of autonomy, privacy, justice, equity, and quality assurance as forming the basis for policy development in this field. Moreover, international epidemiological studies are guided by the principles of informed consent, maximizing benefit, minimizing harm, confidentiality, and avoidance of conflict of interest (20). However, ‘‘[w]hile there are fundamental human values which should form the basis of all bioethical reflection, we should nevertheless have regard to those other cultural values upon which all societies are not necessarily agreed, learning to respect the way different societies do their ethics’’ (11, p.8). The specific scientific aims of the HGP and the HGDP are different. Thus far, the issues of recruitment, consent, and compensation have been more acute in the latter. The only real difference may well be political. The two international projects share many of the same ethical concerns, and, as the increasing study of multifactorial genetic diseases or predispositions within the HGP requires more population-based studies of genetic variation, the two projects are likely to share even more common concerns. This document studies the two projects together with a view to beginning some reflection on the possible elaboration of a common macroethical framework for international collaboration in population genetic research. Leaving aside questions relating to the possible eventual (mis)use of genetic information in areas such as insurance, employment, forensics and so on to concentrate on common concerns and divergent approaches and opinions in worldwide collaborative research endeavours involving DNA sampling, we will examine international, regional, and national policy positions on the topics of recruitment (A), consent (B), confidentiality and access to human genetic material and/or information (C), compensation and commerciality (D), and finally, patents (E). Unless enshrined in law, such policy positions have varying legal weight. In the absence of specific legislation, however, they constitute a viable normative framework for ethical research. This analysis then will underscore this emerging normative framework and the universal character of the human genome and related research, reinforce the need to understand individual and collective diversity and vulnerability, and urge greater respect for the dignity of the human being as human and as a member of a community and for humanity as a species. A. Recruitment In human genetics research, recruitment in research has traditionally been through pedigree and linkage studies in-

volving at-risk or affected families, through targeted population studies and genetic screening programs, and more recently, through direct mutation analysis of unaffected individuals or populations. Voluntariness is the hallmark of such research and translates into the right to decide whether or not to participate (19, 20, 26, 27). With the discovery of genetic factors in common multifactorial conditions (cancer, cardiovascular, etc.), population screening is expanding beyond newborn screening and carrier testing programs. Undoubtedly, this new territory and these new populations will not only affect the standard approaches and ELSI principles governing screening programs but also (like the AIDS epidemic) force a reevaluation of guidelines applicable to population genetics, to epidemiological studies generally (27), and more specifically, to genetic epidemiology. The HGDP seeks the participation of interested populations that have not been intensively studied genetically. If funding shortages caused the Project to have to select among willing populations, it would be more interested in populations with unique cultural, linguistic, or historical attributes and in populations that were rapidly merging with other populations. Although at one time the HGDP was perceived as focusing on indigenous populations, it is now clear that the Project will seek to include all types of populations, indigenous and otherwise (9, 11). Although this broader focus may diminish recruitment concerns in the HGDP, those concerns extend far beyond that Project. As genetic research itself moves toward a greater number of general and targeted genetic screening programs and toward research into the role of genetic factors in common multifactorial conditions, how then can the principle of voluntariness be respected? To answer that question, three concerns must be addressed. The first is that of the ability to communicate effectively scientific information and the purposes of genetic research within a given society and community. A recent study of the mass media in the United States has shown the power of the gene as cultural icon (81), while other studies show the misunderstanding of genetic testing and information and the need for public education and participation (46, 70). Second, genetic conditions have long been associated with fate, with the notion of ‘‘mutants,’’ and with eradication and eugenics. Based on suspected genetic susceptibility, whole populations can be perceived or perceive themselves as at-risk. This issue of stigmatization is closely linked to the third concern, that of racism based on genetic reductionism. While both the HGP and the HGDP promise to prove individual difference and to show that there is no scientific basis for current political and social concepts of race, ‘‘[t]he greatest danger, as always with debates involving biological variation, lies in the interpretation of culturally created concepts such as ‘ethnicity’ or ‘population’ as natural facts from which extrapolations are made to justify exclusionary or containment policies’’ (15, p.604). These varying sociocultural, political contexts and attitudes, together with the differing social representations of human genetics, cannot be ignored. For these reasons, it has been recommended that members and representatives of communities and populations to be studied should be involved in the planning and carrying out of any population genetics research (11, 13, 14, 20).

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SPECIAL FEATURE Indeed, in 1993, both a communique´ from the Rural Advancement Foundation International (RAFI) (13) and the MATAATUA Declaration on Cultural and Intellectual Property Rights of Indigenous Peoples (14) called for a halt to the HGDP and argued for more cooperation and fuller consultation and participation of indigenous peoples. According to the Mataatua Declaration, even prior to obtaining consent of the participants, the ‘‘moral, ethical, socio-economic, physical and political implications [should be] thoroughly discussed, understood and approved by indigenous peoples’’ (14, article 3.5). Similarly, the CIOMS Guidelines generally maintained that ‘‘[i]ndividuals or communities should not be pressured to participate in a study’’ (20, p.13) and that ‘‘to determine the ethical propriety of . . . inducements, they must be assessed in the light of the traditions of the culture’’ (20, p.13). Respect for such voluntariness in recruitment into population studies thus requires that more attention be paid to prevailing cultural norms, more specifically to the issue of consent at both the level of the community and of the individual. B. Consent At the level of populations, concerns with consent in population studies and differing cultural mores and values led to the recommendation in 1991 from the CIOMS that ‘‘[c]onsent is informed when it is given by a person who understands the purpose and the nature of the study, what participation in the study requires the person to do and to risk, and what benefits are intended to result from the study’’ (20, p.11). Moreover, ‘‘[w]hen 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 the group’’ (20, p.12). Under the HGDP, regional committees were set up in 1994 (in North America with representatives from indigenous peoples) and were instructed to ‘‘take steps to ensure that all samples are collected with meaningful informed consent, obtained from the government of the country, the local official authorities, the population sampled as a group, and also from every sampled individual’’ (9, p.75). The HGDP has undertaken to go beyond existing legal mandates by requiring group consent as well as individual consent for any population’s participation in the Project. Indeed, ‘‘[o]ther cultures . . . may place greater emphasis on the advice of leaders who represent the continuity with traditional wisdom, or with the father of a family or group members. Relevant factors for moral decision-making in communitarian societies may derive from sources not as empirically accessible as medical data. The moral and spiritual values which have profoundly shaped the cultures of different population groups may well result in deeply held convictions regarding bodily and familial integrity’’ (11, p.10). According to the HGDP, ‘‘[i]nformed consent means that all those involved have been informed about the process of taking samples, including risks, if any, and the general purposes for which the samples will be used’’ (9, p.75). To this can be added the need to communicate the benefits, or lack thereof, and the possibility of obtaining a written or verbal consent be it individual or,

in some areas, ‘‘verbal group consent may be more appropriate and perhaps sufficient’’ (8, p.7). It remains to be seen, however, whether group consent is always possible or whether such ‘‘consenting populations’’ can so easily be identified on the presumption of a uniform, shared consensus on cultural values and authority. Obviously, funding agencies are bound by the laws of their countries and ‘‘[n]o one method of providing informed consent will be appropriate for every population’’ (2, p.1). As recognized by CIOMS (20) (for epidemiological research generally), what is a meaningful informed consent changes with prevailing cultural norms. The World Medical Association in its ‘‘Declaration on the Human Genome Project’’ has held that ‘‘[o]ne should respect the will of persons screened and their right to decide about their participation and about the use of the information obtained’’ (22, p.151). The ‘‘Revised Outline of a Declaration on the Protection of the Human Genome’’ of UNESCO proposes that ‘‘[n]o operation affecting a person’s genome, can have any purpose other than scientific, therapeutic or diagnostic. Such an operation can only be undertaken subject to a risk/ benefit assessment, and the obtaining of the prior, free and informed consent of the person concerned or, where appropriate, of his or her duly authorized representatives, the relatives and the family, as the case may be’’ (27, article 8). Finally, like the CIOMS guidelines on epidemiological studies (20), recent guidelines on ethical issues in medical genetics by World Health Organization (WHO) advisers make an exception to obtaining informed consent in the case of anonymous testing or screening for epidemiological purposes (29). At the regional level, the Council of Europe has long upheld the principle of informed consent for its member countries (31–37, 39), a principle reiterated in the proposed ‘‘Draft Bioethics Convention’’ (38). This Draft makes specific mention of the right to withdraw at any time (38, article 5) and of the need to obtain another consent before using specimens obtained during an intervention for any other purpose including research (38, article 13). It is this latter issue that is increasingly drawing attention. Indeed, the national reports from all 12 countries under study in this report uphold the principle of informed consent (43, 46, 49, 50, 53, 55–60, 63–66, 68, 69, 71–75). However, it is interesting to note that recently 5 of them have specifically addressed the issue of leftover specimens, the use of banked samples, or the taking of additional amounts for research purposes and the possibility of requiring or waiving another specific consent in such situations. Overall, the general trend is toward requiring an additional consent (43, 46, 61, 69, 75), with the exception of anonymous studies (61, 73–75). This possible secondary use of samples obtained during medical care or the fact of ‘‘consented-to’’ research samples being used for other purposes raises novel ethical problems. Formerly, blood, tissues, cells, etc., obtained during care or those already given for research were presumed to have been abandoned or to belong to the researcher or bank. The recent extension of respect for human inviolability and integrity through the recognition of greater control by the ‘‘sample source’’ as well as the potential commercial value of such samples affects HGP and HGDP researchers. Three approaches need to be distinguished. The first con-

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SPECIAL FEATURE cerns samples obtained with the expectation by the participant or the community and by the researcher or institution (bank) of abandonment and of disposal by the medical community, such material not having any significance and being considered to be more in the nature of ‘‘waste’’ (45, 69). The second approach is when such human material is considered to be the property of the participant or sample source and like all property, subject to the owners’ will regarding disposal (71, 74). The third approach is when such samples are given as a gift. This latter approach is common to countries with social security and health insurance infrastructures and in those where communitarian principles prevail. In such countries, the gift may be presumed or explicit but in any event is seen as contributing to the common good and the advancement of science while avoiding the potential for commercialization and for the person being seen as a commodity (46–47, 49, 52, 55, 57–58, 61, 62, 67, 69). Under the approach of abandonment, any requirement to recontact former patient/participants for a new specific consent for different diagnoses or research could risk greater harm to their personal and familial privacy than it would constitute respect for their integrity. Even so, in the use of these ‘‘old’’ materials, consideration should be given wherever possible to the removal of all identifiers (61, 75). While such anonymity safeguards the privacy of the person, the family, and the community, as well as the confidentiality of the physician–patient relationship under which the sample was taken, it also protects the researcher in the case of new, incidental findings. While clear with regard to rights that can be exercised over samples, the second approach, that of property (71, 74), may expand choices or severely limit uses and require detailed consent forms and additional administrative surveillance and controls, with, again, concomitant risks to personal privacy and confidentiality. The third, that of the gift principle, is consistent with altruistic values and is increasingly taking the form of an expanded form of informed consent. This latest approach provides patient/participants and communities with specific but standardized options concerning choices to be made with regard to types of research (46, 49, 51, 60), banking (51, 60, 61), access by family members (60), removal (75), or destruction (60, 74), or if wished, even no communication of results at all (49). The gift then is conditional on respect of such specific choices by all researchers and laboratories and binds the latter. Irrespective of the approach adopted, there is no doubt that research uses of human genetic material, however obtained, and for whatever project, are becoming constrained. Symbolic of new relationships between the person or community and human genetic material, between the researcher and that person or community, and finally, between the person, the researcher, the community, and the biotechnology industry, the presumption of disinterest no longer holds, and greater transparency, communication, and choices are emerging norms. This reaffirmation of the property–person distinction and of the distinction between the animal, plant, and human species with regard to the ‘‘exploitation’’ of ‘‘natural’’ resources underscores the uniqueness of the human being. While procedural on its face, the fractionation of blanket con-

sent into specific choices based on informed participation then constitutes another step toward respect for individual and collective values and dignity. Equally problematic, however, is the need to respect the latter while ensuring confidentiality and access where needed. C. Access to Human Genetic Material/Information The need to protect personal, medical, and genetic information has been recognized. Nevertheless, access by the persons or communities concerned was often more limited than access by the research community itself. Indeed, international collaborative research has traditionally meant a relative degree of sharing of information and materials among investigators. Renewed interest in potential commercial spin-offs has endangered this free exchange but at the same time concern about such commercialization has fostered calls for greater access and control by the participants themselves. Epidemiologists have traditionally ‘‘aggregate[d] numbers so that individual identities [are] obscured’’ (20, p.16). Personal identifying information then is discarded. With the increasing number of identifiable genetic factors or conditions, the use of informatic technologies, and the accompanying risks of unauthorized release, researchers in human genetics are becoming sensitive to the need to provide greater protection for genetic information on both an individual and a systemic level (78). As concerns international exchange among researchers, HUGO maintains that ‘‘scientific and technology policies of individual countries must facilitate rather than impede the free flow of scientific information’’ (21, p.2). Similarly, a WHO expert advisory group (30) and the proposed UNESCO Declaration hold that states should share genetic information and markers and ‘‘foster the international spread of scientific culture concerning the human genome . . . and cultural co-operation, particularly between industrialized and developing countries’’ (27, article 15). Still at the international level, the 1991 CIOMS Guidelines (20) followed by the 1992 World Medical Association’s ‘‘Declaration on the Human Genome Project’’ (22) and statements from other international bodies (27–30) maintained that data should be confidential and access by researchers or third parties should be subject to the consent of the participant/ patient. It is interesting to note that exceptions to participant/patient control of data and material include not only situations specifically provided for by law but also situations ‘‘justified by the general interest’’ (27, 26), the interests of research (including anonymous research), and the needs of blood relatives (29). While seemingly contradictory on its surface, once confidentiality and tighter controls over access are clarified and ensured for collaborative international research, researchers may well have greater freedom to share samples and data. Issues of confidentiality and access can be raised on two levels. The first is that of confidentiality and access to samples (either collected for specific projects or already banked by local geneticists or epidemiologists), and the second is that of maintaining the ‘‘privacy’’ of the sampled populations themselves and the confidentiality of individual data. This is even more problematic under the HGDP, which involves not

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SPECIAL FEATURE only DNA sampling but also the collection of ethnographic information. Beginning with the issues of confidentiality and access, under the HGDP, it is the duty of regional committees to ‘‘take steps to ensure that privacy of individuals participating in the project is protected. The individual identities must not be made known to the investigators handling the samples and must be respected in culturally appropriate ways’’ (9, p.75). Yet at the same time, ‘‘[e]ach region must be committed to the general principle of sharing data and open access to all qualified researchers’’ (9, p.77). It is here that the choices made by the participants and the institutional policies with regard to genetic information will determine access for current and future research and for other uses of previously banked samples. The North American Committee of the HGDP in its proposed ‘‘Model Ethical Protocol for Collecting DNA Samples’’ upholds the need for confidentiality. Therefore ‘‘[i]nformation disclosed generally through the HGDP database should not include any information that could be used to identify individuals’’ (10, p.37). Like the CIOMS Guidelines then, the burden of proof would be on researchers to demonstrate the need for access to identifying information or to recontact the donor (20). In any event, ‘‘[n]either the central repository nor the individual researcher should normally be empowered to make a decision to release identifying information’’ (10, p.39). Turning now to the level of populations, it is often the choosing of the population of ‘‘interest’’ that in itself constitutes a loss of privacy through the often unintended accompanying stigmatization. The underlying problem here is both a misunderstanding of human genetics that proves variability and difference—and this even within populations—more than it does homogeneity, and the reinforcement of the social representations of genetic disease through genetic reductionism. Such genetic reductionism perceives the gene as the person/population and the person/population as the disease, and thus the person/population becomes the gene. Paradoxically, credibility can be lent to such reductionism by overprotection or even the labeling of populations as special or unique. Respect for privacy at the level of populations, then, can ultimately be achieved only through voluntary participation and through education of the research community, the public, and the media. While working to achieve such understanding, one important recommendation that imports a positive obligation to act where group confidentiality cannot be maintained or is violated is that ‘‘the investigators should take steps to maintain or restore a group’s good name and status’’ (20, p.16). Moreover, as noted in the proposed ‘‘Model Ethical Protocol for Collecting DNA Samples’’: ‘‘[W]e do not believe that researchers should normally encourage populations to seek complete confidentiality’’ (10, p. 39). At the regional level, in conformity with its 1981 ‘‘Convention on the Protection of Individuals with Regard to Automatic Processing of Personal Data’’ (31), the Council of Europe has long upheld the principle of confidentiality of genetic information, as a form of medical information, with some exception being made for access for legally authorized authorities or ‘‘in the case of severe genetic risk for other family members’’ (37, principle 9). Moreover, ‘‘[s]amples collected for a specific medical or scientific purpose may not, without permission of the persons concerned or the persons legally

entitled to give permission on their behalf, be used in ways which could be harmful to the persons concerned’’ (37, principle 13(a)). ‘‘The use of genetic data for population and similar studies has to respect rules governing data protection, and in particular concerning anonymity and confidentiality’’ (37, principle 13). As concerns access, the European Commission has maintained that ‘‘[t]he sharing of all knowledge and distribution of materials will be obligatory’’ (40, rec.2.3). Moreover, ‘‘[d]ata and materials must be readily available to bona fide researchers’’ (40, rec.3.2.7). At the national level, the majority of countries under study are beginning to expand their laws or codes of conduct governing medical confidentiality to include additional protection for genetic information (42, 49, 57, 60–62, 65, 69, 75). Several have begun to study the issue of access to the samples themselves (51, 55, 61, 69, 75). The coding of genetic information and computerization contribute the principal orientations. A recent discussion paper presented to the Australian Health Ethics Committee also addressed the issue of computerized databases and the possibility of creating mechanisms ‘‘whereby the patient or family could be notified of unexpected findings in which they might have an interest’’ (43, p.4). Generally, it is ‘‘considered acceptable to disseminate unlinked, stored biomedical material for research use without consent’’ (50, p.29) or even linked material provided for by law (usually for public health) (50), for law enforcement (74), for family members (22, 29, 37, 45), or if used anonymously, for research or epidemiological purposes (29, 73, 74, 75). When disseminated across borders, personal identifiers should be removed (50). To this, another report has added the proviso that when the samples themselves are sent, there is an obligation under a publicly funded health care system to always keep a copy (49). The latter obligation exists because the sampling itself, the processing of the information, and the very participation of individuals or populations in such regimes are facilitated and funded by such a system and so there is an obligation to ensure that the public will always be able to benefit from such research. Only one report suggests that ‘‘legislation should be enacted to ensure that no person or institution be able to obtain access, even by court order or subpoena, to either the samples used in research or to the specific results, since sources are entitled to a higher level of protection of confidentiality in exchange for allowing their samples to be used for research’’ (75, rec.3). National policies on access and confidentiality go further in singling out and protecting genetic information and DNA samples than at the regional or international levels, but the majority have not yet discussed the issues of compensation and commerciality to the same extent as the international arena. D. Compensation and Commerciality Issues that have already haunted the HGP have been magnified in discussions of the HGDP. Nowhere is this more evident than in the area of compensation of research participants (individuals or populations) and that of possible commercial benefits or spin-offs. Compensation can either be that envisaging payment of some form for participation or that of participating in the eventual economic benefits. Compensation of individual sub-

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SPECIAL FEATURE jects is generally not discussed in international policy statements but the issue of commerciality is. The HGDP, while eschewing commercial funding (7), has not ruled out the possibility of compensating populations in return for participation (2, 9, 10, 12). A recent proposal for a North American protocol of the HGDP noted that certain ‘‘culture[s] may demand that researchers give something of value to the community in return for its participation in the research’’ (10, p. 22). This issue is not new and the Protocol recommends raising the issue with the population and an ethics committee before any participation by members of the population. Furthermore, ‘‘[t]he basic principles that should govern researchers in this connection are: honesty, legality and appropriateness’’ (10, p.23–29). Individual or group compensation for initial participation could, however, easily run afoul of the principle of inalienability of the human body and its constituent parts and be seen as an inducement to consent (79). Indeed, as we will see, providing for some share in eventual benefits would often be more ‘‘appropriate’’ than arrangements for compensation for participation. Suggestions that groups or populations be ‘‘enabled to enter into contracts with funding companies’’ while not ‘‘on the basis of the sale of blood or other bodily tissues but on the basis of their cooperation in a scientific program’’ (11, p.17) may then be too overly broad and inadvertently allow for inducement through payment. Indeed, compensation for participation in genetic research generally by individuals or populations could better take the form of ensuring technology transfer (where so desired), local scientific, technical, and medical training, creation of joint ventures and investments, and the installation and ongoing maintenance of infrastructures (laboratories, medical facilities, libraries, access to computerization). The principle of reciprocity of partnerships may be best achieved by building durable socioeconomic infrastructures or perhaps by standardizing compensation via a percentage figure for the sharing of scientific or eventual economic gains when patents are developed. Whatever approach is adopted, it should be made clear at the outset and be part of the recruitment and informed consent process (10). While the proposed UNESCO Declaration does not address the issue of compensation for participation (27), at the regional level, the Council of Europe’s ‘‘Draft Bioethics Convention’’ maintains that ‘‘[t]he human body and its parts, shall not, as such, give rise to financial gain’’ (38, article 11). Similarly, several countries have explicitly adopted legislation (57, 58, 66) or proposed policies prohibiting financial rewards in exchange for samples (46, 47, 49, 53, 55, 61, 69). This is consistent with the gift-based philosophy of donorship. The gift approach, however, can lead to exploitation of individuals or populations and so in these same countries strict legislative and policy controls govern the issue of patenting. E. Patenting Already in 1992, HUGO publicly maintained that ‘‘human partial cDNA sequences and more generally DNA sequence data obtained in the course of the Human Genome Project should be openly available to the scientific commu-

nity’’ (21, p.2). Further, HUGO did ‘‘not oppose patenting useful benefits derived from genetic information [but did] oppose the patenting of short sequences from randomly isolated portions of genes encoding proteins of unknown function’’ (21, p.1). Similar statements by the International Council of Scientific Unions (23), the first South – North Human Genome Conference (24), and the World Medical Association (22) as well as other international bodies (27, 28) underscore the position that patents should not be awarded for naturally occurring DNA sequences. HUGO has recently reaffirmed and clarified its position because of the dangers of broad patent protection. Indeed, in 1995 it warned against publication or submission of partial sequences to a database that would preclude patenting of innovative disease gene discoveries leading to improved medical diagnostics and therapeutics (28). Thus, only the discovery of biological functions of sequences and the use of genes and gene products in the diagnosis and treatment of human diseases are significant (28). The HGDP has been similarly concerned with patenting issues, all the more so considering cultural sensitivities (86) and the past experiences of many developing countries with other ‘‘natural resources’’ such as plants (9). The HGDP does not have a definitive position on patentability but does on the broader issue of commerciality. It not only refuses commercial funding (10) but also holds that it will not patent or profit from any discoveries based on its collection and will attempt to ensure that should those collections lead to products of commercial value, a fair financial return would go to the relevant participating populations. More recently, it has been suggested that populations should be permitted to contract with regard to patenting issues and commercial discoveries. These conditions could include among others (a) a ban on commercial use without the population’s subsequent express written permission, (b) a ban on commercial use without payment of royalties to the population, (c) a ban on patenting genetic sequences taken from the material (or, at the least, a requirement that any such patents, if procured, be assigned to the population) (7). Yet such an approach, while respectful of the uniqueness of populations, could well undermine universal adherence to and promotion of the principle of inalienability. Indeed, country by country negotiations or other ad hoc approaches could lead to the varying conditions and inequalities that after centuries of exploitation required the international ‘‘Convention on Biological Diversity.’’ The difficulties of this latter a posteriori approach could well serve as an example of the need for a prospective, dynamic, and ongoing normative consensus (80). One approach that would be more consistent with respecting legitimate patent claims and yet upholding the principle of noncommerciality of the inalienability of the human person, of the human body, and of its constituent parts would be for an international agreement on a percentage royalty to be paid to an international body such as UNESCO for the benefit of participating populations (10, 84). Individual participants and populations would be informed of this policy and, consistent with such policy, forego financial interests. This approach would be similar to that already recommended on the regional level by the European Commission in 1991 when it stated: ‘‘[t]he various human

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SPECIAL FEATURE genome programmes worldwide will generate new materials and information of potential commercial value—even if based on DNA sequences which may not themselves be patentable. The ownership and ready availability of materials and information should be resolved in an international context’’ (40, article 3.2.7). It could be argued that within Europe (41), the European Patent Convention could provide for the flexibility needed through a more liberal interpretation of its public order and morality exclusion. At the national level, while the majority of the countries under study endorse the position of noncommerciality (46, 47, 49, 52, 54, 55, 57, 58, 61, 62, 67, 69), only France has specifically legislated on the issue of patents (57). The first two paragraphs of Article L. 611-17 of the Intellectual Property Code now read: ‘‘The following shall not be patentable: (a) Interventions whose publication or realization would be contrary to public order and morality, the realization of such an invention not being considered as such solely because it is prohibited by legislation or a regulatory provision; in this connection, the human body and its elements and products, as well as knowledge of the total or partial structure of a human gene, may not, as such, be subject of a patent’’ (57, article 7). In any event, as mentioned in a recent Norwegian report, however, ‘‘[g]enes that have no known function will not be patentable in Norway because they do not fulfill the requirements of patentability’’ (62, p.84). Thus, the failure to legislate specifically may well be because a strict interpretation of patent law would preclude acceptability, as was the case with the failed NIH attempt to patent sequences (76, 78). Indeed, there is no doubt that ‘‘[g]enes are not excepted from access to patenting and must, according to the current patent laws, be treated in the same way as all other biological material’’ (62, p.84). While current law then may well be sufficient, the patenting issue has become a political one as witnessed by the recent defeat before the European Parliament of the ‘‘Draft European Directive on the Legal Protection of Biotechnological Inventions.’’ This directive aimed to clarify but not to change existing European Patent Law (69, 82). What is needed is a reaffirmation of patenting principles as applicable to human genes and sequences. Participating individuals, populations, researchers, and the biotechnology industry would benefit from the clarification and reaffirmation of the utility/usefulness and novelty criteria. Thus, ‘‘. . . only a combination of a gene and a known utility which is novel and not obvious should be patentable in the context of that utility; and . . . a combination of the same gene and a further novel utility should also be patentable’’ (70, paragraph 205). ‘‘The effect of this should be to ensure that genes are only patentable in the context of a particular utility’’ (70). Finally, irrespective of the resolution of this debate, greater attention should be paid by researchers and industry to ensure that the long-term interests of participating populations (while perhaps not the direct beneficiaries of the financial benefits of eventual patents) are taken into account. This can be achieved through the conservation of a copy of the genetic material, the communication of discov-

eries to the community, and the promotion of scientific development in the community (49). Conclusion This brief overview of the ethical issues in international collaborative research on the human genome underscores the need to commence discussion and reflection on a common framework of guiding principles specific to the area of genetic research in the international arena. With a view to the issues raised by both the HGP and the HGDP by different international, regional, and national bodies and organizations, as well as the mandate of the ethics committee of HUGO, we propose the following 10 principles: Competence, Communication, Consultation, Consent, Choice, Confidentiality, Collaboration, Conflict of Interest, Compensation, and Continual Review. It may seem axiomatic that competence be the first guiding ethical principle. It is, however, with the assurance of both appropriate training and quality control that respect for human dignity begins. Indeed, the implementation of other ethical principles depends on the assurance of competence. The communication of accurate scientific information in understandable language to the populations, families, and persons concerned, taking account of varying sociocultural and political implications and contexts, is the second ethical prerequisite. Communication involves not only the transmission of comprehensive and clear information in differing forms and formats, but also discussion. Consultation should precede recruitment and possible participation. Cultural norms vary, as do perceptions of disease, of disability, of family, and of the place and importance of the individual. Cooperation and respect for voluntariness means that consultation is an ongoing process. Fourth, the informed decision to consent to participate can be individual, familial, or at the level of communities and populations. An understanding of the nature of the research, of the risks and benefits, and of the alternatives is crucial. Such consent should be free from coercion. As a rule, contact for recruitment should be made by the individual and the families within the communities themselves and not directly by the researcher. Anonymous testing for epidemiological purposes is an exception to the requirement of an informed consent. Fifth, the participant should be offered choices with regard to various options regarding, for example, actual or future uses for other identified or unidentified research, for banking, or for access by family members. The choice of whether or not to be informed with regard to results or incidental findings can also be offered. Such choices bind other researchers and laboratories. In this way, personal and community values can be respected. Sixth, recognition of privacy and protection against unauthorized access are ensured by the confidentiality of genetic information. Coding of such information, procedures for controlled access, and policies for the transfer and conservation of samples and information should be developed and put into place prior to sampling. Special consideration should be given to the actual or potential interests of family members. Seventh, collaboration between persons, populations, and

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SPECIAL FEATURE researchers and between programs in the free flow, access, and exchange of information is essential not only to scientific progress but also for the present or future benefit of all participants. Cooperation and coordination between industrialized and developing countries should be facilitated. An integrated approach and standardization of conditions and consent is essential to ensure viable collaboration and comparison of results. Eighth, at the time that information is communicated and before agreement is reached, any actual or potential conflict of interest should be revealed. Such actual or potential conflicts should also be reviewed by an ethical review committee prior to commencement of any research. Honesty and impartiality are the cornerstones of ethical research. Ninth, undue inducement through compensation for individual participants should be prohibited. This prohibition does not include agreements with groups, communities, or populations that foresee technology transfer, local training, joint ventures, provision of health care or of information infrastructures, or the possible transfer of a percentage of royalties to an international body such as UNESCO. Tenth, without continual review, oversight, and monitoring, the enactment of the above principles is at risk. Indeed, without continuing evaluation, the potential for exploitation, for duplicity, for abandonment, and for abuse by all cannot be ignored. Like competence, continual review is a sine qua non, fundamental to making respect for human dignity real in international collaborative genetic research.

APPENDIX Following discussion at the HUGO-ELSI meeting in Washington on October 13–15, 1995, the principles of the discussion document were adopted and modified to read as follows: HUGO Ethical, Legal, and Social Issues Committee Report to HUGO Council Based on the Discussion Paper ‘‘Ethical Issues in International Collaborative Research on the Human Genome: The HGP and the HGDP’’ Statement on the Principled Conduct of Genetic Research2 The Human Genome Project (HGP), proposed in the 1980s and formally initiated in 1990, has as its specific goals identification of all human genes and sequencing of the entire genome. Completion of the HGP in the projected 15 years will provide a source book for biology and medicine. Yet, in this time frame, the function of all genes, singly and in concert, 2 This statement was adopted by HUGO Council on March 21, 1996.

will not be known, nor will the worldwide variation in the genes have been defined. The Human Genome Diversity Project (HGDP) is an international scientific endeavor that complements the HGP by examining the genomic variation of the human species, through analysis of DNA from populations, families, and individuals worldwide. The HGDP promises to help us understand the fundamental unity of humankind, human biological history, population movements, and susceptibility or resistance to various human diseases. The HGP, the HGDP, and other genetic research have given rise to a number of concerns: • Fear genome research could lead to discrimination against and stigmatization of individuals and groups and be misused to promote racism; • Loss of access to discoveries for research purposes, especially through patenting and commercialization; • Reduction of human beings to their DNA sequences and attribution of social and other human problems to genetic causes; • Lack of respect for the values, traditions, and integrity of populations, families, and individuals; and • Inadequate engagement of the scientific community with the public in the planning and conduct of genetic research. The Council of the Human Genome Organization (HUGO) asked its Ethical, Legal, and Social Issues Committee (HUGO-ELSI), comprising experts from a number of countries and disciplines, to provide guidance and procedures that would address these concerns and ensure that ethical standards are met as the HGP and the HGDP proceed. The HUGO-ELSI Committee bases its recommendations on the following four principles: • Recognition that the human genome is part of the common heritage of humanity; • Adherence to international norms of human rights; • Respect for the values, traditions, culture and integrity of participants; and • Acceptance and upholding of human dignity and freedom. The HUGO-ELSI Committee recommends: That scientific competence is the essential prerequisite for ethical research. It includes appropriate training, planning, pilot and field testing, and quality control through continual review. That communication not only be scientifically accurate, but understandable to the populations, families, and individuals concerned and sensitive to their social and cultural context. Communication is a reciprocal process; researchers must strive to understand as well as to be understood. That consultation should precede recruitment of possible participants and should continue throughout the research. Cultural norms vary, as do perceptions of health, disease, and disability, of family, and of the place and importance of the individual. That informed decisions to consent to participate can be individual, familial, or at the level of communities and populations. An understanding of the nature of the research, the risks and benefits, and any alternatives is crucial. Such consent should be free from coercion by scientific or other authorities. Under certain conditions and with proper authority,

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SPECIAL FEATURE anonymous testing for epidemiological purposes and surveillance could be an exception to consent requirements. That any choices made by participants with regard to storage or other uses of materials or information taken or derived therefrom be respected. Choices to be informed or not with regard to results or incidental findings should also be respected. Such choices bind other researchers and laboratories. In this way, personal, cultural, and community values can be respected. That recognition of privacy and protection against unauthorized access be ensured by the confidentiality of genetic information. Coding of such information, procedures for controlled access, and policies for the transfer and conservation of samples and information should be developed and put into place before sampling. Special consideration should be given to the actual or potential interests of family members. That collaboration between individuals, populations, and researchers and between programs in the free flow, access, and exchange of information is essential not only to scientific progress but also for the present or future benefit of all participants. Cooperation and coordination between industrialized and developing countries should be facilitated. An integrated approach and standardization of conditions and consents is essential to ensure viable collaboration and comparison of results. That any actual or potential conflict of interest be revealed at the time information is communicated and before agreement is reached. Such actual or potential conflicts should also be reviewed by an ethical review committee before any research begins. Honesty and impartiality are the cornerstones of ethical research. That undue inducement through compensation for individual participants, families, and populations should be prohibited. This prohibition, however, does not include agreements with individuals, families, groups, communities, or populations that foresee technology transfer, local training, joint ventures, provision of health care or of information infrastructures, reimbursement of costs, or the possible use of a percentage of any royalties for humanitarian purposes. That continual review, oversight, and monitoring are essential for the implementation of these recommendations. Such review should include, where possible, representatives of participants in this research. Indeed, without continuing evaluation, the potential for exploitation, for duplicity, for abandonment, and for abuse by all cannot be ignored. Like competence, continual review is imperative to realizing human dignity in international collaborative genetic research. ACKNOWLEDGMENTS This report has benefited considerably from the very helpful comments of Dr. C. Laberge and Professor H. T. Greely.

REFERENCES A. HGDP 1. HGDP (1992). ‘‘Human Genome Diversity Workshop 1,’’ Stanford, CA.

2. HGDP (1993). ‘‘Summary of Planning Workshop 3(B): Ethical and Human Rights Implications,’’ Bethesda, MD. 3. Greely, H. T. (1993). ‘‘Recommendations Concerning the Human Genome Diversity Project and Ethical and Rights Issues.’’ 4. HUGO (1993). ‘‘The Human Genome Diversity Project, Summary Document’’ Hugo Europe, London. 5. Bodmer, W. (1993), ‘‘The Case for the Human Genome Diversity Project’’ Imperial Cancer Research Fund. 6. HGDP Organizing Committee (1993). ‘‘Answers of the HGDP Organizing Committee to the Questions Asked by the Honourable D. K. Akaka, United States Senator.’’ 7. HGDP North American Committee (1994). ‘‘Answers to Frequently Asked Questions About HGDP.’’ http://lotka.stanford.edu/research/diversity.html. 8. Majumder, P. P. (1994). ‘‘Human Genome Diversity Project, a Proposal for an Indian Role in an International Initiative,’’ Address to the International Bioethics Committee of UNESCO, Paris. 9. Cavalli-Sforza, L. L. (1995). The Human Genome Diversity Project. In ‘‘International Bioethics Committee of UNESCO, Proceedings 1995,’’ Paris. 10. HGDP, North American Committee (1995). Draft ‘‘Model Ethical Protocol for Collecting DNA Samples.’’ 11. Subcommittee on population genetics of the UNESCO International Bioethics Committee (1995). Draft report on ‘‘Bioethics and Human Genetics Research,’’ http://www.biol.tsukuba.ac.jp/ Çmacer/PG.html. 12. ‘‘Human Genome Diversity Project’’ (July 1995). Genome Digest 12. 13. Rural Advancement Foundation International (RAFI) Communique´ (May 1993). ‘‘Patents, Indigenous Peoples, and Human Genetic Diversity,’’ http://www.charm.net/Çrafi/19932.html. 14. First International Conference on the Cultural and Intellectual Property Rights of Indigenous Peoples (June 1993). ‘‘The Mataatua Declaration on Cultural and Intellectual Property Rights of Indigenous Peoples.’’ 15. Lock, M. (1994). Interrogating the Human Diversity Genome Project Soc. Sci. Med. 39: 603. 16. Rural Advancement Foundation International (RAFI) Communique´ (January/February 1994). ‘‘The Patenting of Human Genetic Material,’’ http://www.charm.net/Çrafi/19941.html.

B. International 17. Annas, G. J., and Grodin, M. A. (1992). The Nuremberg Code. In ‘‘The Nazi Doctors and the Nuremberg Code, Human Rights in Human Experimentation,’’ Oxford Univ. Press, Oxford New York. 18. World Medical Association. Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects, adopted by the 18th World Medical Assembly (Helsinki, Finland, June 1964) and amended by the 29th World Medical Assembly (Tokyo, Japan, October 1975), 35th World Medical Assembly (Venice, Italy, October 1983), and the 41st World Medical Assembly (Hong Kong, September 1989). In Bankowski, Z., and Capron, A. M., Eds. (1993). ‘‘Ethics and Research on Human Subjects, International Guidelines, Proceedings of the XXVIth CIOMS Conference,’’ Geneva. 19. CIOMS (1991). The Declaration of Inuyama: Human genome mapping, genetic screening and gene therapy. In ‘‘Genetics, Ethics and Human Values, Proceedings of the XXIVth CIOMS Round Table Conference’’ (Z. Bankowski and A. M. Capron, Eds.) Geneva.

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SPECIAL FEATURE 20. CIOMS (1991). ‘‘International Guidelines for Ethical Review of Epidemiological Studies,’’ Geneva. 21. The Human Genome Organization (1992). ‘‘HUGO Position Statement on cDNAs: Patents.’’ 22. World Medical Association (1993). Declaration on the Human Genome Project. Int. Dig. Health Leg. 44: 150. 23. International Council of Scientific Unions (1993). Statement on gene patenting. Int. Dig. Health Leg. 44: 363. 24. First South–North Human Genome Conference (1993). Declaration on patenting of human DNA sequences. Int. Dig. Health Leg. 44: 362. 25. CIOMS (1993). ‘‘International Ethical Guidelines for Biomedical Research Involving Human Subjects,’’ Geneva. 26. International Workshop on Legal Aspects of the Human Genome Project adopts Bilbao Declaration (1993). Int. Dig. Health Leg. 45: 234. 27. UNESCO (1995). ‘‘Revised Outline of a Declaration on the Protection of the Human Genome,’’ International Bioethics Committee, Paris, http://www.biol.tsukuba.ac.jp/Çmacer/EJ56/ EJ56H.html. 28. Caskey, C. T., et al. (April 1995). HUGO statement on patenting of DNA sequences. Genome Digest 6. 29. Wertz, D. C., et al. (1995). ‘‘Guidelines on Ethical Issues in Medical Genetics and the Provision of Genetic Services,’’ World Health Organization, Geneva. 30. World Health Organization (1995). ‘‘Hereditary Diseases,’’ WHO Technical Report Series, Geneva.

C. Regional 31. Council of Europe. ‘‘Convention for the Protection of Individuals with Regard to Automatic Processing of Personal Data’’ Strasbourg: January 28, 1981. 32. Council of Europe (1981). Recommendation No. R(81) of the committee of ministers to member states on regulations for automated medical data banks. Int. Dig. Health Leg. 32: 740. 33. Council of Europe, P. A., 33rd Session, Adopted, Rec. 934 (1982) on genetic engineering. Int. Dig. Health Leg. 32: 382. 34. Council of Europe (1990). Recommendation No. R (89) 4 of the Committee of Ministers to Member States on the Collection of Epidemiological Data on Primary Health. Int. Dig. Health Leg. 41: 148. 35. Council of Europe (1990). Recommendation No. R(90)3 of the Committee of Ministers to Member States Concerning Medical Research on Human Beings. Int. Dig. Health Leg. 41: 461. 36. Council of Europe, C. M., 442nd meeting, Adopted, Rec. R (90) 13 on Prenatal Genetic Screening, Prenatal Genetic Diagnosis and Associated Genetic Counselling. Int. Dig. Health Leg. 41: 615. 37. Council of Europe, C. M., 470th meeting, Adopted, Rec. R (92) 3 on Genetic Testing and Screening for Health Care Purposes. Int. Dig. Health Leg. 43: 284. 38. Council of Europe. Draft Convention for the Protection of Human Rights and Dignity of Human Beings with Regard to the Application of Biology and Medicine: Bioethics Convention, (Strasbourg: Directorate of Legal Affairs, July 1994), also in (June–July 1994) Bull. Med. Eth. 19. as amended Council of Europe, P.A., First part of its 1995 session (30 January–3 February) on the Draft Bioethics Convention, Adopted, Opinion No. 184 on the Draft Bioethics Convention. 39. European Parliament. Resolution on the Ethical and Legal Problems of Genetic Engineering, Adopted on 16 March 1989,

Official Journal of the European Communities, 17 April 1989; also in (April 1990) Bull. Med. Eth. 8. 40. European Commission, Working Group on the Ethical, Social and Legal Aspects of Human Genome Analysis. Report of 31 December 1991, (WG-ESLA), also in (June 1993) Bull. Med. Eth. 19. 41. Council of Europe, P.A., 1994 Session, 15th Sitting. Adopted, Rec. 1240 (1994) on the Protection and Patentability of Material of Human Origin (1995). Law Human Genome Rev. 2: 226.

D. National

Australia 42. National Health and Medical Research Council (1991). ‘‘Guidelines for the Use of Genetic Registers in Medical Research,’’ Report to the NHMRC by the Medical Research Ethics Committee of NHMRC, Australian Government Publishing Service, Canberra. 43. Australian Health Ethics Committee (1993). Discussion paper ‘‘Use of Routine Blood and Tissue Samples for Research,’’ Australian Health Ethics Committee, Canberra.

Canada 44. Medical Research Council of Canada (1987). ‘‘Towards an International Ethic for Research with Human Beings,’’ Medical Research Council of Canada, Ottawa. 45. Canadian College of Medical Geneticists (1991). Policy statement concerning DNA banking and molecular genetic diagnosis. Clin. Invest. Med. 14: 363. 46. Science Council of Canada (1991). ‘‘Genetics in Canadian Health Care, Report 42,’’ Minister of Supply and Services Canada, Ottawa. 47. Law Reform Commission of Canada (1992). ‘‘Procurement and Transfer of Human Tissues and Organs, Working paper 66,’’ Minister of Supply and Services Canada, Ottawa. 48. Canadian Genome Analysis and Technology (1995). General principles regarding intellectual property rights. Genexpress 3: 12. 49. Fonds de Recherche en Sante´ du Que´bec, Re´seau de ge´ne´tique ´ nonce´ de principes: Me´decine humaine du Que´bec (June 1995). E ge´ne´tique et recherche ge´nomique. Recherche en sante´ 30.

Denmark 50. Danish Council of Ethics (1993). ‘‘Ethics and Mapping of the Human Genome,’’ Danish Council of Ethics, Copenhagen. 51. Danish Council of Ethics (1994). ‘‘Patenting Human Genes—A Report,’’ Danish Council of Ethics, Copenhagen.

France 52. Comite´ consultatif national d’e´thique pour les sciences de la vie et de la sante´. ‘‘Avis sur les proble`mes pose´s par le diagnostic pre´natal et pe´rinatal, Rapport,’’ May 13 1985. 53. Comite´ consultatif national d’e´thique pour les sciences de la vie et de la sante´. ‘‘Avis sur l’application des tests ge´ne´tiques aux e´tudes individuelles, e´tudes familiales et e´tudes de population,’’ June 24 1991. 54. National Ethical Consultative Committee for the Life and Health Sciences (1994). Opinion on the non-commercialization of the Human Genome. Int. Dig. Health Leg. 44: 130. 55. Ministry of Higher Education and Research (1994). ‘‘Report of

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SPECIAL FEATURE the Study Group on the Intellectual Protection of the Results of Research on the Human Genome, Cell Collection, and DNA Sequence Data,’’ Paris. 56. Anonymous (1994). Law No. 94-548 on the processing of nominative data with the objective of research in the health field, and amending Law No. 78-17 of 6 January 1978 on informatics, personal card-indexes, and freedom. Int. Dig. Health Leg. 45: 495. 57. Anonymous (1994). Law No. 94-653 on respect for the human body. Int. Dig. Health Leg. 45: 498. 58. Anonymous (1994). Law No. 94-654 on the donation and use of elements and products of the human body, medically assisted procreation, and prenatal diagnosis. Int. Dig. Health Leg. 45: 473.

Japan 59. Health Science Council (1993). ‘‘Guidelines for Gene Therapy Clinical Research.’’

Netherlands 60. Health Council of the Netherlands (1989). ‘‘Heredity: Science and Society,’’ Health Council of the Netherlands, The Hague. 61. Health Council of the Netherlands (1994). ‘‘Committee on Human Tissue for Special Purposes, Proper Use of Human Tissue,’’ Health Council of the Netherlands, The Hague. 62. Ministry of Health and Social Affairs (1992–1993). ‘‘Biotechnology Related to Human Beings, Report No. 25 to the Storting on Biotechnology related to Human Beings,’’ Ministry of Health and Social Affairs, Oslo.

Norway 63. Anonymous (1994). Act relating to the application of biotechnology in medicine. (June–July) Bull. Med. Eth. 8.

Spain 64. Anonymous (1991). Law No 42/1988 of 28 December 1988 on the donation and use of human embryos and fetuses or their cell, tissues, or organs. Int. Dig. Health Leg. 42: 64.

Sweden 65. Ministry of Health and Social Affairs (1991). ‘‘Swedish Act concerning the Use of Gene Technology on Human Beings and Experiments with Fertilised Ova.’’

Switzerland 66. Amendment of Federal Constitution, August 13 1992, Recueil officiel des lois fe´de´rales, 25 aouˆt 1992, no. 32, 1579; also in (1992) Int. Dig. Health Leg. 42: 745. 67. Acade´mie suisse des sciences me´dicales (1993). Directives me´dico-e´thiques concernant les examens ge´ne´tiques sur l’homme [‘‘Medical-ethical Guidelines for Genetic Investigations in Humans’’]. Bulletin des me´decins suisses 1454.

United Kingdom 68. Yates, J. R. W., Malcolm, S., and Read, A. P. (Clinical Genetics Society) (1989). Guidelines for DNA banking. J. Med. Genet. 26: 245. 69. Nuffield Council on Bioethics (1995). ‘‘Human Tissue: Ethical and Legal Issues,’’ London. 70. Science and Technology Committee (1995). ‘‘Human Genetics: The Science and its Consequences. Third Report of the Science and Technology Committee,’’ Committee Office, House of Commons, London.

United States 71. American Society of Human Genetics (1987). DNA banking and DNA analysis: Points to consider. Am. J. Hum. Genet. 781. 72. National Institutes of Health, Office of Protection from Research Risks (1993). ‘‘Protecting Human Research Subjects, Institutional Review Board Guide Book,’’ Washington, DC. 73. Andrews, L. B., Fullarton, J. E., Holtzman, N. A., and Motulsky, A. G., Eds. (1994). ‘‘Assessing Genetic Risks—Implications for Health and Social Policy,’’ Committee on Assessing Genetic Risks, Institute of Medicine of the National Academy of Science, National Academy Press, Washington, DC. 74. Annas, G. J., Glantz, L. H., and Roche, P. A. (1995). ‘‘Proposal: The Genetic Privacy Act and Commentary,’’ Boston. http:// www-busph.bu.edu/Depts/HealthLaw/. 75. Clayton, E. W. et al. (1995). Informed Consent for Genetic Research on Stored Tissue Samples. J. Am. Med. Assoc. 22: 1786.

D. General Literature 76. Healy, B. (1992). Special report on gene patenting. New Engl. J. Med. 327: 664. 77. Anderson, C. (1992). NIH cDNA patent rejected; backers want to amend law. Nature 359: 263. 78. Knoppers, B.-M., Cadiet, L., and Laberge, C. M., Eds. (1992). ‘‘La ge´ne´tique humaine, de l’information a` l’informatisation,’’ Litec, Paris. 79. Knoppers, B. M., and Chadwick, R. (1994). The Human Genome Project: Under an international ethical microscope. Science 265: 2035. 80. Knoppers, B. M., and Le Bris, S. (1994). Genetic choices: A paradigm for prospective international ethics? Politics Life Sci. 13: 228. 81. Nelkin, D., and Linde, M. S. (1995). ‘‘The DNA Mystique, The Gene as a Cultural Icon,’’ Freeman, New York. 82. Dickson, D. (1995). European parliament rejects bid to stem confusion over gene patents. Nature 374: 103. 83. Pompidou, A. (1995). Research on the human genome and patentability—The ethical consequences. J. Med. Ethics 21: 69. 84. Greely, H. (1995).The Human Genome Diversity Project: Ethical, legal and social issues. In ‘‘Genes, Religions, and Society’’ (T. Peters, Ed.), Yale Univ. Press, New Haven, CT. 85. Knoppers, B. M., and Laberge, C. M., (1995). Research on stored tissues: Persons as sources, samples as persons? J. Am. Med. Assoc. 22: 1806. 86. ‘‘Patent Blather’’ (Nov. 25, 1995) The Economist 87. 87. Butler, D. (1995). Genetic diversity proposal fails to impress international ethics panel. Nature 377: 373. 88. Macer, D. et al. (1996). UNESCO and population genetics. Nature 379: 11.

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