3
Addressing Ethical and Scientific Concerns Through Oversight

The promise of human embryonic stem (hES) cell research as described in Chapter 2 raises ethical concerns that require a public policy response. This chapter addresses the primary ethical concerns, specifically public sensitivities regarding the status of the human embryo, the need to respect those who donate gametes and embryos to research, the mixing of human and nonhuman cells, and the consensus that nuclear transfer (NT) should not be used for reproductive purposes at the present time. Those concerns and the need for uniform practices and standards in the scientific and medical communities, call for an appropriate and calibrated system of oversight. Several countries have already established laws and guidance in this field and some are described in this chapter (additional discussion can be found in Chapter 4). As discussed in Chapter 1, there is a precedent for self-regulation by the scientific community and research institutions in recombinant DNA research. The initiative taken by the scientific community in the 1970s with regard to recombinant DNA research serves as a model for self-governance in hES cell research in the absence of involvement of the federal government. In this chapter the committee recommends a system of local and national oversight of hES cell research. Because in the final analysis the issues involved are scientific and moral rather than financial the proposed oversight system should apply to all hES cell research regardless of the source of funding.

ETHICAL CONCERNS

The principle ethical and religious objection to hES cell research is that the derivation of hES cells involves the destruction of the blastocyst, which is regarded



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Guidelines for Human Embryonic Stem Cell Research 3 Addressing Ethical and Scientific Concerns Through Oversight The promise of human embryonic stem (hES) cell research as described in Chapter 2 raises ethical concerns that require a public policy response. This chapter addresses the primary ethical concerns, specifically public sensitivities regarding the status of the human embryo, the need to respect those who donate gametes and embryos to research, the mixing of human and nonhuman cells, and the consensus that nuclear transfer (NT) should not be used for reproductive purposes at the present time. Those concerns and the need for uniform practices and standards in the scientific and medical communities, call for an appropriate and calibrated system of oversight. Several countries have already established laws and guidance in this field and some are described in this chapter (additional discussion can be found in Chapter 4). As discussed in Chapter 1, there is a precedent for self-regulation by the scientific community and research institutions in recombinant DNA research. The initiative taken by the scientific community in the 1970s with regard to recombinant DNA research serves as a model for self-governance in hES cell research in the absence of involvement of the federal government. In this chapter the committee recommends a system of local and national oversight of hES cell research. Because in the final analysis the issues involved are scientific and moral rather than financial the proposed oversight system should apply to all hES cell research regardless of the source of funding. ETHICAL CONCERNS The principle ethical and religious objection to hES cell research is that the derivation of hES cells involves the destruction of the blastocyst, which is regarded

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Guidelines for Human Embryonic Stem Cell Research by some people as a human being. A second objection, which relates to blastocysts created for research purposes—whether through fertilization or NT—is that it is wrong to create a blastocyst with the intention of destroying it. A third objection is that some of the research depends on donor oocytes, which could result in the exploitation of women. In addition, some people are concerned about the mixing of human and nonhuman cells for research purposes. Finally, some object to the use of NT to derive hES cells because they fear that the use of NT for research purposes could lead to its use to produce a child. The Special Status of the Human Embryo Like all scientific work involving human embryos, hES cell research raises profound questions about the status of the human embryo, the extent to which it is justifiable to use human embryos to expand knowledge and ameliorate human suffering, and the conditions under which these goals may be pursued. Throughout its deliberations the committee was keenly aware that some view human embryos as morally equivalent to born human persons. This position takes several forms. Some argue that the identity of a future born person is present in the embryo. Others identify the moral equivalence of the human embryo to the born human person with the embryo’s potentiality. Still others claim that human dignity is undermined by excessive manipulation of the human embryo regardless of the purpose and that this could lead to the abuse and exploitation of human persons more generally. Yet even in our own society, where many hold this view in a philosophical sense, it has not been adopted as a matter of cultural practice. For example, the natural loss of an embryo in normal human reproduction is not recognized as a death that requires a funeral, and the disposal of human embryos after completion of infertility treatments is not treated as murder by the legal system. Nonetheless, in the United States in particular, hES cell research is eligible for limited federal funding because the current administration wishes to acknowledge the view of some that the destruction of embryos required to obtain new cell lines gives such lines a moral taint. In contrast, many religious traditions—Islam, Judaism, and numerous Protestant denominations—do not recognize the human embryo before 40 days after conception as an entity that should be accorded the same moral status as a person. Among some of these traditions, there is also a strong commitment that faith must be manifest in good works and that the world itself and the persons within it should be objects of strenuous efforts to heal (National Bioethics Advisory Commission (NBAC), 1999b). To be sure, in these traditions the human embryo may have greater moral status than other collections of cells, but not so much that its cells may not be respectfully applied toward the other goals to which the faithful are committed. There is a more general debate about the meaning of human dignity. For some, the use or creation of human embryos in research, or even the very prospect of

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Guidelines for Human Embryonic Stem Cell Research advances in genetics and molecular biology, represent manipulations of life that undermine human dignity. In contrast, others view the effort to heal the sick as a profound moral obligation and the restoration of health and natural functions as the promotion of human dignity. In the latter view, the undifferentiated blastocyst cells that yield hES cells are a resource that should not be squandered. This diversity of deeply held views must be respected. However, that respect does not require that we, as a society, prohibit hES cell research, but rather that our society create institutions for the oversight of this research that, with due moral seriousness, take into account the special status of the human embryo. Respect for Donors of Human Embryos and Gametes Like other modern technologies associated with human reproductive capacities, hES cell research often involves donated embryos or oocytes. There is a set of minimal conditions that applies to the process of obtaining embryos and gametes for research purposes, normally from in vitro fertilization clinics. Those conditions are reflected in policies, guidelines, and practices in the United States and elsewhere. They include restrictions on monetary and other inducements, separation between clinical decisions and decisions to donate, and the requirement of voluntary informed consent of donors through a process that has been approved by an Institutional Review Board (IRB), as specified in federal regulations for the protection of human subjects in research (45 CFR 46.107; see Chapter 4 for further discussion). A measure of respect for donors is the assurance that research using donated materials is limited to qualified investigators and that studies have scientific merit. Those issues are discussed in greater depth below and in Chapter 5. Transferring hES Cells into Nonhuman Animals The transfer of hES cells into nonhuman animals has received less attention than some of the other ethical and policy issues surrounding stem cell research. The transfer of human stem cells (whether adult or embryonic) or their derivatives into nonhuman animals, creating chimeric entities, will be an important laboratory technique in research with both adult and human embryonic stem cells and may have clinical applications as well. As discussed in Chapter 2, research purposes could include understanding the mechanisms by which transplanted cells localize and differentiate in a host and using the cells in preclinical testing. Human cells also could someday be grown into functioning tissues or organs in an animal for later transfer into a patient. A different perception of the unnaturalness of mixing tissues from different sources is the idea that there are fixed species. However, the popular notion that there are clear and distinct lines between species is a notoriously unreliable categorical scheme. Taxonomies developed since Aristotle do not necessarily countenance the idea of natural kinds, and modern scientists differ in their precise definitions of

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Guidelines for Human Embryonic Stem Cell Research interspecies boundaries. There is general agreement in the scientific community that these boundaries are to some extent arbitrary. As discussed in Chapter 2, some chimeras are viewed with equanimity (for example, pig heart valve transplants into humans), and one must be careful to distinguish legitimate concerns from discomfort arising from unfamiliarity. Although moral intuitions about the creation of chimeras may vary, it is a subject of deep moral concern to many thoughtful people for whom the creation of animals with certain kinds or quantities of human tissues, such as neural or germline cells, would be offensive. Accordingly, such research requires careful consideration and review. Among the issues to be considered in the review of such proposals will be the number of hES cells to be transferred, what areas of the animal body would be involved, and whether the cells might migrate through the animal’s body. The hES cells may affect some animal organs rather than others, raising questions about the number of organs affected, how the animal’s functioning would be affected, and whether some valued human characteristics might be exhibited in the animal, including physical appearance. Perhaps no organ that could be exposed to hES cells raises more sensitive questions than the animal brain, whose biochemistry or architecture might be affected by the presence of human cells. Human diseases, such as Parkinson’s disease, might be amenable to stem cell therapy, and it is conceivable, although unlikely, that an animal’s cognitive abilities could also be affected by such therapy. Similarly, care must be taken lest hES cells alter the animal’s germline. Protocols should be reviewed to ensure that they take into account those sorts of possibilities and that they include ethically sensitive plans to manage them if they arise. Various precautions seem reasonable in studies that involve the transfer of hES cells into nonhuman animals and should be considered in any prior review of a protocol. Questions that should be raised in this context include the following Are hES cells required, or can cells from other primates or animals be used? Has sufficient animal work preceded the proposed work involving hES cells? Might the cell transfer result in the animal’s acquiring characteristics that are valued as distinctly human? If hES cells are to be transferred into an animal embryo or fetus, have studies (for example, with ES cells from other species or interspecies chimeras) suggested that the resulting creature would exhibit human characteristics that would be ethically unacceptable to find in an animal? If visible human-like characteristics might arise, have all those involved in these experiments, including animal care staff, been informed and educated about this? Furthermore, donors of gametes and embryos should be informed that some of the hES cells derived from their donated cells and tissues might be transferred into nonhuman animals in the course of developing and testing their therapeutic potential (see Chapter 5).

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Guidelines for Human Embryonic Stem Cell Research Objections to the Use of NT for Reproductive Purposes The ethical concerns about attempts to use NT to create children are well known. They include risks to the mother and the fetus that have been described in numerous reports by other advisory bodies and institutions (NBAC, 1997; NRC, 2002; President’s Council on Bioethics, 2002). As discussed in Chapter 1, this is a matter on which the U.S. National Academies and the scientific community worldwide have spoken with virtually a single voice. Attempts to create a child by means of NT are ethically objectionable at this time because, on the basis of experience with other mammalian species, producing one child might require hundreds of pregnancies and many abnormal late-term fetuses could be produced. Furthermore, some authorities believe that there can never be a fully normal product of NT because of the differences in imprinting between the genes in a transplanted somatic nucleus and those in the oocyte nucleus that it has replaced (Jaenisch, 2004), as well as a failure of epigenetic reprogramming in general. Such concerns led to Food and Drug Administration efforts to prohibit NT for reproductive purposes.1 Even in the absence of moral justification for attempting NT for reproductive purposes, some groups have announced their intention to pursue that objective, even if merely to generate publicity. An oversight system for hES cell research that might include NT as a source of cell lines will reinforce the ethical and scientific consensus that NT for reproductive purposes has no place in legitimate research. The danger that the efforts will continue is far greater in the absence of systematic oversight with its attendant accountability and transparency. THE NEED FOR AN OVERSIGHT SYSTEM As a starting point for its deliberations, the Committee on Guidelines for Human Embryonic Stem Cell Research examined numerous other guidelines and regulations in use now or in the past to identify best practices and common features. Surveys of guidelines and regulations for embryo and/or hES cell research by this committee and others (Walters, 2004) revealed that common features of most, if not all, programs throughout the world include A prohibition on nuclear transfer for reproductive purposes. A prohibition on the culture of human embryos beyond 14 days after fertilization or when the primitive streak has appeared, whichever occurs first. Most existing regulations and guidelines embody broad guiding principles. For example, most require that hES cell research projects aim to advance scientific and medical knowledge to benefit human health. Alternative methods (such as the use of existing hES cell lines or adult stem cells) must have been examined and shown to be 1   See FDA letter to investigators and sponsors at http://www.fda.gov/cber/ltr/aaclone.pdf.

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Guidelines for Human Embryonic Stem Cell Research insufficient for projects that propose to derive new hES cell lines. And research must conform to the highest ethical and scientific standards and be conducted sensitively and in accordance with all regulatory requirements of the nation or state. For example, even under its relatively liberal policy, the United Kingdom, in its Code of Practice for the Use of Human Stem Cell Lines, requires that all hES cell research be conducted under special licenses obtained from the government. The rationale is, in part, to ensure protection of the status of the human embryo: The special regulations which govern the creation and use of human embryonic stem cells reflect the fact that the human embryo has a special moral status. The position taken by many (perhaps most) is that the embryo, unlike an infant, does not have the full rights of a person; however, its human potential gives it an intrinsic value which implies that neither its creation nor its destruction are to be treated casually, as reflected in law. A research license will not be granted unless the HFEA [Human Fertilisation and Embryology Authority] is satisfied that any proposed use of the embryos is necessary for the research and that the research is necessary or desirable for the purposes specified in the 1990 HFE Act and the 2001 Regulations…. Although the use of embryos for these purposes is now permitted under the law, researchers in this field should be sensitive to the fact that some people believe this practice to be morally unacceptable [MRC, 2004]. Many other sets of guidelines also contain provisions to ensure voluntary embryo donation—with a requirement of informed consent—and requirements that the confidentiality of donors be protected. Because there is no federal support in the United States for hES cell research in which new cell lines are derived, the most applicable guidelines come from the Ethics Committee of the American Society for Reproductive Medicine (ASRM, 2000; 2004b). Canada and the United Kingdom also have substantive procedural requirements regarding the recruitment of donors and informed consent. (Those and other approaches are addressed in detail in Chapter 5.) Most guidelines also call for some special oversight body for hES cell research to review documentation of compliance with the guidelines of various government agencies, both domestic and foreign (see Chapters 4 and 5). Oversight is in some cases folded into the evaluation of scientific merit; in others, it is performed by stand-alone ethics review bodies. Finally, most forms of laboratory and clinical research in the United States are subject to substantial local regulation, including provision of protections for human subjects in research, protections for laboratory animals, and the many considerations that must be addressed for research and testing of new drugs and medical devices. (The applicability of those regulatory systems to hES cell research is addressed in Chapter 4.) In considering the ethical and policy issues that arise in connection with hES cell research, the committee subscribes to the consensus of many bioethics bodies throughout the world that a system of oversight of hES cell research should be in place. Examples of current and former national bioethics bodies taking such a view are the 1994 National Institutes of Health Human Embryo Research Panel, the National Bioethics Advisory Commission, the U.K. Human Fertilisation and Em-

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Guidelines for Human Embryonic Stem Cell Research bryology Authority, and others (see Chapter 4 for elaboration). Unfortunately, the U.S. government has not established such a regulatory system, although many regulations are relevant to these activities, and seems unlikely to do so in the near future, especially in the absence of a substantial federal presence in this field because of the current limitations on the use of federal funding. However, nonfederally funded hES cell research is going forward in the absence of federal regulation specific to such research, and it is incumbent on the scientific community to exercise the same sort of self-discipline as it has exercised in the past with regard to novel areas of research, such as recombinant DNA in the 1970s. In the absence of a federal regulatory regime designed specifically to provide comprehensive coverage of hES cell research, the committee proposes an oversight system with both local and national components that meets the important goals identified by the other advisory bodies, including the President’s Council on Bioethics in its report on NT (President’s Council on Bioethics, 2002): To support the current consensus against attempts to create children through NT; To create a forum for further deliberation on these questions; To ensure that legitimate research includes efforts to gather information from animal models and other avenues before utilizing hES cells; and To show respect for the deep moral concerns of those who have ethical objections to the research. RECOMMENDATIONS Institutional Oversight of hES Cell Research The ethical and legal concerns involved in hES cell research make increased local oversight by research institutions appropriate. Because of the complexity and novelty of many of the issues involved in hES cell research, the committee believes that all research institutions engaged in hES cell research should create and maintain Embryonic Stem Cell Research Oversight (ESCRO) committees to Provide oversight for all issues related to derivation and use of hES cell lines. Review and approve the scientific merit of research protocols. Review compliance of all in-house hES cell research with all relevant regulations (see Chapter 4) and the guidelines presented in this report (see Chapter 6). Maintain registries of hES cell research conducted at the institution and hES cell lines derived or imported by institutional investigators. Facilitate education of investigators involved in hES cell research. An ESCRO committee will assist investigators in assessing which regulations

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Guidelines for Human Embryonic Stem Cell Research might apply to proposed research activities (see Chapter 4 for a fuller discussion). It could serve as a clearinghouse for hES cell research proposals and could assist investigators in identifying the types and levels of review required for a given protocol. For example, the creation of a human/nonhuman chimera may involve review by both an IRB and an Institutional Animal Care and Use Committee (IACUC). In some instances, Institutional Biosafety Committees (IBCs), radiation safety committees, and other groups may also have roles to play in research review (see Chapter 4 for further discussion of the roles of these committees). If hES cell research involves potential clinical applications (such as development of products to be tested in humans), FDA regulations will apply. However, care should be taken that the ESCRO committee does not duplicate or interfere with the proper functions of an IRB or other existing institutional committees. The functions of IRBs and ESCRO committees are distinct and should not be confused. One particularly important aspect of regulatory compliance for some hES cell research is protection of donors of blastocysts and gametes, which is a matter for IRB review. On the other hand, laboratory research with existing hES cells is generally not covered by federal regulations governing research with human subjects (Department of Health and Human Services [DHHS] regulations at 45 CFR 46, subparts A through D2) unless the research involves personally identifiable information about a cell line’s progenitors (see Chapter 4). Such research does not need IRB review but should be reviewed by an ESCRO committee. In general, research institutions are likely already to have rules in place for research involving other biological tissues, and, as with any other form of biological or biomedical research, hES cell research would be covered by these rules. But in the case of hES cell research, it will be critically important for investigators and institutions to know the provenance of hES cell lines, particularly if the cell lines are imported to the institution from another site. This would include obtaining an assurance that the process by which the cells were procured was approved by an IRB to ensure that donors provided voluntary informed consent and that risks were minimized (see Chapters 4 and 5). The IRB could be situated at the institution where the cells originated or at the institution where the stem cell research is to be conducted, or it could be independent (non-local). As described in Chapter 5, only one IRB need approve the procurement process, but the institution where the research is to be conducted should obtain evidence of such review. In all cases, the ESCRO committee should 2   DHHS has codified its human subjects protections regulations at 45 CFR 46, subparts A through D. Other agencies have signed onto subpart A, which is referred to as the Common Rule. In this report, DHHS regulations are cited because they are more inclusive than the Common Rule alone, providing protections also to pregnant women, viable fetuses, children, and prisoners. FDA also has codified subpart A of the regulations at 21 CFR 50 and 56 but with slightly different interpretations. In some cases, FDA regulations and HHS regulations might apply to research.

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Guidelines for Human Embryonic Stem Cell Research ensure that the procurement process has been appropriate by requiring documentation that it was approved by an IRB and adhered to basic principles of ethically responsible procurement. (See Chapter 5 for commentary on requirements for informed consent, payment, timing of consent, and coding of samples.) The second role of the ESCRO committee is to review research proposals that involve particularly sensitive kinds of research. It is important to note that the vast majority of in vitro experiments using already derived hES cell lines are unlikely to raise serious ethical issues and will require minimal review. However, proposals to generate additional hES cell lines by any means will require more extensive review. Some other experiments will also warrant careful consideration, including research in which the identity of the donors of the blastocysts or gametes from which the hES cells were derived is readily ascertainable by the investigator and experiments involving implantation of hES cells or human brain cells into nonhuman animals. Because of the sensitive nature of some aspects of hES cell research, it is critical that the scientific community propose and implement limits on what is to be allowed and provide clear guidance on which research activities require greater scrutiny. Thus, a primary activity of the ESCRO committee will be to ensure that inappropriate research is not conducted and that controversial research is well justified and subject to appropriate additional oversight. Oversight will in many instances conform to a higher standard than is currently required by laws or regulations. Among those studies that should not be conducted at this time are any that involve in vitro culture of any intact human embryo, regardless of derivation method, for longer than 14 days or until formation of the primitive streak begins, whichever occurs first. This is a widely recognized international standard that avoids research on embryos after the formation of the precursors of the brain and central nervous system. Research in which hES cells are introduced into nonhuman primate blastocysts, or in which animal or human ES cells are introduced into human blastocysts, should also not be conducted at this time. These kinds of studies could produce creatures in which the lines between human and nonhuman primates are blurred, a development that could threaten to undermine human dignity. Finally, although it is unlikely, hES cells introduced into nonhuman hosts might be able to generate gametes, so any such human/nonhuman chimeras should not be allowed to breed (see Chapter 2 for further discussion). In all those cases, future scientific advances might render the concerns moot or might raise new concerns, so the category of currently nonpermissible experiments will need review in the future (see later discussion of a national review panel). The ESCRO committee must have suitable scientific, medical, and ethical expertise to conduct its own review and should have the resources needed to coordinate the management of the various other reviews that may be required for a particular protocol. Besides scientists and ethicists, its membership should also include at least one person from the community. A pre-existing committee could serve the functions of the ESCRO committee provided that it has the recommended expertise and representation to perform the various roles described in this report.

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Guidelines for Human Embryonic Stem Cell Research For example, an institution might elect to constitute an ESCRO committee from among some members of an IRB. But the ESCRO committee should not be a subcommittee of the IRB, as its responsibilities extend beyond human subject protections. Furthermore, much hES cell research does not require IRB review. Because stem cell research is subject to a greater degree of public interest and scrutiny than most other laboratory and clinical research, the committee believes that each institution should maintain through its ESCRO committee a registry of hES cell lines in use and of investigators working with them and descriptive information on the types of hES cell research in which they are engaged. The purposes of such a registry include facilitating distribution of educational information in light of evolving ethical, legal, or regulatory issues and enabling an institution to respond to public inquiry about the extent of its involvement in hES cell research. The ESCRO committee should also play a central role in educating investigators—including research staff, fellows, and students—on ethical, legal, and policy issues in stem cell research. That might include developing and maintaining a web-based primer, such as those commonly used at research institutions that support human subjects research. The foregoing concerns give rise to the following recommendations. Recommendation 1: To provide local oversight of all issues related to derivation and research use of hES cell lines and to facilitate education of investigators involved in hES cell research, all institutions conducting hES cell research should establish an Embryonic Stem Cell Research Oversight (ESCRO) committee. The committee should include representatives of the public and persons with expertise in developmental biology, stem cell research, molecular biology, assisted reproduction, and ethical and legal issues in hES cell research. The ESCRO committee would not substitute for an Institutional Review Board but rather would provide an additional level of review and scrutiny warranted by the complex issues raised by hES cell research. The committee would also serve to review basic hES cell research using preexisting anonymous cell lines that does not require consideration by an Institutional Review Board. Recommendation 2: Through its Embryonic Stem Cell Research Oversight (ESCRO) committee, each research institution should ensure that the provenance of hES cells is documented. Documentation should include evidence that the procurement process was approved by an Institutional Review Board to ensure adherence to the basic ethical and legal principles of informed consent and protection of confidentiality.

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Guidelines for Human Embryonic Stem Cell Research Recommendation 3: Embryonic Stem Cell Research Oversight (ESCRO) committees or their equivalents should divide research proposals into three categories in setting limits on research and determining the requisite level of oversight: (a) Research that is permissible after notification of the research institution’s ESCRO committee and completion of the reviews mandated by current requirements. Purely in vitro hES cell research with pre-existing coded or anonymous hES cell lines in general is permissible provided that notice of the research, documentation of the provenance of the cell lines, and evidence of compliance with any required Institutional Review Board, Institutional Animal Care and Use Committee, Institutional Biosafety Committee, or other mandated reviews is provided to the ESCRO committee or other body designated by the investigator’s institution. (b) Research that is permissible only after additional review and approval by an ESCRO committee or other equivalent body designated by the investigator’s institution. The ESCRO committee should evaluate all requests for permission to attempt derivation of new hES cell lines from donated blastocysts, from in vitro fertilized oocytes, or by nuclear transfer. The scientific rationale for the need to generate new hES cell lines, by whatever means, must be clearly presented, and the basis for the numbers of blastocysts and oocytes needed should be justified. Such requests should be accompanied by evidence of Institutional Review Board approval of the procurement process. All research involving the introduction of hES cells into nonhuman animals at any stage of embryonic, fetal, or postnatal development should be reviewed by the ESCRO committee. Particular attention should be paid to the probable pattern and effects of differentiation and integration of the human cells into the nonhuman animal tissues. Research in which personally identifiable information about the donors of the blastocysts, gametes, or somatic cells from which the hES cells were derived is readily ascertainable by the investigator also requires ESCRO committee review and approval. (c) Research that should not be permitted at this time: Research involving in vitro culture of any intact human embryo, regardless of derivation method, for longer than 14 days or until formation of the primitive streak begins, whichever occurs first. Research in which hES cells are introduced into nonhuman primate blastocysts or in which any ES cells are introduced into human blastocysts.

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Guidelines for Human Embryonic Stem Cell Research In addition: No animal into which hES cells have been introduced at any stage of development should be allowed to breed. Recommendation 4: Through its Embryonic Stem Cell Research Oversight (ESCRO) committee, each research institution should establish and maintain a registry of investigators conducting hES cell research and record descriptive information about the types of research being performed and the hES cells in use. Investigators who collaborate across national boundaries should respect the ethical standards and procedural protections applicable in all the relevant jurisdictions. Recommendation 5: If a U.S.-based investigator collaborates with an investigator in another country, the Embryonic Stem Cell Research Oversight (ESCRO) committee may determine that the procedures prescribed by the foreign institution afford protections equivalent with these guidelines and may approve the substitution of some or all of the foreign procedures for its own. The committee hesitates to recommend another bureaucratic entity to oversee the biomedical research system, but in this case it believes the burden to be justified because of the special issues involved in hES cell research and the diverse entities that might have a role in the review process in a research institution. A coordination function is crucial. In some cases, smaller institutions may wish to avail themselves of the services of larger facilities that have ESCRO committees. The creation of an ESCRO committee to perform functions unique to hES cell oversight does not relieve institutions or scientific investigators, regardless of their field, of the ultimate responsibility to ensure that they conduct themselves in accordance with professional standards and integrity. In particular, people whose research involves hES cells should work closely with oversight bodies, demonstrate respect for the autonomy and privacy of those who donate gametes and embryos, and be sensitive to public concerns about research involving human embryos. Need for a National Perspective As individual states and private entities move into the field of hES cell research, it is important to initiate a national effort to provide a formal context in which the complex moral and oversight questions associated with this work can be addressed. The state of the science of hES cell research and the clinical practice and public policy surrounding these topics are in a state of flux and are likely to be so for several years. Therefore, the committee believes that some entity needs to be estab-

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Guidelines for Human Embryonic Stem Cell Research lished to review the policies and guidelines covering appropriate practices in this field but not to review and approve specific research protocols, an activity that will best occur at the local institutional level. Such national bodies have been established in most other countries where hES cell research has been debated and approved—such as Australia, Canada, Israel, Singapore, and the United Kingdom (see Chapter 4)—usually under government auspices. Some of those bodies also have responsibility for reviewing individual research proposals, and such centralized review entities may serve well in smaller jurisdictions where public funds are being used in the research. However, in line with the longstanding practice in the United States of using local review boards for human subjects research, animal research, and biohazards, the committee believes that local review of individual research proposals by ESCRO committees (with involvement of IRBs, IACUCs, IBCs, and other panels as described above) will be the best mechanism of oversight of hES cell research. Nonetheless, there will be a need for continuing consideration of new issues that arise from scientific advances, clinical applications, or public policy concerns that will need to be discussed in a central forum. Such a forum should from time to time review the adequacy of the guidelines proposed in this report (Chapter 6) in light of changes in science and the emergence of new issues of public interest. New policies and standards may be appropriate for issues that cannot currently be foreseen. The organization that sponsors the public forum should be one that is respected in the lay and scientific communities, is politically independent without conflicts of interest, and is able to call on suitable expertise to support the effort. Its membership should include nationally and internationally recognized authorities in the scientific, medical, ethical, and legal issues associated with hES cell research, and representatives of the public. The proposed national body must pay careful attention to evidence and argumentation in its deliberations, as well as taking into account the diverse views of the public on these sensitive and evolving issues. To help ensure that these guidelines are taken seriously, the various stakeholders in hES cell research—sponsors, funding sources, research institutions, relevant oversight committees, professional societies, and scientific journals, as well as investigators—should develop policies and practices that are consistent with these guidelines and adhere to the recommendations of the national panel. Funding agencies, professional societies, journals, and institutional review panels can provide valuable community pressure and sanctions to ensure compliance. For example, ESCRO committees and IRBs should require evidence of compliance when protocols are reviewed for renewal, funding agencies should assess compliance when reviewing applications for support, and journals should require that evidence of compliance accompanies publication of results. Recommendation 6: A national body should be established to assess periodically the adequacy of the guidelines proposed in this document and to provide a forum for a continuing discussion of issues involved in hES cell research.

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Guidelines for Human Embryonic Stem Cell Research The Just Distribution of the Benefits of hES Cell Research Billions of dollars will be committed to hES cell research from public and private sources in the coming years. It is not yet clear exactly what specific therapeutic benefits will emerge from this investment, but there is reason for concern that they will not be equitably distributed in our current health-care system. Skeptics may argue that the social investment in science that still requires much research before any health benefits will be realized is not merited when so many basic, often technology-intensive, health services are not adequately provided. The therapeutic possibilities inherent in hES cells can mean vastly improved lives for millions of disease sufferers, and the successful practice of regenerative medicine could yield substantial reductions in health-care expenditures. It is critical that hES cell research, especially as it approaches clinical application, serve the needs of all populations. There must be a concerted effort to ensure diversity not just in the genetic makeup of cell lines but in the approaches to clinical care. Our current health-care system is not well designed for the just distribution of the benefits of research. Besides the excellent scientific work that will surely be accomplished, institutions involved in hES cell research should concern themselves with ensuring genetic diversity in the development of cell lines and in devising health-care systems that can make the long-term benefits of this work widely available. Recommendation 7: The hES cell research community should ensure that there is sufficient genetic diversity among cell lines to allow for potential translation into health-care services for all groups in our society. CONCLUSION The proposed local ESCRO committees and national forum should help to ensure that conventional and well founded research practices and protections apply to hES cell research. Among those practices is the use of in vitro and animal models before interventions that involve human subjects. Protections include minimizing the use of human gametes or embryos and ensuring that recruitment, disclosure, informed consent, and risk assessment procedures are in accord with the highest ethical standards. The consensus on prohibition of NT for reproductive purposes can also be reinforced with a rigorous system of oversight of hES cell research. With this system in place, the scientific community will signal its respect for the views of those who have ethical reservations about the research and provide an opportunity for those views to be expressed. As some have observed, when many people find a practice morally troubling—particularly one that is novel—that is an indication that further consideration is required. An initial reaction of moral alarm need not be

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Guidelines for Human Embryonic Stem Cell Research decisive. Many practices that are now regarded as morally noncontroversial, such as blood transfusions, organ transplants and in vitro fertilization, were once seen by many as shocking and unacceptable; others that are now regarded as unacceptable, such as blood-letting, were conventional. Moral perceptions are sharpened with experience, through the growth of knowledge, and the consideration of various viewpoints. Even if the underlying principles do not change, the interpretation and application of the principles often do. The next chapter addresses the specific regulatory issues that might apply to hES cell research.

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