5
Human Reproductive Cloning: Proposed Activities and Regulatory Context

In this chapter, we describe our understanding of the processes that would be used if anyone conducted human reproductive cloning now or in the near future and the regulatory context in which they would or could operate.

WHAT METHODS ARE LIKELY TO BE USED IF ANYONE CARRIES OUT HUMAN REPRODUCTIVE CLONING NOW OR IN THE NEAR FUTURE?

The methods that might be used now to clone a human would follow the general scheme used to clone other animals. These would be modified according to information peculiar to human biology obtained through research and the observations made while using assisted reproductive technology (ART) procedures. Current technology would be applied for assessing the quality and potential of an embryo before implantation and the health of the fetus during development in a uterus. For preimplantation tests, one or more cells from the preimplantation embryo would be removed and used to test for the quality and integrity of the 46 human chromosomes and for the presence of imprinting errors in one or more genes.

All aspects of such undertakings are open to scientific and clinical questions and uncertainties. The questions and uncertainties were illustrated by the testimony given at the workshop by three people representing organizations that have publicly indicated an intention to carry out reproductive cloning of humans in the near future [1-4]. Their work is



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Scientific and Medical of Aspects: Human Reproductive Cloning 5 Human Reproductive Cloning: Proposed Activities and Regulatory Context In this chapter, we describe our understanding of the processes that would be used if anyone conducted human reproductive cloning now or in the near future and the regulatory context in which they would or could operate. WHAT METHODS ARE LIKELY TO BE USED IF ANYONE CARRIES OUT HUMAN REPRODUCTIVE CLONING NOW OR IN THE NEAR FUTURE? The methods that might be used now to clone a human would follow the general scheme used to clone other animals. These would be modified according to information peculiar to human biology obtained through research and the observations made while using assisted reproductive technology (ART) procedures. Current technology would be applied for assessing the quality and potential of an embryo before implantation and the health of the fetus during development in a uterus. For preimplantation tests, one or more cells from the preimplantation embryo would be removed and used to test for the quality and integrity of the 46 human chromosomes and for the presence of imprinting errors in one or more genes. All aspects of such undertakings are open to scientific and clinical questions and uncertainties. The questions and uncertainties were illustrated by the testimony given at the workshop by three people representing organizations that have publicly indicated an intention to carry out reproductive cloning of humans in the near future [1-4]. Their work is

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Scientific and Medical of Aspects: Human Reproductive Cloning supported by private funds in nonuniversity settings and is likely to be performed outside the United States. The following table provides a summary of the current arguments and counterarguments regarding human reproductive cloning. Responses are based on the literature (see especially [5; 6] and references cited in Chapter 3) and the testimony of other scientists. WHAT PROTECTIONS SHOULD BE PROVIDED TO HUMAN SUBJECTS WHO PARTICIPATE IN HUMAN CLONING? Any participant in human reproductive cloning would require at least the same protection afforded to a participant in any other kind of research. Two overarching international codes provide the basic principles for protecting humans who participate in experiments. The Nuremberg Code [50], was articulated in 1947 by the U.S. Military Tribunal No. 1 at the “Doctor’s Trial.” The Nuremberg Code indicates the following (italics added for emphasis): “1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion, and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.

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Scientific and Medical of Aspects: Human Reproductive Cloning Current Arguments and Counterarguments Regarding Human Reproductive Cloning Provided below is a summary of some of the current arguments and counterarguments regarding human reproductive cloning. The panel’s analysis of each is based on the scientific and medical literature and on presentations at its workshop. Argument 1: Animal-safety data do not apply, because humans are very different from the animals under study [3]. In particular, a recent study [7] indicated that an important imprinted gene in mice is not imprinted in humans; therefore, imprinting errors would not be a problem in cloned humans. Counterargument: Placental function, development, and genetic regulation are similar in humans and animal models, such as mice, so similar nuclear transplantation-related defects would be expected [8]. Numerous studies have emphasized that humans and other organisms have the same basic pathways for governing early embryonic and fetal development. Furthermore, widespread defects in all five of the mammalian species that have been reproductively cloned thus far suggest that the defects would affect basic biological functions in humans. Even if one less gene is imprinted in humans as compared to mice, humans are known to have many imprinted genes (possibly as many as 100), and any number of these are likely to cause problems in reproductively cloned humans. Argument 2: Frequent failures are seen in normal human reproduction; cloning would be no different [3]. Counterargument: Errors in normal human reproduction occur primarily early in pregnancy; many of the women in question are never aware that they are pregnant. In contrast, many of the defects in reproductively-cloned animals arise late in pregnancy or after birth. Argument 3: Inappropriate culture media for the initial cells cause most cloning-related problems [1; 2]. Culture media for human assisted reproductive technologies have been better optimized [2; 3]. Synchronization between the implanted embryo and the recipient uterus has also been better in human than in animal assisted reproductive technology procedures. Counterargument: Culture effects appear to account for only some of the defects observed [9; 10]. Many defects in various organ systems are peculiar to reproductive cloning. Expertise in existing human assisted reproductive technologies is not relevant to these problems, because the defects appear to arise from biological rather than purely technical causes [9]. Argument 4: Those who have cloned animals stress the failures, but there are also many successes in animal reproductive cloning [2; 3]. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

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Scientific and Medical of Aspects: Human Reproductive Cloning   Counterargument: The statement is true, but does not necessarily apply to human reproductive cloning. In humans, the likelihood and benefit of success must be weighed against the probability, severity, and lifelong consequences of failure. Failures are all but certain in any human reproductive cloning attempt at this time, based on the experience with animals, and in humans, the consequences could be far more devastating. The likelihood and benefit of possible success must be weighed against the high probability and severe consequences of failure. Argument 5: Existing preimplantation and postimplantation genetic tests could be used to detect abnormalities, allowing selection of embryos to be implanted and therapeutic abortion in case of any problems. In contrast, there has been no genetic testing and weeding out of animal reproductive clones. In preimplantation testing, two cells could be removed from an eight-cell morula. One cell could be tested for correctness of the chromosome complement and the other for imprinting errors at one or more DNA sites [4]. It has been claimed that such imprinting tests have been performed with DNA from cells after somatic cell nuclear transfer (SCNT) [3], although no data have been presented. Postimplantation testing could include testing for chromosomal errors, the checking of imprinting status at up to 30 sites, and the measurement of production levels from many genes with DNA chips [11] or reverse-transcription polymerase chain reaction [4]. Counterargument: Many errors would not be detectable until late in pregnancy or after birth, when therapeutic abortion would not be an option. Many of the relevant genetic tests have not yet been developed [2; 9]; existing genetic tests appropriate for single-gene inherited disorders or gross chromosomal rearrangements are insufficient because they are not relevant to the major sources of errors expected in human cloning. Ultrasonographic tests cannot detect the small-scale defects in tissues, such as lung, that have had devastating consequences in newborn animal clones [12; 13], and there is insufficient evidence regarding the possible impact of imprinting errors on brain development in humans. Argument 6: Voluntary informed consent allows potential participants to make their own decisions and elect to take the risks if they so choose. Counterargument: Our current regulatory system recognizes that when information is lacking it can be difficult or impossible to inform subjects fully. That is the case with respect to human reproductive cloning because the extent of the risks is unknown, and the greatest risk of abnormality, morbidity, and mortality is borne by the cloned fetus/child, who cannot give informed consent. In addition, there are risks borne by the woman donating the eggs and the gestational mother. When subjects cannot be fully informed, and when a procedure is clearly risky, there is a role for both regulatory agencies and professionals to limit the options available to a subject if the evidence supports such a limitation [14]. Societal concerns can also be taken into account.   6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

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Scientific and Medical of Aspects: Human Reproductive Cloning 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgement required by him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.” Private physician groups have also adopted codes of conduct, including the World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects which was adopted initially in 1964 and revised as recently as October 2000 [51-53]. In the United States, the National Institutes of Health (NIH) established policies for the protection of human participants in 1966, which subsequently became regulations in 1974. The National Commission for the Protection of Human Subjects of Biomedical and Behavorial Research met from 1974 to 1978. Its report, called The Belmont Report, set forth basic ethical principles for the conduct of biomedical and behavorial research involving human participants. These principles are: Respect for Persons involves a recognition of the personal dignity and autonomy of individuals and special protection of those persons with diminished autonomy. Beneficence entails an obligation to protect persons from harm by maximizing anticipated benefits and minimizing risks. Justice requires that the benefits and burdens of research be distributed fairly. The Federal Policy for the Protection of Human Subjects was adopted in 1991. This is sometimes called the “Common Rule” as it provides a uniform human subject protection system for most relevant federal agencies and departments [54]. In addition, the Department of Health and Human Services has adopted additional protections for various populations. One section is particularly relevant to human reproductive cloning research—Subpart B “Additional Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women,

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Scientific and Medical of Aspects: Human Reproductive Cloning and Human In Vitro Fertilization.” The Food and Drug Administration has a separate set of regulations, but they closely parallel the common rule and differ in detail to accommodate FDA’s statutory responsibilities to regulate food, drugs, devices, and biologics. The Common Rule provides more specific procedures than the general codes described above, including the use of Institutional Review Boards (IRBs) (IRB Guidebook 1993; NBAC, 2001). An Institute of Medicine (IOM) report, Preserving Public Trust: Accreditation and Human Participant Protection Programs (2001) [15], states that human-subjects protection should: Ensure that the research design is sound and that a study’s promise for augmenting knowledge justifies the involvement of human participants. Assess the risks and benefits independently of the investigators who carry out the research. Ensure that participation is voluntary and informed. Ensure that participants are recruited equitably and that risks and benefits are fairly distributed. All participating subjects must give informed consent if it is possible, and experimentation involving vulnerable subjects should receive special review and heightened human-subjects protection procedures. An infertile man who wishes to be cloned suffers no risk other than the risk of losing a substantial amount of money. A woman impregnated with a clone faces risks, and the greatest risks of abnormality, morbidity, and death will be borne by the newborn, or older clone, who is in no position to give informed consent. HOW ARE HUMAN-SUBJECTS OF RESEARCH PROTECTED? The current system for ensuring the ethical conduct of research with humans in the United States is centered on review of the proposed research by Institutional Review Boards (IRBs). IRB review of research that involves human subjects, such as experiments in human reproductive cloning, is mandatory under federal regulations under either of two conditions: If the research involves a drug, device, or biologic subject to Food and Drug Administration (FDA) approval, it falls under FDA human-subjects regulations and must be approved by an IRB. If the research is carried out at an institution that accepts federal funds or has an “assurance” agreement with the federal government, it is covered by the federal Common Rule. This requires IRB approval when

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Scientific and Medical of Aspects: Human Reproductive Cloning the research involves human subjects, with a few exceptions not relevant to human reproductive cloning experiments. Many institutions have signed agreements stating that they will extend IRB review to cover all research, whether funded by the federal government or not. Such an extension of the standard assurance is not required, however, and some institutions—including many ART clinics—either have signed only the minimal agreement covering federally funded research or receive no federal research funds and have no assurance document with the federal government. In both cases listed above, work is subject to IRB review only if it is classed as “research” under the regulations, which define research as “a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge” (45 CFR 46.102(d)) [16]. Those proposing human reproductive cloning experiments could claim they are conducting “innovative therapy,” and not “research,” so that their work would fall outside the human-subjects regulatory framework. As described below, however, human reproductive cloning experiments should be intended, at least in part, to contribute to development, testing, and evaluation of a technique that has never been tried in humans. While it might indeed by considered “innovative therapy,” it would also constitute research. IN THE ABSENCE OF A CLONING BAN IN THE UNITED STATES, HOW WOULD HUMAN REPRODUCTIVE CLONING BE REGULATED, IF AT ALL? How does the federal government regulate medical care? In general, the federal government does not have specific powers under the Constitution to regulate medical care, but there are several means by which it regulates medical research and clinical practice via its powers over taxation, spending, and interstate commerce [17]. Funding of a person or organization can be made contingent on that person’s or organization’s following regulations, such as human-subjects regulations that cover federally funded research. Similarly, the federal government can require states to take actions as a prerequisite for receiving funds in a related field, such as the requirement that states regulate in vitro fertilization if they are to receive funding in connection with the Aid to Families with Dependent Children program [17]. Most infertility clinics do not receive federal funds, so it would not be possible for the federal government to regulate them directly on the basis

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Scientific and Medical of Aspects: Human Reproductive Cloning of funding. Some have suggested that clinics could be regulated by the federal government, “whether or not they receive federal funds, if patients travel across state lines to use them, if supplies come from out of state, and if the doctors attend conferences in other states” [18]. Thus, the federal government potentially could either require the states to regulate any human reproductive cloning attempts as a condition of their receiving healthcare-related federal funds or regulate it directly, under its power to regulate interstate commerce (similar to the way it regulates organ transplantation) [17]. In addition, states under their inherent police powers can regulate the licensing of medical personnel and medical facilities. Can institutional review boards regulate human reproductive cloning research? IRB’s can regulate human reproductive cloning research, under some conditions; however, some human reproductive cloning research may fall outside federal oversight. Individuals carrying out new ART procedures can avoid IRB oversight either by claiming that the investigations do not constitute research, and instead characterizing their work as “innovative therapy” or a clinical service, or by avoiding federal funds for the research and conducting the work at institutions that do not have a federal assurance agreement that covers their work. Attempts at human reproductive cloning should be construed as research because, as described under the regulations covering human-subjects protections (45 CFR 46.102) [16], they should be carried out as “systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” Can the Food and Drug Administration regulate human reproductive cloning? Although the FDA does not have authority to regulate the practice of medicine, it does have the authority over entities trying to create drugs or biological treatments. In a 1998 “Dear Colleague” letter, FDA asserted that it had regulatory jurisdiction “over clinical research using cloning technology to create a human being” under the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act (FFDCA) [19]. The assertion was restated in a July 6, 2001, letter. Three reasons have been provided for FDA’s reasoning [22]: Designation of cloning materials as “biological products.” Designation of such products as “drugs.” Regulation of cloning procedures as involving “medical devices.”

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Scientific and Medical of Aspects: Human Reproductive Cloning In its 1997 proposal, FDA argued that reproductive human cloning involves a “biological product” in that the human egg cell must undergo more than minimal manipulation, which occurs when a procedure “alters the biological characteristics (and potentially the functional integrity) of those cells or tissues, or when adequate information does not exist to determine whether the processing will alter the biological characteristics of the cell or tissue” [23]. That proposal has since been clarified by a final rule promulgated on January 19, 2001 [24]. Concerns have been expressed, most recently at a congressional hearing on human reproductive cloning, that such jurisdiction stretches FDA authority too far [20; 21]. FDA has asserted its jurisdiction, so unless it is successfully challenged human cloning will require premarket approval of any cellular or tissue-based products. Some suggest that FDA’s jurisdiction would not be recognized by the courts, because the courts do not consider pregnancy to be a disease and the intended use of cloning products would be to create a new life, not to treat, diagnose, or prevent a pregnancy [22; 25]. FDA has until recently refrained from attempting to regulate ART, which involves many of the same techniques as would be used in human reproductive cloning. In contrast, another commentator recently stated that “as a practical matter…if FDA says it has authority, it does have authority until somebody challenges it and a court says it does not, and courts generally are quite deferential to regulatory agencies who are interpreting their own enabling language” [14]. The initial stages of FDA review are generally confidential. Open FDA advisory committees early in the process have been rare and strongly opposed by industry. Thus, any FDA review of human reproductive cloning research is unlikely to occur in public early in the process without a change in the FDA statute (FFDCA). Furthermore, current FDA review procedures concentrate on safety and efficacy and cannot take ethical issues into account. Can the Recombinant DNA Advisory Committee regulate human reproductive cloning? The Recombinant DNA Advisory Committee [26] at NIH has reviewed experiments involving recombinant DNA and human gene transfer since 1977. Its formal authority is restricted to review of federally funded research, although medical researchers in the private sector have generally also submitted their work for review [26; 27]. The RAC’s authority is to provide advice to federal agencies that can terminate or suspend federal grants and contracts.

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Scientific and Medical of Aspects: Human Reproductive Cloning A similar body could be established to regulate cloning; but unless its terms of establishment differed from those governing the RAC, the new body’s authority would not extend beyond federally funded research. What other policy mechanisms could be used to regulate human reproductive cloning? New legislation or executive action would be required to set up a review system if the system is to cover both public and private sectors and be open to the public. A review body could probably be created under the National Institutes of Health (NIH) authorization statute (although this might not be binding for research that is not federally funded), using the model of human-subjects regulations and recombinant-DNA guidelines of the 1970s. Without explicit legislation, however, the review body’s authority might not extend to privately funded research at institutions that do not have a signed assurance with the federal government. Such authority would have to be established by federal legislation that granted additional powers to NIH, the Office of Human Research Protections, FDA, or a new regulatory body created for the purpose. Another mechanism for restricting human reproductive cloning activities is the tort system, using either the existing negligence standard for medical malpractice or a revised strict liability standard for medical malpractice (proposed by Charo [14]). Especially under the latter system, the threat of litigation would act as a strong deterrent to the practice of any procedure that has a great likelihood of failure. Yet another mechanism would be a regulatory body similar to that in place in the United Kingdom. The UK body—the Human Fertilisation and Embryology Authority—was enacted by Parliament in 1990 and operated voluntarily before then. It oversees and licenses all ART procedures in both the private and public sectors. HOW DOES A MORATORIUM COMPARE WITH OTHER POTENTIAL POLICY INTERVENTIONS RELATED TO HUMAN REPRODUCTIVE CLONING? A moratorium is similar to a ban in its immediate consequences, but as “a suspension of activity pending further analysis or action” [28] it implies that the issue will be revisited later. In contrast, a ban would prohibit by federal statute efforts to clone human beings. The penalties could be criminal or civil. Have others suggested a human reproductive cloning moratorium? The National Bioethics Advisory Commission (NBAC) report on human cloning, issued in 1997 [29], concluded that human reproductive

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Scientific and Medical of Aspects: Human Reproductive Cloning cloning was not safe, in that it imposed unacceptable risks on the life and health of the fetus and the surrogate mother. The NBAC recommended a moratorium on the use of federal funding to support human reproductive cloning. It also suggested that there be a voluntary moratorium in the private sector and that the federal government cooperate with other nations and international organizations to enforce any common aspects of their policies on human reproductive cloning. (The NBAC also recommended federal legislation to prohibit human reproductive cloning.) The Clinton administration’s moratorium restricted the use of federal funding for human reproductive cloning. Those who desire to carry out reproductive cloning in humans, however, are not planning to use federal funds. Voluntary moratoriums have been proposed by various industrial and professional associations, such as the Federation of American Societies for Experimental Biology [30], the American Medical Association [31; 32], the Association of American Medical Colleges [31] and the American Society for Reproductive Medicine [33]. WHAT TYPES OF LEGISLATION ARE UNDER CONSIDERATION WITH RESPECT TO HUMAN REPRODUCTIVE CLONING? US federal laws A number of bills that would regulate human reproductive cloning have been introduced in Congress. In general, they are in two categories. The first set of bills would ban both human reproductive cloning and nuclear transplantation to produce stem cells. The second set would ban only human reproductive cloning. While the present report was being developed, a bill introduced by Representative Dave Weldon was passed by the House of Representatives. It would outlaw, with criminal penalties, the production of a reproductively-cloned human embryo and would also outlaw nuclear transplantation to produce human embryonic stem cell lines. It would also prohibit the importation of any medical treatments from abroad that were created from such activity. Alternatives to that bill, such as the bill of Representative James Greenwood, would ban human reproductive cloning but would permit the use of nuclear transplantation to produce stem cells; the House defeated an amendment to the Weldon bill proposing this alternative. Similar bills are under discussion in the Senate [20]. US state laws California, Michigan, Louisiana, Virginia, and Rhode Island have banned human cloning [34]. Legislation has been proposed in Illinois,

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Scientific and Medical of Aspects: Human Reproductive Cloning Massachusetts, and New York. A number of states (including California and New York) have laws that apply the federal research regulations to research with human beings conducted within the state that is not otherwise covered by the federal rules (because it is not sponsored by a federal agency). Human reproductive cloning in the California statute is defined as “the practice of creating or attempting to create a human being by transferring the nucleus from a human cell from whatever source into a human egg cell from which the nucleus has been removed for the purpose of, or to implant, the resulting product to initiate a pregnancy that could result in the birth of a human being” (California Health and Safety Code 24187 as cited in [35]). Most state laws have difficulties with respect to implementation. For example, if a cow egg were used instead of a human egg, the California law would not apply [35]. A blanket ban on nuclear transplantation could have unintended consequences, such as an inability to use the process for preimplantation genetic diagnosis or the treatment of some mitochondrial diseases. International treaties and laws Several other countries have instituted human reproductive cloning bans. The Council of Europe1 [36], in a protocol signed by 19 nations, banned human reproductive cloning research defined as “any intervention seeking to create a human being genetically identical to another human being, whether living or dead.” The explanatory memorandum to the protocol specifies that human being is to be interpreted according to domestic law; so nuclear transplantation to produce stem cells might be banned in some countries but not others. Germany and the United Kingdom have not signed the protocol, because they are not signatories to the underlying Bioethics Convention. Germany forbids all research on human embryos. In the United Kingdom, human reproductive cloning is now banned by law, but nuclear 1   The Council of Europe is an intergovernmental organization focused on human rights and other issues. Although The Council of Europe is an intergovernmental organization which aims to (1) protect human rights, pluralist democracy and the rule of law; (2) promote awareness and encourage the development of Europe’s cultural identity and diversity; (3) seek solutions to problems facing European society (discrimination against minorities, xenophobia, intolerance, environmental protection, human cloning, AIDS, drugs, organized crime, etc.); (4) help consolidate democratic stability in Europe by backing political, legislative and constitutional reform. The Council of Europe should not be confused with the European Union. The two organizations are quite distinct. The 15 European states, however, are all members of the Council of Europe.

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Scientific and Medical of Aspects: Human Reproductive Cloning transplantation to produce cells and tissues for research or experimental treatment is not prohibited. The foreign ministers of France and Germany intend to launch a joint UN initiative “on the question of human cloning in order to establish its unacceptability as a practice contrary to human dignity, and to enshrine its prohibition in a universal legal instrument” [37]. More up-to-date information about the constantly-changing laws from around the world dealing with human reproductive cloning are collected by the Association of Global Lawyers and Physicians (http://www.glphr.org). WOULD A MORATORIUM ON HUMAN REPRODUCTIVE CLONING HOLD? A voluntary moratorium has worked in the past to delay scientific research. The moratorium leading up to a meeting at Asilomar, California, in 1975 successfully delayed recombinant-DNA research until proper guidelines could be put into place [38-44]. The moratorium was conceived by the molecular biology community and imposed on itself, and it was eventually supplanted by a federally sanctioned set of guidelines and a prospective group review process [28]. The moratorium and guidelines succeeded in part for two reasons that do not pertain to human reproductive cloning today. First, there was a strong consensus on the value of observing the moratorium among the practicing scientists most capable of doing the work, both in the United States and elsewhere. Second, when the Recombinant DNA Advisory Committee was established and its guidelines put into place, the vast majority of research biologists in the United States were funded by NIH or the National Science Foundation, so the sanction—loss of federal grants—was a strong disincentive. A voluntary moratorium is unlikely to work for human reproductive cloning, because reproductive technology is widely accessible in numerous private fertility clinics that are not subject to federal research regulations. Several groups have already signaled their intention to forge ahead despite scientific consensus that the techniques are not ready for human application. Would a ban on human reproductive cloning be legal in the United States? A number of legal scholars believe that a ban on human reproductive cloning would not be considered constitutional in that it might contravene both a right of privacy (specifically, a perceived right to procreative liberty [45; 46]) and a right of scientific inquiry. In addition, it is possible

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Scientific and Medical of Aspects: Human Reproductive Cloning that the courts would rule that an egg or nucleus donor has the right to control what happens to the embryos created. At this time however, there is no reason to expect that the Supreme Court will expand the right to privacy to include human reproductive cloning. In the case of a right of privacy, the Supreme Court has recognized the right of persons to decide whether to “bear or beget a child” [47]. The Supreme Court has not considered whether ART procedures—particularly an asexual procedure, such as reproductive cloning—are accorded the same considerations. Some, however, do not believe that human reproductive cloning should be treated in the same way as other ART procedures with regard to reproductive rights, because it departs too much from sexual reproduction. Difficulty in assigning parentage might, for example, be a competing state interest in relation to the national authority promoting a right of privacy [48]. In the case of a right of scientific inquiry, scientific research is viewed as a means of exercising free speech. This right, although implicit in many Supreme Court cases, has never been explicitly defined [49]. The existence of state and federal restrictions on research with human subjects suggests that there is a difference between research that poses no threat to others and research that may harm human beings or other important interests. FINDINGS 5-1. Those who wish to undertake human reproductive cloning lack the fundamental biological knowledge, demonstration of safety in animals, and testing methods to make it a safe course of action. The panel believes that any such effort would contravene international ethics codes for research on human subjects, such as Article 5 of the Nuremberg Code [50], which states in part that “no experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur.” 5-2. If human reproductive cloning is ever to be undertaken responsibly, it would need to be done systematically with the intention of creating reliable knowledge. Any responsible efforts toward human reproductive cloning would therefore conform to the federal definition of research. As such, whether the source of funding is public or private, the research would be subject to a review by a review board independent of the investigators conducting the research, such as the Institutional Review Board. (Those who wish to reproductively clone humans are more interested in being the first to be successful with human cloning than in collecting reliable knowledge. This “first of its kind” venture, without systematic

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Scientific and Medical of Aspects: Human Reproductive Cloning data collection, is not considered “research” under current federal regulation.) If responsible research on human reproductive cloning were undertaken, it may be considered “innovative therapy,” but that does not escape the need to protect the rights and interests of those participating in the research or the need for independent external review. 5-3. Any future attempt at human reproductive cloning would constitute human-subjects research. As such, it would best be regulated according to the following conditions: The review process would be applied equally to both public- and private-sector research. The review process would be made open to the public. That would not be the case if review were restricted to FDA unless FDA took special measures, such as those recently taken to make data relevant to the safety of gene-transfer trials and transplantation of animal organs public. The review process would (1) decide the criteria that should be used to judge whether protocols are ready for human experimentation (that is, set the rules) and (2) review the protocols involving human experiments to see that they satisfy these criteria (that is, apply the rules). Those two functions could be carried out by a single body or by two distinct bodies. The review process would have to take into account ethical issues beyond clinical safety and efficacy (see, for example, the NBAC report [29]). FDA review does not cover such issues, so FDA review by itself would be incomplete. New legislation or executive action would be required to set up a review system so that it would cover both public and private sectors and be open to the public. 5-4. A voluntary ban or moratorium is unlikely to work, given that reproductive technology is widely accessible in numerous private fertility clinics that are not subject to federal research regulations. A ban enforced by legislation would probably need to carry substantial civil or criminal penalties to have an impact on such activities within the United States. 5-5. If a ban on research in human reproductive cloning is reassessed, participants in any such research efforts would need to be afforded human-subjects protection as described in the Nuremberg and Helsinki codes, US law, and the IOM report Preserving Public Trust: Accreditation and Human Participant Protection Programs (2001) [15]. Such protections include external technical and ethical review by review boards to ensure that proposed experiments are technically and ethically sound. The review boards should be independent of the investigators conducting the research.

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