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Reproduction and Responsibility:

The Regulation of New Biotechnologies


Table of Contents

The President's Council on Bioethics
Washington, D.C.
March 2004
www.bioethics.gov




Chapter Five

Research Involving In Vitro Human Embryos

The biotechnologies of human reproductionare inextricably entangled withresearch that uses or involves early-stage human embryos. Such research provides the experimental groundwork for many of the techniques of assisted reproduction, and it relies on assisted reproduction techniques to produce the ex vivo embryos it uses when it studies disease models and seeks treatments and cures for the sick. Thus, a comprehensive understanding of the current practices, ethical issues, and regulation of reproductive biotechnology requires a consideration of human embryo research.

Before entering the discussion, however, we need to define its scope. Many activities could reasonably be deemed  “human embryo research,” based on the purpose and nature of the activity. If construed broadly, “embryo research” might include novel or experimental in utero or ex utero interventions for therapeutic purposes, intended to benefit mother, embryo, or both. This might include novel assisted reproductive technologies, preimplantation genetic diagnosis, and embryonic gene-transfer—subjects discussed elsewhere in this document. Or “embryo research” might be construed to include research performed on aborted fetuses, fetal tissue, or non-living embryos or embryonic tissue. We opt for a narrower definition, in keeping with our focus on the current regulation of those biotechnologies that touch on human reproduction. We will therefore limit ourselves, in what follows, to considering basic research on early-stage ex utero living embryos not intended for transfer into a woman’s uterus.

I. Techniques and Practices

A. Present Applications of Human Embryo Research

Much of basic embryo research is aimed at improving infertility treatment. Additional research protocols involving human embryos seek general knowledge about early embryonic development, including morphology, biochemical and biophysical properties, and genetic expression. Some embryo researchers seek to enhance basic knowledge about the origins of birth defects. Others seek the development of contraceptives. Still others study cell division in early embryos looking for clues relevant to understanding cancer development and metastasis (particularly cancers affecting reproductive organs). Embryo research is also undertaken to increase understanding of somatic cell nuclear transfer and parthenogenesis. Finally, embryos are used for deriving and studying human embryonic stem cells.

B. Sources of Embryos

Researchers typically procure embryos for research purposes from assisted reproduction clinics—generally, embryos that remain following completion of in vitro fertilization (IVF) treatment and that are no longer wanted for transfer by those who produced them (so-called “spare” embryos). Such researchers submit requests to clinics for embryos that have been explicitly donated for research. As mentioned in Chapter 2, the recent study by the American Society for Reproductive Medicine (ASRM) and RAND on the number of cryopreserved embryos in the United States found that of the nearly 400,000 embryos currently in cryostorage, only 2.8 percent (roughly 11,000) have been designated for donation to research. At the outset of fertility treatment, couples designate what should be done with their embryos in the event of their deaths, divorce, or abandonment. After couples have completed their treatment, they are approached by researchers who make specific requests for embryo donations. Typically, these are researchers who have pre-existing relationships with the assisted reproductive technologies (ART) clinic. In some cases the couple’s fertility specialist may also be the principal researcher requesting donation.

Less often, embryos are created expressly for research. In July 2001, the Jones Institute in Norfolk, Virginia, publicized the fact that its scientists had created more than one hundred embryos in this manner from the gametes of volunteer donors. (Subsequent reports suggest this program has been stopped.) There are no reliable data on the number of researchers now producing embryos solely for research or the number of embryos that have been produced solely for research.

C. Projected Techniques/Recent Experiments

While most embryo research is conducted with embryos produced through IVF using sperm and ova, a range of recent developments in experimental embryology is noteworthy. In July 2003, it was announced that male human cells had been transplanted into a three-day-old female human embryo. Researchers grew the resulting human embryo hybrid (dubbed a “she-male” in the press) for six days before destroying it.1 The purpose of the experiment, according to the head of the research team that conducted it, was to show that cells from a sibling might be transplanted into an embryo in order to prevent the development of certain genetic diseases.2 This experiment was conducted in the United States, with embryos that were donated specifically for the purpose of such experimentation.

Advanced techniques in embryological experimentation have also allowed researchers to create “hybrid” cloned embryos made from human and animal cells. For instance, in August and September of 2003 it was announced that cloned embryos had been created by fusing human skin cells with enucleated eggs from rabbits3 and by fusing female human cells with enucleated oocytes from cows.4

Researchers in South Korea recently produced 30 cloned human embryos (via somatic cell nuclear transfer using the egg donors’ own cumulus cells), grew them to the blastocyst stage (five to six days), and successfully derived a pluripotent embryonic human stem cell line from them.5 This marks the first verified successful cloning of human embryos, and their successful growth to the stage at which embryonic stem cells may be obtained. Although the researchers who accomplished this express no interest in using their technique for procreative purposes, the cloned embryos they produced were cultivated past the developmental stage at which in vitro embryos are typically transferred to a woman’s uterus in an effort to produce a child.

II. Ethical Considerations

The ethical questions connected with embryo research have been discussed in detail in two previous Council reports: Human Cloning and Human Dignity (July 2002) and Monitoring Stem Cell Research (January 2004). We present here the briefest outline of the relevant issues; readers seeking further elaboration should consult Chapter 6 of the cloning report and Chapter 3 of the stem cell report.

First, human embryo research has the potential to do great good, both for infertile couples seeking to conceive children and for countless sick and suffering patients whose diseases or disabilities might be cured or ameliorated by regenerative medicine that made use of embryonic stem cells. Although the promise of such research for human therapies remains speculative, many researchers believe it will offer great benefits to perhaps millions of patients.

The chief ethical concerns raised by the practice of human embryo research arise from the fact that such research generally necessitates the use and destruction of human embryos. Many people regard embryos as human beings at the earliest stage of life, and thus worthy of the same respect and protections that we afford all human persons. Even among many who do not assign human embryos the moral standing of “full persons,” intentional destruction of developing human life is a cause for some ethical disquiet. To regard developing human life as a mere means—even a means to a noble end, such as the alleviation of suffering—presents a moral problem with potentially serious consequences for society as a whole. It might lead to the coarsening of sensibilities in the general culture. It might make respect for human life conditional on the possession of certain capacities, and thus open the door to moral hazards both in research and beyond.

The creation of human embryos solely for research raises additional concerns. Unlike in assisted reproduction, where each embryo is created with a view to conceiving a live-born child, embryos produced solely for research are treated purely instrumentally. They become a “natural resource” for gaining scientific and medical knowledge and, in the process, the techniques of assisted reproduction are severed entirely from the aspiration to produce a human child.

Other ethical hazards include the potential for embryos to be commercialized and the danger that couples undergoing fertility treatment might be subtly or overtly pressured to donate embryos to research against their will. The first concern focuses not so much on the destruction of embryos but on their treatment in the marketplace and the laboratory; the second concern focuses on the treatment of persons involved in creating such embryos—namely, gamete donors and fertility patients. These concerns have been expressed by individuals on all sides of the debate about the moral standing of human embryos.

III. Regulation

A. Federal Law

The federal regulation of human embryo research has a long and complicated history, and public policy debate on embryo research has centered largely on the question of federal funding, not the regulation of embryo research as such. In the 1970s, the regulations governing the protection of human subjects involved in federally funded research provided that “no application or proposal involving human in vitro fertilization may be funded by the Departmenti [until it] has been reviewed by the Ethics Advisory Board (EAB) and the Board has rendered advice as to its acceptability from an ethical standpoint.”6 In 1979, the EAB concluded that federal funding of IVF research was ethically acceptable, subject to certain conditions.ii The secretary of the Department of HEW did not act on this recommendation; the EAB was dissolved in 1980. No subsequent EAB was appointed thereafter. The result was a de facto moratorium on federal funding for embryo research until 1993. Acting on the advice of newly elected President Clinton, Congress passed the National Institutes of Health (NIH) Revitalization Act of 1993, nullifying the requirement that there be an EAB review before an application can be federally funded. Thereafter, NIH Director Harold Varmus convened an advisory panel to consider which types of embryo research, as an ethical matter, should be entitled to federal funding. The NIH Human Embryo Research Panel issued a report in 1994 concluding that certain kinds of embryo research were acceptable for federal funding, others might be acceptable under certain specified conditions, and still others were unacceptable.iii One of the most controversial aspects of the NIH Panel’s conclusions was a qualified endorsement of the creation of embryos solely for purposes of research.iv The Embryo Research Panel submitted its conclusions to the Advisory Committee, which then forwarded them to the NIH director. Before the director could act on the recommendations, however, President Clinton directed NIH not to approve funds for the creation of human embryos solely for research purposes. Director Varmus accepted the remaining recommendations and began to plan for their implementation as a predicate to the funding of embryo research.

Before NIH had the opportunity to approve any proposals for embryo research protocols, however, Congress implemented a statutory ban on federal funding that remains in effect. According to the Dickey-Wicker Amendment to the Department of Health and Human Services (HHS) appropriations bill for fiscal year 1996,7 which has been re-enacted each year since, no federal funds may be used for the following: the creation of a human embryo or embryos for research purposes, or research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero “under 45 C.F.R. 46.208(a)(2) and section 498b of the Public Health Service Act (42 U.S.C. 289g[b]).”v The first referenced statute provides that no fetus in utero can be involved as a subject in any activity covered by Subpart B of Part 46 of Title 45 (federal human subjects protections, described below) unless the risk to the fetus imposed by the research is minimal and the purpose of the activity is the development of important biomedical knowledge which could not be obtained by other means. The second statute (section 498b of the Public Health Service Act) requires that the research risk standard be the same for fetuses that are intended to be aborted and fetuses that are intended to be carried to term. “Human embryo” is defined broadly as “any organism, not protected as a human-subject under 45 C.F.R. 46 . . . that is derived by fertilization, parthenogenesis, cloning, or any other means from one or more human gametes or human diploid cells.”

In light of the legislative restriction on federal funding, in 1998 NIH sought a legal opinion from the HHS Office of the General Counsel on whether NIH funds may be used for research using embryonic stem cells. HHS concluded that the Dickey-Wicker Amendment did not prohibit the federal funding of research “utilizing” (as opposed to deriving) human embryonic stem cells taken from embryos that have already been destroyed using private funding. However, before HHS allocated any funding for such research, the newly elected Bush administration initiated a review of the former administration’s policy for the federal funding of embryonic stem cell research and halted the consideration of research proposals.

On August 9, 2001, President Bush announced his decision to allow federal funds to be used for research on existing human embryonic stem cell lines, so long as the following conditions were met: (1) the derivation process had been initiated prior to August 9, 2001, thus creating no public incentive for future embryo destruction; (2) the embryo from which the stem cell line was derived had already been destroyed and thus had no potential for further development. In addition, the President established the following additional criteria in order for a stem cell line to be eligible for federal funding: the stem cells must have been derived from an embryo that was initially created for reproductive purposes and no longer needed for these purposes, informed consent must have been obtained for the donation of the embryo, and no financial inducements had been provided for donation of the embryo. Because of President Bush's statement, on November 7, 2001, the NIH rescinded a November 21, 2000, guidance on NIH-funded stem cell research insofar as that guidance applied to research on stem cells derived from human embryos.vi As part of the implementation of this funding policy, the NIH has created a Human Embryonic Stem Cell Registry that lists the human embryonic stem cell lines that meet the eligibility criteria.vii

There are currently no federal laws or regulations directly applicable to the use of embryos in privately funded research.

The FDA does not regulate human embryo research unless it is aimed at the development of a “product” subject to its approval.

Embryo research using cloned human embryos—embryos created by somatic cell nuclear transfer—has been the subject of separate legislative activity. On July 31, 2001, and again on February 27, 2003, the House of Representatives passed a bill that would ban the creation of cloned human embryos for any purpose. It would also make illegal the shipment or receipt “for any purpose of an embryo produced by human cloning or any product derived from such embryo.” If enacted, this bill would prohibit research on cloned human embryos and on stem cells extracted from such embryos. As of this writing, the Senate has not acted on the bill.

In addition to specific federal legislation directly addressed to embryo research, there are a number of other federal activities that, less directly, do or might touch embryo research.

1. Secretary's Advisory Council on Human Research Protections(SACHRP).

The charter of SACHRP, which recently replaced the National Human Research Protections Advisory Committee, requires SACHRP to “provide advice relating to the responsible conduct of research involving human subjects” with special emphasis on various special populations, including embryos. Thus, for purposes of the charter of this federal advisory committee, human embryos are human subjects.

2. Human-Subjects Protections.

Entities and individuals that conduct human subjects research are regulated under federal regulations, as well as by the policies and procedures of the institutions at which federally funded research is conducted. (Ex vivo embryos, however, are not considered “human subjects” for these purposes.) There are several regulatory structures that form the basis of the federal government’s jurisdiction over human subjects research. The two major sources of regulation are the Office of Human Research Protections (OHRP) and the Food and Drug Administration (FDA), both housed in HHS. Additionally, NIH, a main source of funding for research, has regulations and policies that must be followed to the extent a research project (or institution) is funded by the NIH. HHS regulations, at 45 C.F.R. Part 46, govern federally funded or supported research on human subjects. Subpart A of the regulations, known as the “Common Rule,” has been adopted and separately codified by fourteen agencies other than HHS.viii Subparts B, C, and D govern research on vulnerable populations: specifically, Subpart B governs research on pregnant women, human fetuses, and neonates; Subpart C governs research on prisoners; and Subpart D governs research on children. OHRP is the office that is charged with developing guidelines interpreting the Common Rule and enforcing its requirements. OHRP determination letters are issued to institutions determined by OHRP to be out of compliance with HHS regulations and provide an additional source of guidance regarding the meaning of the regulations and the government’s enforcement focus.

The Common Rule applies to “all research involving human subjects conducted, supported or otherwise subject to regulation by any Federal Department or Agency” that has adopted its provisions. As a practical matter, the reach of the Common Rule extends beyond federally funded or supported human subjects research to cover all research done at institutions that receive any federal funding. All institutions receiving federal funds to conduct human subjects research are required to enter into an “assurance” with the federal government, under which the institution promises to abide by applicable federal regulations and ethical principles in the conduct of all human subjects research undertaken at the institution.ix The terms of an assurance often apply the ethical principles outlined in the Belmont Report8 and the requirements of the Common Rule, including Subparts B, C, and D, to all research conducted at the institution, regardless of the funding source.

In addition to being limited to institutions that receive federal funds, the scope of the Common Rule’s requirements are further limited by the definition of human subjects research and the regulatory exemptions within the Common Rule that expressly exclude certain types of research from its requirements.9 For example, research that involves the collection or study of existing data—for example, a retrospective chart review—will not be subject to the Common Rule’s requirements if the sources of data are publicly available or the investigator records the data in such a manner that the subjects cannot be identified, directly or through a code linked to the subjects.10  If human subjects research falls within one of the six categories of exempt research, there is no requirement for institutional review board (IRB) review, approval, and continued oversight of the research; nor is there a federal requirement for obtaining the written informed consent of the subject.

One of the main protections of human subjects afforded by the Common Rule is the requirement that human subjects research be reviewed, approved, and monitored by an IRB, an independent ethical body constituted in accordance with the requirements of 45 C.F.R. 46.107. An IRB may approve only such research as meets the criteria in 45 C.F.R. 46.111, and any additional applicable requirements for the special populations governed by Subparts B, C, and D. Specifically, to approve research on human subjects under 45 C.F.R. 46.111, an IRB must conclude that a number of safeguards relating to risks to the subjects, selection of subjects, informed consent, monitoring of subjects, and privacy, are satisfied.x Research approved by an IRB is also subject to continuing review, at intervals appropriate to the degree of risk presented by the study, but at least once a year.11 OHRP has issued detailed guidance regarding the continuing review process, specifying when it should occur and what materials should be reviewed.12

The NIH guidelines on human subjects do not directly cover ex utero embryos, but may touch other participants in such research. For purposes of 45 C.F.R. 46, a “human subject” is a living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. If the identity of the embryo donor(s) can be readily ascertained by the investigator—either because the research is conducted in vivo or because donor identifiers are associated with the embryo—the donor(s) could be “human subjects” within the meaning of 45 C.F.R. 46. Ex utero embryos, as such, have never been treated as “human subjects” for purposes of this section.

Embryos inside a woman’s uterus are covered by the protections under the Common Rule applicable to research on pregnant women and fetuses.xi Pregnant women or fetuses may only be involved in research if the following conditions are met: (1) where scientifically appropriate, preclinical studies and clinical studies have been conducted and provide data for assessing potential risks to pregnant women and fetuses; (2) the risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit to the woman or the fetus; or, if there is no prospect of direct benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means; (3) any risk is the least possible for achieving the objectives of the research; (4) the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means and the woman’s informed consent is obtained; (5) if the research holds out the prospect of direct benefit solely to the fetus and the informed consent of the pregnant woman and the father is obtained, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest; (6) each individual providing consent to the research is fully informed regarding the reasonably foreseeable impact of the research on the fetus or the neonate; (7) if the pregnant individual is a child, as that term is defined under title 45 C.F.R. 46.402(a), assent and permission are obtained in accord with the provisions of Subpart D of the regulations governing research on children; (8) no inducements, monetary or otherwise, will be offered to terminate a pregnancy; (9) the individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and (10) the individuals engaged in the research will have no part in determining the viability of a neonate.

B. State Law

States are the principal sources for the direct regulation of embryo research. State laws vary widely in their application and content. Some states, in an effort to disincentivize abortion, regulate research on aborted fetuses and embryos,xii matters beyond the scope of this document. Additionally, many states define “embryo research” broadly so as to reach experimental practices such as cryopreservation, preimplantation genetic diagnosis, and perhaps gene-transfer. Such statutes are discussed in the parts of this document that address those specific subjects. The following discussion will focus only on regulations that may govern direct research on early-stage in vitro embryos not intended for transfer, and where the aim of the research is to further scientific knowledge and medicine in a general way (unrelated to the specific embryos themselves).

A number of states have regulations potentially applicable to research on in vitro embryos. New Hampshire expressly permits research on in vitro embryos up to fourteen days of development, but prohibits implantation of these embryos once they undergo such experimentation. Additional states also prohibit research on in vitro embryos to various extents.xiii For example, Pennsylvania proscribes any type of “nontherapeutic experimentation” or “nontherapeutic medical procedure” upon any “unborn child,” defined as “an individual organism of the species homo sapiens from fertilization until live birth.”13 Most of these states proscribe such research if not beneficial to the embryo itself. For example, Michigan prohibits research on live human embryos, fetuses, or neonates, if such research substantially jeopardizes the subject’s life or health.14 Illinois, New Mexico, and Utah have statutes that proscribe research on fetuses that might be construed to reach in vitro embryos.

Recently there has been a groundswell of legislation introduced at the state level in response to developments in embryonic stem cell research and human cloning. In Massachusetts, efforts are currently under way to amend the fetal research statute (which now prohibits experimentation on embryos and fetuses unless it is incidental to the study of the human fetus while it is in its mother’s womb) to exempt embryos from its definition of “fetus.” California has recently passed legislation that expressly permits and encourages research involving the derivation of human embryonic stem cells—including research involving the creation and use of cloned embryos. A law recently passed in New Jersey similarly declares that research “involving the derivation and use of human embryonic stem cells and human embryonic germ cells” is permitted, including “somatic cell nuclear transplantation.”15 A related New Jersey law purports to outlaw “cloning,” defined as “replication of a human individual by cultivating a cell with genetic material through the egg, embryo, fetal, and newborn stages into a new human individual.”16 This would seem to be the most permissive of all such state laws that proscribe cloning for reproductive purposes while permitting cloning for biomedical research. Most such laws (like the federal bill recently proposed by Senators Orrin Hatch, Dianne Feinstein, and Arlen Specter17) prohibit the transfer of a cloned embryo to a woman’s uterus. The New Jersey law, by contrast, defines “cloning” in a way that seems to allow the transfer of a cloned embryo to a woman’s uterus, as well as the cultivation of the cloned embryo up to the “newborn” stage.

It bears noting that some of the above-mentioned embryo research statutes have come under judicial scrutiny. Statutes in Illinois, Louisiana, and Utah have been held to be unconstitutionally vague, on the grounds that “experimentation” is not defined clearly enough for practitioners to understand that certain of their activities may be criminal. One court in Illinois went further, striking down a portion of an older statute on the grounds that it could reach certain practices and techniques of assisted reproduction, thus infringing upon a woman’s constitutional right to make reproductive decisions.

C. Professional Self-Regulation

A number of professional organizations and societies have published guidelines and opinions on human embryo research. These are substantially similar to the guidelines proposed by the 1994 NIH Human Embryo Research Panel (discussed elsewhere in this chapter and summarized below). Two that are worth noting are statements from ASRM and the American Academy of Pediatrics (AAP).

ASRM’s 1994 report, entitled “Research on Pre-embryos: Justifications and Limits,” notes what it considers the great benefits of embryo research, and concludes that it is a permissible activity. ASRM further concludes that it is not “prudent at this time” to maintain embryos in vitro beyond fourteen days. The opinion does not seem to take a position on the creation of embryos expressly for research.

ASRM offers guidelines for the donation of embryos in two ethics opinions: “Donating Spare Embryos for Embryonic Stem Cell Research”18 and “Informed Consent and the Use of Gametes and Embryos.”19 These guidelines specify the importance of making sure that potential embryo donors understand the risks and benefits, as well as the purpose and nature of the research and its potential commercial value (and their own lack of entitlement to such value). Additionally, couples are to be told that their decision does not affect their status as patients, that no research embryos will be transferred, and that they may change their minds at any point up until the protocol begins. ASRM advises that clinics should have a policy on privacy and confidentiality. Both members of a couple seeking treatment must agree on donation to research—if they disagree, then no embryos shall be donated. Final consent (confirming the couple’s initially stated preferences for embryo disposition) is to be obtained only after the couple has decided not to continue storing their embryos. ASRM’s opinion on the disposition of “abandoned” embryos precludes the use of such embryos in research. An embryo is deemed “abandoned” if the couple “has not given written instruction for disposition, has not been in contact with the program for a substantial period of time, and has not provided a current address and telephone number.” ASRM notes that it is preferable (though not mandatory) that an individual other than the couple’s fertility specialist be the person who requests donation for research. ASRM concludes that there should be no buying and selling of embryos, though reasonable fees (defined by the contracting parties) may be paid for efforts and costs incurred.

The AAP issued a statement on human embryo research in September 2001 concluding that embryonic stem cell research is sufficiently valuable that it should be funded by NIH and regulated by HHS. The Academy took the position that federally funded embryo research should be approved by IRBs subject to the following conditions (which are similar to those set out by a panel of the NIH in the late 1990s):

  • The embryos are already frozen and are no longer clinically needed.
  • There is a clear separation in the donor decision process between the decision by the donors to create embryos for infertility treatment and the decision to donate frozen embryos for research purposes after they are no longer clinically needed.
  • The decision to donate is strictly voluntary and without monetary inducements.
  • The physician responsible for fertility treatments is not to be the person performing the research on the same frozen embryos, and there should be no monetary relationship, that is, transfer of funds in the research project to the physician responsible for the fertility treatments.
  • There are to be no personal identifiers associated with the embryos used for research.
  • There are to be no restrictions placed by the donor on the type of research performed.
  • The research performed on these frozen embryos can be of no direct benefit to the original donors.
  • The embryo research does not involve research in reproductive cloning, transferring an altered embryo to a woman's uterus, or use of a human embryo in combination with other human or animal embryos.

The Academy also provided guidelines for informed consent. Specifically, informed consent should advise donors that:

  • All identifiers associated with the frozen embryos will be removed.
  • The donors will not receive any future information regarding subsequent testing or research on these embryos.
  • Cells or tissue developed from the embryos may be used at some future time for human transplantation research.
  • Cells or tissues derived from the embryos may be kept indefinitely.
  • The donated frozen embryos may be of commercial value, but the donors will not receive any financial or other benefits from any such commercial development.
  • The research performed on these frozen embryos is not intended to provide direct medical benefit to the donor.
  • The research will not involve the transfer of these embryos to a woman's uterus or involve reproductive cloning or combination of the embryo with any other embryo of human or animal origin.

The American Medical Association (AMA) has similarly issued guidance on human embryo research, supporting the conclusions of the 1994 NIH Human Embryo Research Panel and recommending the creation of a RAC-like body to provide oversight for experiments that involve cloned embryos or cloning techniques. Additionally, the AMA has signaled its support for federal funding of research using early-stage human embryos.

While its conclusions do not have the force of law and were never fully adopted, the principles articulated by the NIH Embryo Research Panel in 1994 have been widely echoed in the policies and ethical opinions of a number of professional societies and organizations. Thus, it is worthwhile to summarize briefly the key conclusions of the Embryo Research Panel. The Panel agreed that federal funding of embryo research in certain areas is permissible for three reasons: (1) the scientific promise of such research is significant; (2) the embryo does not, in the Panel’s view, enjoy the same moral status as a person; and (3) the absence of federal funding (and thus oversight) leads to a status quo in which there is no consistent scientific or ethical review of research protocols.20

The Panel identified and distinguished the categories of research that should receive funding. The first category was research deemed by the Panel to be “acceptable for federal funding,” provided it was conducted in accordance with certain guidelines. These guidelines included requirements that the research be conducted by qualified researchers, according to a valid research design, under the direction of an IRB, with a minimum number of embryos necessary, and with adequate informed consent. Additionally, the Panel advised that there should be no purchase or sale of gametes or embryos (though reasonable compensation for expenses and efforts should be permitted), and there should be equitable selection of gamete and embryo donors to prevent discrimination. Finally, the Panel noted that, subject to certain exceptions, embryos should not be maintained in vitro for more than fourteen days following fertilization.

Types of research deemed “acceptable for funding” include research aimed at improving the outcome of pregnancy and research on the process of fertilization, the genetics of embryonic development, the effects of cryopreservation on the development of oocytes, preimplantation genetic diagnosis, embryonic stem cells (using excess IVF embryos with appropriate informed consent), and oocyte nuclear transfer (in protocols where there is no transfer to a uterus or functional equivalent). Within the category of “acceptable research,” the Panel singled out a subcategory of projects that was acceptable to them for federal funding, but deserving “very careful scrutiny” during the ad hoc review process (recommended by the Panel for research protocols). Such projects include research involving existing embryos where “one of the progenitors received monetary compensation,”xiv and “projects of outstanding merit requiring fertilization of ova as part of the protocol.” As we noted earlier, this latter recommendation was quite controversial and was not accepted by the Clinton administration.

The Panel identified a second category, namely, research “that warrants additional review.” Such research would be presumptively ineligible for federal funding, but this presumption could be overcome by a showing of outstanding merit, and following “explicit consideration of the ethical issues and social consequences.” Research in this category includes cloning by blastomere separation or blastocyst splitting (without transfer), “research between the appearance of the primitive streak and the beginning of closure of the neural tube” (occurring between days 17 and 21 of embryonic development), research using fetal oocytes for fertilization or parthenogenesis (without transfer), research on oocyte nuclear transfer (with subsequent transfer to a woman’s uterus), and embryonic stem cell research involving embryos fertilized exclusively for such research.

The third and final category of research identified by the Panel was projects “considered unacceptable for funding.”  These projects were deemed unacceptable on ethical grounds, including concerns for adverse effects on the well-being of children, women, and men involved in such research; the “special respect” due to the in vitro embryo; concern for “public sensitivities on highly controversial research proposals”; and “concern for the meaning of humanness, parenthood, and the succession of generations.”21 Research that is “unacceptable for federal funding” included the cloning of embryos via blastomere separation or blastocyst splitting (with transfer to a woman’s uterus); preimplantation genetic diagnosis (PGD) for non-medically indicated sex selection; development of human-animal chimeras (with or without transfer); cross-species fertilization (except for clinical protocols exploring “the ability of sperm to penetrate eggs”); research involving transfer of parthenotes to a woman’s uterus; and research involving the transfer of human embryos into nonhuman animals, or “for extrauterine or abdominal pregnancy.”22

IV. Conclusion

There has been significant policy debate and direct legislative action on the question of federal funding for embryo research—culminating in the current policy of funding research that employs a limited number of specifically eligible embryonic stem cell lines. There is no federal regulation of research on in vitro embryos when such research is privately funded and supported. States have widely varying approaches to the subject, ranging from active support and endorsement, to silence (and thus permission), to prohibition of such research. The private sector’s practices on this point seem to reflect the principles articulated by the NIH Human Embryo Research Panel in 1994, namely, that the embryo is entitled to “special respect,” but may be used and destroyed in “worthwhile” research protocols. Additionally, there seems to be some agreement among scientific professional societies that embryos should not be cultivated beyond fourteen days’ development—a limit that has been proposed by a number of bodies, both governmental and nongovernmental.

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Footnotes

i. The Department of Health, Education, and Welfare (DHEW), now called the Department of Health and Human Services (HHS).

ii. These conditions included: informed consent for the use of gametes, the research had to be important and “not reasonably attainable by other means,” and that embryos must not be maintained outside the body beyond fourteen days after fertilization. (DHEW EAB 1979, 106, 107.)

iii. The specific conclusions of the NIH Embryo Research Panel are discussed further, below.

iv. “The Panel believes that the use of oocytes fertilized expressly for research should be allowed only under two conditions. The first condition is when the research by its very nature cannot otherwise be validly conducted. The second condition . . . is when a compelling case can be made that this is necessary for the validity of a study that is potentially of outstanding scientific and therapeutic value.” (Report of the Human Embryo Research Panel, September 1994, pp. 44-45.)

v. A minor technical matter: 45 C.F.R. § 46.208 no longer exists, although the Dickey-Wicker reference to it exists as recently as the Fiscal Year 2003 Consolidated Appropriations Resolution (P.L. 108-07, signed February 20, 2003) and in NIH's March 18, 2003, explanation of the appropriations resolution (Notice NOT-OD-03-035). 45 C.F.R. § 46.208(a)(2) is currently expressed at 45 C.F.R. § 46.204(b).

vi. The guidance was issued following a decision by NIH that the Dickey-Wicker amendment did not prohibit federally funded research preceding or following the destruction of human embryos. Thus, NIH concluded that it could fund research projects on human embryonic stem cell lines that had been previously derived. The November 21, 2000, guidance remains effective with respect to NIH funding of research using germ cells derived from fetal tissue.

vii. The registry is available at escr.nih.gov. For a more complete discussion of the federal legislation and policy developments pertaining to stem cell research, see the Council’s report, Monitoring Stem Cell Research (January 2004), especially Chapter 2, available at www.bioethics.gov.

viii. The FDA has never officially adopted the Common Rule. But FDA regulations governing research on human subjects include requirements that are functionally identical to the Common Rule. Unlike the Common Rule, however, the FDA’s requirements for human subjects research apply regardless of whether the research is federally funded, provided that the prospective product being studied in the clinical investigation is subject to FDA regulation generally (21 C.F.R. §§ 50.1, 56.101). Even clinical investigations that are exempt from the IND requirements (for example, where the results will not be submitted to the FDA and the investigation does not increase the risks to the subjects) must nonetheless be conducted in accordance with FDA’s IRB oversight and informed consent requirements. It is important to note, however, that FDA regulations governing clinical investigations do not apply to the off-label use of an investigational drug or device in the practice of medicine. (See 21 C.F.R. § 312.2(d) [expressly carving out the off-label use of drugs in the practice of medicine]; 812.2(a) [limiting the applicability of Part 812 to clinical investigations to determine the safety and efficacy of a device].)

The FDA requirements for IRB oversight and informed consent are similar to those under the Common Rule. One distinction is noticeable. Whereas the Common Rule provides for IRB waiver of informed consent for certain types of minimal risk research (see 45 C.F.R. § 46.116), waiver of informed consent is limited under FDA regulations to emergency use of an investigational drug or device or research intended to be conducted in an emergency setting, because the use of an investigational device or drug is automatically considered to present at least a minimal risk to the subjects (see 21 C.F.R. §§ 50.23, 50.24).

ix.Historically, there were several forms of assurances, depending on the sort of project involved, and the terms of each assurance would vary depending upon its negotiation. Recently, OHRP instituted the “Federalwide Assurance,” a uniform assurance document that is now required (as of December 31, 2003) for all institutions receiving federal research funds, regardless of what kind of assurance the institution was previously operating under. Although many institutions conducting research receive some form of federal funding requiring them to execute a Federalwide Assurance, there are institutions or other private companies that conduct research solely with private funds and that will therefore not be required to execute an assurance. Although these privately funded research entities may be governed by FDA or state law requirements, or both, they will not be subject to the requirements of 45 C.F.R. § 46.

x. The IRB must conclude that risks to subjects are minimized; risks to subjects are reasonable in relation to anticipated benefits, if any, and the importance of the knowledge that may reasonably be expected to result; selection of subjects is equitable (for example, no one population bears the burden of research without direct benefit; adult subjects should be used for research where possible before children are enrolled, etc.); informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with and to the extent required by 45 C.F.R. § 46.116; informed consent will be appropriately documented, in accordance with and to the extent required by 45 C.F.R. § 46.117; when appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects; and when appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.

xi. The regulation provides protection for “fetuses,” defined as “the product of conception from implantation until delivery.” This legal definition differs from the standard medical definition, which uses the term “embryo” to name the product of conception from the time of fertilization up to eight weeks (well after implantation, which usually occurs before the end of the first week). Thus, if the research is conducted in vivo post-implantation, what might be considered research on an “embryo” by most scientists could be considered research on a “fetus” for purposes of 45 C.F.R. § 46 (and therefore subject to Subpart B).

xii. See, for example, Arizona, Arkansas, California, Florida, Indiana, Kentucky, Missouri, Nebraska, Ohio, Oklahoma, Tennessee, and Wyoming.

xiii. See, for example, Louisiana, Michigan, Minnesota, New Hampshire, New Mexico, Pennsylvania, and South Dakota. Some states, including Maine, Massachusetts, North Dakota, and Rhode Island, prohibit research on embryos or fetuses “before or after expulsion from the mother’s womb.” It is unclear whether these statutes govern research on in vitro embryos.

xiv. The Panel concluded that federal funding is acceptable only for research involving embryos acquired by these means prior to September 1994.

_________________

Endnotes

1. Gleicher, N., et al., “Blastomere transplantation as a possible treatment,” presented at the 19th Annual Meeting of the European Society of Human Reproduction and Embryology, June 29 to July 2, 2003, Madrid, Spain (www.eshre.com).

2. “Sex Cells,” ScienCentral News, July 29, 2003, quoting Dr. Norbert Gleicher, founder of the Center for Human Reproduction.

3. Chen, Y. et al., “Embryonic stem cells generated by transfer of human somatic nuclei into rabbit oocytes,” Cell Research 12:251-264 (2003), reporting on experiments in Shanghai Second Medical University in China, in which human cells were fused with empty rabbit oocytes.

4. “First human clone embryo ready for implantation,” NewScientist.com, September 15, 2003, reporting that fertility practitioner Panayiotis Zavos created human cloned embryos by fusing human cells with empty cow oocytes.

5. See Hwang, W.S., et al., “Evidence of a Pluripotent Human Embryonic Stem Cell Line Derived from a Cloned Human Blastocyst,” Science Express, doi:10.1126/science.1094515 (2004).

6. 45 C.F.R. § 46.204(d) (later repealed).

7. Pub. L. No. 104-99, § 128, 110 Stat. 26.

8. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Bethesda, Maryland: Government Printing Office, 1978.

9. See 45 C.F.R. § 46.101(b).

10. See 45 C.F.R. § 46.101(b)(4).

11. See 45 C.F.R. § 46.109(e).

12. See OHRP Guidance on Continuing Review, July 11, 2002 (http://ohrp.osophs.dhhs. gov/humansubjects/guidance/contrev2002.htm).

13. 18 Pa. Cons. Stat. Ann. §§ 3203, 3216.

14. Mich. Comp. Laws Ann. § 333.2685.

15. N.J. Stat. Ann. 26:2Z-2.

16. N.J. Stat. Ann. 2C:11A-1.

17. S. 303, 108th Congress.

18. Ethics Committee of the American Society for Reproductive Medicine, “Donating Spare Embryos for Embryonic Stem Cell Research,” Fertility and Sterility 78: 957-960 (2002).

19. Ethics Committee of the American Society for Reproductive Medicine, “Informed Consent and the Use of Gametes and Embryos,” Fertility and Sterility 68: 780-781 (1997).

20. National Institutes of Health, Ad Hoc Group of Consultants to the Advisory Committee to the Director, Report of the Human Embryo Research Panel, September 1994, p. x.

21. Ibid., p. 80.

22. Ibid., p. 83.

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