4
Current Regulation of Human Embryonic Stem Cell Research

It would be a mistake to assume that the restrictions on federal funding for human embryonic stem (hES) cell research result in an absence of oversight of such work. At present, many federal regulations already govern various aspects of hES cell research, including

  • Human subjects protection for donors of somatic cells and oocytes and for some donors of embryos.

  • Medical privacy protections.

  • Laboratory standards for investigators whose work will result in products that require Food and Drug Administration (FDA) approval.

  • Safety reviews of laboratory work that involves genetic alteration of hES cell lines.

  • Animal care committee reviews of hES cell research that uses nonhuman animals.

  • Various rules governing the importation of biological materials or the transfer of medical data from other countries.

However, there is a perception that the field is unregulated. In fact, the field is subject to a patchwork of regulations, many not designed with this research specifically in mind, and the patchwork has some gaps in its coverage.

This chapter reviews current state and federal regulation of hES cell research in the United States, noting where gaps in regulatory coverage are addressed by the guidelines proposed later in this report (Chapter 6). It also offers some examples of how the proposed guidelines would operate in conjunction with current regulations



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research 4 Current Regulation of Human Embryonic Stem Cell Research It would be a mistake to assume that the restrictions on federal funding for human embryonic stem (hES) cell research result in an absence of oversight of such work. At present, many federal regulations already govern various aspects of hES cell research, including Human subjects protection for donors of somatic cells and oocytes and for some donors of embryos. Medical privacy protections. Laboratory standards for investigators whose work will result in products that require Food and Drug Administration (FDA) approval. Safety reviews of laboratory work that involves genetic alteration of hES cell lines. Animal care committee reviews of hES cell research that uses nonhuman animals. Various rules governing the importation of biological materials or the transfer of medical data from other countries. However, there is a perception that the field is unregulated. In fact, the field is subject to a patchwork of regulations, many not designed with this research specifically in mind, and the patchwork has some gaps in its coverage. This chapter reviews current state and federal regulation of hES cell research in the United States, noting where gaps in regulatory coverage are addressed by the guidelines proposed later in this report (Chapter 6). It also offers some examples of how the proposed guidelines would operate in conjunction with current regulations

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research and presents comparisons with regulations in other nations that have substantial hES cell research programs. Recommendations about the application of existing regulatory conventions to hES cell research are offered. Finally, although the committee recognizes that successful resolution of intellectual property issues will be critically important in this evolving area of research, it was beyond its charge and beyond its capabilities to address adequately all of the legal issues that will arise. In the context of privately funded research it is particularly difficult to explore mechanisms by which discoveries made using hES cells can be made widely accessible for the benefit of human health. However, the committee believes that best practices can be developed and followed. Several policy statements developed regarding patenting and licensing issues more generally applied in biomedical science can serve as aspirational goals for the hES cell research community. In particular, in 2004 NIH issued Best Practices for the Licensing of Genomic Inventions.1 This document aims to maximize the public benefit whenever Public Health Service-owned or -funded technologies are transferred to the commercial sector. In this document NIH recommends that “whenever possible, non-exclusive licensing should be pursued as a best practice. A non-exclusive licensing approach favors and facilitates making broad enabling technologies and research uses of inventions widely available and accessible to the scientific community.” In addition, the National Academies is developing recommendations for NIH on intellectual property rights in genomic- and protein-related innovation (forthcoming, 2005). The reader is encouraged to review these documents, which aim to facilitate responsible patenting and licensing practices by the scientific community. REGULATION OF PROCUREMENT OF GAMETES, SOMATIC CELLS, AND BLASTOCYSTS Whether it involves receiving donated blastocysts that would otherwise be discarded after infertility treatment or procuring gametes and somatic cells to make blastocysts specifically for research purposes, the procurement process often requires oversight by an Institutional Review Board (IRB), whose membership and functions are described in Department of Health and Human Service (DHHS) regulations at 45 CFR 46.107-115 and in FDA regulations at 21 CFR 56.107-115.2 IRB 1   http://a257.g.akamaitech.net/7/257/2422/06jun20041800/edocket.access.gpo.gov/2004/pdf/04-25671.pdf. 2   DHHS has codified its human subjects protection regulations at 45 CFR 46, Subparts A through D. Other federal research agencies have signed onto Subpart A, which is referred to as the Common Rule. In this report, the DHHS regulations are cited in discussing the protection of human subjects of research because they are more inclusive than the Common Rule alone. The DHHS regulations extend additional protections to vulnerable populations, such as pregnant women, viable fetuses, prisoners, and children. FDA also has codified Subpart A of the regulations at 21 CFR 50 and 56, although with slightly different interpretations. In some cases, FDA regulations and HHS regulations might apply to research.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research review is the primary means of implementing the research protections found in the federal regulations, which generally require that human research be undertaken with the informed and voluntary consent of the subjects, that the risks to subjects be minimized, and that the research be approved and monitored by an IRB. The federal regulations generally are triggered when research is funded by the federal government, when privately funded research is aimed at developing data for a product to be approved by FDA, or when privately funded research takes place at institutions that have agreed to adopt the protections more broadly than required by law. In addition, some states, such as California and New Jersey, have adopted legislation requiring IRB review and many of the substantive protections of the federal regulations with regard to hES cell research conducted in those states.3 Research involving hES cells will require access to human oocytes and blastocysts, which in turn will necessitate some interaction between donors of oocytes and blastocysts and the people or institutions seeking to procure these materials for use in hES cell research. The federal regulations governing human subjects research define human subjects research as involving either obtaining data from a living individual through intervention or interaction with the individual; or obtaining private (i.e., individually identifiable) information about a living individual (45 CFR 46.102(f)). The DHHS Office for Human Research Protections (OHRP) has made it clear that hES cell research “that involves neither interactions nor interventions with living individuals or obtaining identifiable private information is not considered human subjects research [and therefore] IRB review is not required for such research.”4 According to OHRP, merely asking couples whether they wish to donate their surplus blastocysts for research does not render them “human subjects of research” if no data on them are being gathered and there is no substantive interaction with them other than gaining their consent.5 On the other hand, where physical interaction is needed to obtain biological materials, such as in the case of donors whose sperm, oocytes, or somatic cells are used to make blastocysts for research, the interaction brings them under the purview of the human subjects protections system and IRB review is required, even though the donors are not themselves the subjects of scientific study. Thus, their fully informed and voluntary consent is required before such research use. 3   See http://www.ncsl.org/programs/health/genetics/rt-shcl.htm. 4   Guidance for Investigators and Institutional Review Boards Regarding Human Embryonic Stem Cells, Germ Cells and Stem Cell-Derived Test Articles, OHRP/DHHS, Mar. 19, 2002, at 3. 5   OHRP staff briefing to the committee, January 8, 2005, interpreting 45 CFR 46.102(f).

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research Whether it is blastocyst donation or the donation of gametes and somatic cells, even where the federal regulations require informed consent, IRBs are permitted to waive the requirement if certain conditions are met (45 CFR 46. 116(8)(d)), that is, if the research is of minimal risk, waiver of consent would not adversely affect rights and welfare of subjects, and obtaining consent is impracticable. In the case of gamete or somatic cell donation, in which the donors must be present at the time of donation, not all those conditions apply, and waiver of consent cannot be granted. In the case of blastocyst donation, the committee finds that informed consent should be required in all cases (see Chapter 5): a waiver should not be granted even when the specified conditions can be met. Although OHRP requires IRB review of the procurement process for blastocyst donors only under certain conditions, this committee finds that the best way to ensure that protections are in place for all potential donors is to require IRB review at all times for the process by which somatic cells, gametes, and blastocysts are obtained to ensure that risks are minimized and voluntary and informed consent is provided. (Consent issues are addressed in greater detail in Chapter 5.) In contrast, as noted below in the discussion of privacy protections, when research is to be conducted on hES cell lines that have already been derived through a procurement process approved by an IRB, the committee does not find that there is need for additional IRB review of work with coded or anonymous cell lines. Recommendation 8: Regardless of the source of funding and the applicability of federal regulations, an Institutional Review Board or its equivalent should review the procurement of gametes, blastocysts, or somatic cells for the purpose of generating new hES cell lines, including the procurement of blastocysts in excess of clinical need from in vitro fertilization clinics, blastocysts made through in vitro fertilization specifically for research purposes, and oocytes, sperm, and somatic cells donated for development of hES cell lines derived through nuclear transfer. Recommendation 9: Institutional Review Boards may not waive the requirement for obtaining informed consent from any person whose somatic cells, gametes, or blastocysts are used in hES research. Requiring informed consent before donation of gametes, somatic cells, or blastocysts and requiring oversight by such a body as an IRB would bring U.S. practices into conformity with the practices in Australia, Canada, Israel, Singapore, the United Kingdom, and other major centers of hES cell research. That, in turn, will not only ensure the ethical conduct of procurement practices in the United States but also facilitate collaboration with investigators subject to regulations in the other countries.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research THE PRIVACY RULE AND HUMAN SUBJECTS PROTECTIONS FOR RESEARCH WITH BIOLOGICAL MATERIALS: IMPLICATIONS FOR hES CELL RESEARCH In many cases, medical information about donors will be collected at the time of gamete or blastocyst donation. The primary purpose of collecting such information is to permit a coded link to be maintained between the resulting hES cell lines and information about the genetic or infectious disease status of the donors. The information could facilitate some types of research (such as genetics research) or might be needed to enhance suitability screening for downstream tissue transplantation uses (see later discussion of FDA donor suitability rules). How such donor information is collected and managed can affect whether the human subjects protections described above apply and whether federal privacy protections apply. Thus, a key determinant is whether the resulting cell lines will be managed in a way that makes the donors’ identities readily ascertainable to investigators. If so, both sets of protections apply. When investigators wish to work with existing lines rather than obtain materials to derive new lines, those lines may be accompanied by medical or other information about the donors. Work with hES cell lines whose identifiers render identity of the original donors readily ascertainable to the investigators would be a form of human subjects research that requires IRB review because the work might well reveal information about the donors. But properly obscuring donor identities can exempt work with cell lines from the requirement of IRB review. In that situation, OHRP has declared that in vitro research or research in animals that involves the use of an hES cell line that “retains a link to identifying [donor] information” (such as the use of a code) will not be considered human subjects research subject to the federal regulations if the investigator and research institution do not have access to identifiable private information related to the cell line; and a written agreement is obtained from the holder of the identifiable private information related to the cell line providing that such information will not be released to the investigator under any circumstances.6 OHRP has stated that, when those two conditions are satisfied, the research is not considered to involve human subjects, because the donors’ identities cannot be readily ascertained by the investigator or associated with the cell line. By necessary implication, the OHRP Guidance dictates that any hES cell researcher who has access to personally identifiable information regarding the donors, including medi- 6   See also Guidance on Research Involving Coded Private Information or Biological Specimens, OHRP/DHHS, Aug. 10, 2004.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research cal information, will fall within the regulatory purview, and IRB review will be required. Thus, when medical information required for FDA donor suitability rules is collected (see below), human subjects protections are triggered unless the information is carefully coded and managed. In addition to human subjects protections, if donor health information is attached to hES cell lines, federal privacy protections under the Health Insurance Portability and Accountability Act of 1996 (HIPAA; PL 104-191) might apply. The Privacy Rule of HIPAA might be applicable to hES cell research if the investigator obtains personal health information (PHI) on donors and the investigator is a “covered entity” (most likely a provider that transmits information in electronic format, such as a physician or hospital).7 The Privacy Rule would permit PHI obtained by the researcher to be “deidentified,” for example, statistical data would be aggregated or stripped of individual identifiers (45 CFR 164.514(b)) so that it could be used or disclosed without restriction. If an hES cell investigator is employed by a covered entity and does not wish to “deidentify” PHI related to donors of somatic cells, gametes, or blastocysts (presumably because the identifying information may be expected to contribute relevant scientific information or assist in FDA review), HIPAA requires either of these A valid “authorization” from the donor before the PHI is used or disclosed (45 CFR 164.508). Appropriate documentation that an IRB or a privacy board has granted a waiver or alteration of the authorization requirement that satisfies 45 CFR 164.512(i).8 The criteria for approving an authorization waiver or alteration must be consistent with the criteria for IRB waiver of the informed consent: PHI is protected by a plan to guard against unauthorized disclosure, so there is no more than “minimal risk” to privacy; The research could not practicably be conducted without the requested waiver or alteration; and The research could not practicably be conducted without access to and use of the PHI (45 CFR164.512(i)(2)(ii)(A)-(C)). 7   See 65 Fed. Reg. 82,799 (Dec. 28, 2000) (defining covered entities). 8   An example of a situation in which a waiver of authorization requirements may be deemed appropriate by an IRB is a study that involves the use of PHI on numerous people whose contact information is unknown. The research would be impracticable to conduct if authorization were required, and an IRB could waive all the authorization requirements if the waiver criteria were satisfied. If the IRB approves such a waiver, the receipt of the requisite documentation of the approval permits a covered entity to use or disclose PHI in connection with a particular research project without authorization.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research In sum, FDA’s donor suitability rules (discussed below) may require collection of medical record information on donors of somatic cells, gametes, or blastocysts whose biological materials were used to derive new hES cell lines. In such cases, both federal human subjects protections and the Privacy Rule might apply to the research uses of the information, depending on how it is collected and transmitted in conjunction with the cell lines. Thus, if hES cell research involves the transmission of PHI on the donors, which will increasingly be the case as cell lines approach clinical application, it will be important for investigators, institutions, and IRBs to be aware of any Privacy Rule requirements that apply and to seek authorization from donors, as appropriate, for the transmission of health information. Recommendation 10: Investigators, institutions, Institutional Review Boards, and privacy boards should ensure that authorizations are received from donors, as appropriate and required by federal human subjects protections and the Health Insurance Portability and Accountability Act, for the confidential transmission of personal health information to repositories or to investigators who are using hES cell lines derived from donated materials. REGULATION OF IN VITRO AND ANIMAL STUDIES THAT USE hES CELL LINES In general, state law does not affect the practice of in vitro or animal studies with hES cells. There are, however, sources of federal regulation for this research. Once the cell lines are established, as noted above, federal regulations governing human research and HIPAA regulations apply only if information being used or developed might personally identify the original donors and progenitors. Thus, in vitro or animal studies that use hES cell lines do not require IRB review if the tracking codes that link the donors to the cell lines are properly managed. However, a host of other federal regulations apply to even purely laboratory, preclinical research with hES cell lines. Recombinant DNA Research Some of the research being done on hES cell lines will require some degree of genetic manipulation (see Chapter 2 for a description of these experiments). Research institutions are responsible for ensuring that all recombinant DNA research conducted at or sponsored by them is conducted in compliance with the National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules.9 Institutional authority and responsibility place accountability for the safe 9   Available at http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research conduct of such research at the local level, and oversight is managed through an Institutional Biosafety Committee (IBC), a review body registered with NIH and appointed by an institution to review and approve potentially biohazardous lines of research.10 The need for IBCs grew out of the Asilomar Conference, when scientists agreed to self-regulate recombinant DNA research to avoid any potential threats to human health or the environment. Much of that research was initially reviewed case-by-case, not only by IBCs but also by a federal-level committee, the Recombinant DNA Advisory Committee (RAC). Over time RAC’s role has evolved, first toward a focus on human gene transfer therapy study approvals and more recently toward human gene transfer therapy policy development, with authority to approve gene transfer therapy studies lodged solely in FDA’s jurisdiction. To the extent possible, review of individual recombinant DNA research proposals has been delegated to local IBCs, and they remain as the guardians of public safety with regard to all recombinant DNA research and other potentially biohazardous research. They focus their review on safety, not on compliance with human subjects protections or other aspects of state and federal law governing the ethical conduct of scientific research. Many experiments are reviewed and approved by IBCs without any input from RAC. At present, RAC is an advisory committee whose goal is to consider the current state of knowledge and technology regarding recombinant DNA. This includes review but not approval of human gene transfer trials, and assessment of the ability of DNA recombinants to survive in nature and the potential for transfer of genetic material to other organisms. A major role for RAC is to examine clinical trials that involve the transfer of recombinant DNA to humans. Currently, all human gene transfer trials in which NIH funding is involved (either directly or indirectly) are registered with the RAC. Protocols that contain unique and/or novel issues are discussed in a public forum. In addition, RAC advises the NIH director and his/her staff in a number of activities, including the preparation of materials required in legal actions, international coordination of biotechnology regulations, and the review of regulations proposed by other federal agencies. In contrast to RAC’s role, FDA’s role is to determine whether a sponsor may begin studying a gene transfer product and, ultimately, whether it is safe and effective for human use. FDA regulates the products evaluated in human gene transfer clinical trials that are intended for eventual sale in the United States and is responsible for reviewing serious adverse events that occur in a gene transfer study. Animal Care and Use Increasingly, hES cell research might also involve the manipulation of hES cells in a nonhuman animal, such as a mouse. Laboratory work with nonhuman animals 10   See http://www4.od.nih.gov/oba/IBC/IBCrole.htm.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research is governed by its own set of federal laws and regulations, and any hES cell research that involves insertion of hES cells or their derivatives into animals is already subject to animal welfare protections. The Animal Welfare Act constitutes congressional policy to ensure the most humane use of animals in research. Some animals that might be used by hES cell investigators are not covered by the act, but most are covered.11 In addition, the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals requires that each institution receiving PHS support for an activity involving any live vertebrate animals establish an appropriate institutional animal care and use program, including an Institutional Animal Care and Use Committee (IACUC) with specific responsibilities as described in the PHS policy.12 Laboratory Practice In addition to special regulations governing recombinant DNA research and research that uses animals, the federal government has regulations pertaining to the management of laboratories where products that might ultimately be introduced into humans (as in a clinical trial) are being developed. FDA’s Good Laboratory Practice (GLP) regulations establish standards for nonclinical laboratory studies. These do not include basic exploratory studies performed to determine whether a test article has any potential utility or to determine its physical or chemical characteristics but they do encompass in vivo or in vitro experiments in which test articles are studied to determine their safety—an activity that would be characteristic of the preclinical phase of hES cell research. Failure to conform to GLP regulations, although not itself a violation of law, would render any hES cells less useful in the future if they were considered for clinical trials of tissue transplantation or other cell-based therapies.13 Recommendation 11: Investigators and institutions involved in hES cell research should conduct the research in accordance with all applicable laws and guidelines pertaining to recombinant DNA research and animal care. Institutions should consider adopting Good Laboratory Practice standards for some or all of their basic hES cell research. REGULATION OF CLINICAL RESEARCH WITH CELL LINES AND DIFFERENTIATED TISSUE Clinical research aimed at obtaining FDA approval or new labeling of drugs, devices, or biologics is subject to regulation by FDA. It must be conducted in 11   Animal Welfare Act (as amended), 7 USC §§ 2131-56. 12   http://grants.nih.gov/grants/olaw/references/phspol.htm. 13   http://www.fda.gov/ora/compliance_ref/bimo/7348_808/part_I.html.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research compliance with FDA’s regulations governing investigational new drugs (INDs) or investigational device exemptions (IDEs), regardless of source of funding. Thus, all human studies conducted under INDs and IDEs are subject to FDA’s own regulations concerning IRB review and informed consent (21 CFR 50 and 56), which are roughly parallel to the DHHS regulations at 45 CFR 46. Transplantation of hES cells or tissues developed from hES cell lines is a form of “cell-based therapy” and is generally regulated by FDA as a biologic, drug, or device. The regulations entail a variety of premarket notifications and approvals based on safety and efficacy data; the precise requirements depend on the primary mode of action (drug or device), in accordance with the Food, Drug and Cosmetic Act and its amendments (21 USC Section 301 et seq). Biologics are subject to additional precautions based on the Public Health Service Act, aimed primarily at control of transmission of infectious disease (42 USC, Chapter 6A, Part F). Because hES cell research is likely to lead to clinical applications that involve the transfer of cells or tissue into humans they will also be subject to FDA’s comprehensive tissue transplantation regulations.14 Of course, many investigators will be engaged in basic research with no intent to pursue an immediate clinical application, and much of what follows does not necessarily apply to such investigators. But failure to follow FDA’s tissue transplantation regulations may result in FDA’s refusal to use materials from the laboratories in question in later clinical trials. If so, investigators might have to derive new cell lines in accordance with the regulations if their materials are to be acceptable for development into transplantable tissue. FDA’s new, more comprehensive approach to regulating tissue transplantation was announced in February 1997.15 Although only partially implemented as of 2005, FDA already requires registration by all establishments that recover, process, store, label, package, or distribute “human cells, tissues, and cellular and tissue-based products” (HCT/Ps) or that screen or test donors of them. The registration requirement is applicable to establishments involved in the derivation and management of hES cell lines and resulting tissues that will be used for transplantation into humans. In addition, as of May 2005, FDA’s “current good tissue practices” (CGTP) will include rules governing the process for procuring human blastocysts, oocytes, sperm, and somatic cells for use in research leading to clinical applications. The rules will include donor screening to prevent the spread of communicable diseases and a tracking system that will permit tracking from each human cell line or tissue back to the original donor. For work with existing cell lines, CGTP rules already govern the methods and facilities used for the manufacture of HCT/Ps to prevent the introduction or transmission of communicable diseases by these cells, tissues, and products. As with the registration requirements, the rules apply to HCT/Ps that are destined for transplantation into humans. 14   http://www.fda.gov/cber/tissue/tissue.htm. 15   http://www.fda.gov/cber/tissue/tissue.htm.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research Once a donation has been made, the resulting tissue must be coded in a fashion that permits tracking back to the original donor if that is needed, and a summary of relevant information about the donor must accompany the cell line or tissue whenever it is passed to a new facility.16 Because those rules require some kind of tracking system that will maintain a connection between the donor and the endproduct, such as transplantable tissue, the FDA tissue rules have an effect on the operation of human subjects protections, as well as the HIPAA Privacy Rule. The net effects are that Work on completely anonymous hES cell lines will not be human subjects research, but this tissue may well be disfavored by FDA if investigators wish to use it for clinical trials. FDA will prefer that trials use tissue for which there is a traceable history back to the donors and their medical histories. Work on hES cell lines with identifiers linking them to the donors will be subject to federal regulations governing human subjects research and, in the case of covered entities, HIPAA privacy protections unless the identifiers are coded and managed in a fashion that renders the donors effectively unidentifiable to the investigators. Finally, work with hES cell lines that were grown on mouse feeder cells may face a special obstacle if an investigator wishes to use them to develop transplantable tissue for human clinical trials. FDA’s regulations define xenotransplantation to include any procedure that involves the transplantation of human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs. Tissue transplantation from cell lines grown on nonhuman feeder cells would be considered xenotransplantation and would require additional FDA review.17 For hES cell investigators who plan to obtain cell lines from outside the United States, it is worth noting that FDA’s new tissue regulations also govern the importation of cell lines and derived tissues for use in clinical transplantation, and importation must be approved by FDA, whose regulations pursuant to Section 361 of the Public Health Service Act are designed to prevent the transmission of communicable diseases. Also of relevance to researchers working with cell lines from other countries, there are medical privacy requirements in other countries that must be considered whenever transnational collaborations are contemplated.18 For collaborations with 16   See § 1271.55 of the new regulations, as presented in “Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products”, Federal Register Vol. 69, No. 101, amending 21 CFR Parts 210, 211, 820, and 1271, 69 FR 29786 (May 25, 2004). 17   http://www.fda.gov/cber/xap/xap.htm. 18   “New International Guidelines on the Transfer of Personal Health Data,” William R. M. Long and Julia Barnes, Medical Research & Policy News, Volume 4 Number 4, February 16, 2005 Page 157, ISSN 1539-4530.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research members of the European Union, Iceland, Liechtenstein, and Norway, medical information about donors that accompanies cell lines must comply with the guidelines issued by the International Organisation for Standardisation (ISO).19 Those rules generally preclude the transfer of medical data about identifiable persons unless consent has been obtained and the country receiving the data has an adequate system for medical data protection.20 Despite the passage of HIPAA, the United States has not been deemed to have such a system, although individual institutions may devise systems that meet the European requirements. Many forms of hES cell research, however, can be exempted from the rules, provided that the data are rendered anonymous. Under the ISO guidelines, anonymization means rendering data “nonpersonal,” that is, the codes do not directly or indirectly reveal the identity of the donors.21 Given the varied ways in which anonymous is interpreted under HIPAA, ISO guidelines, and federal human subjects research rules, investigators and institutions need to be attentive to the concerns of all appropriate bodies before working with cell lines that are understood to be anonymized. Recommendation 12: hES cell research leading to potential clinical application must be in compliance with all applicable Food and Drug Administration (FDA) regulations. If FDA requires that a link to the donor source be maintained, investigators and institutions must ensure that the confidentiality of the donor is protected, that the donor understands that a link will be maintained, and that, where applicable, federal human subjects protections and Health Insurance Portability and Accountability Act or other privacy protections are followed. U.S. STATE LAW ON hES CELL RESEARCH State law rarely addresses the regulation of medical research. It does, however, often address the status of embryos. In this respect, it is relevant to hES cell research. 19   ISO 22857:2004(E)—“Health informatics—Guidelines on data protection to facilitate trans-border flows of personal health information.” 20   The ISO guidelines are based on four other pieces of transnational legislation: “Recommendations of the Council of the OECD concerning Guidelines on the Protection of Privacy and Trans-border flows of Personal Data” [OECD, Sept. 23, 1980, and “Guidelines for the Security of Information Systems,” OECD, 1996.]; the “Council of Europe Recommendation R(97)5 on the Protection of Medical Data” (Council of Europe Publishing, Strasbourg, Feb. 12, 1997); actions of the U.N. General Assembly, Dec. 14, 1990; and the EU Data Protection Directive (Directive 95/46/EC of the European Parliament and of the Council of Oct. 24, 1995, on the protection of individuals with regard to the processing of personal data and on the free movement of such data. OJL 281, Nov. 23, 1995, p. 31). The latter directive was last amended by Regulation (EC) No. 1882/2003 of the European Parliament and of the Council of Sept. 29, 2003, OJL 289, Oct. 31, 2003, p. 1. 21   Recital 26 of the EU Data Protection Directive provides that the principles of protection shall not apply to data rendered anonymous in such a way that the data subject is no longer identifiable.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research Courts have held that dispositional authority over an embryo in general belongs to the progenitors.22 Moreover, case law suggests that destruction of an embryo does not require the consent of anonymous gamete donors, although in the context of couples who disagreed over the disposition of embryos, the consent of both partners has been required before release of an embryo for reproductive purposes, particularly in the absence of a prior agreement between the partners.23 In the absence of a joint decision regarding disposition, however, current law will result in leaving the embryo in a frozen state. Fertility clinics have sought to avoid such conflicts by asking couples to agree in advance on the terms on which embryos can be released for reproductive use, kept frozen, discarded, or released for research. A number of states, such as Louisiana, Maine, Massachusetts, Minnesota, New Hampshire, North Dakota, Pennsylvania, and Rhode Island, have enacted legislation to prohibit or limit research with human embryos,24 with the definition of embryo occasionally merged with the definition of fetus.25 In some cases, these state laws restricting embryo research have been challenged successfully in court, on grounds such as unconstitutional vagueness.26 But most U.S. states have no laws or regulations specifically addressing hES cell research. Of the laws that do exist, many focus exclusively on nuclear transfer (NT) research. For example, as of March 2005, Arkansas, Iowa, Michigan, North Dakota, and South Dakota had laws that clearly forbid the use of NT for research purposes.27 Missouri forbids the use of state funds for NT research.28 Other states, such as Rhode Island and Virginia (less clear from the text of the law), have banned NT for reproductive purposes but have not addressed its use for research purposes.29 In states that do not forbid NT research, it remains legal and subject to the federal regulations described above. New Jersey and California, however, have adopted laws that add extra state regulation to the field of hES cell and NT research, most notably by expanding the jurisdiction of IRBs to review the research and by prohibiting the sale of embryos.30 In California, however, research funded pursuant to the Proposition 71 initiative will be exempt 22   See York v. Jones, 717 F. Supp. 421 (E.D. Va. 1989); Del Zio v. Presbyterian Hosp., No. 74 Civ. 3558 (CES), 1978 U.S. Dist. LEXIS 14450 (S.D.N.Y. Nov. 9, 1978). 23   See, e.g., In re Marriage of Litowitz, 48 P.3d 261 (Wash. 2002); J.B. v. M.B., 783 A.2d 707 (N.J. 2001); A.Z. v. B.Z., 725 N.E.2d 1051 (Mass. 2000); Kass v. Kass, 696 N.E.2d 174 (N.Y. 1998); Davis v. Davis, 842 S.W.2d 588 (Tenn. 1992). 24   See http://www.kentlaw.edu/islt/TABLEIII.htm (last visited March 24, 2005). 25   See, e.g., Massachusetts, where a statute prohibits the use of embryos for experimental purposes. See Mass. Gen. Laws Ann. ch. 112, 12J (prohibiting experimentation on live fetus either before or after it is implanted in uterus). 26   Forbes v. Woods, 71 F. Supp. 2d 1015 (1999); Lifchez v. Hartigan, 735 F. Supp. 1361 (1990). 27   http://www.ncsl.org/programs/health/genetics/rt-shcl.htm. 28   http://www.ncsl.org/programs/health/genetics/rt-shcl.htm. 29   http://www.ncsl.org/programs/health/genetics/rt-shcl.htm. 30   http://www.ncsl.org/programs/health/genetics/rt-shcl.htm.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research from many aspects of this law and subject instead to new guidelines to be adopted by the newly created California Institute for Regenerative Medicine. State laws on dispositional authority over embryos and on hES cell research are in flux and are largely untested in the courts. Investigators working with NT or hES cell lines are well advised to seek advice on the latest rules applicable in their states. REGULATION OF hES CELL AND NT RESEARCH IN OTHER COUNTRIES There is no international consensus yet on whether and how to pursue hES cell research. For example, in February 2005, a committee of the U.N. General Assembly abandoned attempts to craft a global treaty on NT research and satisfied itself with a plurality vote in favor of a nonbinding resolution calling for a ban on all forms of human cloning or genetics research that are contrary to “human dignity,” a phrase left to the interpretation of member countries.31 Thus, the regulation of hES cell research varies from country to country. In many cases, there is no law explicitly addressing such research. In some countries, such as Poland and Italy, the research is forbidden or substantially curtailed. In others, however, there seems to be a trend toward liberalization of the laws. France and Germany, for example, have taken steps to permit research on cell lines derived from surplus in vitro fertilization (IVF) blastocysts,32 and Japan33 and Sweden34 have lifted restrictions on making blastocysts for research with NT. Given the increasing frequency of international collaboration in hES cell research, it is important to monitor regulatory developments in other countries. As the guidelines recommended by this committee in Chapter 6 require that the provenance of hES cell lines be consistent with the ethical standards and procedures adopted here, understanding the points of similarity and difference between the guidelines and the rules in other countries will help investigators and the ESCRO committees proposed in Chapter 3 to manage collaboration. Some countries place limitations on the importation of cell lines whose origins are inconsistent with their laws. Australia, for example, adopted the Research Involving Human Embryos Act in 2002 and the Human Cloning Act, which prohibits NT for reproductive or therapeutic purposes.35 Of possible importance to U.S. 31   Associated Press, U.N. Group Calls for Cloning Ban, Feb. 18, 2005. 32   “Europe Sends Mixed Signals on Stem-Cell Work,” Victoria Knight, Wall Street Journal Jan. 26 2005. Note that that German liberalization applies only to cell lines produced prior to 2002. See http://www.germany-info.org/relaunch/education/new/edu_stemcells.html. 33   http://web2.innovationworld.net/biotechconnect/000312.html. 34   http://www.geocities.com/giantfideli/art/CellNEWS_Sw_thera_cloning.html. 35   Research Involving Human Embryos Act, 2002, No. 145, 2002, An Act to regulate certain activities involving the use of human embryos, and for related purposes (http://scaleplus.law.gov.au/html/comact/browse/TOCN.htm); Prohibition of Human Cloning Act 2002, No. 144, 2002, An Act to prohibit human cloning and other unacceptable practices associated with reproductive technology, and for related purposes (http://scaleplus.law.gov.au/html/comact/browse/TOCN.htm).

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research investigators seeking to collaborate with Australian centers, Australia forbids the importation of cloned, parthenogenetic, androgenetic, or chimeric embryos (a chimeric embryo is defined as one in which nonhuman cells have been introduced into a human embryo). It is also an offense to create a human embryo by any method other than fertilization and for any purpose other than for the treatment of infertility. So-called hybrid embryos are specifically forbidden and such entities are defined to include an animal egg into which the nucleus of a human cell has been introduced. Commercial trading in human eggs, sperm, or embryos is not allowed. Those bans are backed by criminal sanctions with prison terms of up to 15 years, depending on the offense. Australia’s law allows research to be performed on embryos remaining in excess of clinical need, and the consent requirements for donors are consistent with those outlined in this committee’s recommendations (see Chapter 5). Research is subject to oversight by a new committee, the National Health and Medical Research Council Licensing Committee, which has the authority to review research programs, grant licenses, and maintain a database regarding the licenses granted. That committee also has the authority to inspect licensee facilities to ensure compliance with its licensing conditions. The United Kingdom has adopted an approach that depends on a central licensing authority, called the Human Fertilisation and Embryology Authority (HFEA). The role of HFEA is to monitor and license clinics that carry out any of the established IVF or other assisted reproductive technology procedures and to regulate human embryo research and the storage of reproductive materials. As in the present committee’s Recommendation 8 above, donors in the United Kingdom must give consent for use of their gametes or embryos in research. Egg and sperm donors are paid a nominal fee and reasonable expenses.36 HFEA will grant a license to make embryos for research only if the research program meets the purposes outlined in U.K. law. Allowable research purposes include increasing knowledge of genetic disorders, developing better contraceptive techniques, and advancing the treatment of infertility. As of early 2005, HFEA had granted 28 research licenses, including 10 related to hES cells and two related to parthenogenesis.37 Two licenses were granted for work with NT blastocysts.38 The United Kingdom also has created a Stem Cell Bank, launched by the Medical Research Council in September 2002. The bank exists to establish fully characterized and quality-controlled cell lines (see Chapter 5 for a discussion on banking). The cell lines will be supplied to accredited scientific research teams and eventually to pharmaceutical companies to enable the development of broad-ranging cell therapies.39 36   http://www.hfea.gov.uk/PressOffice/Archive/34673456). 37   http://www.hfea.gov.uk/Research. 38   See “British to Clone Human Embryos for Stem Cells,” Rick Weiss, Washington Post, February 9, 2005; Page A02; see also http://www.hfea.gov.uk/PressOffice/Archive/1092233888. 39   http://www.hfea.gov.uk/PressOffice/Backgroundpapers/Stemcellresearch.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research Israel does not have a central licensing authority, but it does have well-developed guidelines emerging out of the work of the Bioethics Advisory Committee of the Israel Academy of Sciences and Humanities, and, because the Health Ministry delegates decisions regarding new genetic research involving human beings to the Helsinki Committee for Genetic Experiments on Human Subjects, it also has a centralized review process for hES cell research.40 Consistent with the guidelines proposed in this report, the Israeli guidelines require informed consent from donors of surplus blastocysts. The guidelines state that best practices include mentioning research uses from the beginning of the IVF process and separating the medical team responsible for the IVF treatment and donation from the scientific teams involved in embryo research who receive the donation. As in the recommendations made in the next chapter, buying and selling of embryos is forbidden in Israel, but making new embryos solely for research, including blastocysts made by NT, is permissible. Research and possible applications must be justifiable in terms of the benefit that it offers humanity, and confidentiality and privacy of the donors should be respected. As in the recommendation proposed in Chapter 3 for purely in vitro work on hES cell lines, Israel allows such work to be conducted without further need for specific ethical authorization. In June 2002, Singapore’s Bioethics Advisory Committee released its report Ethical, Legal and Social Issues in Human Stem Cell Research, Reproductive and Therapeutic Cloning, in which it recommended that NT be permitted under centralized regulation. Consistent with the guidelines proposed here, the regulatory framework should require the informed voluntary consent of donors, prohibit the commerce and sale of donated materials, require strong scientific justification before making new embryos solely for research purposes, and stipulate that no one shall be under a duty to participate in any manner of research on human stem cells to which he or she has a conscientious objection. The report has been presented to the relevant ministries, and the government will decide on the recommendations later.41 Canada is still debating legislation to regulate assisted reproductive technologies and embryo research, but it operates under guidelines that incorporate both centralized and local review. Under the guidelines issued by the Canadian Institute for Health Research,42 review and approval by the central Stem Cell Oversight Committee, by local research ethics boards (REBs), and, where appropriate, by animal care committees is required for all research involving the derivation, in vitro study, and clinical trial of hES cell lines. At any time, however, the local REB or animal care committee may refer an hES cell research proposal to the Stem Cell Oversight Committee for ethics review if it considers the research to be within the oversight committee’s purview according to the above criteria. Such decisions by the 40   http://www.academy.ac.il/bioethics/articles/embryonic_ibc_report.pdf. 41   www.bioethics-singapore.org. 42   http://www.cihr-irsc.gc.ca/e/15349.html.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research REB or animal care committee are not subject to appeal. Like the guidelines recommended in this report, the Canadian guidelines require a medical rationale for the research, the informed consent of donors, protection of donors’ privacy, and a prohibition on payment to donors (see Chapter 5). And like the current policy of the U.S. government (but unlike that of New Jersey or California), the Canadian guidelines prohibit public financial support for making embryos solely for research or of research in which hES cells are combined with a nonhuman embryo.43 CONCLUSION Despite the lack of federal funding for most hES cell research underway in the United States, several sets of federal regulations govern various aspects of hES cell research—human subjects protections for oocyte and some blastocyst donors, medical privacy protections, laboratory and safety standards, animal welfare requirements, and rules governing the importation of biological materials or the transfer of medical data from other countries. In many other countries where hES cell research is permitted and publicly funded, its practice is regulated by statute or other government policy. Those regulations address matters such as whether embryos may be made solely for research purposes; whether they may be made using NT, parthenogenesis, or androgenesis; whether human hES cells may be combined with nonhuman materials; and whether facilities and researchers must be licensed before engaging in hES cell research. As hES cell research in the United States increases, it is essential that institutions and investigators adhere to existing applicable regulatory requirements, and given the increasing frequency of international collaboration in hES cell research, it will be important to monitor regulatory developments in other countries. The ESCRO committees proposed in this report will be charged with ensuring that U.S. investigators follow standards and procedures consistent with current regulations and with the guidelines recommended in this report. Various jurisdictions differ in their mechanisms for oversight and review. As discussed in Chapter 3, the committee recommends both local review of hES cell research by an institutional ESCRO committee and the establishment of a national body to serve as a forum for considering new developments in the scientific, clinical, and public policy issues surrounding hES cell research and for periodic review of the relevant guidelines. The distinction between local review and oversight and national consideration of larger policy issues is in line with current U.S. practice in other fields. An analogy is the current use of local institutional IBCs to regulate recombinant DNA research and the RAC to consider policy issues related to gene therapy. The dual mechanism will fulfill oversight and monitoring functions equivalent to the various systems mandated by other countries. 43   http://www.cihr-irsc.gc.ca/e/1487.html.

OCR for page 63
Guidelines for Human Embryonic Stem Cell Research This page intentionally left blank.