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2008 Amendments to the National Academiesâ Guidelines for Human Embryonic Stem Cell Research INTRODUCTION The National Academiesâ report Guidelines for Human Embryonic Stem Cell Research (NRC and IOM, 2005) was developed by the Committee on Guidelines for Human Embryonic Stem Cell Research and released in April 2005. The body of the report provided the background and rationale for the choices involved in formulating the Guidelines, which were compiled in its final chapter. Because human embryonic stem (hES) cell research touches on many ethical, legal, scientific, and policy issues, the Guidelines are intended to make explicit how research with hES cells can be pursued most respon- sibly. The Guidelines are intended to address researchers primarily in the United States, but they may be applicable internationally as well. The 2005 publication of the Guidelines offered a common set of ethi- cal standards for a field that, because of the absence of comprehensive federal funding, was lacking national standards for research. Although the Guidelines have proved useful since 2005, it was recognized soon after their initial issuance that some aspects of them needed clarification in light of experience and that they must be kept up to date given the rapid pace of scientific developments in the field of stem cell research. The National Academies established the Human Embryonic Stem Cell Research Advisory Committee for that purpose in 2006 with support from the Ellison Medical Foundation, the Greenwall Foundation, and the Howard Hughes Medical Institute. It issued its first set of amendments to the Guidelines in 2007 (NRC and IOM, 2007).
Guidelines for Human Embryonic Stem Cell Research Statement of Task of the Human Embryonic Stem Cell Research Advisory Committee The Advisory Committee will meet 2 to 3 times per year over a period of 36 months to (1) monitor and review scientific developments and changing ethical, legal, and policy issues related to human embryonic stem cell research, (2) discuss the need for revisions to the Guidelines for Human Embryonic Stem Cell Research, and (3) prepare periodic reports to update the Guidelines as needed. Minimal but neces- sary changes may be issued as letter reports, but more extensive modifications may necessitate the preparation of traditional reports to fully provide the rationale for the changes. Sources of information that will be considered by the Advisory Committee will include public symposia organized by the Committee to review developments in stem cell science and how these impact the ethical and policy issues surrounding hES cell research. The Human Embryonic Stem Cell Research Advisory Committee contin- ues to engage in a number of efforts to gather information about the need, if any, for revision of the Guidelines. For example, the Committee conducted three regional meetings (in southern California, Chicago, and the Boston area) in the first half of 2007 for those involved in institutional Embryonic Stem Cell Research Oversight (ESCRO) committees to hear from people in the field about their experiences in implementing the Guidelines and any problems they have encountered. In addition, the Committee participated in a day-long session on ESCRO committees at the annual meeting of Public Responsibility in Medicine and Research (PRIM&R) in December 2007 to gather more feedback from the community. The Committee also met in March and August 2007 and in February 2008 to hear from invited speakers who addressed issues that the Commit- tee has taken under consideration for potential further amendments to the Guidelines. Finally, the Committee is planning a second symposium (its first was held in November 2006) for November 2008 to hear invited speakers review the latest scientific developments, describe how the developments might affect analyses of associated ethical issues, and identify possible effects on the workability or justifiability of the current Guidelines. The meeting will
2008 Amendments focus in part on recent developments in moving toward clinical translation of stem cell therapeutics. The Committee has also established an electronic mailing list for ESCRO committee members and staff to communicate and share questions and answers, and members of the Committee have been actively soliciting input from their colleagues and receiving comments via a Web site established for the purpose. As it did in 2007, the Committee identified issues that appeared to warrant consideration of revisions of the Guidelines. The present report ad- dresses those issues in a second brief set of amendments. Most important, the Committee is issuing this second set of amendments to address new sci- entific developments in reprogramming of somatic cells to pluripotency by adding a new section (Section 7) and revising other relevant sections of the Guidelines. It is also issuing several other minor amendments to â¢ larify the obligations of investigators to notify and obtain approval C from their institutionsâ ESCRO committees before initiating any hES cell experiments and to provide for the possibility of âexpedited reviewâ of some hES cell experimental protocolsâSection 1.3(a), Section 6.1, and Section 6.2. â¢ larify what is included in âdirect expensesâ for allowable reim- C bursements to women donating oocytesâSection 3.4(b). â¢ urther enumerate the registration and auditing responsibilities of F institutions conducting hES cell research to improve public access to information and ensure that ESCRO committees are carrying out their responsibilities appropriatelyâSection 2.0. In addition, inconsistencies in the original numbering of the Guidelines have led to some confusion. Various sections of the Guidelines, particularly within Section 1, have been renumbered in these amendments for greater clarity. Future deliberations of the Committee will address items for which ad- ditional information-gathering and more extensive debate and discussion may be necessary. For example, based on the National Institutes of Health (NIH) determination that the pre-2001 âpresidentialâ lines were derived from embryos donated with informed consent and without financial induce- â ttp://www.nationalacademies.org/stemcells h â ormerly F Section 1.2(a). As explained below, several sections of the Guidelines, particu- larly within Section 1, are being renumbered in these amendments for greater clarity.
Guidelines for Human Embryonic Stem Cell Research ment (NIH, 2001), the 2007 Guidelines deemed those lines to have been ac- ceptably derived (see Sections 1.4 and 1.5 and associated discussion in NRC and IOM, 2007). In light of questions raised when the present report was already near completion about the derivation or use of some of those lines (Streiffer, 2008), and as per its charge, the Committee will monitor develop- ments as to the ethics and policy regarding the lines in question in order to consider whether any future changes in the Guidelines are warranted. Stem cell research oversight committees are, of course, free to set their own policies about the use of these lines according to the principles outlined in Section 1.6 of the Guidelines (as renumbered in this document). The Committee is also aware that the scientific and oversight communities desire additional guid- ance on how to evaluate research that requires the development of chimeras. In response, the Committee has added some text in the new Section 7.3(c) [as well as 1.3(b)] and also plans to address research involving chimeras at the meeting it is organizing for November 2008. These amended Guidelines supersede those issued in 2005 and 2007 by the Committee on Guidelines for Human Embryonic Stem Cell Research and the Human Embryonic Stem Cell Research Advisory Committee, re- spectively. It is important that the clarifications and amendments presented here be interpreted in the context of the complete set of amended Guidelines, which is included at the end of this report (Appendix A). In addition, the glossary included in the 2005 Guidelines for Human Embryonic Stem Cell Research (NRC and IOM, 2005) has been amended by adding definitions for the terms hPS cells and multipotent, and the entire glossary is reprinted as Appendix B. APPLICABILITY OF THE GUIDELINES TO NON-EMBRYONIC HUMAN PLURIPOTENT STEM CELLS The original Guidelines released in 2005 were addressed specifically to research with hES cell lines, although institutions and investigators conduct- ing research on human adult stem cells or fetal stem cells were encouraged to âconsider which individual provisions of these guidelines are relevant to their research.â Because the Guidelines were developed primarily for research with hES cells, however, it was not made explicit which provisions of the Guidelines might apply to other types of stem cells. There have been several recent reports on reprogramming of somatic cells to pluripotency (for definitions see glossary, Appendix B). In light of the production of so-called induced pluripotent stem (iPS) cell lines derived
2008 Amendments by introducing sets of genes into, first, murine somatic cells (Takahashi and Yamanaka, 2006) and, later, human somatic cells (Takahashi et al., 2007; Yu et al., 2007; Park et al., 2008), it seems prudent to consider more explicitly which provisions of the Guidelines should apply also to stem cells of types other than hES cells. This is not to suggest that the need for research with hES cells is supplanted by the availability of other pluripotent stem cells. It is far from clear at this point which cell types will prove to be the most useful for regenerative medicine, and it is likely that each will have some utility. Such iPS cells are currently derived by introduction of retroviruses that carry the inducing genes. This derivation procedure raises serious is- sues about their potential for use in therapy, inasmuch as it is known that inserted retroviruses can cause cancer, and research will be necessary to develop alternative means to derive iPS cells or to circumvent the potential tumorigenicity. Furthermore, the demonstration that iPS cells are indeed pluripotent relies on careful comparisons with hES cells; for either cell type to be used therapeutically in regenerative medicine, methods need to be developed to promote their differentiation into specialized cell types and to evaluate the safety of introducing cell populations that may contain some pluripotent cells into patients. Much further research will be required on both hES and iPS cells to develop the required procedures, including drawing appropriate comparisons between them. Understanding of the potential for differentiation of hES cells, iPS cells, or, indeed, adult multipotent (capable of differentiation into a limited spectrum of differentiated cell types) stem cells will require testing in animals and screening for potential tumorigenic- ity. Therefore, issues arising from such human-animal chimera experiments pertain to all these cell types. For those reasons and in response to inquiries from the scientific com- munity, the Human Embryonic Stem Cell Research Advisory Committee has consulted with experts and carefully considered potential modifications of the Guidelines to cover other pluripotent and multipotent stem cells, which the Committee presents herein. The intention is not to extend unnecessarily the oversight of stem cell research where it is already adequately monitored under existing regulations and guidelines. For example, derivation of human pluripotent stem cell lines from sources other than embryos does not involve ethical or policy issues beyond those normally encountered in sampling any tissue from human subjects, although use of such cells may raise issues similar to those for embryonically derived cells. Derivation of iPS cells and â Amultipotent stem cell can give rise to other types of cells but it is limited in its ability to differentiate. An example is found in the multipotent stem cells in bone marrow that give rise to all blood cells but not other cell types.
Guidelines for Human Embryonic Stem Cell Research of other non-embryonic human pluripotent stem cells (hereafter referred to as hPS cells) does not require special stem cell expertise and is adequately covered by current Institutional Review Board (IRB) regulations. It does not require additional review by an ESCRO committee. The Committee notes in particular that under federal regulations, even IRBs would not be required to review the generation of hPS cells from existing anonymized somatic cells from surgical waste, tissue banks, or commercial entities that provide tissue for research, nor would they be required to review the generation of hPS cells from cadaveric tissue, whether or not it is anonymized. Similarly, with few exceptions, purely in vitro experiments with hPS cells do not raise ethical concerns beyond those encountered with any human cell line and also do not require ESCRO committee review. However, as mentioned above, introduction of any hPS cells and in- troduction of some multipotent stem cells (such as neural stem cells) into animals raises issues similar to those pertaining to hES cells. The earlier ver- sions of the Guidelines placed responsibility for review of such experiments with hES cells in the hands of ESCRO committees and Institutional Animal Care and Use Committees (IACUCs), and it is logical to do the same for hPS cells and for stem cells with more limited potential for differentiation. The revisions presented in this document provide guidance on the levels of review for various categories of experiments with iPS and other hPS cells and on categories of research for which such review is not necessary. Most of the changes appear in a new Section 7, âRecommendations for Research on Non-Embryo-Derived Human Pluripotent Stem Cells (hPS Cells)â, al- though some provisions of Sections 1, 3, 4, and 5 are also affected, as follows (new or revised wording is underlined, and deleted text appears in strikeout form): From Section 1 1.1 What These Guidelines Cover â 1.1(a) These guidelines cover all derivation of hES cell lines and all research that uses hES cells derived from ( i) blastocysts made for reproductive purposes and later obtained for research from in vitro fertilization (IVF) clinics, (ii) blastocysts made specifically for research using IVF, (iii) somatic cell nuclear transfer (NT) into oocytes.
2008 Amendments â 1.1(b) Many, but not all, Some of the guidelines and concerns addressed in this report are common to other areas types of human stem cell research; as such, certain of these Guidelines should also apply to those other types of research. For example, such as (i) research that uses human adult stem cells. (ii) research that uses fetal stem cells or embryonic germ cells derived from fetal tissue; such research is covered by federal statutory restrictions at 42 USC 289g-2(a) and federal regulations at 45 CFR 46.210. (iii) esearch that uses human pluripotent stem (hPS) cells r derived from non-embryonic sources, such as spermato- gonial stem cells and âinduced pluripotentâ stem cells derived from somatic cells by introduction of genes or otherwise (so-called iPS cells), and other pluripotent cells yet to be developed. R ecommendations as to which guidelines apply to other hPS cells are collected in Section 7 below. Institutions and investigators conducting research using such materials with adult and fetal stem cells should also consider which individual provisions of these guidelines are relevant to their research. â 1.1(c) The guidelines do not cover research that uses nonhu- man stem cells. From Section 3 3 .1 An IRB, as described in federal regulations at 45 CFR 46.107, should review all new procurements of all gametes, blastocysts, or somatic cells for the purpose of generating new hES or hPS cell lines. This includes the procurement of blastocysts in excess of clinical need from infertility clinics; blastocysts made through IVF specifically for research purposes; and oocytes, sperm, and somatic cells donated for development of hES cell lines derived
Guidelines for Human Embryonic Stem Cell Research through NT or by parthenogenesis or androgenesis; and hPS cells derived by any means and that require human subjects review. 3 .6 In the context of donation of gametes, blastocysts, or somatic cells for hES cell research, or for hPS cell research that requires human subjects review, the informed-consent process should, at a minimum, provide the following information: (a) statement that the blastocysts, gametes, or somatic cells A will be used to derive hES or hPS cells for research that may include research on human transplantation. (b) statement that the donation is made without any re- A striction or direction regarding who may be the recipient of transplants of the cells derived, except in the case of autologous donation. (c) statement as to whether the identities of the donors will A be readily ascertainable to those who derive or work with the resulting hES or hPS cell lines. (d) f the identities of the donors are retained (even if coded), I a statement as to whether donors wish to be contacted in the future to receive information obtained through studies of the cell lines. (e) assurance that participants in research projects will An follow applicable and appropriate best practices for do- nation, procurement, culture, and storage of cells and tissues to ensure, in particular, the traceability of stem cells. (Traceable information, however, must be secured to ensure confidentiality.) (f) statement that derived hES or hPS cells and/or cell lines A might be kept for many years. (g) statement that the hES or hPS cells and/or cell lines might A be used in research involving genetic manipulation of the cells or mixing of human and nonhuman cells in animal models. (h) isclosure of the possibility that the results of study of D the hES or hPS cells may have commercial potential and a statement that the donor will not receive financial or any other benefits from any future commercial development. (i) statement that the research is not intended to provide A direct medical benefit to the donor(s) except in the case of autologous donation.
2008 Amendments (j) statement that embryos will be destroyed in the process A of deriving hES cells. (k) statement that neither consenting nor refusing to donate A embryos for research will affect the quality of any future care provided to potential donors. (l) statement of the risks involved to donors. A I n addition, donors could be offered the option of agreeing to some forms of hES cell research but not others. For example, donors might agree to have their materials used for deriving new hES cell lines but not want their materials used, for example, for NT. The consent process should fully explore whether donors have objections to any specific forms of research to ensure that their wishes are honored. Investigators and stem cell banks are, of course, free to choose which cell lines to accept, and are not obligated to accept cell lines for which maintaining informa- tion about specific research use prohibitions would be unduly burdensome. N ew derivations of stem cell lines from banked tissues obtained prior to the adoption of these guidelines are permissible provided that the original donations were made in accordance with the le- gal requirements in force at the place and time of donation. This includes gametes, blastocysts, adult stem cells, somatic cells, or other tissue. In the event that these banked tissues retain identi- fiers linked to living individuals, human subjects protections may apply. From Section 4 4 .6 Investigators must document how they will characterize, validate, store, and distribute any new hES cell lines and how they will maintain the confidentiality of any coded or identifiable information associated with the lines (see Section 5.0 below). Investigators are encouraged to apply the same procedures and standards for characterization, validation, storage, and distribu- tion to hPS cell lines.
10 Guidelines for Human Embryonic Stem Cell Research From Section 5 5 .0 BANKING AND DISTRIBUTION OF hES CELL LINES T here are several models for the banking of human biological materials, including hES cells. The most relevant is the U.K. Stem Cell Bank. The guidelines developed by this and other groups generally adhere to key ethical principles that focus on the need for consent of donors and a system for monitoring adherence to ethical, legal, and scientific requirements. As hES cell research advances, it will be increasingly important for institutions that are obtaining, storing, and using cell lines to have confidence in the value of stored cellsâthat is, that they were obtained ethi- cally and with the informed consent of donors, that they are well characterized and screened for safety, and that the conditions under which they are maintained and stored meet the highest scientific standards. Institutions engaged in hES research should seek mechanisms for establishing central repositories for hES cell linesâthrough partnerships or augmentation of existing quality research cell line repositoriesâand should adhere to high ethical, legal, and scientific standards. At a minimum, an institutional registry of stem cell lines should be maintained. Institutions are encouraged to consider the use of the same procedures for bank- ing and distribution of hPS cell lines. Section 7 7 .0 Recommendations for Research on non- embryo-derived human pluripotent stem cells (hPS CELLS) 7.1 Derivation B ecause non-embryo-derived hPS cells are derived from human material, their derivation is covered by existing IRB regulations concerning review and informed consent. No ESCRO committee review is necessary, although the IRB may always seek the advice of an ESCRO committee if it seems desirable. The IRB review
2008 Amendments 11 should consider proper consent for use of the derived hPS cells. Some of the recommendations for informed consent that apply to hES cells also apply to hPS cells (see Section 3.6), including informed consent to genetic manipulation of resulting pluripotent stem cells and their use for transplantation into animals and hu- mans and, potentially, in future commercial development. 7.2 Use in in Vitro Experiments U se of hPS cells in purely in vitro experiments need not be sub- ject to any review beyond that necessary for any human cell line except that any experiments designed or expected to yield gametes (oocytes or sperm) should be subject to ESCRO com- mittee review. 7.3 Use in Experiments Involving Transplantation of hPS Cells into Animals at Any Stage of Development or Maturity 7.3(a) Research involving transplantation of pluripotent hu- man cells derived from non-embryonic sources into nonhuman animals at any stage of embryonic, fetal, or postnatal development should be reviewed by ESCRO committees and IACUCs, as are similar experiments that use hES cells. 7.3(b) ESCRO committees should review the provenance of hPS cells as they review the provenance of hES cells (see Section 1.6) to ensure that the cell lines were derived according to ethi- cal procedures of informed consent as monitored by an IRB or equivalent oversight body. 7.3(c) Proposals for the use of hPS cells in animals should be considered in one of the following categories: ( i) Permissible after currently mandated reviews and proper documentation [see Section 1.3(a)]: experiments that are ex- empt from full ESCRO committee review but not IACUC review (experiments that involve only transplantation into postnatal animals with no likelihood of contributing to the central nervous system or germ line).
12 Guidelines for Human Embryonic Stem Cell Research ( ii) Permissible after additional review by an ESCRO commit- tee, as described in Section 2.0 of the Guidelines [see Section 1.3(b)]: experiments in which there is a significant possibil- ity that the implanted hPS cells could give rise to neural or gametic cells and tissues. Such experiments need full ESCRO committee and IACUC review and would include generation of all preimplantation chimeras and neural transplantation into embryos or perinatal animals. Particular attention should be paid to at least three factors: the extent to which the implanted cells colonize and integrate into the animal tissue; the degree of differentiation of the implanted cells; and the possible effects of the implanted cells on the function of the animal tissue. (iii) Should not be conducted at this time [see Section 1.3(c)]: (1) xperiments that involve transplantation of hPS cells E into human blastocysts. (2) esearch in which hPS cells are introduced into nonhu- R man primate embryos, pending further research that will clarify the potential of such introduced cells to contribute to neural tissue or to the germ line. 7.4 Multipotent Neural Stem Cells I t is also relevant to note that neural stem cells, although not pluripotent, are multipotent and may have the potential to con- tribute to neural tissue in chimeric animals. ESCRO committees should decide whether they wish to review and monitor such experiments with neural stem cells in a similar fashion. 7.5 Prohibition on Breeding N o animal into which hPS cells have been introduced such that they could contribute to the germ line should be allowed to breed. â eferring R to cells of the nervous system that give rise to both neurons and glia.
2008 Amendments 13 7.6 Guidance for Banking and Distribution I nstitutions should consider the value of banking and distributing hPS cells using the guidance and rules that are already in place for hES cells and the value of including hPS cell lines in their registries. CLARIFication of THE MEANING OF âPROPER NOTIFICATIONâ Section 1.3 (formerly Section 1.2) of the Guidelines specifies research that is âpermissible after currently mandated review and proper notification of the relevant research institutionâ (emphasis added). Section 1.3(a) clarifies which documentation is required for determining the provenance of the cell lines, but it does not address what âproper notificationâ entails. Similarly, Sections 6.1 and 6.2 concerning research use of hES cell lines refer to ânoti- ficationâ and ânoticeâ but do not specify what notification entails. Use of the word ânotificationâ has led some ESCRO committee rep- resentatives to ask whether the Guidelines intend that investigators fulfill this requirement by merely informing ESCRO committees that the research would be occurring (that is, the investigator would determine and inform, but the ESCRO committee would have no role). That is not what was in- tended. The discussion in the 2005 report states that the âESCRO committee should ensure that the procurement process has been appropriate by requir- ing documentation that it was approved by an IRB and adhered to basic principles of ethically responsible procurementâ (NRC and IOM, 2005, pp. 54-55). Thus, the ESCRO committeeânot the investigatorâmust decide whether the proposed research is purely in vitro research with existing hES cell lines that meet appropriate standards for procurement. The original Guidelines Committee intended that notification involve the ESCRO committee but allow expedited review procedures, such as those used in the context of IRBs. The federal regulations for IRBs outline the procedure as follows (45 CFR 46.110): Under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among members of the IRB. In reviewing the research, the reviewers may ex- â ttp://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.110. h
14 Guidelines for Human Embryonic Stem Cell Research ercise all of the authorities of the IRB except that the reviewers may not disapprove the research. . . . (c) Each IRB which uses an expedited review procedure shall adopt a method for keeping all members advised of research proposals which have been approved under the procedure. ESCRO committees are therefore called on to establish procedures for reviewing purely in vitro research that uses previously and appropriately derived hES cell lines; these reviews may be expedited at the discretion of an ESCRO committee. The former Section 1.2(a) [renumbered as 1.3(a)] of the Guidelines is therefore revised to clarify this point. 1 .3(a) hES cell research permissible after currently mandated reviews P urely in vitro hES cell research that uses previously derived hES cell lines is permissible provided that the ESCRO committee or equivalent body designated by the investigatorâs institution (see Sec- tion 2.0) receives documentation of the provenance of the cell lines, including (i) documentation of the use of an acceptable informed- consent process that was approved by an Institutional Review Board (IRB) or foreign equivalent for their derivation (consistent with Section 3.6) and (ii) documentation of compliance with any additional required review by an Institutional Animal Care and Use Committee (IACUC), Institutional Biosafety Committee (IBC), or other institutionally mandated review. To determine whether the proposed research meets the requirements of this section, the ES- CRO committee may choose to conduct an expedited review of such research proposals. In this context, âexpedited reviewâ means that the ESCRO committee chair or others designated by the committee chair can act on behalf of the committee to determine that the hES cells have been acceptably derived (see Section 1.6) and report to the entire committee. In addition, Sections 6.1 and 6.2 are revised to be consistent with the changes in the newly revised and renumbered 1.3(a):
2008 Amendments 15 6 .1 Institutions should require documentation of the provenance of all hES cell lines, whether the cells were imported into the institu- tion or generated locally. Notice to The institution should obtain include evidence of IRB approval of the procurement process and of adherence to basic ethical and legal principles of procurement as described in Sections 1.3(a) and 1.6. In the case of lines imported from another institution, documentation that these criteria were met at the time of derivation will suffice. 6 .2 In vitro experiments involving the use of already derived and coded hES cell lines will not need review beyond the notification required review described in Sections 1.3(a) and in Section 6.1. PUBLIC OPENNESS AND ESCRO COMMITTEE AUDITS Research that uses hES cells remains controversial in the United States and is still subject to intense political scrutiny. Therefore, it is important to sustain public confidence in the integrity of the institutions and researchers conducting hES cell research; this is one of the reasons that the Guidelines were developed. The Human Embryonic Stem Cell Research Advisory Com- mittee continues to believe that it is in the interests of researchers and their institutions to ensure that the Guidelines of the National Academies or other relevant bodies (such as state regulations and guidelines of the International Society for Stem Cell Research) are being appropriately implemented to ensure that both the public and policy-makers may have a high level of confidence that institutions and their researchers are conducting the research responsibly. As part of this assurance, the public should have reasonable ac- cess to information on the types of hES cell research being conducted at an institution and evidence that the research conforms to the requirements of the guidelines being followed by that institution. For those reasons, the committee is amending the Guidelines in two ways. First, Section 2.0 calls for registries of hES cell research to be maintained by institutional ESCRO committees. Although the original intent was that the information in a registry be available to the public, this intent was not explicit in the Guidelines. The committee is therefore amending the wording of Section 2.0 to make that clear. Second, although the committee cannot impose legally enforceable requirements, it is adding a strong suggestion that institutions at which hES cell research is being conducted carry out pe-
16 Guidelines for Human Embryonic Stem Cell Research riodic audits (for example, every 3-5 years) of their ESCRO committees to ensure that these groups are performing their duties as intended as a good management practice. The emphasis of the audits should be on documenting decisions regarding the acceptability of research proposals and on verifying that cell lines in use at the institution were acceptably derived. Institutions should also make at least the general findings and preferably the details of the audits available to the public. The amended wording (underlined) of Section 2.0 is as follows: 2 .0 ESTABLISHMENT OF AN INSTITUTIONAL EMBRY- ONIC STEM CELL RESEARCH OVERSIGHT COMMITTEE T o provide oversight of all issues related to derivation and use of hES cell lines and to facilitate education of investigators involved in hES cell research, each institution should have activities in- volving hES cells overseen by an Embryonic Stem Cell Research Oversight (ESCRO) committee. This committee could be internal to a single institution or established jointly with one or more other institutions. Alternatively, an institution may have its pro- posals reviewed by an ESCRO committee of another institution, or by an independent ESCRO committee. An ESCRO committee should include independent representatives of the lay public as well as persons with expertise in developmental biology, stem cell research, molecular biology, assisted reproduction, and ethical and legal issues in hES cell research. It must have suitable scien- tific, medical, and ethical expertise to conduct its own review and should have the resources needed to coordinate the management of the various other reviews required for a particular protocol. A pre-existing committee could serve the functions of the ESCRO committee provided that it has the recommended expertise rec- ommended here and representation to perform the various roles described in this report. For example, an institution might elect to constitute an ESCRO committee from among some members of an IRB. But the ESCRO committee should not be a subcom- mittee of the IRB, as its responsibilities extend beyond human subject protections. Furthermore, much hES cell research does not require IRB review. The ESCRO committee should
2008 Amendments 17 (a) rovide oversight over all issues related to derivation and P use of hES cell lines. (b) eview and approve the scientific merit of research R protocols. (c) Review compliance of all in-house hES cell research with all relevant regulations and these guidelines. (d) aintain registries of hES cell research conducted at the M institution and hES cell lines derived or imported by in- stitutional investigators. An institution conducting stem cell research should make information from the registries (including, but not necessarily limited to, project abstracts and sources of funding) available to the public and the media through the institutionâs Web site. (e) Facilitate education of investigators involved in hES cell research. An institution that maintains its own ESCRO committee should conduct periodic audits of the committee to verify that it is carry- ing out its responsibilities appropriately. Auditable records include documentation of decisions regarding the acceptability of research proposals and verification that cell lines in use at the institution were acceptably derived (see Section 1.6). Institutions should make the results of the audits available to the public. An institution that uses an external ESCRO committee should nevertheless ensure that the registry and educational functions of an internal ESCRO committee are carried out by the external ESCRO committee on its behalf or internally by other administra- tive units. Those institutions that use external ESCRO committees are also responsible for ensuring that these committees are likewise carrying out their responsibilities appropriately. CLARIFICATION OF POLICY REGARDING REIMBURSEMENT OF OOCYTE DONORS It was pointed out in the report Guidelines for Human Embryonic Stem Cell Research (NRC and IOM, 2005) that although there is widespread con- sensus that donors should not be paid for blastocysts donated for research,
18 Guidelines for Human Embryonic Stem Cell Research there is less of a consensus about inducements for women to donate oocytes or for men to donate sperm for research purposes. Oocyte donation solely for research purposes is the issue of most concern because of its invasiveness, its inconvenience, and the risks posed by the procedure (reviewed in IOM and NRC, 2007). If the need for oocytes in hES cell research increases, however, it is possible that donations from clinical procedures or for nonfinancial mo- tives may prove insufficient to meet the demand. In such cases, investigators might want to recruit oocyte donors, and it is from this circumstance that the issue of whether such donors should be paid arises. Guidelines for Human Embryonic Stem Cell Research contained a long discussion (Chapter 5) of the arguments for and against payment of oocyte donors, which will not be repeated here. In short, one side argues for fair and just remuneration of participants in research, in which inducements are commonly provided for competent adult research subjects provided that the research risks are reasonable in relation to the potential research benefits. Furthermore, because payment is legal and widely practiced for egg dona- tion for reproductive purposes, many find the forbidding of payment in the research context difficult to justify. Others, however, oppose any payment, whether for research or reproduction. Typically, they caution against any form of payment that may create an âundue inducementâ that could com- promise a prospective donorâs evaluation of the risks posed by donation or the voluntariness of her choices. Furthermore, opponents of payment often embed their objections in a larger set of concerns about the âcommodifica- tion of life,â which also apply to payment for human tissue of any sort and to the patenting of genes and other issues. Complicating these principled debates are more pragmatic concerns: whether (and how much) payment is needed to ensure a sufficient supply of oocytes for nuclear transfer and other forms of specialized stem cell research, and the interchangeability of cell lines, material transfers, and the future of collaborative stem cell research if various state and national jurisdictions have different rules regarding reim- bursement and compensation for oocyte donors. The recommendation made by the Committee on Guidelines for Human Embryonic Stem Cell Research in 2005 was that women who undergo hor- monal induction to generate oocytes specifically for research purposes should be reimbursed only for direct expenses incurred as a result of the procedure, as determined by an Institutional Review Board. Thus, the National Acad- emiesâ Guidelines prohibit cash or in-kind payments for donating oocytes for research purposes. As pointed out in the earlier report (NRC and IOM,
2008 Amendments 19 2005) that position was based in part on the recognition that payments to oocyte donors raise concerns that might undermine public confidence in the responsible management of hES cell research. The report also noted that the recommendation was intended to ensure consistency between procurement practices in the United States and in other countries that have major hES cell research programs and with the limitations enacted in specific states, facilitat- ing collaboration among investigators in the United States and abroad. Since that time, however, California has provided a useful model in its finalized regulations (Title 17 CA Code of Regulations, Section 100020) that allows reimbursement of oocyte donors for âpermissible expenses,â which are clearly defined to include âactual lost wages.â The state of Massachusetts has a similar policy. Although the original National Academiesâ Guidelines did not specifically mention lost wages as a reimbursable category of direct expenses, institutions and states that perform or support hES cell research should view the National Academiesâ Guidelines as open to the interpreta- tion that âlost wagesâ is a legitimate category of reimbursable expenses. To make that explicit, the wording of Section 3.4(b) is modified as follows (new wording underlined): 3.4(b) Women who undergo hormonal induction to generate oo- cytes specifically for research purposes (such as for NT) should be reimbursed only for direct expenses incurred as a result of the procedure, as determined by an IRB. Direct expenses may include costs associated with travel, housing, child care, medical care, health insurance, and actual lost wages. No payments beyond reimbursements, cash or in-kind, should be provided for donating oocytes for research purposes. Similarly, no payments beyond re- imbursements should be made for donations of sperm for research purposes or of somatic cells for use in NT. The committee does not find persuasive the argument that this change has the effect of assigning differing values to the oocytes of different women based on their relative salaries. Reimbursement for lost wages is not a âpriceâ be- ing paid for oocytes. The intent is to leave all donors no better off, but also no worse off.