Appendix A
National Institutes of Health Guidelines for Research Using Human Stem Cells1

I.
Scope of Guidelines

These Guidelines apply to the expenditure of National Institutes of Health (NIH) funds for research using human embryonic stem cells (hESCs) and certain uses of induced pluripotent stem cells (See Section IV). The Guidelines implement Executive Order 13505.


Long-standing HHS [Department of Health and Human Services] regulations for Protection of Human Subjects, 45 C.F.R. 46, Subpart A establish safeguards for individuals who are the sources of many human tissues used in research, including non-embryonic human adult stem cells and human induced pluripotent stem cells. When research involving human adult stem cells or induced pluripotent stem cells constitutes human subject research, Institutional Review Board review may be required and informed consent may need to be obtained per the requirements detailed in 45 C.F.R. 46, Subpart A. Applicants should consult http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.


It is also important to note that the HHS regulation, Protection of Human Subjects, 45 C.F.R. Part 46, Subpart A, may apply to certain research using hESCs. This regulation applies, among other things, to research involving individually identifiable private information about a living



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Appendix A National Institutes of Health Guidelines for Research Using Human Stem Cells1 I. Scope of Guidelines These Guidelines apply to the expenditure of National Institutes of Health (NIH) funds for research using human embryonic stem cells (hESCs) and certain uses of induced pluripotent stem cells (See Section IV). The Guidelines implement Executive Order 13505. Long-standing HHS [Department of Health and Human Services] regula- tions for Protection of Human Subjects, 45 C.F.R. 46, Subpart A establish safeguards for individuals who are the sources of many human tissues used in research, including non-embryonic human adult stem cells and human induced pluripotent stem cells. When research involving human adult stem cells or induced pluripotent stem cells constitutes human subject research, Institutional Review Board review may be required and informed consent may need to be obtained per the requirements detailed in 45 C.F.R. 46, Subpart A. Applicants should consult http://www.hhs. gov/ohrp/humansubjects/guidance/45cfr46.htm. It is also important to note that the HHS regulation, Protection of Human Subjects, 45 C.F.R. Part 46, Subpart A, may apply to certain research using hESCs. This regulation applies, among other things, to research involving individually identifiable private information about a living 1 Available at . 9

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Appendix A 10 individual, 45 C.F.R. § 46.102(f). The HHS Office for Human Research Protections (OHRP) considers biological material, such as cells derived from human embryos, to be individually identifiable when they can be linked to specific living individuals by the investigators either directly or indirectly through coding systems. Thus, in certain circumstances, IRB review may be required, in addition to compliance with these Guidelines. Applicant institutions are urged to consult OHRP guidances at http:// www.hhs.gov/ohrp/policy/index.html#topics. To ensure that the greatest number of responsibly derived hESCs are eligible for research using NIH funding, these Guidelines are divided into several sections, which apply specifically to embryos donated in the U.S. and foreign countries, both before and on or after the effective date of these Guidelines. Section II (A) and (B) describe the conditions and review processes for determining hESC eligibility for NIH funds. Further information on these review processes may be found at www. NIH.gov. Sections IV and V describe research that is not eligible for NIH funding. These guidelines are based on the following principles: 1. Responsible research with hESCs has the potential to improve our understanding of human health and illness and discover new ways to prevent and/or treat illness. 2. Individuals donating embryos for research purposes should do so freely, with voluntary and informed consent. As directed by Executive Order 13505, the NIH shall review and update these Guidelines periodically, as appropriate. II. Eligibility of Human Embryonic Stem Cells for Research with NIH Funding For the purpose of these Guidelines, “human embryonic stem cells (hESCs)” are cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and

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Appendix A 11 tissues of the three primary germ layers.2 Although hESCs are derived from embryos, such stem cells are not themselves human embryos. All of the processes and procedures for review of the eligibility of hESCs will be centralized at the NIH as follows: A. Applicant institutions proposing research using hESCs derived from embryos donated in the U.S. on or after the effective date of these Guidelines may use hESCs that are posted on the new NIH Registry or they may establish eligibility for NIH funding by submitting an assurance of compliance with Section II (A) of the Guidelines, along with supporting information demonstrating compliance for admin- istrative review by the NIH. For the purposes of this Section II (A), hESCs should have been derived from human embryos: 1. that were created using in vitro fertilization for reproductive purposes and were no longer needed for this purpose; 2. that were donated by individuals who sought reproductive treatment (hereafter referred to as “donor(s)”) and who gave voluntary written consent for the human embryos to be used for research purposes; and 3. for which all of the following can be assured and documenta- tion provided, such as consent forms, written policies, or other documentation, provided: a. All options available in the health care facility where treat- ment was sought pertaining to the embryos no longer needed for reproductive purposes were explained to the individual(s) who sought reproductive treatment. b. No payments, cash or in kind, were offered for the donated embryos. c. Policies and/or procedures were in place at the health care facility where the embryos were donated that neither con- senting nor refusing to donate embryos for research would affect the quality of care provided to potential donor(s). 2 On February 23, 2010, NIH issued a request for public comment in the Federal Register on changing this definition to the following: For the Purpose of the Guidelines, ‘human embryonic stem cells (hESCs)’ are pluripotent cells that are derived from early stage human embryos, up to and including the blastocyst stage, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers. As of the publication of this report, no revisions have been formally issued. Readers are encouraged to consult for the NIH current guidelines.

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Appendix A 12 d. There was a clear separation between the prospective donor(s)’s decision to create human embryos for reproduc- tive purposes and the prospective donor(s)’s decision to do- nate human embryos for research purposes. Specifically: i. Decisions related to the creation of human embryos for reproductive purposes should have been made free from the influence of researchers proposing to derive or utilize hESCs in research. The attending physician responsible for reproductive clinical care and the re- searcher deriving and/or proposing to utilize hESCs should not have been the same person unless separa- tion was not practicable. ii. At the time of donation, consent for that donation should have been obtained from the individual(s) who had sought reproductive treatment. That is, even if potential donor(s) had given prior indication of their intent to donate to research any embryos that remained after reproductive treatment, consent for the donation for research purposes should have been given at the time of the donation. iii. Donor(s) should have been informed that they re- tained the right to withdraw consent for the donation of the embryo until the embryos were actually used to derive embryonic stem cells or until information which could link the identity of the donor(s) with the embryo was no longer retained, if applicable. e. During the consent process, the donor(s) were informed of the following: i. that the embryos would be used to derive hESCs for research; ii. what would happen to the embryos in the derivation of hESCs for research; iii. that hESCs derived from the embryos might be kept for many years; iv. that the donation was made without any restriction or direction regarding the individual(s) who may receive medical benefit from the use of the hESCs, such as who may be the recipients of cell transplants.; v. that the research was not intended to provide direct medical benefit to the donor(s);

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Appendix A 13 vi. that the results of research using the hESCs may have commercial potential, and that the donor(s) would not receive financial or any other benefits from any such commercial development; vii. whether information that could identify the donor(s) would be available to researchers. B. Applicant institutions proposing research using hESCs derived from embryos donated in the U.S. before the effective date of these Guide- lines may use hESCs that are posted on the new NIH Registry or they may establish eligibility for NIH funding in one of two ways: 1. By complying with Section II (A) of the Guidelines; or 2. By submitting materials to a Working Group of the Advisory Committee to the Director (ACD), which will make recom- mendations regarding eligibility for NIH funding to its parent group, the ACD. The ACD will make recommendations to the NIH Director, who will make final decisions about eligibility for NIH funding. The materials submitted must demonstrate that the hESCs were derived from human embryos: 1) that were created using in vitro fertilization for reproductive purposes and were no longer needed for this purpose; and 2) that were donated by donor(s) who gave voluntary written consent for the human embryos to be used for research purposes. The Working Group will review submitted materials, e.g., consent forms, written policies or other documentation, tak- ing into account the principles articulated in Section II (A), 45 C.F.R. Part 46, Subpart A, and the following additional points to consider. That is, during the informed consent pro- cess, including written or oral communications, whether the donor(s) were: (1) informed of other available options pertain- ing to the use of the embryos; (2) offered any inducements for the donation of the embryos; and (3) informed about what would happen to the embryos after the donation for research. C. For embryos donated outside the United States before the effective date of these Guidelines, applicants may comply with either Section II (A) or (B). For embryos donated outside of the United States on or after the effective date of the Guidelines, applicants seeking to

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Appendix A 14 determine eligibility for NIH research funding may submit an assur- ance that the hESCs fully comply with Section II (A) or submit an assurance along with supporting information, that the alternative procedural standards of the foreign country where the embryo was donated provide protections at least equivalent to those provided by Section II (A) of these Guidelines. These materials will be reviewed by the NIH ACD Working Group, which will recommend to the ACD whether such equivalence exists. Final decisions will be made by the NIH Director. D. NIH will establish a new Registry listing hESCs eligible for use in NIH funded research. All hESCs that have been reviewed and deemed eligible by the NIH in accordance with these Guidelines will be posted on the new NIH Registry. III. Use of NIH Funds Prior to the use of NIH funds, funding recipients should provide as- surances, when endorsing applications and progress reports submitted to NIH for projects using hESCs, that the hESCs are listed on the NIH registry. IV. Research Using hESCs and/or Human Induced Pluripotent Stem Cells That, Although the Cells May Come from Eligible Sources, Is Nevertheless Ineligible for NIH Funding This section governs research using hESCs and human induced pluripo- tent stem cells, i.e., human cells that are capable of dividing without differentiating for a prolonged period in culture, and are known to de- velop into cells and tissues of the three primary germ layers. Although the cells may come from eligible sources, the following uses of these cells are nevertheless ineligible for NIH funding, as follows: A. Research in which hESCs (even if derived from embryos donated in accordance with these Guidelines) or human induced pluripotent stem cells are introduced into non-human primate blastocysts. B. Research involving the breeding of animals where the introduction of hESCs (even if derived from embryos donated in accordance with these Guidelines) or human induced pluripotent stem cells may con- tribute to the germ line.

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Appendix A 15 V. Other Research Not Eligible for NIH Funding A. NIH funding of the derivation of stem cells from human embryos is prohibited by the annual appropriations ban on funding of hu- man embryo research (Section 509, Omnibus Appropriations Act, 2009, Pub. L. 111-8, 3/11/09), otherwise known as the Dickey Amendment. B. Research using hESCs derived from other sources, including somatic cell nuclear transfer, parthenogenesis, and/or IVF embryos created for research purposes, is not eligible for NIH funding.

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