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Guidelines for Human Embryonic Stem Cell Research 5 Recruiting Donors and Banking hES Cells The emergence of assisted reproductive technology (ART) more than 20 years ago has enabled many couples to overcome fertility problems. Nationwide, 107,587 ART procedures were performed in 2001 at 385 medical centers in the United States and U.S. territories; they resulted in the birth of 40,687 infants from 29,344 pregnancies (Wright et al., 2004). Nationally, 75 percent of ART treatments used fresh, fertilized embryos from the patients’ own oocytes; 14 percent used thawed embryos from the patients’ oocytes; 8 percent used fresh, fertilized embryos from donor oocytes; and 3 percent used thawed embryos from donor oocytes. Thus, procedures can involve gametes from the couples themselves or from donors. Various ART procedures result in the production of more embryos than are needed. Couples can choose to cryopreserve (freeze) and store these “extra” embryos for future attempts at establishing pregnancy. Embryos are often cryopreserved in in vitro fertilization (IVF) practices because transfer of more than three embryos per cycle increases risks for the mother and offspring and cryopreserved embryos offer fairly high pregnancy rates upon eventual transfer (Klock, 2004). Frozen embryos accumulate at a rate of about four per cycle. It is estimated that more than 400,000 embryos are stored in the United States (Hoffman et al., 2003), and there are nearly 16,000 embryos in storage in Canada (Baylis et al., 2003). Once a couple decides to terminate their fertility treatment, for whatever reason, they have a number of options regarding the disposition of these embryos: they can donate them to another couple, they can make them available for quality assurance activities, they can donate them for research purposes, they can dispose of them, or they can store them indefinitely (Hoffman, et al., 2003). Many industrialized countries have developed laws or guidelines to govern the disposition of em-
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Guidelines for Human Embryonic Stem Cell Research bryos. National regulations vary from eternal preservation to 5-year and 10-year preservation limits (Moutel et al., 2002; Grubb, 1996). In addition to excess blastocysts, there might be excess gametes—oocytes and sperm that have been collected for IVF procedures from the couples themselves or from donors—that are no longer needed for reproductive purposes. Women not seeking infertility treatments might elect to donate oocytes for research purposes as an adjunct to a clinical intervention (such as oophorectomy) or as a straightforward altruistic donation specifically for research. A number of studies have shown that some couples are willing to donate unneeded blastocysts for research purposes—as many as 25 percent in some studies (Bangsboll et al., 2004; Burton and Sanders, 2004; Klock, 2004; McMahon et al., 2003). The attitudes of couples who have undergone IVF range from almost parental concern for the embryos to regarding them as medical byproducts with little relationship to a couple’s having a living child. Respondents positively disposed to donation commented on their desire not to waste blastocysts, a desire to help infertile couples, or a desire to advance scientific knowledge. Those with negative views commented on the embryo as a potential child and expressed concerns about a perceived lack of control over the type of research to be performed (McMahon et al. 2003). Ethical principles dictate that potential donors of gametes or blastocysts for human embryonic stem cell (hES cell) research be able to make voluntary and informed choices about whether and how to donate their materials for research and that there be a clear option of “informed refusal,” that is, the right to preclude any research use of embryos. Because of concerns about possible coercion or exploitation of potential donors and controversy regarding the moral status of embryos, it is important that precautions be taken in recruiting donors and ensuring their informed voluntary consent. Some of the protections offered through existing federal regulations can be adapted for application to hES cell research, such as adherence to principles of informed consent and a requirement that an Institutional Review Board (IRB) review the consent process. In addition, Food and Drug Administration (FDA) regulations should be considered for some types of research, specifically if there is a need to retain identifying information about the donors. That has implications for the consent process and for plans to protect confidentiality and privacy of information. Because of privacy concerns, certain provisions of the Health Insurance Portability and Accountability Act (HIPAA) might also apply. (Those regulatory requirements were discussed in Chapter 4.) In this chapter, the committee makes specific detailed recommendations for IRB review of procurement (as recommended in the previous chapter); for the consent processes for obtaining somatic cells, gametes, and blastocysts for use in hES cell research; and for storing and maintaining cell lines once derived. Important safeguards must be in place to ensure that materials are collected ethically and that, once obtained, they are used for scientifically meritorious research (see also Chapters 2 and 3) with the confidentiality of donors protected.
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Guidelines for Human Embryonic Stem Cell Research REVIEW OF THE PROCUREMENT AND INFORMED CONSENT PROCESS As discussed in Chapter 4, although the federal regulations governing human subjects research apply directly only to federally sponsored research or research conducted to secure FDA approval, many research institutions have implemented policies that require that all human subjects research conducted at the institution—regardless of the source of funding—abide by the federal requirements, primarily IRB review and the need for voluntary informed consent of subjects. If an institution abides by the research regulations, it must invoke IRB review whenever human subjects research is conducted unless the research is exempt under the regulations. In addition, if hES cell lines obtained from donated materials are maintained with tracking codes, which might be required for research intended for clinical application, such research could transform donors into “research subjects” because study of the tissue could reveal information about them (unless the information was coded in such a way as to be unidentifiable by the investigator). Because FDA donor-suitability rules for transplants of cells or tissues from hES cell lines (discussed in Chapter 4) will probably require such tracking back to the donors, best practices suggest treating the donors as though they might be research subjects—that is, obtaining IRB review and approval of the consent process—to avoid problems later. In addition, even in the absence of tracking information, the process of donation could benefit from IRB experience in assessing the potential for inducements and risks and in reviewing the consent processes—all of which is relevant to the recruitment of donors of somatic cells, gametes, and blastocysts. As discussed in Chapter 4, this committee recommends that an IRB review the process by which material is obtained and that in all cases donors of cells, gametes, or blastocysts provide their informed consent. That requirement should extend to donors of gametes used in the IVF process. Recommendation 13: When donor gametes have been used in the in vitro fertilization process, resulting blastocysts may not be used for research without consent of all gamete donors. The committee recognizes that this recommendation might eliminate from research some blastocysts that are in excess of clinical need, but that should not impose a major impediment to research, and the requirement for voluntary informed consent of all donors is an absolute prerequisite. Thus, a researcher who wishes to obtain human oocytes or blastocysts for hES cell research must either request and obtain IRB review at his or her own institution (if one exists) to ensure that the informed consent provisions of the federal regulations at 45 CFR 46.116-117 and FDA regulations at 21 CFR 50.20-27 are followed or require that the fertility clinic have its own process for obtaining review from some other duly constituted IRB. The hES cell researcher should maintain a written record documenting the IRB review. IRB documentation should include an assur-
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Guidelines for Human Embryonic Stem Cell Research ance of compliance with the relevant requirements in this report and relevant regulations and a copy of the consent form used for procurement purposes. Ensuring that Donation Is Voluntary Preceding sets of guidelines have emphasized the critical requirement of voluntary donation, including the explicit prohibition of monetary inducement or promise of therapeutic benefit. The original National Institutes of Health guidelines for hES cell research developed in 2000 stated “To ensure that the donation of human embryos in excess of the clinical need is voluntary, no inducements, monetary or otherwise, should have been offered for the donation of human embryos for research purposes. Fertility clinics and/or their affiliated laboratories should have implemented specific written policies and practices to ensure that no such inducements are made available.” Likewise, the Canadian guidelines state “Neither the oocyte nor the sperm from which the embryos were created, nor the embryos themselves, were obtained through commercial transactions, including exchange for service.” The European Commission and the U.K. Medical Research Council have instituted similar prohibitions. And the provisions of California’s Proposition 71, passed in 2004, similarly prohibit payment to donors. Thus, there is virtual unanimity that to avoid any temptation for individuals to create extra embryos for research purposes, no payments should be offered for donation of residual embryos created for reproductive purposes in IVF programs. It is also agreed that there should be no added expense or burden to patients when residual blastocysts are donated and all storage costs for frozen blastocysts should be assumed by the investigators once donation has been confirmed. The explanation of such unanimity might lie in the view that the treatment of the developing human embryo as an entity deserving of respect may be undermined by the introduction of a commercial motive into the solicitation or donation of fetal or embryonic tissue for research purposes. But although the potential for pressure is probably greatest when financial incentives are present, some nonfinancial incentives also should be avoided. For example, a donor’s decisions should not be influenced by anticipated personal medical benefits or by concerns about the quality of later care. Any suggestion of personal benefit to a donor or to a person known to the donor should be avoided. (For obvious reasons, the use of nuclear transfer [NT] to develop hES cells for autologous transplantation requires that the recipient be specified.) Thus, a potential donor should be informed that there is no obligation to donate, that no personal benefit will accrue as a result of a decision to donate (except in cases of autologous transplantation), and that no penalty will result from a decision to refuse to donate. Similarly, people who elect to donate stored blastocysts for research should not be reimbursed for the costs of storage before the decision to donate, because this may be interpreted as an incentive to donate.
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Guidelines for Human Embryonic Stem Cell Research Recommendation 14: To facilitate autonomous choice, decisions related to the production of embryos for infertility treatment should be free of the influence of investigators who propose to derive or use hES cells in research. Whenever it is practicable, the attending physician responsible for the infertility treatment and the investigator deriving or proposing to use hES cells should not be the same person. Recommendation 15: No cash or in kind payments may be provided for donating blastocysts in excess of clinical need for research purposes. Recruiting and Paying Donors of Gametes for Research Purposes Although there is widespread consensus that donors should not be paid for blastocysts they donate for research, there is less consensus about inducements for women to donate oocytes or men to donate sperm for research purposes. It is probably least problematic when women opt to donate oocytes for research in conjunction with a clinical procedure already scheduled (such as IVF or oophorectomy). It is most problematic in the case of oocyte donation solely for research purposes, because the invasiveness and risks of the procedure suggest that financial remuneration is most deserved, but at the same time there is a greater likelihood of enticing potential donors to do something that poses some risk to themselves. Of course, some women might wish to donate oocytes solely for research for nonfinancial motives; such a desire might exist among women who have family or friends affected by a particular disease that might be better understood or treated in the future if hES cells were used. If the need for oocytes in hES cell research increases, it is possible that donations from clinical procedures or for nonfinancial motives may prove insufficient to meet the demand. In such cases—for example, for research involving NT or for research requiring blastocysts that have not been frozen—investigators might want to recruit oocyte donors. In the context of human subjects research, use of advertising to recruit subjects is not considered objectionable, but it is deemed worthy of review. In the context of clinical research, FDA considers direct advertising for study subjects to be the start of the informed consent process and subject selection; therefore, advertisements should be reviewed and approved by an IRB. No matter how donors are recruited, the issue of whether they should be paid remains. Paying research subjects is “a common and long-standing practice in the United States” (Dickert et al., 2002; Anderson and Weijer, 2002), perhaps because of the need to provide incentives as part of recruitment and because moral principles of fairness and gratitude support providing payment to those who bear the burdens of research on behalf of society. But how much money gamete donors should receive and what they should receive payment for (for example, time, inconvenience, dis-
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Guidelines for Human Embryonic Stem Cell Research comfort, or level of risk) are still contested because of fears that remuneration—or some level of remuneration—will undermine voluntary informed consent. Although the consensus is that remuneration of participants in research should be just and fair, there is little agreement in theory or in practice about what constitutes just or fair payment. Moreover, federal regulations and guidance are relatively quiet on the subject, warning about “undue influence” without specifying what counts as undue. One difficulty is that “undue influence” depends on context. The level at which remuneration is set will influence the decisions of some more than others. A major ethical concern is that payments should not be so high as to create an undue influence or offer undue inducement that could compromise a prospective donor’s evaluation of the risks or the voluntariness of her choices. That concern is greatest when studies involve significant risks. Other concerns are that payments should not be so low as to recruit disproportionately high numbers of economically disadvantaged persons and that they should compensate participants fairly for their contribution to research. In its guidance on “Payment to Research Subjects,” FDA notes that “financial incentives are often used when health benefits to subjects are remote or nonexistent. The amount and schedule of all payments should be presented to the IRB at the time of initial review. The IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that neither are coercive or present undue influence” (21 CFR 50.20). In particular, the FDA guidance indicates that payment should be prorated for the time of participation in the study rather than extended to study completion, because the latter could compromise a participant’s right to withdraw at any time. Many argue that research subjects, or in this case gamete donors, should be paid for their time and inconvenience, as well as their direct expenses, but are concerned about providing payment for incurring risk, a practice that some ethicists would rule out altogether. However, attitudes may differ considerably when the risk is a minor and transient symptom or discomfort (such as sleepiness or dizziness) rather than a substantial harm. Some arguments for limiting payment to time and inconvenience reflect a belief that participation in research should be an altruistic act. It is almost certainly true, however, that the prospect of financial remuneration motivates many people to participate in research and that it is often a necessary and sometimes a sufficient condition for their participation. Thus, although payments to volunteers in research studies can be characterized as compensation, honoraria, or inducements, it is widely agreed that volunteers should be reimbursed for direct expenses. Similarly, offering a small or token honorarium after participation is generally accepted. The consensus is less clear on whether volunteers should be paid for time and lost wages. Some consider that a form of compensation and there is disagreement about whether amounts should depend on income. The value placed on a person’s time depends in part on the person’s socioeconomic status, but there are concerns about using poverty as a justification for perpetuating differential payments.
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Guidelines for Human Embryonic Stem Cell Research Inducements are commonly provided for competent adult research subjects and some argue that oocyte donation should be treated in a similar fashion and that it is inappropriately paternalistic to prohibit competent women from making an informed choice. Others believe that the reproductive context makes this special and that payment should be prohibited. Underlying those principled concerns is a more pragmatic debate about whether (and how much) payment is needed to ensure a sufficient supply of oocytes for stem cell research. Recommendation 16: Women who undergo hormonal induction to generate oocytes specifically for research purposes (such as for nuclear transfer) should be reimbursed only for direct expenses incurred as a result of the procedure, as determined by an Institutional Review Board. No cash or in kind payments should be provided for donating oocytes for research purposes. Similarly, no payments should be made for donations of sperm for research purposes or of somatic cells for use in nuclear transfer. This recommendation is 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. Following the recommendation will ensure consistency between procurement practices here and in other countries that have major hES cell research programs, thus facilitating international collaborations and the sharing of hES cell lines across national borders. It also ensures consistency with the limitations enacted in California in Proposition 71, facilitating collaboration between California investigators and those in the rest of the country. The committee recognizes the strengths of all the arguments surrounding this issue. The recommendation should not be interpreted as a commentary on commercial IVF practices, but as a narrow policy position specifically with respect to hES cell research. Further, as with all the policies recommended by the committee, this policy should be regularly reviewed and reconsidered as the field matures and the experiences under other policies can be evaluated. Finally, it is important to note that oocyte donation is not without risks. Oocyte donors undergoing ovulation induction have a small risk of severe ovarian hyperstimulation syndrome (OHSS). OHSS may affect 2-5 percent of women undergoing stimulation and can sometimes require hospital admission (Orvieto, 2005; ASRM, 2004a; Endo et al., 2002). Careful monitoring and adjustment of the medication regimen during the stimulation treatment can reduce the risk of OHSS. Risks posed by donation must be clearly articulated and understood by the prospective donor. In the United States—where insurance coverage varies and often does not cover research-related costs—the donor must be informed of whether and how much compensation is available if she is injured as a result of research. In general, compensation is not assured.
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Guidelines for Human Embryonic Stem Cell Research TIMING OF THE DECISION TO DONATE EXCESS BLASTOCYSTS It is widely accepted that, whenever possible, donors’ decisions to dispose of their blastocysts should be made separately from their decisions to donate them for research. Potential donors should be allowed to provide blastocysts for research only if they have decided to have those blastocysts discarded instead of donating them to another couple or storing them. If the decision to discard the blastocysts precedes the decision to donate them for research purposes, the research will determine only how their destruction occurs, not whether it occurs (NBAC, 1999a). The U.K. Medical Research Council guidelines emphasize the separation of tissue collection from the practice of research: “Those collecting embryos or adult cells/tissues, or involved in the process of fetal termination, and those responsible for the clinical care of the donor, should not knowingly be involved in research on those human tissues.” That separation may not always be possible, particularly because the couple may be informed of several options simultaneously at the outset of treatment for infertility or after its completion. Some infertility programs provide patients with multiple consent forms at the outset of treatment, forms that include options to donate to research, discard, or transfer any embryos that remain. When embryos are created for infertility treatment, couples are often asked to stipulate what should be done with frozen embryos in the event of future contingencies, such as death, divorce, or the inability of the clinic to contact them at a later date (ASRM, 2002). In addition, given growing public awareness about hES cell research, some couples might request at the outset of treatment that they be provided the opportunity to donate unneeded embryos to research. However, even if couples indicated at the outset of their clinical treatment that they chose to donate excess embryos for research, that decision must be confirmed before the embryos are thawed for research use (Lo et al., 2004). Recommendation 17: Consent for blastocyst donation should be obtained from each donor at the time of donation. Even people who have given prior indication of their intent to donate to research any blastocysts that remain after clinical care should nonetheless give informed consent at the time of donation. Donors should be informed that they retain the right to withdraw consent until the blastocysts are actually used in cell line derivation. INFORMED CONSENT REQUIREMENTS Prospective donors of blastocysts or gametes that remain after infertility treatment and donors of gametes for research should receive timely, relevant, and appropriate information to make informed and voluntary choices. Before considering the potential research use of the blastocysts, a prospective donor should have been
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Guidelines for Human Embryonic Stem Cell Research presented with the option of storing the embryos, donating them to another woman or couple, donating them to research, or discarding them. The current regulatory system specifies basic elements of information that must be provided to prospective participants during the informed consent process. In the context of donation for research, disclosure should ensure that potential donors understand the risks involved, if any. Donors should be told of all options concerning the care and disposition of their embryos, including freezing for later use, donation to others for reproductive use, research use, or discard without research use (Lo et al., 2004). To the extent possible, donors should be informed of the variety of future research uses before giving consent to donate blastocysts for research. Written informed consent must be obtained from all those who elect to donate blastocysts or gametes. Comprehensive information must be provided to all donors that is readily accessible and at a level that will enable an informed decision to be made. Potential Discovery of Clinically Significant Information If the identity of the donor is to be retained in a way that is ascertainable to the investigator, donors should be informed of the possibility that relevant clinical information might be discovered in the course of the research (for example, a genetic mutation conferring carrier status). There is ongoing debate about whether findings from research should be communicated to research subjects (donors would be considered subjects if identifiable information about them were known to researchers), either upon completion of a study or at some later date in time. This issue is relevant to all research, not just research involving hES cell lines. The obligation to report such findings to the donors depends in large part on the reliability of the findings and the significance of the information to human health. MacKay has written that preliminary results do not yet constitute “information” since “until an initial finding is confirmed, there is no reliable information” to communicate to subjects, and that “even … confirmed findings may have some unforeseen limitations” (MacKay, 1984). McKay and others have argued that subjects should not be given information about their individual research results until the findings have been confirmed through the development of a reliable, accurate, and valid confirmatory test (MacKay, 1984; Fost and Farrell, 1989). On the other hand, those who believe that persons have the right to research results cite the principle of autonomy, which dictates that persons have a right to know what has been learned about them, and that therefore, interim results should be shared with subjects (Veatch, 1981). Confusion about the appropriateness of returning individual research findings has increased as a result of HIPAA’s Standards for Privacy of Individually Identifiable Health Information (the Privacy Rule; see Chapter 4). The Privacy Rule provides an individual the right of access to information about himself or herself, including personal research results obtained in the course of clinical care, with
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Guidelines for Human Embryonic Stem Cell Research limited exceptions. The Privacy Rule not only gives patients a right to see their own records but also requires that patients be notified of their right to see such records. This regulatory requirement is most likely to lead to an increase in the number of persons who are aware of and exercise their right to request and receive research findings, all of which will have implications for the researcher. Investigators will have to be prepared to include, and IRBs to review, plans for how to respond to subjects’ requests for disclosure of research findings. Clearly, in the clinical context it is the utility and validity of the information that should dictate a decision to recontact individuals. It is less clear whether an investigator, who has no therapeutic relationship with the person, has the same obligation. Another important requirement must be considered in the decision to report research findings to subjects—the Clinical Laboratory Improvement Amendments of 1988 (CLIA). CLIA regulations do not permit the return of research results to patients or subjects if the tests were not conducted in a CLIA-approved laboratory. Thus, if a research laboratory is not CLIA-approved, it should not be reporting its results to subjects. In some circumstances, repeating the test in a CLIA-approved laboratory may be feasible and appropriate. In any case, donors should be clearly informed in the consent process whether they will have the opportunity to receive individual results from the project. Whether it is appropriate to return the results will depend on several factors and should be subject to IRB review. Recommendation 18: In the context of donation of gametes or blastocysts for hES cell research, the informed consent process, should, at a minimum, provide the following information: A statement that the blastocysts or gametes will be used to derive hES cells for research that may include research on human transplantation. A statement that the donation is made without any restriction or direction regarding who may be the recipient of transplants of the cells derived, except in the case of autologous donation. A statement as to whether the identities of the donors will be readily ascertainable to those who derive or work with the resulting hES cell lines. If the identities of the donors are retained (even if coded), a statement as to whether donors wish to be contacted in the future to receive information obtained through studies of the cell lines. An assurance that participants in research projects will follow applicable and appropriate best practices for donation, 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.) A statement that derived hES cells and/or cell lines might be kept for many years.
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Guidelines for Human Embryonic Stem Cell Research A statement that the hES cells and/or cell lines might be used in research involving genetic manipulation of the cells or the mixing of human and nonhuman cells in animal models. Disclosure of the possibility that the results of study of the hES cells may have commercial potential and a statement that the donor will not receive financial or any other benefits from any future commercial development; A statement that the research is not intended to provide direct medical benefit to the donor(s) except in the case of autologous donation. A statement that embryos will be destroyed in the process of deriving hES cells. A statement that neither consenting nor refusing to donate embryos for research will affect the quality of any future care provided to potential donors. A statement of the risks involved to the donor. In 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 might 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. ADHERENCE TO STANDARDS OF CLINICAL CARE Clinical facilities providing ART services have an obligation to protect the rights and safety of their patients and to behave in an ethical manner. Researchers must not pressure members of the fertility treatment team to generate more embryos than necessary for the optimum chance of reproductive success. An IVF clinic, or other third party responsible for obtaining consent and/or collecting materials should not be able to pay for or be paid for the material it obtains (apart from specifically defined, cost-based reimbursements). Placing such restrictions on paying those who obtain the embryos discourages the creation during routine infertility procedures of excess embryos that would later be used for research purposes. Finally, no member of the medical or nursing staff should be under any duty to participate in providing donor information or securing donor consent for research use of gametes or blastocysts if he or she has a conscientious objection. However, this privilege does not extend to the appropriate clinical care of a donor or recipient. Recommendation 19: Consenting or refusing to donate gametes or embryos for research should not affect or alter in any way the quality of care provided to prospective donors. That is, clinical staff must provide appropriate care to patients without prejudice regarding their decisions about disposition of their embryos.
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Guidelines for Human Embryonic Stem Cell Research Recommendation 20: Clinical personnel who have a conscientious objection to hES cell research should not be required to participate in providing donor information or securing donor consent for research use of gametes or blastocysts. That privilege should not extend to the care of a donor or recipient. Recommendation 21: Researchers may not ask members of the infertility treatment team to generate more oocytes than necessary for the optimal chance of reproductive success. An infertility clinic or other third party responsible for obtaining consent or collecting materials should not be able to pay for or be paid for the material obtained (except for specifically defined cost-based reimbursements and payments for professional services). Restricting payment of those who obtain the embryos discourages the production of excess embryos during routine infertility procedures for later use in research. Other measures can be taken to ensure that conflicts of interest are appropriately managed. For example, the embryologist in the ART program who makes the determination that an oocyte has failed to fertilize or develop sufficiently for implantation should not be a member of the hES research team. BANKING AND DISTRIBUTION OF CELL LINES Once donated materials are obtained from couples or individuals, several additional standards should be applied to the storage, maintenance, and distribution of cell lines for research use. People and institutions responsible for these activities must maintain the highest ethical, legal, and scientific standards (Brivanlou et al., 2003). Cell lines might be stored at several institutions as part of individual research collections or might be deposited in more central repositories or banks. Developing standardized practices for obtaining, screening, processing, validating, and storing cell lines, and distributing them to users will provide confidence to researchers and the public that the materials are of high quality and of optimal use to researchers. Several models exist for the banking of human biological materials. The most relevant is the U.K. Stem Cell Bank, which was established to provide researchers with an independent national stem cell resource:1 The Cell Bank will offer a vital resource to support the advance of research in this exciting area. At the same time it will develop important safeguards, by ensuring that cell lines which could ultimately provide the basis for clinical treatment are appropriately characterized and also handled and stored under conditions that are 1 http://www.nibsc.ac.uk/divisions/cbi/stemcell.html.
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Guidelines for Human Embryonic Stem Cell Research properly controlled. This will not only provide high quality starting materials to facilitate the development of stem cell therapy, but, in providing a centralized resource for researchers, should also reduce the use of surplus embryos for the development of stem cell lines by individual teams. One of the conditions of the U.K. bank’s establishment was the development of an extensive code of practice for its operations (Medical Research Council, 2004). In addition, it has a clear system of governance, which involves a steering committee for policy, a management committee, and a user and clinical liaison committee. Tissue-banking policies and practices in connection with a wide array of human cells, tissues, and organs have been established by several public and private entities in the United States, including the National Cancer Institute,2 the National Heart, Lung and Blood Institute,3 and private entities, such as Coriell4 and the American Type Culture Collection.5 In addition, the U.S. Office for Human Research Protections (OHRP) has issued two guidance documents: Issues to Consider in Research Use of Stored Data or Tissues6 and Guidance on Research Involving Coded Private Information or Biological Specimens.7 The guidelines developed by those groups and the U.K. Stem Cell Bank 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. For example, a common requirement is that any identifiable tissue (including coded tissue) that is collected requires IRB review at the site of collection and informed consent of the subject. In addition, most require that, when possible, the informed consent process include information about the repository and the conditions under which materials will be shared. Other policies address the need to protect the privacy of donors. Several models exist for protecting subjects whose specimens are used for research, including the honest-broker model, in which a tissue bank trustee ensures strict control of information flows associated with research that uses banked tissues (see the model developed by OHRP8). Procedurally, it is common practice that there be a clear policy and system for evaluating requests for samples to see whether each request is consistent with the conditions for sharing samples and with the original informed consent. At the repository management level, there typically are requirements for safety, security, and risk assessments; validation of submitted material; culturing and ex- 2 www.cancerdiagnosis.nci.nih.gov/specimenes/brochure.html; www.cancerdiagnosis.nci.nih.gov/specimens/legal.html. 3 www.nhlbi.nih.gov/funding/policies/repos-gl.htm. 4 http://locus.umdnj.edu/. 5 http://www.atcc.org/. 6 http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm. 7 http://www.hhs.gov/ohrp/humansubjects/guidance/cdebiol.pdf. 8 http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm.
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Guidelines for Human Embryonic Stem Cell Research pansion of cell line; process control; packaging, labeling, and distribution; and documentation and data management. Those requirements, in addition to routine quality assurance and control, will be as critical in hES cell research as in any other field that uses human materials. 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 cells—that is, that they were obtained ethically 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. Recommendation 22: Institutions that are banking or plan to bank hES cell lines should establish uniform guidelines to ensure that donors of material give informed consent through a process approved by an Institutional Review Board, and that meticulous records are maintained about all aspects of cell culture. Uniform tracking systems and common guidelines for distribution of cells should be established. Recommendation 23: Any facility engaged in obtaining and storing hES cell lines should consider the following standards: (a) Creation of a committee for policy and oversight purposes and creation of clear and standardized protocols for banking and withdrawals. (b) Documentation requirements for investigators and sites that deposit cell lines, including A copy of the donor consent form. Proof of Institutional Review Board approval of the procurement process. Available medical information on the donors, including results of infectious-disease screening. Available clinical, observational, or diagnostic information about the donor(s). Critical information about culture conditions (such as media, cell passage, and safety information). Available cell line characterization (such as karyotype and genetic markers). A repository has the right of refusal if prior culture conditions or other items do not meet its standards. (c) A secure system for protecting the privacy of donors when materials retain codes or identifiable information, including but not limited to
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Guidelines for Human Embryonic Stem Cell Research A schema for maintaining confidentiality (such as a coding system). A system for a secure audit trail from primary cell lines to those submitted to the repository. A policy governing whether and how to deliver clinically significant information back to donors. (d) The following standard practices: Assignment of a unique identifier to each sample. A process for characterizing cell lines. A process for expanding, maintaining, and storing cell lines. A system for quality assurance and control. A website that contains scientific descriptions and data related to the cell lines available. A procedure for reviewing applications for cell lines. A process for tracking disbursed cell lines and recording their status when shipped (such as number of passages). A system for auditing compliance. A schedule of charges. A statement of intellectual property policies. When appropriate, creation of a clear Material Transfer Agreement or user agreement. A liability statement. A system for disposal of material. (e) Clear criteria for distribution of cell lines, including but not limited to evidence of approval of the research by an Embryonic Stem Cell Research Oversight committee or equivalent body at the recipient institution. The committee also notes and commends recent efforts at the federal level by the National Institutes of Health9 to encourage the sharing and dissemination of important research resources. Restricted availability of unique research resources, such as hES cell lines, upon which further studies are dependent, can impede the advancement of research. To the extent possible, the committee encourages practices that make cell lines readily available in a timely fashion to the research community for further research, development, and application. 9 See NIH’s Policy on Sharing of Model Organisms for Biomedical Research at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html.
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Guidelines for Human Embryonic Stem Cell Research SUMMARY Individuals and couples who voluntarily and with full information donate somatic cells, gametes, or blastocysts for hES research must be assured that the research will be meritorious and that all possible efforts will be made by those with responsibility for handling, storing, and using resulting cell lines to protect donor confidentiality. The combination of IRB review of the procurement process and a process of fully informed consent before donation will contribute to the ethical conduct of the research. Once hES cells are derived, the proper banking and distribution of hES cell lines will maintain the covenant between donor and scientific community.
Representative terms from entire chapter: