Zettler, Patricia; Wolf, Leslie E. JD, MPH; Lo, Bernard MD
Human stem cell (hSC) research has the potential to answer fundamental scientific questions regarding human development and the pathogenesis of disease and to develop new treatments for degenerative diseases such as Alzheimer disease, Parkinson disease, and diabetes. Because such research also raises ethical concerns,1–7 careful oversight is needed to ensure that it is carried out according to strict ethical and scientific standards. Academic health centers (AHCs), which are at the forefront of this innovative research, need to convene new institutional panels to review and oversee hSC research.
Guidelines for Stem Cell Research
National Academy of Sciences guidelines
In May 2005, a National Academy of Sciences (NAS) report, Guidelines for Human Embryonic Stem Cell Research, recommended that research institutions establish embryonic stem cell research oversight committees (ESCROs) to “ensure that inappropriate research is not conducted and that controversial research is well justified and subject to appropriate oversight.”8 Because this report was carried out and peer reviewed under the auspices of the NAS, its recommendations are likely to be widely adopted. The NAS recognized that human embryonic stem cell (hES) research presents complex and novel ethical issues that are beyond the scope of existing institutional review boards (IRBs) and institutional animal care and use committees (IACUCs).
Donors of embryos and gametes for stem cell research must be protected. Some hSC research may not require IRB review but may still raise ethical concerns. Federal regulations governing human subjects research do not require IRBs to review research with existing hSC lines that are not linked to personally identifiable information.9 However, it is ethically important for researchers and research institutions using stem cell lines derived at other institutions to verify that these lines were derived with IRB approval, free and informed consent, and minimization of risks. Furthermore, IRBs typically lack the expertise and time to review the specific ethical issues raised by stem cell research. The special status of the human embryo requires justification of the “scientific rationale for the need to generate new [embryonic stem cell] lines” and the “basis for the number of blastocysts and oocytes needed.”8 Additional oversight also is necessary because “the implantation of human embryonic stem cells or human brain cells into nonhuman animals”8 raises ethical concerns that human characteristics might be transmitted into nonhuman animals.4 This blurring of lines between humans and other animals “may threaten to undermine human dignity.”8 Studies to implant human cells into animals require IACUC review. However, because IACUCs are charged only with animal use and welfare, they are unlikely to address the issue of blurring of species lines.
California state guidelines
In 2004, California voters approved $3 billion for hSC research in the state for 10 years, making the state the largest funder of hSC research in the United States. The California Institute for Regenerative Medicine (CIRM), the state agency that will administer this funding, will require institutions receiving its grants to establish a stem cell research oversight committee (SCRO).10 In adopting the term “SCRO,” CIRM omitted “embryo” from the NAS name for the oversight committee because CIRM may fund all types of hSC research, not just embryonic stem cell research, and its regulations apply to all research it funds. In this article, we use the term “SCRO,” excluding the “embryo” distinction, because important ethical issues may be raised by research with hSCs that are not embryonic in origin.
The interim California regulations that are currently in effect for CIRM-funded research adopted the NAS guidelines. The final regulations, which have not yet gone into effect, differ from the NAS guidelines regarding institutional oversight committees in several respects.10 First, according to the CIRM, a SCRO must contain at least one nonscientist member who is not affiliated with the research institution, and at least one patient advocate. Second, SCRO committee members may not participate in the review of a project if they have a conflict of interest. Third, the CIRM regulations provide additional protections for women donating oocytes for stem cell research. Fourth, the chancellor, chief executive officer, or equivalent official of the institution receiving a CIRM grant must designate an institutional official responsible for overseeing compliance with the regulations. The CIRM regulations are not merely recommendations for CIRM-funded research—they are legally binding.
Establishing guidelines in AHCs across the nation
In light of the NAS recommendations and the CIRM regulations, many AHCs across the country are establishing, or thinking about establishing, SCROs. Although the NAS report and CIRM regulations provide the rationale and the charge for SCROs, research institutions will need to develop more specific policies and procedures for their particular needs on many practical issues, such as SCRO membership, quorum, conflicts of interest, coordination with other oversight committees, and expedited review. AHCs have extensive experience with IRBs and IACUCs, which also oversee research. However, because these committees have different functions from SCROs, the organization and procedures of SCROs will require fresh thinking. AHCs, which train the next generation of scientists, should take the lead in developing best practices for oversight of hSC research.
The University of California San Francisco (UCSF) established a SCRO in 2003. The UCSF SCRO complies with both the NAS recommendations and the CIRM guidelines, but it goes beyond these guidelines by developing detailed policies and procedures unique to UCSF. The UCSF experience may help other AHCs establish oversight committees to oversee research in this rapidly developing field in a responsible and efficient manner.
The UCSF History of Stem Cell Research Oversight
In 2003, UCSF established the Human Gamete, Embryo, and Stem Cell Research committee, an institutional committee that oversees research with gametes, embryos, and all types of hSCs. The UCSF committee was formed to address novel ethical issues raised by innovative stem cell research. The committee was originally charged with recommending institutional policies on ethical issues regarding gamete, embryo, and stem cell research and to review protocols involving such research for the IRB. After the release of the 2005 NAS report, the committee was given oversight and compliance responsibilities. The initial focus on ethics rather than compliance encouraged the committee to think about ethical issues that are not adequately covered by existing guidelines or legal requirements. Because this article addresses the oversight of stem cell research, we refer to the UCSF committee in its present form as a SCRO, because that is the role it serves.
In developing policies and procedures, the UCSF SCRO followed several overarching principles. First, the committee must be accountable, documenting its reasoning and maintaining consistency across similar cases. Second, reviewers should be experts in relevant fields. Ethical and scientific review should be tightly linked because the scientific and ethical issues in stem cell research cannot be adequately addressed separately. Third, protocol reviewers must be independent of the research team.
In reviewing stem cell research, the UCSF SCRO has identified several salient ethical issues. First, the informed consent process is particularly important for derivation of new stem cell lines.1,3 Individuals donating materials have different preferences as to what types of research they will allow to be pursued with their reproductive cells. To respect donors, investigators should not use stem cell lines for research to which the donors object. The consent process must ensure that donors appreciate that different kinds of stem cell research may be carried out and that some future types of studies cannot be anticipated. Second, clinical trials involving transplantation of multipotent stem cells require special attention because the cells might differentiate into unintended cell types or integrate into unintended sites, causing adverse events. In contrast to a traditional IRB or IACUC, the scientific expertise of the SCRO can help identify and evaluate these potential medical risks.
To ensure that the UCSF SCRO committee has scientific and ethical expertise pertinent to stem cell research, its members come from a broad range of disciplines (List 1). AHC leaders play an active role in identifying faculty members who have appropriate expertise and who can work together to approach problems in an interdisciplinary manner. The SCRO and its chair are appointed by the executive vice chancellor and provost, and all members report to him. Members’ terms are currently open ended.
The SCRO must review and approve an hSC study before the investigators proceed with the study. The SCRO communicates its decision in writing to the IRB and investigators. Decisions are enforced through the executive vice chancellor, as is the case with IRB decisions. If the investigator does not agree with an SCRO decision, the investigator may submit his or her reasons for disagreement and request that the committee reconsider the study.
Review of Protocols
The following case studies demonstrate how the committee’s strong scientific expertise allows more rigorous and thoughtful protocol review than would occur in a traditional IRB or IACUC review.
Study 1: Introduction of human progenitor cells into nonhuman blastocysts
An investigator proposed to transplant mesenchymal progenitor cells derived from an existing anonymized hES line into chick embryos. This proof-of-principle study would establish that the cells could form bone tissue. The investigator did not specify an endpoint in the protocol.
A developmental biologist on the UCSF SCRO pointed out that, in the chick, limb morphology can be seen after day 12 of embryonic development. The NAS report mentions that ethical concerns might be raised if hSCs transplanted into animals affect the animal’s cognitive abilities or alter the animal’s germline.11 However, this scientist pointed out that transferring human morphological characteristics to nonhuman animals, such as features resembling a human hand in a chick limb bud, can be both ethically problematic and also scientifically unnecessary. He suggested that to establish proof of principle that the transplanted cells were indeed progenitor cells, histological confirmation of integration earlier than day 12 might be adequate. This review illustrates the value of integrated scientific and ethical review: a scientific suggestion regarding the endpoint of the study resolved the ethical concerns. These combined scientific and ethical issues would not ordinarily be considered during IRB and IACUC review; indeed, the study was eligible for an exemption from IRB review under federal regulations because the stem cell line had been anonymized.
Study 2: Donation of materials for derivation of new stem cell lines
Researchers presented a protocol for the donation of fresh embryos that failed to develop sufficiently to be implanted in utero and the donation of frozen embryos remaining after a woman had completed infertility treatment.
Donation of fresh embryos raises concerns about the consent process and about conflicts between optimal infertility treatment and stem cell research. The UCSF IRB requested that the SCRO take the lead in reviewing these protocols. The SCRO has more time and expertise for in-depth discussions because it reviews fewer protocols and has more members who are knowledgeable about infertility clinical practice and hSC research. The SCRO decided that consent was needed from gamete donors as well as from the woman or couple in infertility treatment.1 The experience of infertility physicians and a former infertility patient persuaded the SCRO that the treating physician should be the one raising the topic of research to avoid the intrusion of third parties, but that physicians should not know whether their patients agree to donate materials for research. For the donation of fresh embryos for research, SCRO members pointed out that the determination by the embryologist that an embryo is suitable for implantation is a matter of judgment. Hence, the embryologist should not know whether a woman has agreed to research donation and also should receive no funding from research grants, to avoid even the appearance of conflict of interest. Moreover, for frozen embryo donations from another state, which might have different laws from California’s regarding embryo research, the SCRO required that the legal affairs office must determine that no laws would be violated in accepting them.1
What kinds of protocols need review?
At this early stage in stem cell research, there is relatively little experience with review of stem cell studies. Rather than prescribe guidelines at the onset for what kinds of protocols need review, the UCSF SCRO initially decided to review all stem cell research protocols. Using its experience with these protocols, the SCRO is establishing guidelines as to which protocols require full review, which are eligible for expedited review, and which do not need SCRO review. For example, SCRO review of study 1 above revealed new ethical concerns, which that the NAS report did not highlight, regarding the introduction of anonymized human progenitor cells in nonhuman blastocysts. As a result, the SCRO has decided to continue to review such protocols in full committee.
The SCRO decided that clinical protocols using cord blood stem cells or autologous adult stem cells could be adequately reviewed by the IRB because they are not pluripotent stem cells. The SCRO is reviewing such protocols on an expedited basis to ensure that they do not raise new SCRO-related issues. The CIRM regulations do not require SCRO review of such protocols.
The NAS report recommended that in vitro studies with previously derived, anonymized stem cell lines do not require (E)SCRO review, provided that documentation is submitted to demonstrate that the original derivation was approved by an IRB and that informed consent was obtained for donation of materials used to derive the stem cell line. The UCSF SCRO currently reviews these protocols through expedited review, but it is likely to allow such protocols to be approved after administrative review and confirmation that appropriate documentation has been presented.
Expedited review in practice
Protocols that may be eligible for expedited review are reviewed by the chair of the SCRO and one other committee member who has scientific expertise relevant to the protocol. Expedited review usually is completed within a few days of submission to the SCRO. If both reviewers recommend expedited approval, all committee members receive a copy of the protocol along with the reviewers’ recommendations. However, additional discussion occurs only if another committee member requests review by the full committee.
Procedures for full SCRO review
The UCSF SCRO has adopted a lead-reviewer system for full review of studies. For each protocol, there are three lead reviewers: one with scientific expertise pertinent to the specific protocol, one with ethics expertise, and one nonaffiliated committee member. These lead reviewers start the committee deliberations by presenting their analyses. The SCRO may add ad hoc reviewers as necessary. For example, when reviewing a Phase 1 clinical trial of stem cell transplantation using cells derived from fetal tissue, the SCRO added as ad hoc reviewers a physician who is knowledgeable about the disease being studied and a physician–investigator who had reviewed another clinical trial in the disease in question for a National Institutes of Health (NIH) committee. After committee discussion, the SCRO may approve the protocol, request modifications or further justifications, or disapprove the protocol.
The SCRO focuses on issues particular to the use of embryos, gametes, or stem cells and, as discussed below, neither duplicates nor replaces the work of the IRB. The SCRO communicates its decisions in writing to the other relevant committees such as the IRB or IACUC and to the investigators. The research described in the protocol may not commence until all required oversight committees have given approval.
Protocol volume and review timeline
Currently, the SCRO receives and reviews one or two protocols per month. In a span of 10 months from May 2005 through February 2006, the SCRO received 12 protocols. Nine of these underwent full review, and three were eligible for and underwent expedited review. These protocols were reviewed a median of 11 days after the SCRO committee had received the protocol (mean 11.8 days, standard deviation 9.6).
A quorum ensures sufficient breadth of expertise and viewpoints to adequately review protocols. The UCSF SCRO decided on a quorum of five members; other institutions might decide that a different number is appropriate. The five-member quorum must include at least one member with relevant science expertise, one with ethics expertise, and one who is an unaffiliated member. The SCRO does not require a certain percentage of members to be present for deliberations; because members have numerous responsibilities and frequent scheduling conflicts, SCRO membership is large enough that no member is required to attend each meeting for the committee to possess adequate expertise. The goal of SCRO membership selection is to ensure that there is sufficient expertise to review the protocols in each quorum, even if several committee members cannot attend a particular meeting, without creating a burden on any member.
Conflicts of interest
When protocols are reviewed at an NIH study section or by an IRB, committee members must recuse themselves if they have a conflict of interest such as being named in the protocol as an investigator or consultant or having a direct financial interest in the study.12 UCSF SCRO members with such conflicts of interest must recuse themselves from the deliberation and vote, but they may be present to respond to the committee’s questions before discussion and voting.
Members may recuse themselves for other reasons if they feel that doing so is appropriate. However, because there are few faculty with scientific expertise in stem cell research, required recusal for many other relationships, such as when a committee member has trained one of the investigators or collaborated on a prior project, may not be feasible for the SCRO. Furthermore, several UCSF SCRO members hold leadership positions, such as department chairs and program directors, and many members supervise some stem cell researchers. Members with such relationships do not serve as primary reviewers, but they may participate in committee discussions and vote on protocols. Members are encouraged to disclose relationships that do not merit recusal but that might affect their own reviews or the appearance of impartiality.
Record of meetings
The UCSF SCRO audio tapes meetings, then produces minutes from these recordings and the meeting notes. The minutes provide a formal record of the committee’s rationale and decisions and help assure the accountability and transparency of the proceedings. The need to provide a formal record also encourages the committee members to be more explicit in their discussions and to articulate clearly the reasons for their decisions. Because UCSF is a public institution, SCRO minutes and records are publicly available under the California Public Records Act.13 Interested parties may obtain the records after appropriate advice from the campus office of legal affairs and any necessary redaction to ensure that the records are consistent with state law, university policies, and specific agreements with research sponsors. Audiotapes are stored in a locked cabinet and may be consulted for the details of any discussion. Only committee members and staff have access to the actual audiotapes.
Coordination with other oversight committees
SCROs should coordinate their scientific and ethical review with other institutional oversight committees, such as IRBs and IACUCs, so that reviews are carried out in a timely manner. AHC leadership can work with these different committees to facilitate such coordination. At UCSF, for example, a stem cell investigator completes only one set of standardized electronic forms, which are sent to both the SCRO and the IRB. A supplement to the standard IRB application addresses stem cell issues for the SCRO. An extension of this common computerized application system to include IACUC applications is under development.
Full reviews by the SCRO and IRB have usually been carried out within the same week, so the additional oversight has not delayed research projects. The SCRO ordinarily does not make formal comments on matters that are within the scope of IRB expertise, such as wording of consent forms. However, the SCRO may informally communicate suggestions about consent forms to the IRB through individuals who sit on both committees. On some protocols, such as Study 2 discussed above, the IRB specifically asks the SCRO for advice on the consent process or the risk/benefit ratio, which are ordinarily within the expertise of the IRB but may be affected by the component of stem cell research.
California law requires that all hES and adult hSC research be reviewed by an IRB.14 In other states, IRBs may not need to review all stem cell research. The federal Common Rule exempts from IRB review research that does not involve human subjects (e.g., basic science protocols with existing anonymized stem cell lines). In particular, the donation of biological materials does not require IRB review in the state of California if the investigator does not intervene or interact with donors and does not obtain identifiable private information about donors.9,15 However, researchers deriving new hSC lines will generally want to obtain identifiable information about donors so they can use the cell lines in the future for transplantation. The U.S. Food and Drug Administration requires that donors of human cells and cell-based products be screened and tested to prevent the transmission of communicable diseases.16 To minimize the transmission of genetic diseases through stem cell transplantation, it would also be prudent for researchers to screen donors for a family history of serious genetic conditions.3
All SCRO members are volunteers and receive no compensation or salary support for their time. The chair spends about 5 to 10 hours a month reviewing protocols, researching stem cell issues, working on policies, and planning meetings. Support staff spend about 10 hours per month scheduling meetings, coordinating reviews, preparing minutes from audiotapes and notes, carrying out background research, and helping to draft and revise policies. Because the committee chair also conducts research on ethical issues in stem cell research, the amount of time the chair is required to devote to background research might be greater at other institutions.
Taking the Lead
In summary, the experience at UCSF demonstrates that the review of stem cell protocols strengthens the science and ethics of innovative protocols and can be accomplished efficiently. SCRO review addresses issues that are not currently considered by other oversight committees. AHCs should take the lead in developing effective oversight of stem cell research, just as they are taking the lead in scientific investigation.
The authors have received research support from the Greenwall Foundation. Members of the UCSF Human Gamete, Embryo, and Stem Cell Committee that developed the procedures and policies described in this article are Arturo Alvarez-Buylla, PhD, Elizabeth Blackburn, PhD, Marcelle I. Cedars, MD, Virginia Fleming, JD, Elena Gates, MD, Linda C. Giudice, MD, PhD, MSc, Arnold R. Kriegstein, MD, PhD, Pui-Yan Kwok, MD, PhD, Michelle Oberman, JD, MPH, Jennifer O’Brien, MA, Renee Reijo Pera, PhD, Didier Y.R. Stainier, PhD, Greta Schnetzler, JD, Ara Tahmassian, PhD, Richard M. Wagner, MA, Mary T. Wuerth, BS, and Keith R. Yamamoto, PhD.
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8 National Academy of Sciences. Guidelines for Human Embryonic Stem Cell Research. Washington, DC: National Academy Press; 2005.
9 Department of Health and Human Services. Protection of Human Subjects. 45 CFR Part 46.116; 2005.
10 California Institute for Regenerative Medicine. Proposed CIRM MES Regulations; Recommended by the Scientific and Medical Accountability Standards Working Group; Approved with revisions by the ICOC the 2/10/2006. Available at: (http://www.cirm.ca.gov/laws/pdf/Regulations.pdf
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11 National Research Council and Institute of Medicine. Guidelines for Human Embyonic Stem Cell Research. Washington, DC: National Academies Press; 2005.
13 Cal Gov Code §§ 6250 et seq; 2006.
14 Cal Health & Saf Code § 125300; 2006.
16 Food and Drug Administration. Elibility Determinations for Donors of Human Cells, Tissus, and Cellular and Tissue-Based Products. 21 CFR Parts 210, 211, 820 and 1271; 2006.