Reections on Governance Models for the Clinical Translation of Stem Cells

Jeremy Sugarman

central promise of human embryonic stem cell research is the potential to develop viable therapeutic approaches to a range of devastating diseases and conditions. Despite excitement over such advances, there are scientic and medical reasons to be cautious as stem cells and their products are introduced into patients. In response to such concerns, the International Society for Stem Cell Research (ISSCR) as well as ad hoc groups and individuals have offered approaches to governance of this research.1 While there are similarities among these governance models and they are in principle easily endorsable, in this paper I raise a set of concerns related to their implementation, suggesting areas where gathering data may facilitate more appropriate oversight. Next, I suggest areas that seem to have been neglected as these governance models have been developed so that they may be on the agendas of those seeking to revise these models in the future. Finally, I describe how some of the concerns that have arisen in considering the appropriate governance of stem cell research may be useful in science and translational research more broadly.

Governance Models for Oversight of Stem Cell Research

A variety of scientific, ethical, legal, and political forces prompted professional organizations to craft guidelines regarding the ethical oversight of embryonic stem cell research. These general guidelines concentrate on laboratory-based research, some of which heretofore would not be subject to substantial external oversight unless it involved work with non-human animals. While a comprehensive review is beyond the scope of this paper, I provide a basic sketch of the guidelines issued by the National Academy of Science (NAS) and the ISSCR, which are arguably the most prominent of those in the eld to help place proposals related to specic governance models for clinical translational research into context. National Academy of Science In 2005, the NAS issued guidelines focusing on human embryonic stem cell research. Central to the governance model is institutional oversight through an Embryonic Stem Cell Research Oversight (ESCRO) committee.2 The composition and function of ESCROs are strikingly similar to other governance models used for human subjects research (i.e., Institutional Review
Jeremy Sugarman, M.D., M.P.H., M.A., is the Harvey M. Meyerhoff Professor of Bioethics and Medicine at the Berman Institute of Bioethics and the Department of Medicine at Johns Hopkins University in Baltimore, Maryland. law, science, and innovation: the embryonic stem cell controversy summer 2010

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Boards, or IRBs) and research with non-human animals (i.e., Institutional Animal Care and Use Committees, or IACUCs) in the United States. For instance, ESCROs are comprised of individuals with different expertise who conduct prospective review of proposed research. ESCROs are charged with assessing the provenance of cell lines, a review of the procurement process for gametes, blastocysts, and cells used for embryonic stem cell research (including stipulations regarding informed consent, compensation, and adherence to standards of care), and to determine if the proposed research is acceptable. Subsequently, the NAS chartered the Human Embryonic Stem Cell Research Advisory Committee to review these guidelines and amend them as appropriate. To date, the NAS has issued two sets of amendments. In 2007, the main modifications included clarications regarding the assessment of provenance, grandfathering the use of embryonic stem cell lines that had been approved for U.S. federal funding, permitting the importation of stem cell lines, and permitting ESCROs to serve multiple institutions.3 In 2008, the NAS expanded the scope of its guidelines to incorporate considerations regarding research involving human pluripotent cells and made additional clarications to the guidelines.4 International Society for Stem Cell Research In 2006, the ISSCR issued a similar set of guidelines for stem cell research.5 Under the ISSCR guidelines, prospective review of research is to be conducted by a Stem Cell Research Oversight Committee (SCRO), reecting the broader reach of these guidelines compared to the initial NAS guidelines which focused on human embryonic stem cell research. The ISSCR guidelines also have provisions regarding consent and the nancial aspects of research. In order to encourage compliance, the ISSCR provided resources such as sample consent documents and material transfer agreements on its web site.6

In 2008, the ISSCR issued guidelines specic to the clinical translation of stem cell research.7 These guidelines largely assume a stepwise process involving science progressing from in vitro research, to in vivo research with non-human animals, to rst in human trials, to larger scale clinical trials. Accordingly, the guidelines cover each of these steps. However, the guidelines also step outside this staged paradigm a bit and include recommendations regarding innovation and social justice. At each stage of clinical translation, independent review and oversight, voluntary informed consent, and patient monitoring along with adverse event reporting and publication of results are emphasized.8 In terms of the conduct of review and oversight, the ISSCR guidelines rely primarily upon existing oversight mechanisms, especially IRBs. Nevertheless, they stress the importance of supplementing the process with expertise related to stem cells. Based upon a literature review and critical deliberation, Bernard Lo and colleagues offered guidelines for clinical trials in stem cell transplantation.9 Akin to the ISSCR guidelines, they assume a staged research paradigm and suggest that  t]hese clinical trials should follow ethical prin[ ciples that guide all clinical research. Additional requirements to strengthen trial design, coordinate scientic and ethics review, verify that participants understand key features of the trial and ensure publication of the ndings are also warranted because of the highly innovative nature of the intervention, limited experience in humans, and the high hopes of patients who have no alternative effective treatments.10 Finally, suggestions regarding how to approach the ethical challenges involved with testing cell-based interventions for neurological conditions were published based upon the deliberations of an interdisciplinary working group. Specically, the group addressed issues related to evaluating the risks, safety, and benets of these trials, determining and evaluating cell line provenance, and determining inclusion criteria, informed consent, and the ethics of conducting early human trials in the public spotlight.11 Here too, a staged research paradigm is privileged. Overall, the proposed governance models elaborate on what is now a traditional research ethics paradigm, assuming that in most cases there will be a staged process which proceeds seriatim from bench research to rst in human studies to larger scale clinical trials. As such, they emphasize independent oversight primarily through existing mechanisms. Although additional approaches are also suggested, the existing
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Governance Models for the Clinical Translation of Stem Cells

A variety of factors (including advances in stem cell science, clinical experience with cell-based interventions, and reports of some cell-based interventions being delivered to patients without evidence from clinical research concerning their safety and efficacy) were associated with attention to developing appropriate governance models for the clinical translation of stem cells. This included specific guidelines by ISSCR as well as other ad hoc groups which I describe in turn.

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mechanisms are bolstered by adding specic content expertise related to stem cells. Further, given the morally controversial status of human embryonic stem cell research and uncertainties regarding the fate of embryonic stem cells introduced into humans, these approaches emphasize the need for a robust informed consent process as well as close and prolonged monitoring of those who receive stem cell based interventions. In addition, substantial attention is given to the reporting of risks, with some emphasis on publishing negative ndings to avert exposing others to potentially harmful interventions.

ple, for early phase trials the term gene-therapy has been criticized appropriately since it connotes that the experimental intervention is likely to be therapeutic, even though this is what is being tested.14 Accordingly, efforts should be taken to assess the denotative and connotative meanings of terms used to describe experimental cell-based interventions in efforts to enhance informed consent for them. In addition to a more comprehensive disclosure, current proposals suggest the need to monitor the informed consent process to ensure that potential research participants comprehend the information provided. While this seems promising, it leaves several important questions unanswered: While the proposed governance models and Who will monitor the consent process? What expertise do they need to have to do such monrecommendations in large part seem quite itoring? How will they know what is a good sensible, certain aspects warrant scrutiny consent process? When should they monitor? What effects might this have on the potential before they are adopted. research participants? Further, while attention is being focused on comprehension, it is arguably critical that other aspects of the Challenges for Implementation informed consent process, such as ensuring adequate While the proposed governance models and recomdecision making capacity of those asked to consent mendations in large part seem quite sensible, certain and that consent is voluntary. However, experience aspects warrant scrutiny before they are adopted. Here, measuring the informed consent process reveals that I examine some of the recommendations regarding doing these tasks well can be difficult.15 As such, those consent and monitoring since they appear to rest on who set out to monitor the informed consent process certain empirical assumptions that may not be comfor research involving cell-based interventions would pletely correct and implementing them will likely be be advised to begin with methods used in other areas associated with unanticipated challenges. of clinical research to measure the quality of consent rather than attempt to develop them de novo or reduce Informed Consent the process to a simple quizzing of potential particiThere seems to be sufficient empirical evidence suppants. As models for conducting such monitoring are porting the claim that obtaining informed consent implemented, they should be disseminated for broad for research can be difficult.12 Accordingly, efforts to review and critique. enhance the informed consent process, especially for cell-based interventions that pose uncertain risks and Monitoring perhaps some important trade-offs from receiving Given the biological uncertainties associated with standard medical care, are welcome. The suggestions cell-based interventions, it is essential that those who for enhancing informed consent for research involving receive them be monitored over time not only for cell-based interventions to date seem to focus on addsigns of benet, but also for any anticipated or unaning information to be disclosed during the informed ticipated events. The information obtained from such consent process. For example, the source of stem cell monitoring will be invaluable to help ensure the welllines should be disclosed given that there is moral disbeing of patients who receive these interventions and agreement over the use of stem cell lines that were creto informing scientists and clinicians. Further, such ated by destroying a human embryo, and the uncerinformation will also be critical for those charged with tainty regarding the fate of transplanted cells should the ethical oversight of this research including Institube underscored. While this information is indeed tional Review Boards (IRBs), Data Safety Monitoring important, adding information alone is an insufficient Committees, and regulators. The nature of the uncermeans of ensuring that informed consent is obtained. tainty surrounding the safety of many cell-based interAs is true in other areas of clinical and translational ventions would support arguments in favor of enhancresearch, the fact that the endeavor itself is experiing communication among these different oversight mental can be difficult to communicate.13 For exambodies.16
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Despite the need for acquiring long-term data regarding efficacy and safety of cell-based interventions, it is not necessarily clear that patients who agree to participate in early trials will be willing to undergo long-term follow-up with potentially invasive monitoring, such as tissue biopsies. From a scientic perspective such data are obviously desirable, but gathering them must be balanced against the willingness of patients to provide them. Accordingly, in designing trials of cell-based interventions, it may be prudent to conduct some formative research to help develop feasible approaches to long-term follow-up and monitoring.

Areas That Warrant Attention

The new mechanisms of oversight delineated in recent guidelines for stem cell research were developed in response to a range of scientic, ethical, and practical concerns, building on existing structures and models, such as IRBs and IACUC (Institutional Care and Use Committees). Experience is only now being gained using these new governance structures. Consequently, learning how different SCROs or ESCROs are working with these guidelines can be useful to others interested in forming such bodies or improving their nascent policies and procedures.17 Thus, those engaged in using these governance models are encouraged to describe and disseminate their experiences. Regardless, the predominant governance models that have been proposed rely largely upon institutional-level committee oversight. While this may be appropriate for much of the current generation of basic stem cell science, translation of some of this work to the bedside may involve very complex decisions that may eclipse the expertise of those working in a single institution. This research clearly requires special scrutiny.18 Therefore, it may be useful to consider how such research might be reviewed. As suggested by Lo and his colleagues a higher level review might be modeled after the Recombinant DNA Advisory Committee (RAC) that has successfully exercised oversight of gene transfer research.19 The RAC model of review of research seems well suited to the clinical translation of some cell-based interventions due to its similarities to gene-transfer research; however, establishing such an approach will demand the expenditure of substantial resources. Nevertheless, it might also be useful to consider holding conferences to examine specic issues related to emerging scientic, clinical, and ethical issues in the clinical translation of cell-based interventions. Faced with analogous issues in gene-transfer research, Gene Therapy Policy Conferences are occasionally convened to gather experts to discuss cutting edge research in 254

detail.20 For instance, one such conference evaluated the scientic, medical, and ethical issues surrounding in utero gene transfer research.21 The two-day conference convened a group of individuals with appropriate expertise. As a result of the deliberations, the RAC determined that it would be premature for this sort of research to move forward.22 The ISSCR and/or the NAS could use their convening power to conduct such conferences related to the clinical translation of cellbased interventions. Finally, it would be unfortunate if those promulgating guidelines simply assume that the good ideas behind the guidelines will necessarily redound in benets. Rather, it would seem prudent to learn from these early experiences to see how they perform in practice. A set of critical question should be addressed. First, does the governance model perform in practice in a manner consonant with what was proposed? How, if at all, are research proposals changed as a result of oversight? How long is the delay associated with the review process? Is there a learning curve associated with oversight such that experienced groups can conduct a review of good quality in less time than inexperienced groups? What are the costs associated with these governance mechanisms? What benefits are realized in the review process? Answers to these sorts of questions might then inform those promulgating guidelines as to how they should be rened and any unnecessary bureaucratic processes be abandoned.

Lessons for Science and Translational Research

As described earlier, most of the attention to the challenges associated with the clinical translation of stem cells has largely followed a traditional research ethics paradigm which assumes a staged, linear approach to scientic progress. While this approach is coherent and addresses many critical issues, it is clearly incomplete with respect to the clinical translation of stem cells as exemplied by recommendations concerning medical innovation and stem cell tourism, claims for increased transparency and publication of negative results, and social justice. These three areas are likely important not only for stem cell research, but also for clinical translational research in general. I briey discuss each of them in turn. Innovation While basic science concerning stem cells proceeds, some patients with currently incurable conditions have been obtaining cell-based interventions despite the lack of formal published evidence concerning safety or efficacy regarding them.23 This practice raises substantial concerns for patients safety and well-being
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since the use of unproven interventions likely puts patients at risk of harm, thus violating clinicians duciary responsibilities towards their patients. In addition, should the process or outcomes of the use of such cell-based interventions be untoward, the entire eld of stem cell science may be tarnished even if most scientists and clinicians proceed with a more measured approach to clinical translation. Despite these important concerns, it must also be realized that not all medical discoveries resulted from a paradigm of staged research from bench to animal studies to rst-in-human experiments to large-scale trials. Thus, it is conceivable that some cell-based

interventions in other trials.26 This approach of broad, peer-reviewed publication should help to encourage a balanced and accurate description of the state of the science. Such descriptions may help to avoid inappropriately inating the hopes of patients who understandably desire access to benecial interventions. As with medical innovation, this approach seems equally prudent for other elds of cutting edge science. Social Justice Reecting the trend toward increased involvement of the public in science and attention to health disparities, the ISSCR guidelines for clinical translation pay

Explicit attention to developing governance models for translational research involving cell-based interventions promise to help mitigate some of the ethical complexities associated with this exciting endeavor. Perhaps an unanticipated benet of these models is that they may provide useful approaches for other forms of clinical and translational research, since many of the challenges being faced may not be unique to the clinical translation of stem cells. However, not surprisingly, as with any new governance mechanism there are a range of issues that still need to be addressed in order for them to help fulll their promise.
interventions could be working to achieve some clinical benet. However, current descriptions of these efforts tend to be limited to patient testimonials and not careful descriptions of methods and outcomes. Thus, those engaged in using cell-based interventions are not contributing to the creation of knowledge regarding them, which may ultimately end up in greater harm to the populations of patients with these diseases. This needs to be corrected. In response to these practical issues and tensions, the ISSCR offered recommendations for medical innovation.24 While there are not yet reports about how they work in practice, there is no reason to assume that they would not be viable for other elds of medical practice. Further, assessing them in other elds may help to rene them. Transparency and Publication Given the hype that has been associated with some discoveries involving stem cell science and the need for the careful peer review of research to ensure its accuracy, the ISSCR recommends intensive peer review and publication before public announcements of discoveries.25 Importantly, there is also a need to publish informative, but negative, results so that other patients are neither harmed nor exposed to ineffective explicit attention to the issue of social justice.27 While the language and approach used in these guidelines may be unfamiliar to those accustomed to standard models of research governance, it is now clear that these issues warrant serious attention by those engaged in the scientic and clinical enterprises as well as their oversight. Therefore, they may nd applicability and renement in scientic domains beyond the clinical translation of stem cells.

Concluding Comments
Explicit attention to developing governance models for translational research involving cell-based interventions promise to help mitigate some of the ethical complexities associated with this exciting endeavor. Perhaps an unanticipated benet of these models is that they may provide useful approaches for other forms of clinical and translational research, since many of the challenges being faced may not be unique to the clinical translation of stem cells. However, not surprisingly, as with any new governance mechanism there are a range of issues that still need to be addressed in order for them to help fulll their promise.

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SYMPO SIUM tions for Neurologic Conditions: Ethical Challenges for Early Human Trials, Neurology 71, no. 4 (2008): 1-6. 12.  J. Sugarman, D. C. McCrory, D. Powell, A. Krasny, B. Adams, E. Ball, and C. Cassell, Empirical Research on Informed Consent, Hastings Center Report 29, no. 1 (1999): S1-S42. 13.  J. Sugarman, N. E. Kass, S. N. Goodman, P. Perentesis, P. Fernandes, and R. R. Faden, What Patients Say About Medical Research, IRB 20, no. 4 (1998): 1-7. 14.  N. M. P. King, Rewriting the Points to Consider: The Ethical Impact of Guidance Document Language, Human Gene Therapy 10, no. 1 (1999): 133-139. 15.  J. Sugarman, P. W. Lavori, M. Boeger, C. Cain, R. Edson, V. Morrison, and S. S. Yeh, Evaluating the Quality of Informed Consent, Clinical Trials 2, no. 1 (2005): 1-8. 16.  H. A. Taylor, L. Chaisson, and J. Sugarman, Enhancing Communication Among Data Monitoring Committees and Institutional Review Boards, Clinical Trials 5, no. 3 (2008): 277282. 17.  P. Zettler, L. Wolf, and B. Lo, Establishing Procedures for Institutional Oversight of Stem Cell Research, Academic Medicine 82, no. 1 (2007): 6-10; J. Sugarman and A. Siegel, How to Determine Whether Existing Human Embryonic Stem Cell Lines Can Be Used Ethically, Cell Stem Cell 3, no. 3 (2008): 238-239; J. Sugarman and A. W. Siegel, When Embryonic Stem Cell Lines Fail to Meet Consent Standards, Science 322, no. 5900 (2008): 379. 18.  C. Levine, R. Faden, C. Grady, D. Hammerschmidt, L. Eckenwiler, and J. Sugarman, on behalf of the Consortium to Examine Clinical Research Ethics, Special Scrutiny: A Targeted Form of Research Protocol Review, Annals of Internal Medicine 140, no. 3 (2004): 220-223. 19.  See Lo, et al. supra note 1. 20.  Office of Biological Activities, National Institutes of Health. Appendix L, available at <http://oba.od.nih.gov/oba/rac/ guidelines_02/Appendix_L.htm> (last visited April 7, 2010). 21.  National Institutes of Health (NIH), Gene Therapy Policy Conference: Prenatal Gene Transfer: Scientic, Medical, and Ethical Issues, January 7-8, 1999, available at <http://oba. od.nih.gov/oba/rac/gtpcconc.pdf> (last visited April 7, 2010); J. Sugarman, Ethical Considerations in Leaping from Bench to Bedside, Science 285, no. 5436 (1999): 2071-2072. 22.  Recombinant DNA Advisory Committee, RAC Statement, March 11, 1999, available at <http://oba.od.nih.gov/oba/rac/ racinutero.pdf> (last visited April 7, 2010). 23.  D. Lau, U. Ogbogu, B.Taylor, T. Stanski, D. Menon, and T. Cauleld, Stem Cell Clinics Online: The Direct-to-Consumer Portrayal of Stem Cell Medicine, Cell Stem Cell 3, no. 6 (2008): 591-594; S. Kiatpongsan and D. Sipp, Monitoring and Regulating Offshore Stem Cell Clinics, Science 323, no. 5921 (2009): 1564-1565. 24.  See ISSCR, supra note 7. 25.  Id. 26.  Id.; see Lo, et al., supra note 1. 27.  Id. (ISSCR).

Acknowledgement

Professor John Robertson instigated work on this paper and provided very helpful comments on an earlier version.

References

1.  B. Lo, A. Kriegstein, and D. Grady, Clinical Trials in Stem Cell Transplantation: Guidelines for Scientic and Ethical Review, Clinical Trials 5, no. 5 (2008): 517-522; B. Lo, Case-Based Reasoning in Stem Cell Clinical Trials: The Case of Parkinson Disease, Journal of Law, Medicine & Ethics 38, no. 2 (2010); D. Magnus, Translating Stem Cell Research: Challenges at the Research Frontier, Journal of Law, Medicine & Ethics 38, no. 2 (2010). 2.  National Academy of Sciences, Guidelines for Human Embryonic Stem Cell Research (Washington, D.C.: National Academies Press, 2005). 3.  National Academy of Sciences, 2007 Amendments to the National Academies Guidelines for Human Embryonic Stem Cell Research (Washington, D.C.: National Academies Press, 2007). 4.  National Academy of Sciences, 2008 Amendments to the National Academies Guidelines for Human Embryonic Stem Cell Research (Washington, D.C.: National Academies Press, 2008). 5.  International Society for Stem Cell Research, Guidelines for the Conduct of Human Embryonic Stem Cell Research, 2006, available at <http://www.isscr.org/guidelines/ISSCRhESCguidelines2006.pdf> (last visited April 7, 2010). 6.  See International Society for Stem Cell Research, Guidelines for the Conduct of Human Embryonic Stem Cell Research, available at <http://www.isscr.org/guidelines/index.htm> (last visited April 7, 2010). 7.  International Society for Stem Cell Research, Guidelines for the Clinical Translation of Stem Cells, 2008, available at <http:// www.isscr.org/clinical_trans/pdfs/ISSCRGLClinicalTrans.pdf> (last visited April 7, 2010). 8.  I. Hyun, O. Lindvall, L. Ahrlund-Richter, E. Cattaneo, M. Cavazzana-Calvo, G. Cossu, M. De Luca, I. J. Fox, C. Gerstle, R.A. Goldstein, G. Hermeren, K. A. High, H. O. Kim, H.P. Lee, E. Levy-Lahad, L. Li, B. Lo, D. R. Marshak, A. McNab, M. Munsie, H. Nakauchi, M. Rao, H. M. Rooke, C. S. Valles, A. Srivastava, J. Sugarman, P. L. Taylor, A. Veiga, A. L. Wong, L. Zoloth, and G. Q. Daley, New ISSCR Guidelines Underscore Major Principles for Responsible Translational Stem Cell Research, Cell Stem Cell 3, no. 6 (2008): 607-609. 9.  See Lo et al., supra note 1. 10.  Id., at 517. 11.  D. J. Mathews, J. Sugarman, H. Bok, D. M. Blass, J. T.Coyle, P. Duggan, J. Finkle, H. T. Greely, A. Hillis, A. Hoke, R. Johnson, M. Johnston, J. Kahn, D. Kerr, J. Kurtzberg, S. M. Liao, J. W. McDonald, G. McKhann, K. B. Nelson, M. Rao, A. Regenberg, A. W. Siegel, K. Smith, D. Solter, H. Song, A Vescovi, W. Young, J. D. Gearhart, and R. Faden, Cell-Based Interven-

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