Working Group on Human Trials of Cell Based Interventions for Neurological Conditions
 
The Working Group on Human Trials of Cell Based INterventions for Neurological Conditions

Summary            Participants                       Products            References

Summary
Objectives
The specific objectives of this project were to provide the public (including disease advocacy groups and the patients and families they represent), policymakers, biomedical researchers, and those who oversee research with human subjects with a thorough and informed analysis of: 1) the nature of moral challenges to standard concerns of research ethics posed by the first human trials of stem cell based interventions for neurological conditions and alternatives for how these challenges should be addressed; and 2) whether, to what extent, and under what conditions the transplantation of non-autologous cells to patients with neurological conditions poses risks to personal identity and, in so far as such risks exist, alternatives for how they should be addressed.

Project Significance Experimentation with human beings is essential to medical progress, but it also has the potential to be morally perilous, particularly when the research involves seriously ill patients or novel paradigms or interventions. Human trials of cell based interventions for neurological conditions will necessarily include both of these elements. Any first proof of concept intervention occurs in a context where the risks of the intervention are relatively unknown. Unlike drug trials where the interventional agent’s properties, activities, and ramifications are frequently well established, the initial stem cell trials will be the first steps into a novel paradigm. Additionally, the extensive regulatory structure and preclinical and clinical research methods used to evaluate new medical treatments are more sophisticated in the area of drug development than in the use of biologics. As exemplified by the field of human gene transfer, new biological agents pose especially difficult problems for risk assessment, selection of appropriate assays for clinical outcomes, and selection of study populations. These fundamental difficulties ratchet up concerns about interventional safety, trial design, and informed consent. As such, it is imperative to proactively and dispassionately consider all aspects of early human trials for stem cell based interventions.

The fact that the early human trials of cell based therapies for neurological disorders will likely entail transplanting donor stem cells (or their derivatives) into the central nervous system is likely to further amplify concern about these trials. Transplantation, as a field, has been dogged by concerns about personal identity. There was considerable public resistance to the idea of heart transplantation, much of which was related to concerns about the meaning for self of having someone else’s heart. With advances in neuroscience and public understanding, we have increasingly come to perceive the essence of a person, conceptualized as the soul or otherwise, as situated within the brain. As such, it seems reasonable to anticipate that the public concern that arose around heart transplantation will similarly arise around cell transplantation in the brain. Indeed, speculation about brain transplantation has been a mainstay in both philosophical literature and science fiction for decades.

Our previous research suggests that it is unlikely that cell based interventions for neurological disorders pose serious challenges to personal identity. At the same time, the possibility cannot be entirely dismissed, both because of the moral and political importance of taking potential public concerns seriously and because it is at least theoretically possible that under the “most favorable” conditions some impact on cognition, mood or behavior could result. The working group focused on trials with young children, fetuses, or adults with substantial brain damage; all contexts in which impact from a stem cell transplant on cognition, mood or behavior is more likely.
 
Project Results and Dissemination
Three papers have been developed as a direct result of the working group meetings, meeting the objectives set out for this group. The first of these, an issue-spotting paper, identifies and explains the most significant challenges anticipated in human trials of cell-based interventions for neurological conditions. This paper is in press at the journal Neurology. A second paper addresses the appropriate role for animal models in deciding when to move to human trials. This paper has been submitted to the Journal of Cerebral Blood Flow and Metabolism. A third paper explores the possibility of changes in cognition, mood or behavior and the potential for challenges to personal identity with cell based interventions for neurological conditions. This third paper is undergoing final edits and will be submitted for peer-reviewed publication quite soon. We anticipate that the publication of at least some of these papers will be covered by the national press and thus that our findings will come to the attention of the public, as well as policymakers. Since one of our objectives is to inform the public, including disease advocacy groups and the patients and families they represent, we will actively seek to disseminate the findings of the Working Group to the public at large, to patient groups, and to policymakers. The papers will be posted, for public access, on the Berman Institute website, and we will distribute reprints of our papers to organizations that have a particular stake in cell based research for neurological conditions, such as the Christopher Reeve Paralysis Foundation, the Michael J. Fox Foundation for Parkinson’s Research, the Alzheimer’s Association, and the International Society for Stem Cell Research. We will also continue our efforts to communicate directly with the public policy community by providing relevant Congressional staff with reprints of our papers. Finally, we will distribute reprints of our papers internationally to leading researchers and clinicians.
 
Project Challenges
The topic matter for this Working Group is both rapidly evolving and complex. One major challenge is staying abreast of this rapidly evolving field and anticipating future developments and changes accurately so that our Working Group can be provided with useful briefing materials and a meaningfully framed playing field in which to analyze the practical and ethical issues raised by early human trials of cell based interventions for neurological conditions. This also presented a challenge in crafting conclusions and recommendations that are both timely and durable, and that can avoid being quickly eclipsed by scientific advances.
 
Lessons Learned
It is clear from our work on this project that the issues faced in moving forward with human trials of cell based interventions for neurological conditions are exceptionally complex and challenging. Many of the ethical issues raised were not new, per se. What is, perhaps, novel is that human trials of cell based interventions for neurological conditions present complex challenges across a wide range of issues. As noted, this work combines all the challenges of working in the central nervous system with all the added challenges associated with transplantation and assessing cell-based interventions. This leaves these human trials at the highly charged and daunting end of many ‘ethical-challenge’ spectra. At the same time, there is ample motivation to move forward with research, as these interventions offer promise for treating a wide range of conditions, many of which are currently poorly managed by existing treatments. As demonstrated by the three papers, our working group was able to raise numerous warning flags and craft many recommendations for moving forward cautiously with this challenging and promising work.
Participants:
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  • Hilary Bok, Ph.D.
  • Joseph T. Coyle, M.D.
  • Ted Dawson, M.D., Ph.D.
  • Valina L. Dawson, Ph.D.
  • Patrick Duggan, A.B.
  • Ruth Faden, Ph.D., M.P.H.
  • Julia Finkel, B.A.
  • John D. Gearhart, Ph.D.
  • Henry T. Greely, J.D.
  • Argye Hillis, M.D., M.A.
  • Ahmet Höke, M.D., Ph.D.
  • Richard Johnson, M.D.
  • Michael Johnston M.D.
  • Jeffrey Kahn, Ph.D.
  • Douglas Kerr, M.D./Ph.D.
  • Patricia King, J.D.
  • Joanne Kurtzberg, M.D.
  • S. Matthew Liao, D.Phil.
  • Debra J.H. Mathews, Ph.D., M.A.
  • John W. McDonald, III, M.D., Ph.D.
  • Guy McKhann, M.D.
  • Karin B. Nelson, M.D.
  • Mahendra Rao, M.D., Ph.D.
  • Peter V. Rabins, M.D., M.P.H.
  • Alan Regenberg, M.Be.
  • Jeffrey D. Rothstein, M.D., Ph.D.
  • Andrew W. Siegel, J.D., Ph.D.
  • Kirby Smith, Ph.D.
  • Davor Solter, M.D., Ph.D.
  • Hongjun Song, Ph.D
  • Jeremy Sugarman, M.D., M.P.H., M.A.
  • Richard Traystman, Ph.D
  • Angelo L. Vescovi, Ph.D.
  • Jason R. Yanofski, M.D.
  • Wise Young, M.D., Ph.D.
    Products:
     
     
  • Greene M, Schill K, Takahashi S et al. Ethics: Moral issues of human-non-human primate neural grafting. Science 2005 July 15;309(5733):385-6.
  • Siegel AW. The moral insignificance of crossing species boundaries. Am J Bioeth 2003;3(3):33-4.
     
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    LESSONS FROM ANALOGOUS RESEARCH:

     

     

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