Andrew W. Siegel

Safety issues in cell-based intervention trials

We report on the deliberations of an interdisciplinary group of experts in science, law, and philosophy who convened to discuss novel ethical and policy challenges in stem cell research. In this report we discuss the ethical and policy implications of safety concerns in the transition from basic laboratory research to clinical applications of cell-based therapies derived from stem cells. Although many features of this transition from lab to clinic are common to other therapies, three aspects of stem cell biology pose unique challenges. First, tension regarding the use of human embryos may complicate the scientific development of safe and effective cell lines. Second, because human stem cells were not developed in the laboratory until 1998, few safety questions relating to human applications have been addressed in animal research. Third, preclinical and clinical testing of biologic agents, particularly those as inherently complex as mammalian cells, present formidable challenges, such as the need to develop suitable standardized assays and the difficulty of selecting appropriate patient populations for early phase trials. We recommend that scientists, policy makers, and the public discuss these issues responsibly, and further, that a national advisory committee to oversee human trials of cell therapies be established.

CELL-BASED INTERVENTIONS FOR NEUROLOGIC CONDITIONS: ETHICAL CHALLENGES FOR EARLY HUMAN TRIALS

Background: Attempts to translate basic stem cell research into treatments for neurologic diseases and injury are well under way. With a clinical trial for one such treatment approved and in progress in the United States, and additional proposals under review, we must begin to address the ethical issues raised by such early forays into human clinical trials for cell-based interventions for neurologic conditions. Methods: An interdisciplinary working group composed of experts in neuroscience, cell biology, bioethics, law, and transplantation, along with leading disease researchers, was convened twice over 2 years to identify and deliberate on the scientific and ethical issues raised by the transition from preclinical to clinical research of cell-based interventions for neurologic conditions. Results: While the relevant ethical issues are in many respects standard challenges of human subjects research, they are heightened in complexity by the novelty of the science, the focus on the CNS, and the political climate in which the science is proceeding. Conclusions: Distinctive challenges confronting US scientists, administrators, institutional review boards, stem cell research oversight committees, and others who will need to make decisions about work involving stem cells and their derivatives and evaluate the ethics of early human trials include evaluating the risks, safety, and benefits 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. Further study and deliberation by stakeholders is required to move toward professional and institutional policies and practices governing this research.

The role of animal models in evaluating reasonable safety and efficacy for human trials of cell-based interventions for neurologic conditions.

Progress in regenerative medicine seems likely to produce new treatments for neurologic conditions that use human cells as therapeutic agents; at least one trial for such an intervention is already under way. The development of cell-based interventions for neurologic conditions (CBI-NCs) will likely include preclinical studies using animals as models for humans with conditions of interest. This paper explores predictive validity challenges and the proper role for animal models in developing CBI-NCs. In spite of limitations, animal models are and will remain an essential tool for gathering data in advance of first-in-human clinical trials. The goal of this paper is to provide a realistic lens for viewing the role of animal models in the context of CBI-NCs and to provide recommendations for moving forward through this challenging terrain.

How to Determine Whether Existing Human Embryonic Stem Cell Lines Can Be Used Ethically

International Society for Stem Cell Research. (2006). Guidelines for the conduct of human embryonic stem cell research. http://www.isscr.org/guidelines/index.htm.Merriam-Webster Online. (2008). “Provenance.” http://www.merriam-webster.com/dictionary/provenance.Stemride International. (2008). List of hESC lines. http://www.stemride.com/products_lines.htm.

Research ethics: When embryonic stem cell lines fail to meet consent standards

It does not necessarily follow that just because an embryonic stem line was not derived according to current consent standards it ought not to be used.

Philosophical Issues in Human Pluripotent Stem Cell Research

There are few areas of scientific inquiry that have been as fraught with controversy as human pluripotent stem cell research. This research has implicated issues in metaphysics, ethics, and political philosophy. The issues include, among others, the question of when a human life begins, the moral status of the human embryo, whether there is a moral distinction between creating embryos for research and creating them for reproductive ends, the ethics of creating human/non-human chimeras, and the challenge of constructing public policy in a pluralistic society in which there are opposing views about the ethics of the research. It is important that stem cell biology education extend beyond an inquiry into the biological properties of stem cells and further address the philosophical questions that bear on the pursuit of research in the field. This chapter provides an overview of these issues.