Intracranial Stem Cell-Based Transplantation: Reconsidering the Ethics of Phase 1 Clinical Trials in Light of Irreversible Interventions in the Brain

Abstract

Stem-cell-based transplantation is the subject of early clinical investigations as a possible therapy for degenerative diseases of the brain. Given the novelty of the strategy, the potential for direct benefit to research subjects is at best very uncertain. Yet conducting these trials for the sole or main purpose of generating safety data is ethically disputable because the risks and burdens of intracranial cell transplantation are such that they cannot be offset solely by the value of the generalizable knowledge expected to be gained. The typical rationale for delaying the initial assessment of efficacy to the second phase of clinical trials, that is, the need to first define a safe dose range, is not relevant to cell-based brain transplantation trials because stem cells are proliferative cells and transplants are irreversible. Given the intervention's high risks and burdens, and the probable involvement of subject populations unable to consent in a large proportion of future trials, there may be an ethical duty to make the assessment of clinically relevant efficacy a primary objective of phase 1 trials. This would entail maximizing the value of preclinical efficacy studies, incorporating primary efficacy endpoints in the protocols, and selecting subject populations with an open therapeutic window. In addition, initial safety and efficacy data for a specific product should be first collected in consenting adults whenever possible. If such conditions were met, aspirational therapeutic goals would attenuate the ethically contentious nature of these trials, even in the absence of a clear therapeutic warrant.

Keywords:

• brain
• human subjects
• morality/ethics
• transplantation

Acknowledgments

This research was funded by the Canadian Institutes of Health Research, MOP 77670, Therapeutic Hopes, and Ethical Concerns: Clinical Research in the Neurosciences. I am grateful to Françoise Baylis and Jonathan Kimmelman, who offered constructive critical comments on an earlier version of this article and encouraged me to develop my arguments even though they may not share my views. I also thank Tim Krahn, Frederic Gilbert, Jim Hess, and three anonymous reviewers for their helpful comments.

Notes

Under exceptional circumstances, the U.S. Code of Federal Regulations allows approval of high-risk pediatric clinical trials that do not hold the prospect of direct benefits commensurate with the risks involved (45 CFR 46.407). The mechanism known as “407 approval,” which is rarely used (Kopelman and Murphy 2004) and has not been used for the current SCBI-B trials, requires federal rather than local review.

Searching the 2010 NIH trial database with the keywords “randomized” and “phase 1” retrieves 1482 trials.