- BIOETHICS FORUM ESSAY
Geron’s hESC Trial for Spinal Cord Injury: The Risk of Therapeutic Misconception
In late January 2009, the Food and Drug Administration (FDA) in the United States approved Geron’s first-in-human embryonic stem cell trial for spinal cord injury patients. At the time, media pundits noted that this decision coincided with the inauguration of President Barack Obama. Since then, President Obama has overturned the ban on federal funding for research involving the derivation of human embryonic stem cells (hESCs) – a ban introduced in August 2001 by President George W. Bush.
It is anticipated that President Obama’s decision will not only increase research in the U.S. to derive hESCs, but will also affect the flow of applications to the FDA for approval of clinical trials involving the transplantation of hESCs. Consequently, Geron’s trial is precedent-setting not only in terms of the science, but also in terms of the ethics and the politics of hESC research. It most certainly will constitute a reference point for future hESC trials.
The goal of Geron’s world premiere Phase I trial (which still needs IRB approval) is to test the safety of hESC-derived oligodendrocyte progenitor cells and to identify any potential adverse effects. As with all Phase I trials, this trial is not directed at achieving therapeutic results for the eight to ten spinal cord injury patients that will be enrolled as research participants.
The target population for Geron’s trial are patients who had a complete thoracic spinal cord injury seven to fourteen days earlier. (These patients would be categorized by the American Spinal Cord Injury Association as type A (ASIA-A).) They will receive an injection of hESC-derived oligodendrocyte progenitor cells.[i] These cells are differentiated into oligodendrocyte precursor cells that myelinate axons in the central nervous system. Their therapeutic potential, according to Geron, rests in the cells remyelinating properties that may contribute to producing neurotrophic factors (elements that improve neuronal survival and function) resulting in enhanced locomotion. Pending the completion of the Phase I safety trials, and assuming there is sufficient confidence in the findings (specifically, that they do not pose severe risks of tumorgenesis or immune rejection), the GRNOPC1 cells will then be tested to determine whether they can promote functional recovery following spinal cord injury in a patient.
In the 2008 Guidelines for the Clinical Translation of Stem Cells published by the International Society for Stem Cell Research, Recommendation 20 (c) highlights the importance of minimizing “misconceptions patients may have about the potential for therapeutic efficacy.” The importance of this recommendation is clear when we consider the details of the proposed Geron hESC trial for spinal cord injury. While the downstream potential therapeutic benefits of this research are promising, there is the very real risk that prospective research participants will not appreciate that these benefits are downstream, owing to the therapeutic misconception.
A key ethics question is whether Geron has mechanisms or strategies in place to assess whether spinal cord injury patients who might consent to research participation have a clear appreciation and understanding of the risks and the future consequences of participating in this novel Phase 1 trial. Will prospective research participants overestimate the benefits and underestimate the risks? How can Geron ensure that mistaken beliefs about the potential for therapeutic effect do not give research participants a mistaken understanding of the harm-benefit ratio? The aims of research are distinct from the aims of providing care. Although research may happen to provide (some) care in the process of the study, its primary purpose is knowledge production. Given the risk of misestimation of both benefits and harms, to what extent might hoped-for, indirect effects of research influence the patient’s reasons for participating in the trial?
Even if Geron has taken appropriate measures to ensure that the design for this first-in-human trial is both scientifically valid and reasonably safe, patients still may not appreciate the risks of harm that they are assuming at the time of enrollment. Recent spinal cord injury patients may be legally competent, but may not be able to make meaningfully autonomous decisions regarding participation in the proposed Phase I trial owing to the complexity of the research and the short time between acute injury and trial participation. Consent to research participation must be sought and obtained seven to fourteen days after what will have been a traumatic, life-changing injury. How can Geron avoid exploiting the hopes of patients? Informed consent is an important mechanism for respecting patient autonomy, but this may be insufficient under the circumstances. Arguably, this issue deserves greater attention in the ISSRC Guidelines.
Geron’s hESC trial for spinal cord injury may turn out to be a wonderful development. Before it goes forward, however, ethical questions about patients’ misconceptions of the potential for therapeutic efficacy must be carefully addressed.
[i] H.S. Keirstead et al., “Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Transplants Remyelinate and Restore Locomotion after Spinal Cord Injury,” The Journal of Neuroscience 25, no. 19 (2005): 4694-705.