Ethical challenges in translational pluripotent stem cell research: Justifying leaps of faith

Abstract

Pluripotent stem cells have great potential for regenerative medicine, but the inherent uncertainty of first-in-human trials combined with the technical complexity of pluripotent stem cells make early-phase pluripotent stem cell trials ethically very challenging. This thesis has addressed these ethical challenges. After substantial in-vitro research and animal testing of a medical intervention, a leap of faith needs to be taken when it is tested for the first time in humans. Indeed, in order to examine whether an intervention is safe (and effective) for humans, research participants need to be exposed to it. These participants thus face unknown risks, as no information is yet available on safety in humans. For pluripotent stem cells these risks are higher than for the traditional small molecule- drugs. For clinical research to be ethical, the risks to research participants need to be balanced by the anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly. For the sole purpose of gaining knowledge, we should not expose humans to potential harm; the ultimate justification of involving humans in research lies in the anticipated social value of the intervention. At the moment only the validity of the clinical research proposal is a prerequisite for research to take place. We recommend making the anticipated social value a prerequisite as well, to increase the ethical acceptability of FIH studies. Another way to increase the acceptability of these innovative FIH studies, can be to challenge the current research paradigm. In certain cases it may be is ethically desirable to move efficacy testing forward to FIH studies. Although the default aim of FIH studies should remain examining risks, for (pluripotent) stem cell interventions it seems ethically desirable for participants to have at least a chance to benefit. Moreover, promising interventions may be identified in FIH studies and not discarded before their efficacy could be judged. Indeed, the safety of interventions is judged based on risks ánd efficacy. We believe the balance of risks and social value differentiates FIH studies from other clinical trials to the extent that they should be given unique status in international guidelines on ethical conduct. FIH research participants need additional safeguards both because of the high uncertainties regarding risks, and the high uncertainties regarding social value. It is important to establish a more systematic method to assess anticipated social value, in order for participants not to enrol in what may be futile trials. Notwithstanding the many difficulties this carries with it, we provide some of necessary steps needed to assess the anticipated social value of the intervention.