As the clinical trial landscape for patients with disorders of consciousness (DoC) expands, consideration of associated ethical challenges and opportunities is of ever-increasing importance. Responsible conduct of research in the vulnerable population of persons with DoC, including those with coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), covert cortical processing (CCP), and cognitive motor dissociation (CMD), demands proactive deliberation of unique ethical issues that may arise and the adoption of robust protections to safeguard patients, surrogates, and other key stakeholders. Here we identify and critically evaluate four central categories of ethical considerations in clinical trials involving participants with DoC: (1) autonomy, respect for persons and informed consent of individuals with liminal consciousness; (2) balancing unknown benefits and risks, especially considering the epistemological gap between behavior and consciousness that complicates ordinary ascription of subjective states; (3) disclosure to surrogates and clinical teams of investigational results pertaining to consciousness; and (4) justice considerations, including equitable access to clinical trial enrollment across communities and geographies. We outline guiding principles and research opportunities for clinicians, neuroethicists, and researchers engaged in DoC clinical trials to advance ethical study design and deployment in this complex yet crucial area of investigation.
