Table 1.

DoC Clinical Trials: Salient Ethical Challenges, Considerations for Researchers & Selected Regulatory Guidance.

Ethical Challenge	Key Considerations for Researchers	Relevant Regulatory Codes & Conventions
Autonomy and informed consent for persons with liminal consciousness	Voluntary and informed consent is anchored to respect for autonomy. Instead of disenfranchising patients with DoC from research participation due to decisional incapacity, trials involving participants with DoC who cannot consent must consider alternative pathways to ensure responsible inclusivity and preserve participant autonomy, including surrogate consent.	Convention on Human Rights and Biomedicine (Oveido Convention) EU regulation No 536/2014 (“clinical trials on medicinal products for human use”); Directive 2001/20/EC Code of Federal Regulations (CFR); Common Rule Declaration of Helsinki (1964, updated 2013) Belmont Report
Balancing and communicating atypical and often unknown benefits and risks	Determination of risks and benefits in DoC clinical trials may prove particularly challenging, as participants with DoC typically cannot report on their subjective experiences. Risks may thus be unknown or imperceptible, and benefits could be difficult to rigorously appraise. While behavior-based, electrophysiologic, or neuroimaging indices of improvement might be measured, the epistemological gaps between behavior, brain activity and subjective phenomenology complicate ordinary ascription of subjective states on the sole basis of an observed change in behavior or brain activity. To improve the understanding and communication of risks and benefits associated with DoC clinical trial participation, investigators should disambiguate direct, indirect, absolute and relative risks and potential benefits, and when possible, endeavor to estimate the magnitude and likelihood of each [134,135,136].	Declaration of Helsinki (1964, updated 2013) Belmont Report Code of Federal Regulations NIMH Guidance on Risk-Based Monitoring
Disclosure of investigational results pertaining to consciousness to surrogates and clinical teams	During a clinical trial involving participants with DoC, it is possible that results will be obtained that shed light on the participant’s level of consciousness and/or capacity for recovery in clinical contexts of diagnostic and prognostic uncertainty. In such circumstances, important questions arise surrounding whether, how and to whom such investigational results ought to be disclosed, and how to characterize the value of such information [70,146,154,155,156,157]. Determination of whether, when and how to disclose research results demands case-by-case consideration, given the plurality of factors that might bear on these decisions and their potential impact on participants, surrogates and research data integrity. These questions should be proactively discussed during the study design phase and written into the protocol and consent procedure [147,148,149,150,151]. Consensus has been growing among ethicists, legal scholars and regulators in favor of more regular return of research results where appropriate. Opportunities exist for embedded neuroethics research to capture and critically evaluate the experiences and perspectives of key stakeholders involved in such studies, particularly surrounding information disclosure practices. Investigators must work closely with clinicians, IRBs and ethicists to harmonize approaches to disclosing such findings to primary medical teams and families, informed by emerging neuroethics principles [146].	HHS Secretary’s Advisory Committee on Human Research Protections (SACHRP) Guidance Convention on Human Rights and Biomedicine (Oveido Convention) 2017 Consensus Study Report of the National Academies of Sciences, Engineering and Medicine (NASEM), “Returning Individual Research Results to Participants: Guidance for a New Research Paradigm.” The NASEM framework emphasizes that “[a]s the potential value of the result to participants and the feasibility of return increase, the justification for returning results becomes stronger.”
Justice considerations, including equitable DoC clinical trial access and accrual	Despite an increase in DoC clinical trials over the past decade, access and enrollment remains highly irregular, especially in remote or underserved areas. Racial, ethnic and language-based disparities are also prevalent across a variety of clinical trial domains. Ethical considerations of justice and equity demand close attention to these potential disparities, and necessitate strategies to democratize access to DoC clinical trial enrollment and enhance representativeness.	NIH Revitalization Act of 1993, 21st Century Cures Act (2016) NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research (2017) FDA Guidance Document (2020) “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry” (FDA-2019-D-1264)
Post-trial obligations and expanded access	Researchers should consider obligations to participants and surrogates after trial concludes, along with approaches to expanded access/compassionate use of the investigational intervention in persons with DoC with no alternative treatment options.	FDA Guidance Document on Expanded Access to Investigational Drugs for Treatment Use (FDA-2013-D-0446, 2021) NIH Policy 3014-502 - Expanded Access, Including Emergency Use of Investigational Drugs, Biologics, and Medical Devices (Updated 2021) European Medicines Agency (EMA) Guideline on compassionate use of medicinal products, pursuant to Article 83 of Regulation (EC) No 726/2004 (2007)