Ethical Considerations for Enrolling "Invested Parties" in Large-Scale Clinical Studies: Insights from the RECOVER Initiative.

Research institutions often lack policies addressing the risks and benefits of enrolling "invested parties" such as investigators, research staff, and patient, caregiver, and community representatives (groups most affected by a disease or intervention) in studies where they have direct involvement. Invested parties may have both strong motivations to study the condition or intervention and to participate as study subjects. More guidance is needed to promote appropriate access to research participation and mitigate potential risks. This article addresses the gap in guidance by presenting an ethical framework and practical guidelines for the enrollment of invested parties. Drawing from experiences with the Researching COVID to Enhance Recovery (RECOVER) Initiative, a large multisite observational cohort study, we argue that invested parties should not be categorically excluded from enrollment in their own research studies if certain criteria are met and appropriate safeguards are in place. We underscore the need to balance inclusion with fairness, promote valid voluntary informed consent, ensure data privacy, protect scientific validity, and mitigate unique risks to invested parties as participants. Additionally, we recommend regular reporting and empirical assessment to evaluate the impact of enrolling invested parties on participants and study outcomes.

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.