key: cord-334847-lf1grybz authors: Lynch, Holly Fernandez; Dickert, Neal W; Zettler, Patricia J; Joffe, Steven; Largent, Emily A title: Regulatory Flexibility for COVID-19 Research date: 2020-07-07 journal: J Law Biosci DOI: 10.1093/jlb/lsaa057 sha: doc_id: 334847 cord_uid: lf1grybz Clinical research is critical to combatting COVID-19, but regulatory requirements for human subjects protection may sometimes pose a challenge in pandemic circumstances. Although regulators have offered some helpful guidance for research during the pandemic, we identify further compliance challenges regarding IRB review and approval, informed consent, emergency research, and research involving incarcerated people. Our proposals for regulatory flexibility in these areas seek to satisfy the goals of protecting participants and promoting the development of high-quality evidence to improve patient care. These recommendations may have relevance beyond the COVID-19 pandemic to enhance the efficiency of research oversight and participant protection more broadly. Clinical research to understand, treat, and prevent COVID-19 is both crucial and highly regulated. Most intervention studies are subject to Food and Drug Administration (FDA) requirements and federally funded research with human subjects must follow requirements imposed by the Common Rule. Strict regulatory compliance may be challenging amidst a public health emergency, but participant protection and high-quality science remain essential.(1) In recognition of these considerations, FDA and the Office for Human Research Protections (OHRP) within the Department of Health and Human Services (HHS) have issued guidance on conducting research during the COVID-19 pandemic.(2) Although this guidance offers a helpful start, gaps remain and additional regulatory flexibility is warranted in some instances. COVID-19 research has been running at a remarkable pace,(3) challenging the capacity of both investigators and institutional review boards (IRBs). To ensure that this research proceeds efficiently and ethically, we offer suggestions to proactively address regulatory compliance challenges regarding IRB review and approval, informed consent, and inclusion of vulnerable populations. IRBs should also exercise the regulatory flexibility currently available to them (Table 1) . Although the pandemic is changing rapidly, the virus remains a substantial public health threat without adequate therapeutic or prophylactic interventions, suggesting that our recommendations for flexibility will remain relevant for some time. They will also be useful in the face of future pandemics and should be considered for research more broadly. As part of its Coronavirus Treatment Acceleration Program (CTAP), 15 FDA is conducting "ultra-rapid protocol review," often within 24 hours, for research subject to IND and IDE requirements. 16 Many IRBs are also taking steps to speed review of COVID-19 protocols, including through disease-specific review boards, prioritization over non-COVID submissions, and more frequent meetings. These approaches can, however, strain board capacity, especially at academic institutions where membership may not be as deep as for commercial boards. Additionally, many members are juggling added professional and personal obligations due to the pandemic. To address these challenges, research sites should rely on review conducted by other boards with sufficient capacity and expertise whenever possible. This is required for multisite research subject to the Common Rule (unless a site"s board has been designated the IRB of record), but is also permitted more broadly. 17 Additionally, FDA and OHRP should consider adjusting quorum requirements through enforcement discretion or regulatory waiver procedures. Most COVID-19 interventional research will require review at convened IRB meetings. Quorum for such meetings requires a majority of the total board membership, including the presence of at least one member whose primary concerns are in nonscientific areas. 18 Because IRBs must comprise at least 5 members satisfying certain criteria, the minimum quorum to satisfy regulatory standards is 3 members. 19 Allowing larger boards to break into meetingspecific sub-boards, each with adequate expertise and representation, would reduce their quorum requirements. This, in turn, would allow the assignment of fewer COVID-19 protocols per reviewer and permit members to attend fewer meetings, easing the burden on each member and allowing more time and attention for rigorous review. This approach would entail fewer reviewers per protocol than might otherwise be the case, but if additional reviewers lack sufficient time to review all the protocols assigned to them, that tradeoff seems appropriate. Moreover, under this flexible approach, no meeting-specific subboard would comprise fewer than 3 participating members, the minimum number of reviewers deemed acceptable by the regulations. Although institutions already have the authority to revise their IRB charters to split larger IRBs into smaller ones, our proposal is more flexible because it would allow IRBs to make membership adjustments meeting-by-meeting as needs change in real time. This may be especially useful as sites re-open to non-COVID research, in addition to their COVID-19 portfolios, thereby further increasing IRBs workloads. As noted above, FDA guidance specifies acceptable procedures to obtain informed consent in the face of isolation requirements for COVID-19 patients and physical distancing requirements that may affect surrogate decisionmakers. 20 In these circumstances, FDA recommends using electronic consent, including via the COVID MyStudies App newly developed by the agency for this purpose. It also describes an alternative process involving a combination of phone or video conferencing, provision of the consent form by someone already entering a patient"s room, signed documentation, and either a witness attestation of signature or 20 FDA, supra note 2. reasonably drawn from those data. 27 Regulators should therefore clarify the standard for disclosure, including which disclosures require reconsent and amended forms versus other mechanisms of information sharing. At a minimum, participants should be informed of new agency warnings (e.g., recent FDA statements and actions regarding hydroxychloroquine), 28 government treatment recommendations, 29 and new product approvals or emergency use authorizations relevant to trial participation decisions. 30 In contrast, the disclosure standard should exclude new information gleaned from outside reports based on preprints without peerreview or interim findings from incomplete research, which may be more misleading than informative. In addition, rather than expecting each IRB and investigator to engage in the difficult and potentially duplicative work of parsing new COVID-19 data for trial participants, FDA"s CTAP could maintain an up-to-date website to serve as a source of reliable guidance relevant to COVID-19 study participation. Because COVID-19 can entail rapid development of severe, acute respiratory failure and other acute, life-threatening conditions, some protocols may need to be conducted under regulations for emergency research that allow subjects to be enrolled under an exception from informed consent (EFIC). 31 The primary challenge for COVID-19 EFIC research is that the regulations require, prior to IRB approval, consultation with individuals from communities "in which the research will be conducted and from which the subjects will be drawn." 32 This has traditionally been a lengthy process, often involving face-to-face contact with stakeholders, which will be difficult for COVID-19 research given urgency and the likely need to continue physical distancing for some time. Regulators should therefore encourage IRBs to focus on rapid identification of high-priority community concerns from key stakeholders. Appropriate stakeholders will be site and condition-specific; they may include community advocates and advisory boards, religious and cultural leaders, and government leaders. Involvement of patients and family members at high risk for COVID-19 or who have experienced related conditions are also critical, as is attention to the views and concerns of minority groups and socioeconomicallydisdavantaged individuals disproportionately affected by this disease. Regulators and IRBs should recognize that these efforts may need to be more focused than in other contexts and that researchers will predominantly need to rely on remote consultation methods, including webinars, 13 online surveys, and telephone calls. However, it is critical that genuine efforts to solicit community views not be abandoned. In light of open questions about how best to treat COVID-19, clinical care for patients suffering from moderate to severe disease often involves trial participation. This makes it important to consider including people who are incarcerated, 33 given the substantial risk of infection associated with their confinement. 34 Yet, as a vulnerable population, the inclusion of incarcerated people in research is subject to additional regulatory safeguards. Biomedical research funded by HHS may involve "prisoners" as subjects when the research examines practices that have "the intent and reasonable probability of improving the health or well-being of the subject," among other circumstances. 35 This determination must be made by OHRP and is not left up to IRBs. 36 Moreover, when this research requires assignment to control groups that may not benefit from participation, OHRP is required to consult with experts in penology medicine and ethics, as well as to publish public notice of intent to allow such research. 37 In addition to these authorizations, HHS-funded research involving "prisoners" may only be approved by an IRB that has a "prisoner representative" amongst its membership, which 15 population without any specific intention to include them. In addition, OHRP should pursue waiver of the requirement that such research be reviewed by a specially constituted IRB, given that the inclusion of people who are incarcerated may not have been contemplated at the time of study approval and the difficulty of securing timely special review once an eligible patient presents for enrollment. BOP should also seek a waiver to permit those in its custody to participate in these potentially beneficial studies. To the extent that state and local rules limit the research participation of incarcerated people, adjustments to those rules may be necessary as well. When people who are incarcerated are not specifically targeted for research, relying on traditional IRB approval standards and consent requirements should offer sufficient protection while also facilitating their access to possible research benefits. The COVID-19 pandemic should not be viewed as an opening to opportunistically reduce participant protections. Yet, it presents an invitation to revisit regulatory requirements and their conventional interpretations to evaluate which are truly necessary and which may constitute unjustified barriers to research. In that regard, we must acknowledge that while human subjects research regulations and guidance are often important means of participant protection, existing approaches are not evidence-based and therefore should not be presumed to be more effective than or otherwise preferable to less burdensome alternatives. 40 OHRP should authorize the inclusion of "prisoners" in certain types of research offering the prospect of direct benefit when enrolled alongside general populations, and should seek to permit such research to proceed based on routine IRB review BOP should also seek to permit such research to proceed with individuals in its See also Bowles v finding an interpretation of an agency"s "own regulations," is "controlling unless "plainly erroneous or inconsistent with the regulation Erin Fuse Brown & Aaron Kesselheim, The Regulatory Accountability Act of 2017 -Implications for FDA Regulation and Public Health Attacking Auer and Chevron Deference: A Literature Review What Kisor Means for the Future of Auer Deference: The New Five-Step Kisor Deference Doctrine, Notice & Comment FDA, supra note 2 Developing Drugs and Biological Products for Treatment or Prevention FDA, supra note 2 EU Governments Ban Malaria Drug for COVID-19 Study on Hydroxychloroquine Use Questioned by 120 Researchers and Medical Professionals, THE GUARDIAN Cautions Against Use of Hydroxychloroquine or Chloroquine for COVID-19 Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems Biomedical Advanced Research and Development Authority (BARDA), Revocation of Emergency Use Authorization for chloroquine phosphate and hydroxychloroquine sulfate distributed from the Strategic National Stockpile Therapeutic Options we use the terms "people who are incarcerated" or "incarcerated people," except where directly quoting regulations that use the term "prisoners COVID-19 in Prisons and Jails in the United States Flattening the Curve for Incarcerated Populations -Covid-19 in Jails and Prisons, 382 NEW ENG She is the founder and co-chair of the Advancing Effective Research Ethics Oversight Consortium (AEREO), a member of a subcommittee of the U.S. Department of Health and Human Services Secretary"s Advisory Committee for Human Research Protections, a board member of Public Responsibility in Medicine and Research (PRIM&R) and the American Society of Law, Medicine, and Ethics, and a member of the NYU Working Group on Compassionate Use and Preapproval Access Dickert receives research funding from NIH, AHRQ, and the Greenwall Foundation Zettler reports serving as an expert witness retained by the Direct Purchaser Class Plaintiffs in In re Suboxone Antitrust Litigation Largent has no disclosures