Portal de Periódicos da CAPES

COVID-19 Ethics and Research

2020; Elsevier BV; Volume: 95; Issue: 6 Linguagem: Inglês

10.1016/j.mayocp.2020.04.019

1942-5546

Karen M. Meagher, Nathan W. Cummins, Adil E. Bharucha, Andrew D. Badley, Linda L. Chlan, R. Scott Wright,

Palliative Care and End-of-Life Issues

As of April 27, 2020, the coronavirus disease 2019 (COVID-19) pandemic involved 2,916,338 reported cases and had claimed 205,923 lives.1European Centers for Disease ControlSituation Update Worldwide.https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-casesGoogle Scholar Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading in almost every country, causing widespread health challenges and social instability. People most vulnerable to COVID-19 include those with underlying health conditions.2Centers for Disease Control and Prevention (CDC)Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19).https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.htmlDate accessed: March 18, 2020Google Scholar Yet the pandemic is disrupting clinical trials addressing these same health conditions.3Continuum ClinicalCOVID-19 Live Updates: Find the latest information from Continuum on how COVID-19 is impacting clinical trial enrollment and retention.https://continuumclinical.com/blog/covid-19-live-updatesDate accessed: March 22, 2020Google Scholar There were more than 300,000 studies being conducted worldwide registered on clinicaltrials.gov. in March 2020.4U.S. NationalLibrary of Medicine ClinicalTrials.gov. Trends, Charts, and Maps.https://clinicaltrials.gov/ct2/resources/trendsDate accessed: March 22, 2020Google Scholar Hence, there is a necessity to continue some ongoing research studies safely, a critical need for novel research into the prevention and treatment of COVID-19, and we must try to anticipate the ethical and social implications of this global pandemic. This commentary is directed at these two pressing ethical questions: How can clinical trials be conducted ethically in the midst of the current global pandemic? What social and ethical issues prompted by COVID-19 merit further research? For clinical trials, the challenges are unprecedented and amplified by the sheer specificity of different study needs. Ongoing trials are at various stages in their natural history (ie, not actively recruiting, actively recruiting, or closed for recruitment). Each trial is also accountable to a variety of local, national, and international organizations including funders, regulatory bodies, and institutional review boards. Driven by the need to adapt to a dynamic environment, these stakeholders have been identifying and implementing measures to maintain research and minimize the risks of exposure to participants and researchers. Resources permitting, one option is to continue trials that have the potential to have high impact (eg, a potentially life-saving medication) or moderate impact (eg, disease-modifying agents) on participants' health (eg, Johns Hopkins, 2020).5Johns Hopkins University HubResearch preparedness: Human subjects.https://hub.jhu.edu/novel-coronavirus-information/research-preparedness/research-preparedness-human-subjects/Date accessed: March 22, 2020Google Scholar By contrast, studies that advance the science but do not offer participants a prospect of direct benefit should probably be paused, also to conserve resources and protect subjects from inadvertent exposure to those who are asymptomatic but infected with COVID-19. Other options include providing follow-up care and research tests at facilities closer to home or virtually using video conferencing technologies, and shipping study-related investigational products directly to participants when appropriate.6Perakslis E.D. Using digital health to enable ethical health research in conflict and other humanitarian settings.Conflict and Health. 2018; 12 (Accessed March 22, 2020): 23https://doi.org/10.1186/s13031-018-0163-zCrossref PubMed Scopus (20) Google Scholar,7Cancer Therapy Evaluation Program (CTEP)Memorandum on interim guidance for clinical trial activities affected by the new coronavirus.ctep.cancer.gov/content/docs/Memorandum_on_Interim_Guidance_for_Clinical_Trial_Activities_Affected_by_the_Novel_Coronavirus-3-13-2020.pdfDate accessed: March 20, 2020Google Scholar,8McDermott M.M. Newman A.B. Preserving clinical trial integrity during the coronavirus pandemic..JAMA. 2020; (Epub ahead of print. https://doi.org/10.1001/jama.2020.4689)Crossref PubMed Scopus (150) Google Scholar Deciding which studies should continue to enroll new participants or provide follow-up visits is partly influenced by the local prevalence and health care burden of COVID-19. Research decisions vary considerably by geographic distribution, among institutions, and can be updated frequently, often daily, including decisions to increase research activities as infection control and response improve. Some studies have been closed for enrollment, including those informed by prior research ethics debates on closing studies due to futility or lack of initial benefit.9Mueller P.S. Montori V.M. Bassler D. et al.Ethical issues in stopping randomized trials early because of apparent benefit.Ann Intern Med. 2007; 146: 878-881Crossref PubMed Scopus (143) Google Scholar However, ceasing or slowing studies is not always the safest option for participants.10Lawton J. White D. Rankin D. et al.Staff experiences of closing out a clinical trial involving withdrawal of treatment: qualitative study.Trials. 2017; 18: 61Crossref PubMed Scopus (17) Google Scholar Indeed, it is important to continue or appropriately transition studies that have the potential to directly benefit participants. Elements of studies, such as ancillary care or access to investigational drugs and/or devices, might be maintained even if other research protocol aspects are modified. Honoring our commitment to foundational research ethics principles of respect for persons, beneficence, and justice is demanding, especially when such tenets could very well be in tension.11National Commission for the Protection of Human Subjects of Biomedical and Behavioral ResearchThe Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. (DHEW Publication OS 78-0012). Office of Human Research Protections.https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.htmlDate accessed: March 22, 2020Google Scholar Acknowledging the core function of human research protections, European clinical trials guidelines, and US Food and Drug Administration guidance emphasize that in cases where prioritizing participant safety and data validity conflict "subject safety always prevails."12Clinical Trials Expert Group (CTEG) of the European Commission, the Clinical Trials Facilitation and Coordination Group (CTFG) of the Heads of Medicines Agencies (HMA) and the GCP Inspectors' Working Group, coordinated by the European Medicines Agency (EMA)Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic.https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdfDate accessed: March 22, 2020Google Scholar Nevertheless, enacting the priority of protecting research participant safety amid the pandemic is not always clear-cut. For example, altering clinical trial follow-up plans may compromise participant safety and impact beneficence if key safety assessments are missed due to social distancing, shelter in place local regulations, and suspension of travel options. A variety of guidelines have been released to inform research response. Recent US Food and Drug Administration guidance provides recommendations for ongoing studies, development of contingency plans as conditions change, and reporting of COVID-19 impact in study reports.13Food and Drug Administration (FDA)Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic Guidance for Industry, Investigators, and Institutional Review Boards.https://www.fda.gov/media/136238/downloadDate accessed: March 20, 2020Google Scholar Elsewhere, agencies are clarifying what constitutes a protocol deviation. For example, the National Cancer Institute has advised that for some clinical trials, providing care locally or remotely is not considered a protocol deviation.7Cancer Therapy Evaluation Program (CTEP)Memorandum on interim guidance for clinical trial activities affected by the new coronavirus.ctep.cancer.gov/content/docs/Memorandum_on_Interim_Guidance_for_Clinical_Trial_Activities_Affected_by_the_Novel_Coronavirus-3-13-2020.pdfDate accessed: March 20, 2020Google Scholar The National Institutes of Health also have guidance for participant safety and granting of extensions and administrative supplements.14National Institutes of Health (NIH)Guidance for NIH-funded Clinical Trials and Human Subjects Studies Affected by COVID-19.https://grants.nih.gov/grants/guide/notice-files/NOT-OD-20-087.htmlDate accessed: March 20, 2020Google Scholar The need for nuanced and iterative decisions for each clinical trial is also placing additional demands on already overstretched institutional review board resources and staff.15De Vries R.G. Forsberg C. What do IRBs look like? What kind of support do they receive?.Account Res. 2002; 9: 199-216Crossref PubMed Scopus (55) Google Scholar Furthermore, pandemic-associated mortality and morbidity may impose additional impediments to post-pandemic follow-up activities by researchers, research ethics committees, and regulators, thus straining the tenuous research system even further. Proactive measures to mitigate such consequences are necessary. Modern medicine depends on evidence-based therapies to guide treatment across all disease states. While the pandemic is rapidly evolving, there is no specific treatment available for patients diagnosed with COVID-19.2Centers for Disease Control and Prevention (CDC)Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19).https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.htmlDate accessed: March 18, 2020Google Scholar Current clinical practice relies on supportive care such as mechanical ventilation to manage acute hypoxemic respiratory failure and treatment of seconary infections.2Centers for Disease Control and Prevention (CDC)Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19).https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.htmlDate accessed: March 18, 2020Google Scholar There is a compelling need to provide an evidence base that informs improved standards of care, develops novel interventions, and guides management. Randomized controlled trials (RCTs) are most ethically controversial when offering potential participants randomization into a placebo arm that could result in individual harm, especially serious physical harm including additional pain, suffering, or death as well as randomization into an active treatment arm where benefit of treatment is not established and unrecognized treatment-associated harm may exist.16Adebamowo C. Bah-Sow O. Binka F. et al.Randomised controlled trials for Ebola: practical and ethical issues.Lancet. 2014; 384: 1423-1424Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar Ethical issues of clinical research are heightened when the condition (COVID-19 in this case) being investigated has an actual or perceived high mortality risk; activation of trials, including oversight processes, must and can be conducted rapidly without compromising human subjects research protections.17Zhang H. Shao F. Gu J. et al.Ethics committee reviews of applications for research studies at 1 hospital in China during the 2019 novel coronavirus epidemic..JAMA. 2020; (Epub ahead of print. https://doi.org/10.1001/jama.2020.4362)Crossref Scopus (34) Google Scholar,18Watters J.T. Pitzen J.H. Sanders L.J. et al.Transforming the activation of clinical trials.Clin Pharmacol Ther. 2018; 103: 43-46https://doi.org/10.1002/cpt.898Crossref PubMed Scopus (6) Google Scholar Despite informed consent practices, uncertainty during emergencies can exacerbate and create new possibilities for social, racial, and economic divisions; in research there is very real risk of undermining community trust.19London A.J. Clinical research in a public health crisis: the integrative approach to managing uncertainty and mitigating conflict.Seton Hall Law Rev. 2009; 39: 1173-1202PubMed Google Scholar RCTs are often considered the ideal for grounding causal inference, although importantly, RCTs also exhibit epistemic limits for addressing population health.20Frieden T.R. Evidence for health decision making — beyond randomized, controlled trials.N Engl J Med. 2017; 377: 465-475Crossref PubMed Scopus (505) Google Scholar Adaptive and pragmatic clinical trial designs are often proffered as alternatives, but these designs also present challenging trade-offs between the type of knowledge produced and the prioritization of direct benefits provided to participants.16Adebamowo C. Bah-Sow O. Binka F. et al.Randomised controlled trials for Ebola: practical and ethical issues.Lancet. 2014; 384: 1423-1424Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar,21Edwards S.J.L. Ethics of clinical science in a public health emergency: drug discovery at the bedside.Am J Bioeth. 2013; 13: 3-14Crossref PubMed Scopus (33) Google Scholar, 22Presidential Commission for the Study of Bioethical Issues (PCSBI). Ethics and Ebola: Public Health Planning and Response.https://bioethicsarchive.georgetown.edu/pcsbi/sites/default/files/Ethics-and-Ebola_PCSBI_508.pdfGoogle Scholar, 23Cook D.J. Marshall J.C. Fowler R.A. Critical illness in patients with COVID-19: mounting an effective clinical and research response.JAMA. 2020; (Epub ahead of print. https://doi.org/10.1001/jama.2020.5775)Crossref PubMed Scopus (33) Google Scholar In all COVID-19 RCTs, participants in the control arm would receive supportive care2Centers for Disease Control and Prevention (CDC)Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19).https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.htmlDate accessed: March 18, 2020Google Scholar and best-in-class medical therapy for any associated comorbidities. Developing a standard of supportive care for RCTs that spans sites around the world is both practically and ethically challenging. Pre-existing socioeconomic differences and health infrastructures within communities may drive local and regional differences in what is standard of care. Moreover, supportive care standards might also change over time, including in response to emerging data informing better care and to dynamic resource constraints as the COVID-19 pandemic unfolds. Supportive care variability creates both scientific and ethical challenges.24Miller F.G. Silverman H.J. The ethical relevance of the standard of care in the design of clinical trials.Am J Respir Crit Care Med. 2004; 169: 562-564Crossref PubMed Google Scholar If standards of supportive care are not consistent across sites, study results might be confounded by extraneous variables. If standards of supportive care are unachievable in low-resource settings, study findings might not be generalizable to these contexts. During the 2014–2016 Ebola outbreak in West Africa, the national bioethics commission recommended allowing contextual variability of supportive care in clinical trials, such that research participants receive the "best supportive care sustainably available in the community in which the research is conducted."22Presidential Commission for the Study of Bioethical Issues (PCSBI). Ethics and Ebola: Public Health Planning and Response.https://bioethicsarchive.georgetown.edu/pcsbi/sites/default/files/Ethics-and-Ebola_PCSBI_508.pdfGoogle Scholar Contextual differences in supportive care have occurred during the current COVID-19 pandemic; for example, integrative medicine practices are part of supportive care in China but perhaps not elsewhere.25Chan K.W. Wong V.T. Tang S.C.W. COVID-19: An update on the epidemiological, clinical, preventive and therapeutic evidence and guidelines of integrative Chinese–Western medicine for the management of 2019 novel coronavirus disease [published online ahead of print].Am J Chin Med. 2020; : 1-26https://doi.org/10.1142/S0192415X20500378Crossref PubMed Scopus (266) Google Scholar Meanwhile, the WHO is currently developing a "master protocol" to harmonize practices such as supportive therapy to direct coordinated multi-site adaptive COVID-19 RCTs.26World Health Organization (WHO)A coordinated Global Research Roadmap.https://www.who.int/blueprint/priority-diseases/key-action/Roadmap-version-FINAL-for-WEB.pdf?ua=1Date accessed: March 20, 2020Google Scholar, 27World Health Organization (WHO)Ethical standards for research during public health emergencies: Distilling existing guidance to support COVID-19 R&D.https://www.who.int/blueprint/priority-diseases/key-action/liverecovery-save-of-ethical-standards-for-research-during-public-health-emergencies.pdf?ua=1Date accessed: March 20, 2020Google Scholar, 28Dean N.E. Gsell P.-S. Brookmeyer R. et al.Creating a framework for conducting randomized clinical trials during disease outbreaks.N Engl J Med. 2020; 382: 1366-1369Crossref PubMed Scopus (57) Google Scholar As with other pandemics, COVID-19 has revealed the interdependence of a globalized world. We must bear shared responsibility for solutions as we collectively confront the problem. Clinically actionable data must diffuse rapidly, even when such knowledge does not meet the rigorous standards of clinical trials.29Moorthy V. Henao Restrepo A.M. Preziosi M.P. et al.Data sharing for novel coronavirus (COVID-19).Bull World Health Organ. 2020; 98: 150Crossref PubMed Scopus (119) Google Scholar,30Angus D.C. Optimizing the trade-off between learning and doing in a pandemic.JAMA. 2020; (Epub ahead of print. https://doi.org/10.1001/jama.2020.4984)Crossref Scopus (120) Google Scholar Novel interventions to prevent and treat COVID-19 are needed all over the world. Likewise, there is a similar need for reciprocity. Affluent nations often have more capacity to conduct clinical trials. The knowledge clinical trials produce—and the innovations that result—must be informed by a commitment to justice in ensuring equitable access to resultant interventions. A firm commitment to global equity might seem like an unreachable ideal in a crisis manifesting so differently across continents. Our current research and development pipelines are not designed to produce large quantities of vaccines, drugs, or devices at low cost to fill unmet public health needs.31Bottazzi M.E. Hotez P.J. "Running the Gauntlet": Formidable challenges in advancing neglected tropical diseases vaccines from development through licensure, and a "Call to Action".Hum Vaccin Immunother. 2019; 15: 2235-2242Crossref PubMed Scopus (18) Google Scholar In vaccine researcher Peter Hotez's recent US Congressional testimony, he contended that these systems failures are a main reason coronavirus research was not prioritized before the current pandemic.32Hotez P. Beyond coronaviruses: understanding the spread of infectious diseases and mobilizing innovative solutions.https://science.house.gov/imo/media/doc/Hotez%20Testimony.pdfGoogle Scholar If we are not careful, these same factors will contribute to exacerbated global health disparities when responding to the current or a future coronavirus outbreak, even if an effective prevention and/or treatment are discovered. The psychosocial impact of the current crisis also prompts several pressing questions. Could there be a mental health toll if social distancing occurs for extended periods? What additional support do health professionals need when scarcity of personal protective equipment creates high levels of anxiety for personal and familial safety? These are just a few of the social and ethical questions raised by the COVID-19 pandemic.33Berlinger N. Wynia M. Powell T. et al.Ethical Framework for Health Care Institutions Responding to Novel Coronavirus SARS-CoV-2 (COVID-19) Guidelines for Institutional Ethics Services Responding to COVID-19. The Hastings Center.https://www.thehastingscenter.org/wp-content/uploads/HastingsCenterCovidFramework2020.pdfGoogle Scholar Bioethics and social science research can be integral to improving current and future infectious disease research, policy, and practice.34Gaist P. Stirratt M.J. The roles of behavioral and social science research in the fight against HIV/AIDS: a functional framework.J Acquir Immune Defic Syndr. 2017; 75: 371-381Crossref PubMed Scopus (21) Google Scholar,35Stern A.M. Markel H. International efforts to control infectious diseases, 1851 to the Present.JAMA. 2004; 292: 1474-1479Crossref PubMed Scopus (54) Google Scholar Because a full discussion of all these topics is beyond the scope of this commentary, we focus on the importance of research in moral distress as a starting point. Moral distress is a concept that emerged from nursing ethics and has expanded to all health professions, encompassing instances in which a health professional believes he or she knows the morally right thing to do but is unable to do so.36Jameton A. Nursing Practice: The Ethical Issues. Prentice-Hall, Englewood Cliffs, NJ1984Google Scholar,37Hamric A.B. Borchers C.T. Epstein E.G. Development and testing of an instrument to measure moral distress in healthcare professionals.AJOB Prim Res. 2012; 3: 1-9Crossref PubMed Scopus (345) Google Scholar COVID-19 could create the type of uncertainty and constrained choices in which health professionals struggle to act according to familiar best practices. Previous public health and humanitarian emergencies have produced moral distress, providing us important evidence for anticipating these challenges should they arise in the weeks and months ahead.38Hunt M. Chénier A. Bezanson K. et al.Moral experiences of humanitarian health professionals caring for patients who are dying or likely to die in a humanitarian crisis.J Int Humanitarian Action. 2018; 3: 12Crossref Google Scholar Moral distress is a useful area for further bioethics and social science investigation because it can illuminate the underlying content and sources of the most pressing ethical concerns among health professionals. Sources of moral distress previously identified include institutional policies that have unintended consequences, and decisional hierarchies that can compromise a sense of professional integrity.36Jameton A. Nursing Practice: The Ethical Issues. Prentice-Hall, Englewood Cliffs, NJ1984Google Scholar,37Hamric A.B. Borchers C.T. Epstein E.G. Development and testing of an instrument to measure moral distress in healthcare professionals.AJOB Prim Res. 2012; 3: 1-9Crossref PubMed Scopus (345) Google Scholar,39Epstein E.G. Hamric A.B. Moral distress, moral residue and the crescendo effect.J Clin Ethics. 2009; 20: 330-342PubMed Google Scholar However, moral distress can be difficult to disentangle from other forms of psychological anxiety and trauma induced by stress and crisis response. This distinction is crucial to ensuring health care professionals receive the mental health resources needed to sustain their efforts and personal wellbeing, given the link of moral distress to compassion fatigue and burnout.40Austin C.L. Saylor R. Finley P. Moral distress in physicians and nurses: impact on professional quality of life and turnover.Psychol Trauma. 2017; 9: 399-406Crossref PubMed Scopus (144) Google Scholar Exploring the distinct moral concerns at the core of moral distress is also important. Such research can be coupled with investigations into resilience, including the institutional structures and practices that most support frontline health care providers through these times of crisis. Clinical research and social science research tend to embrace the long timeframe needed for cautious and deliberate knowledge production. However, prioritized research efforts now can be designed in ways that are sensitive to the exigencies of the moment. The global research community must act now to meet needs of patients and health care professionals both in the short term, and when this public health emergency subsides. The purpose of this commentary is to join the conversation to design research for health policy and practice grounded simultaneously in rigorous, ethical evidence, the highest standards of professionalism, and the experiences of health care professionals.