How informative were early SARS-CoV-2 treatment and prevention trials? a longitudinal cohort analysis of trials registered on ClinicalTrials.gov.

BACKGROUND: Early in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic. METHODS: Based on prespecified eligibility criteria, we created a cohort of Phase 1/2, Phase 2, Phase 2/3 and Phase 3 SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We excluded trials evaluating behavioural interventions and natural products, which are not regulated by the U.S. Food and Drug Administration (FDA). We evaluated trials on 3 criteria of informativeness: potential redundancy (comparing trial phase, type, patient-participant characteristics, treatment regimen, comparator arms and primary outcome), trials design (according to the recommendations set-out in the May 2020 FDA guidance document on SARS-CoV-2 treatment and prevention trials) and feasibility of patient-participant recruitment (based on timeliness and success of recruitment). RESULTS: We included all 500 eligible trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.9% (95% Confidence Interval 23.7-36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%. CONCLUSIONS: Less than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic.

Surgery during COVID-19 crisis conditions: can we protect our ethical integrity against the odds?

COVID-19 is reducing the ability to perform surgical procedures worldwide, giving rise to a multitude of ethical, practical and medical dilemmas. Adapting to crisis conditions requires a rethink of traditional best practices in surgical management, delving into an area of unknown risk profiles. Key challenging areas include cancelling elective operations, modifying procedures to adapt local services and updating the consenting process. We aim to provide an ethical rationale to support change in practice and guide future decision-making. Using the four principles approach as a structure, Medline was searched for existing ethical frameworks aimed at resolving conflicting moral duties. Where insufficient data were available, best guidance was sought from educational institutions: National Health Service England and The Royal College of Surgeons. Multiple papers presenting high-quality, reasoned, ethical theory and practice guidance were collected. Using this as a basis to assess current practice, multiple requirements were generated to ensure preservation of ethical integrity when making management decisions. Careful consideration of ethical principles must guide production of local guidance ensuring consistent patient selection thus preserving equality as well as quality of clinical services. A critical issue is balancing the benefit of surgery against the unknown risk of developing COVID-19 and its associated complications. As such, the need for surgery must be sufficiently pressing to proceed with conventional or non-conventional operative management; otherwise, delaying intervention is justified. For delayed operations, it is our duty to quantify the long-term impact on patients' outcome within the constraints of pandemic management and its long-term outlook.

A literature review of consent declines and consent withdrawals in randomized controlled trials conducted during the COVID-19 pandemic.

Objectives: We evaluated the extent of consent declines and consent withdrawals during the COVID-19 pandemic as seen in published randomized controlled trials (RCTs) and compared it with non-COVID-19 RCTs published at the same time and two historical controls. Methods: PubMed/Medline only was searched using key-word "COVID-19" and "RCTs" separately, and filtered for COVID-19 RCTs and non-COVID-19 RCTs respectively, published during a nine-month period (1 Feb - 1 Nov 2020). Exclusions were study protocols, observational studies, interim analysis of RCT data and RCTs with missing data. Primary outcome measures were the proportion of consent declines and consent withdrawals as percentage of total participants screened and randomized respectively in COVID-19 RCTs. We compared consent declines and consent withdrawals of COVID-19 RCTs with non-COVID-19 RCTs and two earlier studies on the same topic that served as historical controls (non-pandemic setting). Results: The search yielded a total of 111 COVID-19 RCTs and 49 non-COVID-19 RCTs. Of these, 39 (35.13%) COVID-19 RCTs and 11 (22.45%) non-COVID-19 RCTs were finally analysed. A total of 770/17759 (4.3%) consent declines and 100/7607 (1.31%) consent withdrawals were seen in 39 COVID-19 RCTs. A significant difference was observed in consent declines between COVID-19 vs non-COVID-19 RCTs [4.3% vs 11.9%, p < 0.0001] and between COVID-19 RCTs vs two historical controls [(4.3% vs 8.6%, p < 0.0001) and (4.3% vs 21.1%, p < 0.0001), respectively]. Conclusion: RCTs conducted during the COVID-19 pandemic appear to have significantly lower consent declines relative to non-COVID-19 RCTs during pandemic and RCTs conducted in non-pandemic settings.

Ethical Considerations in Chemotherapy and Vaccines in Cancer Patients in Times of the COVID-19 Pandemic.

The COVID-19 situation is a worldwide health emergency with strong implications in clinical oncology. In this viewpoint, we address two crucial dilemmas from the ethical dimension: (1) Is it ethical to postpone or suspend cancer treatments which offer a statistically significant benefit in quality of life and survival in cancer patients during this time of pandemic?; (2) Should we vaccinate cancer patients against COVID-19 if scientific studies have not included this subgroup of patients? Regarding the first question, the best available evidence applied to the ethical principles of Beauchamp and Childress shows that treatments (such as chemotherapy) with clinical benefit are fair and beneficial. Indeed, the suspension or delay of such treatments should be considered malefic. Regarding the second question, applying the doctrine of double-effect, we show that the potential beneficial effect of vaccines in the population with cancer (or those one that has had cancer) is much higher than the potential adverse effects of these vaccines. In addition, there is no better and less harmful known solution.

SARS-CoV-2 Human Challenge Trials: Rethinking the Recruitment of Healthy Young Adults First.

In the midst of the ongoing Covid-19 pandemic, researchers across the globe are still working to develop effective vaccines. To expedite this process even further, human challenge trials have been proposed by the World Health Organization (WHO) as an alternative to conventional approaches. In such trials, healthy volunteers are deliberately infected with the pathogen of interest, enabling scientists to study the infection process and facilitate further research on treatments or prophylactics, including vaccines. While human challenge trials would offer a collective benefit to society, minimizing the risks is always difficult. Ethical controversy thus inevitably surrounds these trials. Typically, healthy young adults are recruited to serve as the first candidate subjects for human challenge trials because they are generally considered to represent a low-risk population. Here, we present three reasons for doubt about this healthy-young-adults-first criterion and give justification for also recruiting healthy older adults (or not-young adults), meaning those over 30 years of age, to participate in such trials for SARS-CoV-2.

Coronavirus Disease 2019 (COVID-19) Clinical Trial Oversight at a Major Academic Medical Center: Approach of Michigan Medicine.

Clinicians, eager to offer the best care in the absence of guiding data, have provided patients with coronavirus disease 2019 (COVID-19) diverse clinical interventions. This usage has led to perceptions of efficacy of some interventions that, while receiving media coverage, lack robust evidence. Moving forward, randomized controlled clinical trials are necessary to ensure that clinicians can treat patients effectively during this outbreak and the next. To do so, academic medical centers must address 2 key research issues: (1) how to effectively and efficiently determine which trials have the best chance of benefiting current and future patients and (2) how to establish a transparent and ethical process for subject recruitment while maintaining research integrity and without overburdening patients or staff. We share here the current methods used by Michigan Medicine to address these issues.

Inclusion of pregnant women in COVID-19 treatment trials: a review and global call to action.

Inclusion of pregnant women in COVID-19 clinical trials would allow evaluation of effective therapies that might improve maternal health, pregnancy, and birth outcomes, and avoid the delay of developing treatment recommendations for pregnant women. We explored the inclusion of pregnant women in treatment trials of COVID-19 by reviewing ten international clinical trial registries at two timepoints in 2020. We identified 155 COVID-19 treatment studies of non-biological drugs for the April 7-10, 2020 timepoint, of which 124 (80%) specifically excluded pregnant women. The same registry search for the July 10-15, 2020 timepoint, yielded 722 treatment studies, of which 538 (75%) specifically excluded pregnant women. We then focused on studies that included at least one of six drugs (remdesivir, lopinavir-ritonavir, interferon beta, corticosteroids, chloroquine and hydroxychloroquine, and ivermectin) under evaluation for COVID-19. Of 176 such studies, 130 (74%) listed pregnancy as an exclusion criterion. Of 35 studies that evaluated high-dose vitamin treatment for COVID-19, 27 (77%) excluded pregnant women. Despite the surge in treatment studies for COVID-19, the proportion excluding pregnant women remains consistent. Exclusion was not well justified as many of the treatments being evaluated have no or low safety concerns during pregnancy. Inclusion of pregnant women in clinical treatment trials is urgently needed to identify effective COVID-19 treatment for this population.

Does a Public Health Crisis Justify More Research with Incarcerated People?

Covid-19 has infected thousands and killed hundreds in prisons, jails, and immigration detention facilities across the United States. Responding to this crisis, leading medical researchers have called for expanding opportunities for people in prison to participate in vaccine trials. These calls, like current regulations, focus on individualized risk assessments around consent, coercion, and harm, while ignoring the unnaturalness of deprivation conditions in U.S. prisons. We need new frameworks of analysis that refocus on structural, rather than individual, risk assessments. Integrating structural perspectives-including skepticism of claims of scarcity, avoidance of representational distortions, and attention to institutional agency-into our existing, overly individualistic frameworks might permit the design of more ethical research projects involving people who are incarcerated. Still, the unnatural deprivations of incarceration might be so great that research subjects might need to be removed from prison entirely in order to ethically participate in research.

Pulmonary Abnormalities in Liver Disease: Relevance to Transplantation and Outcome.

Pulmonary disease in liver cirrhosis and portal hypertension (PH) constitutes a challenging clinical scenario and may have important implications with regard to prognosis, liver transplantation (LT) candidacy, and post-LT outcome. Pre-LT evaluation should include adequate screening for pulmonary diseases that may occur concomitantly with liver disease as well as for those that may arise as a complication of end-stage liver disease and PH, given that either may jeopardize safe LT and successful outcome. It is key to discriminate those patients who would benefit from LT, especially pulmonary disorders that have been reported to resolve post-LT and are considered "pulmonary indications" for transplant, from those who are at increased mortality risk and in whom LT is contraindicated. In conclusion, in this article, we review the impact of several pulmonary disorders, including cystic fibrosis, alpha 1-antitrypsin deficiency, hereditary hemorrhagic telangiectasia, sarcoidosis, coronavirus disease 2019, asthma, chronic obstructive pulmonary disease, pulmonary nodules, interstitial lung disease, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension, on post-LT survival, as well as the reciprocal impact of LT on the evolution of lung function.

Fair and equitable subject selection in concurrent COVID-19 clinical trials.

Clinical trials emerged in rapid succession as the COVID-19 pandemic created an unprecedented need for life-saving therapies. Fair and equitable subject selection in clinical trials offering investigational therapies ought to be an urgent moral concern. Subject selection determines the distribution of risks and benefits, and impacts the applicability of the study results for the larger population. While Research Ethics Committees monitor fair subject selection within each trial, no standard oversight exists for subject selection across multiple trials for the same disease. Drawing on the experience of multiple clinical trials at a single academic medical centre in the USA, we posit that concurrent COVID-19 trials are liable to unfair and inequitable subject selection on account of scientific uncertainty, lack of transparency, scarcity and, lastly, structural barriers to equity compounded by implicit bias. To address the critical gap in the current literature and international regulation, we propose new ethical guidelines for research design and conduct that bolsters fair and equitable subject selection. Although the proposed guidelines are tailored to the research design and protocol of concurrent trials in the COVID-19 pandemic, they may have broader relevance to single COVID-19 trials.

Ethical Implications of Resuming Elective Orthopedic Surgery During the COVID-19 Pandemic.

The COVID-19 pandemic has had unprecedented impact on the United States health care system. One of the consider-ations was the decision to halt elective orthopedic surgery to preserve consumption of scarce resources. However, as the number of COVID-19 cases decrease, there will be discus-sions regarding the modality of resuming elective orthopedic surgery. Ethical considerations will come to the forefront in terms of determining the best course of action, patient selection, resource rationing, and financial implications. These factors will be examined through the lens of the four tenets of bioethics, beneficence, maleficence, autonomy, and justice, to elucidate the best approach in ethically manag-ing elective orthopedic surgery during a global pandemic.