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.

Reopening schools safely in the face of COVID-19: Can cluster randomized trials help?

The COVID-19 pandemic has highlighted the challenges of evidence-based health policymaking, as critical precautionary decisions, such as school closures, had to be made urgently on the basis of little evidence. As primary and secondary schools once again close in the face of surging infections, there is an opportunity to rigorously study their reopening. School-aged children appear to be less affected by COVID-19 than adults, yet schools may drive community transmission of the virus. Given the impact of school closures on both education and the economy, schools cannot remain closed indefinitely. But when and how can they be reopened safely? We argue that a cluster randomized trial is a rigorous and ethical way to resolve these uncertainties. We discuss key scientific, ethical, and resource considerations both to inform trial design of school reopenings and to prompt discussion of the merits and feasibility of conducting such a trial.

COVID-19 Trial Enrollment for Those Who Cannot Consent: Ethical Challenges Posed by a Pandemic.

The current coronavirus disease 2019 (COVID-19) pandemic has triggered an intense global research effort to inform the life-saving work of frontline clinicians who need reliable information as soon as possible. Yet research done in pressured circumstances can lead to ethical dilemmas, especially for vulnerable research subjects. We present the case of a child with neurocognitive impairment who is diagnosed with COVID-19 infection after presenting with fever and a seizure. The child lives in a group home and is in the custody of the state; her parents lost parental rights many years ago. Some members of the health care team want to enroll her in a randomized clinical trial evaluating an experimental treatment of COVID-19. For minor patients to enroll in this clinical trial, the institutional review board requires assent of patients and consent of guardians. An ethics consult is called to help identify relevant concerns in enrollment. In the accompanying case discussion, we address historical perspectives on research involving people with disabilities; proper management of research participation for people with disabilities including consent by proxy, therapeutic misconception, and other threats to the ethical validity of clinical trials; and the potentially conflicting obligations of researchers and clinicians.

Data monitoring committees for clinical trials evaluating treatments of COVID-19.

The first cases of coronavirus disease 2019 (COVID-19) were reported in December 2019 and the outbreak of SARS-CoV-2 was declared a pandemic in March 2020 by the World Health Organization. This sparked a plethora of investigations into diagnostics and vaccination for SARS-CoV-2, as well as treatments for COVID-19. Since COVID-19 is a severe disease associated with a high mortality, clinical trials in this disease should be monitored by a data monitoring committee (DMC), also known as data safety monitoring board (DSMB). DMCs in this indication face a number of challenges including fast recruitment requiring an unusually high frequency of safety reviews, more frequent use of complex designs and virtually no prior experience with the disease. In this paper, we provide a perspective on the work of DMCs for clinical trials of treatments for COVID-19. More specifically, we discuss organizational aspects of setting up and running DMCs for COVID-19 trials, in particular for trials with more complex designs such as platform trials or adaptive designs. Furthermore, statistical aspects of monitoring clinical trials of treatments for COVID-19 are considered. Some recommendations are made regarding the presentation of the data, stopping rules for safety monitoring and the use of external data. The proposed stopping boundaries are assessed in a simulation study motivated by clinical trials in COVID-19.

[The naked king in the pandemic: about the production and communication of scientific knowledge at the time of SARS-CoV-2.] / Il re nudo nella pandemia: sulla produzione e comunicazione del sapere scientifico ai tempi di SARS-CoV-2.

The SARS-CoV-2 pandemic has lifted the veil about how medical knowledge is produced and disseminated. Action Bias, together with economic, academic and media-related interests, has concurred to generate and spread low-value and even unreliable information about some hypothetical therapeutic interventions for CoViD-19. Not only this "infodemic" has weakened people's ability to make informed health choices, but it also has influenced the process of new evidence generation through the violation of the equipoise principle. The CoViD-19 infodemic has further highlighted the need for reliable health information and for people to enter the process of understanding and promoting valuable research. Through a randomized controlled trial, the Informed Health Choices project has shown that it is not impossible neither quixotic to better orient people about health choices since primary school. Similar competencies should be disseminated to everyone through sources that are selected and validated for their capability of reporting evidence based health information about the effects of treatments.

Clinical trials and the COVID-19 pandemic.

"...but why think? Why not try the experiment?..." John Hunter (1728-1793), in a letter to Edward Jenner. August 2nd, 1775. When Galen of Pergamum (2nd c. A.D.), physician, philosopher and experimentalist, sought to ascertain the therapeutic properties of Theriac, an antidote of repute against poisons, he resorted to an experiment. Theriac or Theriaca was a compound drug, containing in some versions used in antiquity numerous components; Galen's own composition included over 70 ingredients! One of its uses was as an antidote against snakebites, a frequent peril for the Roman armies marching on in sandals. Galen spent most of his life in Rome and was elevated to Imperial Physician at the court of Marcus Aurelius, who apparently took daily doses of Theriac, which among other components included opium. Describing the experiment to his friend Pison, Galen wrote, "as I could not possibly conduct a trial on humans, I experimented on roosters" For his experiment, Galen, studied two groups of roosters, but he doesn't tell us how many animals he included in each category. Both groups were exposed to poisonous snakebites. All roosters who were fed with theriac prior to exposure to viper bites survived, whereas in the second group that had not received prophylactic Theriac, all roosters died. Not only is Galen's methodology remarkable, preceding the modern randomised trial by eighteen centuries, but more importantly, it is notable for his ethical stance at a time when sensitivities about human rights, prevalent in our times, were largely absent in societies of widespread slavery. For example, Mithridates VI (132-63 BC), the King of Pontus who is credited with the first use of Theriac, tested its efficacy on criminals and slaves. For his experiment Galen used the random allocation of treatment, today's prospective randomised clinical trial, implemented in the evaluation of novel therapies, widely used internationally, particularly in cancer research! This experimental method used for ascertaining the efficacy of new drugs became established after the second half of the 20th century and is now firmly entrenched as a research tool. On the other hand, the retrieval of information from observational studies or non-randomised series is considered scientifically inferior and is often dismissed or ignored as irrelevant or anecdotal. Such is the compulsion for the randomised study that in the midst of the COVID-19 pandemic, respected physicians and scientists appeared in the media hesitant to recommend the use of protective facial masks, as there was no evidence of benefit for their use from prospective randomised studies in the general population! Logic had no place in the argument! COVID-19, caused by the SARS-CoV-2 new corona virus, brought to the fore the randomised trial, as well as, the ethical dilemmas that surround the allocation of treatment at random, in the face of a devastating pandemic. Anthony Fauci, distinguished infectious diseases expert and an adviser to the President of the USA, at a recent briefing from the Situation Room of the White House, endorsed categorically and unreservedly the randomised trial for the evaluation of drugs potentially effective against SARS-CoV-2, in patients afflicted with COVID-19. A few days later on April 8th, 2020, Professor Sotiris Tsiodras, scientific advisor to the Greek Government for COVID-19 and an expert on infectious diseases, when asked by a journalist about chloroquine, he responded, "Antony Fauci is correct. Nevertheless, we give the drug to everyone, that is, not half of the patients will receive it, and the other half will not". If we accept that the randomised trial represents the unique, impregnable method of evaluating new treatments-several clinicians dispute this dogma. -the question arises how will treatments be allocated to patients? According to the Declaration of Helsinki participation of a subject in a clinical trial requires their explicit written consent. Will, a potentially hypoxic patient rapidly deteriorating, be able to understand what is being asked of them, and will that patient be in a position to provide consent? And if that patient refuses to be randomised, what are the options? Is it his/her right to request the active treatment that a fellow patient is receiving in the next bed? Although the Declaration of Helsinki allows the option of no treatment or even placebo, where no known treatment is available for a certain condition, such as COVID-19, it also emphasizes that "while the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects". Consider now the physicians and nurses on the first line of the battle against the pandemic; to the enormous pressures and risks that they experience daily, they may have to endure the added psychological burden of the randomised trial, knowing that half of their patients are receiving the promising drug, whilst the other half are denied the chance of potential benefit. When during the Medical Research Council's randomized trial of streptomycin, one senior physician contracted tuberculosis, the Medical Research Council obtained supplies for him outside the trial. In this brief instance of medical history, the equipoise, the scientific imperative, all arguments and other justifications for providing treatment at random, were thrown out of the window in favour of the human factor! Why is randomization necessary? Because-it is presumed-the process of randomising subjects, protects the study from the selective inclusion of patients with favourable characteristics, thus inadvertently allowing or facilitating a falsely favourable result for the drug or treatment under investigation. However, the process of randomising patients does not necessarily result in the randomisation of the characteristics of their disease. Exactly because of this, at the end of a randomised study, even if the prognostic variables are evenly represented and balanced in the strata, further confirmation of the result is sought with a statistical multifactorial analysis. Such multifactorial analyses can also be applied to a non-randomised group of patients engaged in the trial of a new drug. Since the middle of the 20th century a generation of physicians have been trained to dismiss, or are incapable of evaluating the validity of a treatment beyond the established etiquette of the randomised study. This, some have argued, constitutes intellectual indolence, it is not scientific robustness. Pandits foresee that the world will be different after the end of this pandemic. Perhaps human ingenuity will seek new investigative methods that will render the randomised clinical trial obsolete, both, on methodological and ethical grounds. Until then and even if we have to accept the scientific supremacy of the randomised study in the evaluation of novel therapies, the ethical considerations in the unprecedented circumstances of a relentless pandemic demand a more humane approach, befitting the beneficent precepts of the Hippocratic tradition.