Uses of equipoise in discussions of the ethics of randomized controlled trials of COVID-19 therapies.

BACKGROUND: Early in the COVID-19 pandemic, the urgent need to discover effective therapies for COVID-19 prompted questions about the ethical problem of randomization along with its widely accepted solution: equipoise. In this scoping review, uses of equipoise in discussions of randomized controlled trials (RCT) of COVID-19 therapies are evaluated to answer three questions. First, how has equipoise been applied to COVID-19 research? Second, has equipoise been employed accurately? And third, do concerns about equipoise pose a barrier to the ethical conduct of COVID-19 RCTs? METHODS: Google Scholar and Pubmed were searched for articles containing substantial discussion about equipoise and COVID-19 RCTs. 347 article titles were screened, 91 full text articles were assessed, and 48 articles were included. Uses of equipoise were analyzed and abstracted into seven categories. RESULTS AND DISCUSSION: Approximately two-thirds of articles (33/48 articles) used equipoise in a way that is consistent with the concept. They invoked equipoise to support (1) RCTs of specific therapies, (2) RCTs in general, and (3) the early termination of RCTs after achieving the primary outcome. Approximately one-third of articles (15/48 articles) used equipoise in a manner that is inconsistent with the concept. These articles argued that physician preference, widespread use of unproven therapies, patient preference, or expectation of therapeutic benefit may undermine equipoise and render RCTs unethical. In each case, the purported ethical problem can be resolved by correcting the use of equipoise. CONCLUSIONS: Our findings highlight the continued relevance of equipoise as it supports the conduct of well-conceived RCTs and provides moral guidance to physicians and researchers as they search for effective therapies for COVID-19.

[Covid-19 and clinical-epidemiological research in Italy: proposal of a research agenda on priority topics by the Italian association of epidemiology]. / Covid-19 e ricerca clinico-epidemiologica in Italia: proposta di un'agenda di ricerca su temi prioritari da parte dell'Associazione italiana di epidemiologia.

BACKGROUND: the Covid-19 pandemic has provoked a huge of clinical and epidemiological research initiatives, especially in the most involved countries. However, this very large effort was characterized by several methodological weaknesses, both in the field of discovering effective treatments (with too many small and uncontrolled trials) and in the field of identifying preventable risks and prognostic factors (with too few large, representative and well-designed cohorts or case-control studies). OBJECTIVES: in response to the fragmented and uncoordinated research production on Covid-19, the   italian Association of Epidemiology (AIE) stimulated the formation of a working group (WG) with the aims of identifying the most important gaps in knowledge and to propose a structured research agenda of clinical and epidemiological studies considered at high priority on Covid-19, including recommendations on the preferable methodology. METHODS: the WG was composed by 25 subjects, mainly epidemiologists, statisticians, and other experts in specific fields, who have voluntarily agreed to the proposal. The agreement on a list of main research questions and on the structure of the specific documents to be produced were defined through few meetings and cycles of document exchanges. RESULTS: twelve main research questions on Covid-19 were identified, covering aetiology, prognosis, interventions, follow-up and impact on general and specific populations (children, pregnant women). For each of them, a two-page form was developed, structured in: background, main topics, methods (with recommendations on preferred study design and warnings for bias prevention) and an essential bibliography. CONCLUSIONS: this research agenda represents an initial contribution to direct clinical and epidemiological research efforts on high priority topics with a focus on methodological aspects. Further development and refinements of this agenda by Public Health Authorities are encouraged.

Preserving equipoise and performing randomised trials for COVID-19 social distancing interventions.

In the coronavirus disease 2019 (COVID-19) pandemic, a large number of non-pharmaceutical measures that pertain to the wider group of social distancing interventions (e.g. public gathering bans, closures of schools, workplaces and all but essential business, mandatory stay-at-home policies, travel restrictions, border closures and others) have been deployed. Their urgent deployment was defended with modelling and observational data of spurious credibility. There is major debate on whether these measures are effective and there is also uncertainty about the magnitude of the harms that these measures might induce. Given that there is equipoise for how, when and if specific social distancing interventions for COVID-19 should be applied and removed/modified during reopening, we argue that informative randomised-controlled trials are needed. Only a few such randomised trials have already been conducted, but the ones done to-date demonstrate that a randomised trials agenda is feasible. We discuss here issues of study design choice, selection of comparators (intervention and controls), choice of outcomes and additional considerations for the conduct of such trials. We also discuss and refute common counter-arguments against the conduct of such trials.

Restarting Orthopaedic Care in a Pandemic: Ethical Framework and Case Examples.

The question about how to resume typical orthopaedic care during a pandemic, such as coronavirus disease 2019, should be framed not only as a logistic or safety question but also as an ethical question. The current published guidelines from surgical societies do not explicitly address ethical dilemmas, such as why public health ethics requires a cessation of nonemergency surgery or how to fairly allocate limited resources for delayed surgical care. We propose ethical guidance for the resumption of care on the basis of public health ethics with a focus on clinical equipoise, triage tiers, and flexibility. We then provide orthopaedic surgery examples to guide physicians in the ethical resumption of care.

[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.