The TOTAL trial dilemma: A survey among professionals on equipoise regarding fetal therapy for severe congenital diaphragmatic hernia.

OBJECTIVE: Running randomized clinical trials (RCT) in fetal therapy is challenging. This is no different for fetoscopic endoluminal tracheal occlusion (FETO) for severe left-sided Congenital Diaphragmatic Hernia (CDH). We assessed the knowledge, attitude and practice (KAP) of maternal-fetal medicine specialists toward the antenatal management of CDH, and the randomized controlled clinical (RCT) "Tracheal Occlusion To Accelerate Lung growth-trial." METHODS: A cross-sectional KAP-survey was conducted among 311 registrants of the 18th World Congress in Fetal Medicine. RESULTS: The overall knowledge of CDH and FETO was high. Remarkably only 45% considers prenatal prediction of neonatal outcome reliable. Despite, in their clinical practice they perform severity assessment (80%) and refer families for FETO either within the context of an RCT (43%) or on patient request (32%). Seventy percent perceives not offering FETO on patient demand seems as if no treatment is provided to a fetus with predicted poor outcome. Only 20% of respondents considers denying access to FETO on patient demand not as a psychological burden. CONCLUSION: Often the views of individual respondents contradicted with their clinical practice. It seems that, for severe CDH, clinicians face personal and practical dilemmas that undermine equipoise. To us, this indicates the tension between the clinical and scientific obligations physicians experience.

[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.

Clinician-researchers and custodians of scarce resources: a qualitative study of health professionals' views on barriers to the involvement of teenagers and young adults in cancer trials.

BACKGROUND: Equipoise and role conflict have been previously identified as important factors in professionals' engagement with trials, inducing behaviours which can impact on recruitment. We explored these phenomena as potential explanations for the low levels of involvement of teenagers and young adults (TYA) with cancer in clinical trials in oncology. METHODS: We report findings from interviews with 30 purposively sampled direct-care professionals involved in delivering cancer care and/or facilitating clinical trials in Scotland. We undertook qualitative descriptive analysis, focussed on identifying key issues and themes. RESULTS: Interviewees largely identified as clinician-researchers and portrayed oncology as a specialty in which research was integral to care. They saw their primary responsibility as ensuring patients received the best treatment, but asserted that, in general, trials provided a vehicle for optimal care. Role conflict in its traditional form was rarely evident; however, other tensions were manifest. Professionals found the significant time costs of delivering trials difficult to reconcile with the increasing pressures on clinical services. They felt a responsibility to make prudent choices about the trials with which to engage. Guided by utilitarian principles, these choices were oriented towards benefiting the largest number of patients. This favoured trials in high volume diseases; as TYA tend to have rarer forms of cancer, professionals' support for-and TYA's access to-relevant trials was, by default, more limited. CONCLUSIONS: Neither lack of individual equipoise nor experiences of traditional forms of role conflict accounted for the low levels of involvement of TYA with cancer in clinical trials. However, prominent tensions around the management of scarce resources provided an alternative explanation for TYA's limited access to cancer trials. The prevailing approach to decision-making about whether and which trials to support was recognised as contributing to inequalities in access and care. Professionals' choices, however, were made in the context of scarcity, and structured by incentives and sanctions understood by them as signalling governmental priorities. A franker discussion of the extent and distribution of the costs and benefits of trials work is needed, for change to be achieved.

[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.

The Real-World Ethics of Adaptive-Design Clinical Trials.

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical trials are conducted. Policy-makers are swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs.

Stakeholders' views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs.

BACKGROUND: We explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders' attitudes towards the implementation of pragmatic trials in the drug development process. METHODS: We conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients' organizations) through telephone or face-to-face sessions. Interviews were structured around the question "what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials." Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets. RESULTS: We interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with "real-world" practice reducing the knowledge value of trial results. CONCLUSIONS: We identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.

Equipoise between radial artery and right internal thoracic artery as the second arterial conduit in left internal thoracic artery-based coronary artery bypass graft surgery: a multi-institutional study†.

OBJECTIVES: Multiple arterial coronary artery grafting (MABG) improves long-term survival compared with single arterial CABG (SABG), yet the best second arterial conduit to be used with the left internal thoracic artery (LITA) remains undefined. Outcomes in patients grafted with radial artery (RA-MABG) versus right internal thoracic artery (RITA-MABG) as the second arterial graft were compared with SABG. METHODS: Multi-institutional, retrospective analysis of non-emergent isolated LITA to left anterior descending coronary artery CABG patients was performed using institutional Society of Thoracic Surgeon National Adult Cardiac Surgery Databases. 4484 (54.5%) SABG [LITA ± saphenous vein grafts (SVG)], 3095 (37.6%) RA-MABG (RA ± SVG) and 641 (7.9%) RITA-MABG (RITA ± SVG) patients were included. The RITA was used as a free (68%) or in situ (32%) graft. RA grafts were principally anastomosed to the ascending aorta. Long-term survival was ascertained from US Social Security Death Index and institutional follow-up. Triplet propensity matching and covariate-adjusted multivariate logistic regression were used to adjust for baseline differences between study cohorts. RESULTS: Compared with the SABG cohort, the RITA-MABG cohort was younger (58.6 ± 10.2vs65.9 ± 10.4, P < 0.001), had a higher prevalence of males (87% vs 65%, P < 0.001) and was generally healthier (MI: 36.7% vs 56.7%, P < 0.001, smoking: 56.8% vs 61.1%, IDDM: 3.0% vs 14.4%, CVA: 2.6% vs 10.0%). The RA-MABG cohort was generally characterized by a risk profile intermediate to that of SABG and RlTA-MABG. Unadjusted 5-, 10- and 15-year survival rates were best in RITA-MABG (95.2%, 89% and 82%), intermediate in RA-MABG (89%, 74%, 57%) and worst in SABG (82%, 61% and 44%) cohorts (all P < 0.001). Propensity matching yielded 551 RA-MABG, RITA-MABG and SABG triplets, which showed similar 30-day mortality. Late survival (16 years) was equivalent in the RA-MABG and RITA-MABG cohorts [68.2% vs 66.7%, P = 0.127, hazard ratio (HR) = 1.28 (0.96-1.71)] and both significantly better than SABG (61.1%). The corresponding SABG versus RITA-MABG and SABG versus RA-MABG HRs (95% confidence interval) were 1.52 (1.18-1.96) and 1.31 (1.01-1.69) with P < 0.002 and P = 0.038, respectively. CONCLUSIONS: RA-MABG or RITA-MABG equally improve long-term survival compared with SABG and thus should be embraced by the Heart Team as the therapy of choice in LITA-based coronary artery bypass surgery.

Logistic, ethical, and political dimensions of stepped wedge trials: critical review and case studies.

BACKGROUND: Three arguments are usually invoked in favour of stepped wedge cluster randomised controlled trials: the logistic convenience of implementing an intervention in phases, the ethical benefit of providing the intervention to all clusters, and the potential to enhance the social acceptability of cluster randomised controlled trials. Are these alleged benefits real? We explored the logistic, ethical, and political dimensions of stepped wedge trials using case studies of six recent evaluations. METHODS: We identified completed or ongoing stepped wedge evaluations using two systematic reviews. We then purposively selected six with a focus on public health in high, middle, and low-income settings. We interviewed their authors about the logistic, ethical, and social issues faced by their teams. Two authors reviewed interview transcripts, identified emerging issues through qualitative thematic analysis, reflected upon them in the context of the literature, and invited all participants to co-author the manuscript. RESULTS: Our analysis raises three main points. First, the phased implementation of interventions can alleviate problems linked to simultaneous roll-out, but also brings new challenges. Issues to consider include the feasibility of organising intervention activities according to a randomised sequence, estimating time lags in implementation and effects, and accommodating policy changes during the trial period. Second, stepped wedge trials, like parallel cluster trials, require equipoise: without it, randomising participants to a control condition, even for a short time, remains problematic. In stepped wedge trials, equipoise is likely to lie in the degree of effect, effectiveness in a specific operational milieu, and the balance of benefit and harm, including the social value of better evaluation. Third, the strongest arguments for a stepped wedge design are logistic and political rather than ethical. The design is advantageous when simultaneous roll-out is impractical and when it increases the acceptability of using counterfactuals. CONCLUSIONS: The logistic convenience of phased implementation is context-dependent, and may be vitiated by the additional requirements of phasing. The potential for stepped wedge trials to enhance the social acceptability of cluster randomised trials is real, but their ethical legitimacy still rests on demonstrating equipoise and its configuration for each research question and setting.

Ethical considerations for outcome-adaptive trial designs: a clinical researcher's perspective.

In a typical comparative clinical trial the randomization scheme is fixed at the beginning of the study, and maintained throughout the course of the trial. A number of researchers have championed a randomized trial design referred to as 'outcome-adaptive randomization.' In this type of trial, the likelihood of a patient being enrolled to a particular arm of the study increases or decreases as preliminary information becomes available suggesting that treatment may be superior or inferior. While the design merits of outcome-adaptive trials have been debated, little attention has been paid to significant ethical concerns that arise in the conduct of such studies. These include loss of equipoise, lack of processes for adequate informed consent, and inequalities inherent in the research design which could lead to perceptions of injustice that may have negative implications for patients and the research enterprise. This article examines the ethical difficulties inherent in outcome-adaptive trials.

Ethics and eplerenone.

The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies.

Clinical equipoise and risk-benefit assessment.

Clinical equipoise is widely regarded as an ethical requirement for the design and conduct of randomized controlled trials (RCTs). Underlying clinical equipoise is the norm that no patient should be randomized to treatment known (or believed by the expert clinical community) to be inferior to the established standard of care. This implies that patient-subjects should not be exposed to net risks in control groups of randomized trials - risks that are not compensated by the prospect of direct medical benefits from the control intervention. However, proponents of clinical equipoise have no moral objections to permitting net risks for 'nontherapeutic' research procedures employed in clinical trials. This differential assessment makes risk-benefit assessment of randomized trials incoherent. In this article, I examine critically four arguments in defense of clinical equipoise as a requirement for risk-benefit assessment. Each of these arguments fails to support clinical equipoise, leading to the conclusion that we should dispense with this principle in risk-benefit assessment of RCTs.

Ethical issues in the design of randomized trials: to sham or not to sham.

The placebo effect is based on the expectations of the patient regarding the effectiveness of the treatment. The high levels of stress and rituals involved with surgery can lead to a strong placebo effect. However, the ethical principles of performing sham surgery to measure any placebo effect have been questioned, and sham-controlled surgical trials are rarely conducted. While there are a number of ethical principles that must be considered to justify the implementation of a sham-controlled surgical clinical trial, four areas deserve particular attention: equipoise, risk minimization, informed consent, and deception. Particularly in orthopaedics, where equipoise is common, sham-controlled trials may be important to ensure that inferior or ineffective treatments do not become standard practice.

How good is "good enough"? The case for varying standards of evidence according to need for new interventions in HIV prevention.

In 2010, randomized controlled trials (RCTs) of two different biomedical strategies to prevent HIV infection had positive findings. However, despite ongoing very high levels of HIV infection in some countries and population groups, it has been made clear by regulatory authorities that the evidence remains insufficient to support either product being made available outside of research contexts in the developing world for at least two years. In addition, prevention trials in endemic areas will continue to test new interventions against placebo. But the judgments of evidentiary standards are never value-neutral. Using the recent trials and their contexts as case studies, we examine the basis for these decisions, which will potentially delay access to scientific innovation to the people who are most urgently in need of it.