Practical psychiatry: On therapeutic equipoise - Principles of a balanced approach to psychiatric treatments.

OBJECTIVE: There are many burgeoning treatments, and a large range of therapeutic options for 21st century psychiatry. This paper briefly comments upon considerations for balancing treatment to suit the patient, their illness, and their milieu. CONCLUSIONS: Therapeutic equipoise, for psychiatric care, is an aspiration rather than a position easily achieved. In day-to-day clinical practice, there will be unexpected demands and barriers that cannot always be accommodated or surmounted. Psychiatrists can work collaboratively with patients, carers, and colleagues in conceptualising and care-planning to avoid extremes of therapeutic hubris and despair, and to adapt evidence-based care more effectively so that it is suited to the patient and their circumstances.

Ethics of Adaptive Designs for Randomized Controlled Trials.

Over recent decades, adaptive trial designs have been used more and more often for clinical trials, including randomized controlled trials (RCTs). This rise in the use of adaptive RCTs has been accompanied by debates about whether such trials offer ethical and methodological advantages over traditional, fixed RCTs. This study examined how experts on clinical trial methods and ethics believe that adaptive RCTs, compared to fixed ones, affect the ethical character of clinical research. We conducted in-depth interviews with 17 researchers from bioethics, epidemiology, biostatistics, and/or medical backgrounds. While about half believed that adaptive trials are more complex and may thus threaten autonomy, these respondents also expressed that this challenge is not insurmountable. Most respondents expressed that efficiency and potential for participant benefit were the main justifications for adaptive trials. There was tension about whether adaptive randomization in response to increasing information disrupts clinical equipoise, with some respondents insisting that uncertainty still exists and therefore clinical equipoise is not disrupted. These findings suggest that further discussion is needed to increase the awareness and utility of these study designs.

What do we talk about when we talk about "equipoise"? Stakeholder interviews assessing the use of equipoise in clinical research ethics.

INTRODUCTION: Equipoise, generally defined as uncertainty about the relative effects of the treatments being compared in a trial, is frequently referenced as an ethical standard for the conduct of randomized clinical trials. However, it seems to be defined in several different ways and may be used differently by different individuals. We explored how clinical researchers, chairs of research ethics boards, and philosophers of science define and reason with this term. METHODS: We completed semi-structured interviews about clinical trial ethics with 15 clinical researchers, 15 research ethics board chairs, and 15 philosophers of science/bioethicists. Each participant was asked a standardized set of 10 questions, 4 of which were specifically about equipoise. All interviews were conducted telephonically and transcribed. Responses were grouped and analysed via a modified grounded theory method. RESULTS: Forty-three respondents defined equipoise in 7 logically distinct ways, and 2 respondents could not explicitly define it. The most common definition, offered by 14 respondents (31%), defined "equipoise" as a disagreement at the level of a community of physicians. There was significant variability in definitions offered between and within groups. When asked how they would "operationalize" equipoise - i.e. check or test for its presence - respondents provided 7 alternatives, the most common being in relation to a literature review (15/45, 33%). The vast majority of respondents (35/45, 78%) felt the concept was helpful, though many acknowledged that the lack of a clear definition or operationalization was problematic. CONCLUSION: There is significant variation in definitions of equipoise offered by respondents, suggesting that parties within groups and between groups may be referring to different concepts when they reference "equipoise". This non-uniformity may impact fairness and transparency and opens the door to potential ethical problems in the evaluation of clinical trials - for instance, a patient may understand equipoise very differently than the researchers enrolling her in a trial, which could cause her agreement to participate to be based upon false premises.

Review of Clinical Equipoise: Examples from Oncology Trials.

BACKGROUND: The current standards that govern clinical research have been shaped over the years through many historical, social, and political events. The third principle of the Belmont Report, Justice, guides the scientific community toward the equal distribution of benefits and risks in research involving human subjects. Clinical equipoise is the status of genuine uncertainty by the investigator about the superiority of one treatment arm over the other. The term clinical equipoise was proposed to provide an ethical ground to conduct randomized controlled clinical trials. OBJECTIVE: The objective of this review is to provide the reader with an overview of the emergence of the term equipoise and its utilization in randomized controlled trials. METHODS: In the current review article, the major oncology clinical trials and relevant patents were reviewed for the application/utilization of clinical equipoise. RESULTS: The concept of clinical equipoise has been challenged, and different alternatives were proposed. Yet, these alternatives received numerous critiques and failed to fully replace equipoise. In addition, several patents related to anticancer agents tested in the described studies were examined. No specific reference was made as part of the patent to the status of clinical equipoise. Alternatively, a description of the study arms was provided. CONCLUSION: There is a need for revisiting the concept of equipoise and its suggested alternatives for its ethical essence while addressing related challenges.

Ethical considerations on placebo-controlled vaccine trials in pregnant women / Consideraciones éticas sobre los ensayos de vacunas controlados con placebo en mujeres embarazadas / Considerações éticas sobre estudos de vacina controlada com placebo em gestantes

Abstract Placebo use in clinical trials, whenever a proven effective treatment exists, is one of the most debated topics in contemporary research ethics. This article addresses the ethical framework for placebo use in clinical trials assessing vaccine efficacy in pregnant women. Vaccine trial participants are healthy at the outset and some must be infected during the study to demonstrate the product's efficacy, meaning that placebo-treated participants are under risk of serious and irreversible harm. If effective vaccines exist, such risk precludes placebo use. This interdiction should be extended to any clinical trial of vaccine efficacy in pregnant women, because a demonstration of clinical efficacy in nonpregnant individuals and comparable immunogenic responses in pregnant women are predictors of efficacy in pregnancy as well. Moreover, product effectiveness in real-world use scenarios can be ascertained by observational studies conducted after its inclusion in vaccination campaigns.

Resumen El uso de placebo en ensayos clínicos es uno de los principales temas debatidos sobre la ética en investigación contemporánea cuando existe un tratamiento eficaz probado. Este artículo aborda la ética en el uso de placebo en ensayos clínicos sobre la eficacia de vacuna en mujeres embarazadas. Las participantes en los ensayos de vacunas estaban sanas al inicio del estudio, y algunas fueron vacunadas durante el estudio para demostrar la eficacia del producto. Las participantes tratadas con placebo corren el riesgo de sufrir daños graves e irreversibles. Si existen vacunas efectivas, este riesgo impide el uso de placebo. Este impedimento debe extenderse a cualquier ensayo clínico de eficacia de vacuna en embarazadas, pues la eficacia clínica demostrada en mujeres no embarazadas y las respuestas inmunogénicas comparables con las embarazadas son predictores de eficacia en el embarazo. Además, la efectividad del producto se constata en estudios observacionales realizados tras las campañas de vacunación.

Resumo O uso de placebo em ensaios clínicos, quando um tratamento comprovadamente eficaz existe, é um dos principais tópicos debatidos na ética em pesquisa contemporânea. Este artigo aborda o quadro ético para o uso de placebo em ensaios clínicos que avaliam a eficácia de vacina em gestantes. Participantes em ensaios de vacina são saudáveis no início e alguns devem ser inoculados durante o estudo para demonstrar a eficácia do produto. Ou seja, participantes tratados com placebo estão sob risco de danos graves e irreversíveis. Se existirem vacinas eficazes, esse risco impede o uso de placebo. Essa interdição deve ser estendida a qualquer ensaio clínico de eficácia de vacina em gestantes, pois a demonstração de eficácia clínica em não gestantes e as respostas imunogênicas comparáveis em gestantes também são preditoras de eficácia na gravidez. Ademais, a eficácia do produto em cenários reais de uso pode ser verificada por estudos observacionais realizados após sua inclusão em campanhas de vacinação.

To tether or fuse? Significant equipoise remains in treatment recommendations for idiopathic scoliosis.

PURPOSE: Vertebral body tethering (VBT) continues to grow in interest from both a patient and surgeon perspective for the treatment of scoliosis. However, the data are limited when it comes to surgeon selection of both procedure type and instrumented levels. This study sought to assess surgeon variability in treatment recommendation and level selection for VBT versus posterior spinal fusion (PSF) for the management of scoliosis. METHODS: Surgeon members of the Pediatric Spine Study Group and Harms Study Group were queried for treatment recommendations and proposed upper instrumented vertebra (UIV) and lower instrumented vertebra (LIV) selection for PSF and VBT based on 17 detailed clinical vignettes. Responses were subdivided in each clinical vignette according to surgeon experience and treatment recommendations with assessment of intra-rater reliability. Binomial distribution tests were used to establish equipoise, selecting p < 0.10 to indicate the presence of a treatment choice with consensus set > 70% agreement. For treatment choice, responses were assessed first for consensus on the decision to proceed with PSF or VBT. RESULTS: Thirty-five surgeons with varied experience completed the survey with 26 surgeons (74%) completing the second follow-up survey. Overall, VBT was the recommended treatment by 47% of surgeons, ranging by clinical vignette. Consensus in treatment recommendation was present for 6 clinical vignettes including 3 for VBT and 3 for PSF, with equipoise present for the remaining 11. Of the 17 vignettes, 12 demonstrated moderate intra-observer reliability including the 3 consensus vignettes for VBT. Sanders stage ≤ 3 and smaller curve magnitude were related with VBT recommendation but neither age nor curve flexibility significantly influenced the decision to recommend VBT. Surgeons with high VBT volume, ≥ 11 VBT cases/year, were more likely to recommend VBT than those with low volumes (0-10 cases per year (p < 0.0001)). High VBT volume surgeons demonstrated consensus in VBT recommendation for Lenke 5/6 curves (75% mean recommendation). High VBT volume surgeons had a significantly higher VBT recommendation rate for Lenke 1A, 2A curves (71.8% vs 48.0%, p = 0.012), and Lenke 3 curves (62% vs 26.9%, p = 0.023). Equipoise was present for all vignettes in low volume surgeons. In addition, high VBT volume surgeons trended toward including more instrumented levels than low VBT volume surgeons (7.17 vs 6.69 levels). CONCLUSION: Significant equipoise is present among pediatric spine surgeons for treatment recommendations regarding VBT and PSF. Surgeon-, patient-, and curve-specific variables were identified to influence treatment recommendations, including surgeon experience, curve subtype, deformity magnitude, and skeletal maturity. This study highlights the need for continued research in identifying the optimal indications for VBT and PSF in the treatment of pediatric spinal deformity.

An Objective Measure of Decisional Clarity to Assess Decision Aid Effectiveness in Situations with Equipoise: A Randomized Trial.

BACKGROUND: Decision aids can help patients make medical decisions, which is especially advantageous in situations with equipoise. However, when there is no correct answer, it is difficult to assess whether a decision aid is helpful. The goal of this research is to propose and validate an objective method for measuring decision aid effectiveness by quantifying the clarity participants achieved when making decisions. DESIGN: The measure of decisional clarity was tested in a convenience sample of 131 college-aged students making hypothetical decisions about 2 treatment options for depression and anxiety. The treatments varied with respect to potential benefits and harms. Information was presented numerically or with an accompanying data visualization (an icon array) that is known to aid decision making. RESULTS: Decisional clarity was better with the icon arrays. Furthermore, the results showed that decisional clarity can be used to identify situations for which patients will be more likely to struggle making their decision. These included situations for which financial considerations were relevant to the decision and situations for which the probabilities of potential benefits were higher. LIMITATIONS: The measure of decisional clarity and the situations identified as lacking clarity should be validated with a larger, more representative sample. CONCLUSIONS: These findings demonstrate that decisional clarity can be used to both empirically evaluate the effectiveness of a decision aid as well as test factors that can cloud clarity and disrupt medical decision making. IMPLICATIONS: Researchers and medical providers interested in developing decision aids for situations with equipoise can use decisional clarity as an objective measure to assess the effectiveness of their decision aid. Financial considerations and higher probabilities may also cloud judgments. HIGHLIGHTS: An objective measure of decisional clarity is supported.Decisional clarity can be used to evaluate decision aids in the context of equipoise for which there is no objectively correct choice.Decisional clarity can also be used to identify scenarios for which patients are likely to struggle to make a medical decision.

The PReliMinAry (Pain Relief in Major Amputation) Survey.

OBJECTIVES: Major Lower Limb Amputation (MLLA) is associated with significant peri- and post-operative pain and has been identified as a research priority by patient and healthcare groups. The PReliMinAry survey was designed to evaluate existing MLLA analgesia strategies; identifying areas of equipoise and informing future research. METHODS: A targeted multi-national, multi-disciplinary survey was conducted via SurveyMonkey® (October 5, 2020-November 3, 2020) and advertised via social media and society email lists. The 10-questions explored 'pain-team' services, pre-operative neuroleptic medication, pre-incision peripheral nerve blocks and catheters, surgically placed nerve catheters, post-operative adjunctive regimens, future research engagement and equipoise. RESULTS: Seventy-six responses were received from 60 hospitals worldwide. Twelve hospitals(20%) had a dedicated MLLA pain team, 7(12%) had none. Most pain teams (n = 52; 87%) assessed pain with a 0-10 numerical rating scale. Over half of respondents "never" preloaded patients with oral neuroleptic agents(n= 42/76; 55%). Forty-seven hospitals(78%) utilized patient controlled opioid analgesia. Most hospitals are able to provide pre-incision loco-regional peripheral nerve blocks, nerve catheters and surgical nerve catheters (95%, 77%, and 90% respectively), but use was variable. Ultrasound(US) guided peripheral nerve catheters were "infrequently" or "never" used in 57% of hospitals, whilst 23% "infrequently" or "never" utilize surgically placed nerve catheters. CONCLUSIONS: The survey revealed a preference towards 'single-shot' nerve blocks and surgical catheters. A difference between the use of US guided nerve catheters and those surgically placed likely reflects the difference of literature evaluating these techniques. Most respondents felt there was equipoise surrounding future trials evaluating nerve blocks/catheters, but less so for surgical catheters.

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.