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Whose choice is equipoise in clinical trials
Matt Morgan is an Honorary Senior Research Fellow at Cardiff University, Consultant in Intensive Care Medicine and Research and Development lead for critical care at University Hospital of Wales, and an editor of BMJ OnExamination. He is on twitter: @dr_mattmorgan. His first book “
Critical – Science and stories from the brink of life
” published in May 2019
Matt Wise is a Consultant in Intensive Care Medicine and Research and Development lead for Specialist Services at University Hospital of Wales.
Disclosures/conflicts: none. This work is original.
Paul Dark,Consultant in Critical Care Medicine, NIHR Clinical Research Network National Specialty Lead for Critical Care and Chair in Critical Care Medicine, University of Manchester. He is on twitter:
Doctors constantly strive towards what is best for patients. Good doctors try to make accountable decisions based on integration of clinical experience, medical evidence and patient preferences – a stable three legged stool that is safe to sit on. Great doctors do the same but realise that such decisions can only ever be based on the best evidence at that time. Ultimately such decisions may in the future be shown to have been wrong.
With less than one in ten interventions in critical care being based upon high quality evidence(1), we must be honest with ourselves and our patients. Although public awareness programs and quality improvement initiatives are common, these should be based upon best evidence driving knowledge translation for patient benefit. It may come as a surprise that these uncertain treatments include even simple concepts such as how much oxygen we should use when people are critically ill(2). Admitting this uncertainty about fundamental treatments can be hard.
In order to improve the care of our patients, we need to advance the evidential basis for our own practice. This involves addressing the remaining nine out of ten interventions that lack evidence head-on, challenging assumed, potentially outdated, or frankly wrong knowledge. This comes from a position of equipoise.
Even when trials are based on acknowledged evidence gaps, then funded, designed and delivered, we stumble against a new barrier -
. Whilst the trial committees, funders, ethical committees and collaborators all maintain equipoise, individual treating doctors will sometimes prevent trials from being conducted in their own institutions. Their reasons are noble - they want to do what they feel is right for patients and be early adopters. The problem is that feelings do not save lives
Things that we have felt to be right in the past have a regular habit of actually causing harm(3-5). Some people feel best in the safe, understandable and predictable world of demonstrable physiology at the bedside as an end in itself. Understand and correct the physiology and you can deliver treatments that feel right. However, whilst physiology is important, adaptive physiology in critical illness is complex and instead we need to strive towards meaningful patient outcomes as the stick by which to judge our feelings.
Getting the right balance is hard. How should “equipoise” be decided (5)? Should it be by country, by hospital, by department or by an individual? We worry that an individual’s feelings about what works and what doesn’t may negatively impact on clinical trials. They may restrict sites from contributing towards important research, reduce recruitment rates, increases the costs of research, waste public money and ultimately be bad for patients. More than 30 years ago Benjamin Freedman writing on ‘equipoise and the ethics of clinical research’ suggested that the concept of ‘clinical equipoise’ should refer to genuine uncertainty in the expert medical community rather than on the part of individual investigators(5). Despite the passage of time researchers still find themselves encountering the same issues today.
As most trials in critical care are funded from the public purse, we need an agreed solution. There should be a social responsibility for equipoise as we strive to create new evidence for patient benefit. Too often the lack of generalisable medical evidence means that complex decisions are based only on clinical experience and patient preference. The original stable, three legged stool becomes too unsteady to safely sit upon. The development of clinical research networks both in the UK and internationally can help, outsourcing difficult evidential challenges to those best placed to balance them. This allows individual clinicians to focus on the job of integrating their outputs with clinical experience and patient preference whilst allowing equipoise to answer the questions for which uncertainty presides.
1. Zhang Z, Hong Y, Liu N. Scientific evidence underlying the recommendations of critical care clinical practice guidelines: a lack of high level evidence. Intensive Care Med. Springer Berlin Heidelberg; 2018 Jul;44(7):1189–91.
2. Schjørring OL, Perner A, Wetterslev J, Lange T, Keus F, Laake JH, et al. Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU)-Protocol for a randomised clinical trial comparing a lower vs a higher oxygenation target in adults with acute hypoxaemic respiratory failure. Acta Anaesthesiologica Scandinavica. 2019 Mar 18;18(15):711.
3. Chohan SS, McArdle F, McClelland DBL, Mackenzie SJ, Walsh TS. Red cell transfusion practice following the transfusion requirements in critical care (TRICC) study: prospective observational cohort study in a large UK intensive care unit. Vox Sang. 2003 Apr;84(3):211–8.
4. Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D'Urso P, et al. Decompressive Craniectomy in Diffuse Traumatic Brain Injury. N Engl J Med. 2011 Apr 21;364(16):1493–502.
5. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987 Jul 16;317(3):141–5.