Research Article: Considering Usual Medical Care in Clinical Trial Design

Date Published: September 29, 2009

Publisher: Public Library of Science

Author(s): Liza Dawson, Deborah A. Zarin, Ezekiel J. Emanuel, Lawrence M. Friedman, Bimal Chaudhari, Steven N. Goodman

Abstract: Liza Dawson and colleagues discuss the scientific and ethical issues associated with choosing clinical trial designs when there is no consensus on what constitutes usual care.

Partial Text: In 2002, a clinical trial designed to evaluate optimal ventilation practice [1],[2] for patients with acute respiratory distress syndrome (ARDS) sparked a major controversy. Critics charged that management of ARDS in the different arms of the study did not adequately reflect usual medical care, and alleged that it was essential for scientific and ethical reasons to have a usual care comparison arm in the study. The controversy over trial design enmeshed the National Institutes of Health (NIH), the Office for Human Research Protections (OHRP) and the critical care research community. The trial was put on hold and reviewed by two independent expert panels. Experts pointed to the need for further analysis of the scientific and ethical issues involved in choosing trial designs when there is no consensus on standard of care.

There may be scientific, ethical, and/or practical reasons for having an arm in a clinical trial that employs usual care. If researchers hypothesize that a new intervention is better than or at least equivalent to current clinical practice, then one trial arm needs to reflect usual care. Ethically, the clinical care community must be in a state of equipoise prior to randomizing patients to different interventions [3], although there is no universal view on how to evaluate or resolve disagreements on the existence of equipoise in a particular scenario. If clinicians or investigators believe that usual care is effective, a usual care comparison may increase trial acceptability. A usual care arm might improve relevance, external validity, or the practicality of the study.

Five types of difficulties can arise in defining a comparison group, and several of these conditions often coexist: (1) disputes about evidence; (2) low level of utilization of best methods; (3) trade-offs relating to physician and patient preferences for different treatments; (4) an insufficient preexisting evidence base to guide treatment selection; and (5) individually customized medical care for conditions with no standard practice guidelines.

Experts may disagree about interpretation of the available evidence and about whether current treatments have been validated by research (Box 1). This lack of consensus on which treatments should be considered “standard” can lead to divergent views on the selection of a comparison group, and more fundamentally, dispute about what research question is most relevant [7],[8].

Proven interventions may not be widely used [9] because of low physician confidence or knowledge, difficulty in implementation, cost, side effects, or patient heterogeneity.

Two or more treatments for a single condition may be characterized by different profiles of performance across different measures or side effects. Regimens can be chosen on the basis not only of effectiveness but also side effects or quality of life [13],[14]. Treatment choices may be made on the basis of disease or patient characteristics, on physician or patient preferences, or all of these factors (Box 3).

Often, treatments used in clinical practice have been insufficiently evaluated in rigorous clinical trials. This problem may occur with non-drug interventions or with drugs that have not been tested against relevant comparators. Clinical trial data may be scanty, of poor quality, or based on irrelevant patient populations; many treatments have not been systematically evaluated in randomized clinical trials (RCTs) [20]–[22]. With this lack of evidence it may not be clear which treatment is preferable, or even if a given treatment is better or worse than nothing.

Selection of customized treatment based on physician assessment of individual patient characteristics [24] can lead to scientific and practical challenges in measuring effectiveness in clinical trials [25]. When many patient characteristics are relevant, it would require impossibly large trials to encompass all the stratified patient subgroups needed to individually test all the factors used in decision-making. In such situations, physicians may object to protocolized usual care treatment groups in clinical trials, based on a belief that physician discretion in treatment choices provides superior outcomes [26]–[33]. In addition, data, especially from explanatory trials, come from carefully selected populations that differ in major ways from patients treated in the community.

The choice of comparison arms in clinical trials can be challenging when there is no clear-cut uniform standard of care. A variety of non-mutually exclusive factors can feed the lack of consensus: differing interpretations of existing evidence, inadequate evidence, different balancing of trade-offs, a failure or inability to implement evidence-based therapies, or a belief in customized care.



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