The Prompted Optional Randomization Trial: A New Design for Comparative Effectiveness Research

Randomized controlled trials are the gold standard for medical evidence because randomization provides the best-known protection against confounding of results.Randomization has practical and ethical problems that limit the number of trials that can be conducted, however. A different method for collecting clinical data retains the statistically useful properties of randomization without incurring its practical and ethical challenges.A computerized prompt introduces a random element into clinical decision-making that can be instantly overridden if it conflicts with optimal patient care. This creates a weak form of randomization that still eliminates the effect of all confounders, can be carried out without disturbing routine clinical care, and arguably will not require research-grade informed consent.Clinicians who care for patients with common chronic diseases such as diabetes, hypertension, and dyslipidemia often must choose among multiple drugs with similar indications. For example, although solid clinical trial data establish that a diabetic who is inadequately treated by metformin will have better glycemic control with the addition of either a sulfonylurea or a dipeptidyl peptidase-4 inhibitor, data on which combination is more effective are lacking.1 Without randomized controlled trials that make the direct comparison, clinicians have to rely on anecdote, expert opinion, and observational cohort studies to choose between these two drug classes. Because these choices differ significantly in their potential cost and may lead to different clinical outcomes, policymakers and researchers increasingly call for comparative effectiveness research designed to inform this kind of decision.2Anecdote and expert opinion rank at the bottom of the hierarchy of evidence.3 Cohort studies rank higher, and they are easy to conduct because they simply observe the outcomes associated with exposure to a treatment and do not intrude into clinical decision-making. But this simplicity comes with the cost of increased vulnerability to bias and confounding, particularly confounding by indication.4,5 Confounding by indication occurs when exposure to treatment is associated with both measured and unmeasured qualities of the patient, such as the underlying severity of disease. If patients with more severe disease tend to receive a particular treatment, that treatment may falsely appear to cause worse outcomes. Development of better databases and methodologies, such as propensity scores and instrumental variables, has attempted to address this problem, but the randomized controlled trial remains by far the most trusted technique for eliminating confounding and bias.3,4Randomized controlled trials are not available to answer many clinical questions because of the effort and expense involved and the ethical problems created by randomization. Randomization intrudes directly into a clinician’s prescribing decisions. It means exchanging a personalized treatment decision for one made by chance. Under most circumstances, patients should give informed consent for research before being randomized. Even with informed consent, ethicists debate when random assignment can be ethical. One influential standard, clinical equipoise, holds that randomization can be ethical as long as no consensus exists in the clinical community that one treatment is better than the other. This is in contrast to the more stringent standard, personal equipoise, which calls for each individual investigator to have no treatment preference at all.6These practical and ethical concerns may make some useful randomized controlled trials infeasible. Suppose clinicians want to know whether drug A or drug B is a more effective treatment for diabetes. In a network of outpatient clinics, the choice between A and B might be made hundreds of times a year, enough to support a well-powered clinical trial. However, approaching hundreds of patients to determine eligibility, recruit them, and obtain informed consent would be expensive and disruptive to clinical care. Furthermore, physicians might decline to participate because they want to make an individualized choice for many of their patients.If the question is sufficiently important clinically or the financial stakes are high enough, these barriers will be overcome. However, for many questions of modest but real importance, the need to obtain informed consent and ensure equipoise may be enough to prevent anybody from conducting a randomized controlled trial. This fact has preoccupied clinical researchers for many years.7 The current sense that comparative effectiveness research is a crucial tool for policymakers to contain health care costs and clinicians to make evidence-based decisions only makes the issue more acute.2 Ethical standards cannot be compromised, but any way to make high-quality clinical research easier while still fully protecting patients would be valuable.