October 2009, Vol. 16, No. 4 342 Cancer Control Background: Progress in clinical medicine relies on the willingness of patients to take part in experimental clinical trials, particularly randomized controlled trials (RCTs). Before agreeing to enroll in clinical trials, patients require guarantees that they will not knowingly be harmed and will have the best possible chances of receiving the most favorable treatments. This guarantee is provided by the acknowledgment of uncertainty (equipoise), which removes ethical dilemmas and makes it easier for patients to enroll in clinical trials. Methods: Since the design of clinical trials is mostly affected by clinical equipoise, the “clinical equipoise hypothesis” has been postulated. If the uncertainty requirement holds, this means that investigators cannot predict what they are going to discover in any individual trial that they undertake. In some instances, new treatments will be superior to standard treatments, while in others, standard treatments will be superior to experimental treatments, and in still others, no difference will be detected between new and standard treatments. It is hypothesized that there must be a relationship between the overall pattern of treatment successes and the uncertainties that RCTs are designed to address. Results: An analysis of published trials shows that the results cannot be predicted at the level of individual trials. However, the results also indicate that the overall pattern of discovery of treatment success across a series of trials is predictable and is consistent with clinical equipoise hypothesis. The analysis shows that we can discover no more than 25% to 50% of successful treatments when they are tested in RCTs. The analysis also indicates that this discovery rate is optimal in helping to preserve the clinical trial system; a high discovery rate (eg, a 90% to 100% probability of success) is neither feasible nor desirable since under these circumstances, neither the patient nor the researcher has an interest in randomization. This in turn would halt the RCT system as we know it. Conclusions: The “principle or law of clinical discovery” described herein predicts the efficiency of the current system of RCTs at generating discoveries of new treatments. The principle is derived from the requirement for uncertainty or equipoise as a precondition for RCTs, the precept that paradoxically drives discoveries of new treatments while limiting the proportion and rate of new therapeutic discoveries. From the Center for Evidence-Based Medicine and Health Outcomes Research and the Clinical Translational Science Institute at the Uni- versity of South Florida, Tampa, Florida, and the Departments of Malig- nant Hematology and Health Outcomes and Behavior at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted January 9, 2009; accepted May 11, 2009. Address correspondence to Benjamin Djulbegovic, MD, PhD, USF Health Clinical Research, 12901 Bruce B. Downs Blvd, MDC02, Tampa, FL 33612. E-mail: bdjulbeg@health.usf.edu Dr Djulbegovic receives grant/research support from the Research Program on Research Integrity, Office of Research Integrity, and National Institutes of Health (grants: No 1R01NS044417-01, 1 R01 NS052956-01, and 1R01CA133594-01 NIH/ORI). Funding agencies had no role in the preparation, review, or approval of this manu- script. Dr Djulbegovic reports no significant relationship with the companies/organizations whose products or services may be ref- erenced in this article. trials. Clinical trials, particularly well-designed random- ized controlled trials (RCTs), are widely considered to be the most important vehicle for generating evidence about successful treatments that can improve disease and patient outcomes. 2 Before agreeing to enroll in clin- ical trials, patients require guarantees that they will not knowingly be harmed and will have an optimal chance of receiving the best available treatments. The patient knows that a researcher cannot guarantee favorable out- comes. Nevertheless, researchers usually have a premo- nition that one treatment will be more effective than the other; otherwise, they would never embark on the par- ticular trial. However, researchers cannot test all their ideas in RCTs; they are constrained by ethical precepts and pragmatic limitations. A key ethical precept is that an RCT should be done only if the physicians and patients are uncertain about the relative effects of the new and standard treatments to be compared. 3 This requirement for uncertainty 4,5 represents a fundamental principle that protects patients from knowingly being exposed to infe- rior treatments, while at the same time drives therapeutic advances in clinical medicine, as discussed below. Introduction In its article #4, the Declaration of Helsinki 1 states: “Medical progress is based on research which ulti- mately must rest in part on experimentation involv- ing human subjects.” Indeed, progress and discoveries cannot occur with- out the willingness of patients to be enrolled in clinical The Paradox of Equipoise: The Principle That Drives and Limits Therapeutic Discoveries in Clinical Research Benjamin Djulbegovic, MD, PhD Special Report Cancer Control Journal of the Moffitt Cancer Center ®