title: The paradox of equipoise: the principle that drives and limits therapeutic discoveries in clinical research.
abstract: 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.
authors.affiliation: Center for Evidence-Based Medicine and Health Outcomes Research and the Clinical Translational Science Institute, the University of South Florida, Tampa, Florida 33612, USA. bdjulbeg@health.usf.edu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Djulbegovic
mesh_terms: D006801:Humans; D010358:Patient Participation; D016032:Randomized Controlled Trials as Topic / Q000941:ethics* / Q000379:methods*; D012107:Research Design