Validity of enriched enrollment, randomized withdrawal trials.

Letter To Editor: It is with interest that we read the article by Moore et al., “Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain: a new framework for design and reporting,” published in the August 2015 issue of PAIN. The authors concluded that, enriched enrolment, randomised withdrawal trials (EERW), if properly designed, conducted, and reported, are entirely appropriate in the context of chronic pain for explaining whether a treatment is efficacious and for pragmatically supporting decisions over its use. Studies using EERW in pain are likely to map onto clinical practice, and therefore, promise greater translational impact. However, we believe that trial efficacy could be easily inflated by the methodology of EERW. Like Moore et al. acknowledged, “Because most of the drug interventions tested were associated with significant central nervous system adverse events, it is likely that patients would recognise an abrupt change to placebo on randomisation, and this could affect their pain response. ” Because there was no standard on how gradual the medication taper should be, ie, some did and others did not, medication withdrawal in the placebo arm could very likely amplify the therapeutic differences between drug group and placebo group, reflected by more patients in the placebo arm prematurely withdrawing from the trial (either for lack of efficacy or intolerable side effects) or reporting negative experiences at the end of the trial. We believe that not only that this could widen the analgesic differences between the placebo and drug groups but also expand the “reported” adverse events within the placebo arm. Interestingly, Furlan et al. conducted a study to compare results from EERW trials and non-EERW trials of opioids for chronic noncancer pain. They found no differences in efficacy between EERW and non-EERW trials; however, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness, or dry skin/itching compared with non-EERW trails. We wonder if any of the reported adverse events were contributed by withdrawal symptoms, as these individuals had already gone through the open-label titration selection. The rise of personalizedmedicinemightmake itmore difficult to defend gold standards of randomized controlled trials (RCTs) in diagnostic and in therapeutic practice. Personalized medicine refocuses clinical attention away from the “typical” patients analyzed by RCTs onto the idiosyncrasies, genetic or otherwise, of individual patients. In a recent article by Nicholas J. Schork, entitled “Personalized medicine: Time for one-person trials,” published in the April 2015 Issue of “Nature,” he opined, “Classical clinical trials harvest a handful of measurements from thousands of people. Precisionmedicine requires different ways of testing interventions. Studies that focus on a single person, known as N-of-1 trials, will be a crucial part of the mix. Aggregated results of many N-of-1 trials, all performed in the same way, will offer information about how to better treat subsets of the population or even the population at large. ” We wonder whether EERW may represent a meaningful comprise between classical randomized clinical trials and newly emerging N-of-1 trials. Obviously, using standardized protocols guide, the tapering off of all centrally acting drugs before switching to placebo may be an important step to improving the validity of EERW trials.