Evaluation of the Cardiovascular Risk of Naltrexone-Bupropion: A Study Interrupted.

The challenge of assessing the cardiovascular safety of the recently approved naltrexone-bupropion combination for treatment of obesity originates in the complex issues involving the LIGHT trial, published in this issue of JAMA.1 In 2011, in response to concerns regarding the cardiovascular effects of this combination medication, including elevations in blood pressure, the US Food and Drug Administration (FDA) asked the sponsor, Orexigen, to support a definitive safety study.2 Investigators designed the LIGHT study to randomize approximately 9000 patients to receive treatment with naltrexone-bupropion vs placebo and follow them up for about 5 years until approximately 400 major adverse cardiovascular events had occurred. With a noninferiority design, the study was powered to exclude a 1.4-fold increase in cardiovascular risk associated with the medication. The LIGHT protocol included a preplanned interim analysis after 25% of the major adverse cardiovascular events of interest (including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) had been accrued. The goal of this interim analysis was to assess whether naltrexone-bupropion was associated with more than a 2-fold increase in the risk of major cardiovascular events. In most clinical trials, such a review is handled in confidence by the data monitoring committee, without disclosure of data to the sponsor or researchers unless the trial needs to be stopped. In this case, however, for the purpose of initial market approval, the sponsor was also required to share the results of the LIGHT interim analysis with the FDA. The FDA’s use of interim analyses of ongoing safety studies is relatively new. About 8 years ago, after several medications for diabetes were found to have previously unappreciated cardiovascular risks, the agency faced an unappealing choice: either (1) continue to approve drugs based primarily on efficacy studies of glycemic control for diabetes and risk learning about serious cardiovascular risk after approval or (2) delay consideration of new therapies until years of cardiovascular safety data had been collected. In 2008, the FDA issued a guidance statement for the development of drugs for diabetes that reflected a creative compromise between safety and new drug development.3 For initial approval, the FDA required manufacturers to provide enough data to show that the upper limit of the 95% confidence interval for the risk ratio of the risk of cardiovascular events was less than 1.8. Then, as a condition of market approval, sponsors had to conduct a postmarketing trial that, either alone or combined with the preapproval data in a meta-analysis, would demonstrate that the upper 95% confidence interval for cardiovascular risk was less than 1.3. The new approach accepted the possibility that a medication might meet its initial end point, gain approval, and then fail its final end point—an outcome that might lead to clinical confusion and regulatory uncertainty. To implement this 2-step safety evaluation more efficiently, sponsors of diabetes drug trials asked the FDA for permission to handle both parts with a single cardiovascular safety trial. In this model, interim results would be used to secure approval; the trial would continue; and the final results would determine whether the postmarketing requirement had been met. This strategy, however, introduced a new challenge to the process: keeping the interim results confidential. The 2 primary risks associated with the release of interim results are the potential to compromise the conduct of the trial and the potential to misinterpret the results of the trial.4 Early knowledge of interim results may affect the behavior of sponsors, investigators, and participants in the trial as well as the actions of physicians and patients in the community. Recruitment or retention of trial participants may be jeopardized. If the interim results are perceived to be negative, patients in the study may be inclined to drop out of the trial or stop taking their medications. If interim results are perceived to be positive, and the medication is commercially available, physicians may steer some patients to the therapy rather than to the study. These behaviors are difficult to detect and may jeopardize the integrity of the trial. At a public hearing held by the FDA in August 2014, there was broad agreement that, assuming the trial is not being stopped, the clinical community should be able to learn no more about an interim safety analysis than that the prespecified end point had been met.5 This is essentially the same level of understanding that investigators have when data monitoring committees permit their trials to continue. The new approach to cardiovascular safety for diabetes drugs, with its statistically sound design, has increased the number of clinical trials6 and has functioned as planned for several drugs, including saxagliptin7 and alogliptin.8 In both cases, the interim analyses showed a relative risk of less than 1.8 as indicated by the FDA guidance, the companies maintained the confidentiality of the results, the drugs were approved, and the final studies met their end points. For the review of naltrexone-bupropion, the FDA agreed to a similar approach for an obesity drug for the first time. Problems first became evident in fall 2013, when the interim analysis was presented to the data monitoring committee. The committee objectedtothesponsor’sdataaccessplanonthegroundsthat“business interests do not provide a sufficient justification for gaining accesstoconfidentialinformationonefficacyorsafety. ”9 ThecomRelated article page 990 Opinion