Evaluation of the Cardiovascular Risk of Naltrexone-Bupropion

The challenge of assessing the cardiovascular safety of the re- cently approved naltrexone-bupropion combination for treat- ment 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 cardiovas- cular effects of this combination medication, including eleva- tions 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 ma- jor adverse cardiovascular events had occurred. With a nonin- feriority design, the study was powered to exclude a 1.4-fold in- crease in cardiovascular risk associated with the medication.

The LIGHT protocol included a preplanned interim analy- sis after 25% of the major adverse cardiovascular events of in- terest (including cardiovascular death, nonfatal myocardial in- farction, 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 re- view is handled in confidence by the data monitoring commit- tee, without disclosure of data to the sponsor or researchers un- less 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 stud- ies is relatively new. About 8 years ago, after several medica- tions for diabetes were found to have previously unappreci- ated 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 cardio- vascular safety data had been collected.

In 2008, the FDA issued a guidance statement for the de- velopment of drugs for diabetes that reflected a creative com- promise between safety and new drug development.3 For ini- tial approval, the FDA required manufacturers to provide enough data to show that the upper limit of the 95% confidence inter- val 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 com- bined with the preapproval data in a meta-analysis, would dem- onstrate that the upper 95% confidence interval for cardiovas-

cular 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 effi- ciently, sponsors of diabetes drug trials asked the FDA for per- mission to handle both parts with a single cardiovascular safety trial. In this model, interim results would be used to secure ap- proval; 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 spon- sors, investigators, and participants in the trial as well as the actions of physicians and patients in the community. Recruit- ment 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 integ- rity 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 pre- specified end point had been met.5 This is essentially the same level of understanding that investigators have when data moni- toring 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 main- tained the confidentiality of the results, the drugs were ap- proved, and the final studies met their end points.

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