Controversial, Ill-Fated Obesity Drug Trial Published In JAMA

The final– but now largely useless– results of the cardiovascular safety trial of the obesity drug Contrave have now been published in JAMA, one year after the trial’s dramatic and scandalous crash and burn.

By way of background: Contrave is a combination of naltrexone and bupropion marketed as a weight loss drug by Orexigen and Takeda. It was approved by the FDA in 2014 and was the first obesity drug to be approved on the basis of a novel FDA program in which obesity and diabetes drugs could gain approval before final results were available from a cardiovascular outcomes trial (CVOT). Instead, approval was dependent on a pre-specified interim analysis of LIGHT, a CVOT which was designed to rule out a significant increase in cardiovascular risk.

Problems emerged when the trial’s data and monitoring committee performed its first interim analysis after the 9,000-patient trial had reached 25% of its primary endpoint events (major adverse cardiovascular events). This analysis contained only 94 events: 59 in the placebo group and 35 in the Contrave group, representing a highly promising but extremely tenuous 41% reduction in relative risk. The results were supposed to be held in strict confidence, but Orexigen shared them with over one-hundred people both within and outside the company. When the FDA found out about the leak they  said that the trial should continue but that a second additional cardiovascular outcomes trial would have to be performed.

But then the problem got worse. Way worse. Last year in March the results of the interim analysis were made public– and provoked a firestorm– when Orexigen included the interim results in a patent application.  Orexigen’s stock price spiked immediatley after the interim data became known– provoking suspicions that this had been the motivation all along for the company’s actions. But the negative reaction to the premature disclosure of the data was overwhelming. In May the trial’s executive committee said the trial had been impossibly compromised and announced that the trial would be prematurely terminated. Following the brief spike the stock price has since dropped precipitously, as the negative impacts of the scandal have become apparent.

The newly published results in JAMA indicate that the early highly promising findings from the trial were very unlikely to be confirmed if the trial had continued to the end. In the new analysis, which includes 50% of the originally planned endpoint events, there were 102 endpoint events in the placebo group and 90 events in the treatment group, representing a much more modest 12% reduction in relative risk (p=ns), indicating “that any potential benefit suggested in the earlier analysis was no longer apparent.”

Further, the investigators wrote, this finding “does not establish non-inferiority for the prespecified margin of 1.4,” which was the main object of the trial. In other words, because of the early termination the trial was unable to either confirm or deny whether Contrave met the predetermined criteria for cardiovascular safety. “Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial,” the investigators concluded.

The Dark Tunnel At The End Of LIGHT

The authors reflected on some of the many issues raised by the whole episode. One key issue is trial confidentiality: “The events leading to the termination of the study serve as a valuable reminder of the importance of maintaining confidentiality during ongoing trials. Premature release of interim data can result in inappropriate prejudgment about the benefits or risks of the studied therapy and make completion of the trial highly problematic.”

In an accompanying editorial, Joshua Sharfstein (Johns Hopkins), a former deputy commissioner of the FDA, and Bruce Psaty (Univeristy of Washington), write that “the FDA should pursue additional safeguards to prevent breakdowns in sponsor-investigator relationships and avoid the dissolution of future trials. For example, the agency should consider having data monitoring committees report interim results directly to the FDA, not to the sponsor.”

“The LIGHT study should serve as an important message to sponsors of clinical trials. … Repeated breaches of confidentiality may leave the FDA no alternative other than to require that full safety studies be conducted prior to product approval. The demise of the LIGHT trial is a reminder that basing approval on interim safety data is a carefully drawn compromise, not an entitlement.”

In an email interview, Steve Nissen (Cleveland Clinic), the principal investigator of the trial, explained why the trial had been discontinued: “We strongly considered continuing, but so many participants had stopped blinded study drug that we would not have reached the required number of events to answer the principal question. It isn’t possible to assess safety when the principal ITT analysis includes mostly patients not taking the drug under study.”

“Take a look at the graphic showing adherence, which we included so that everyone would be aware of this concern. The inappropriate release of the interim data essentially destroyed our ability to complete the trial as planned. Keep in mind that FDA had already determined that a new trial would be required.”

Sanjay Kaul (Cedars Sinai) sent the following comment: “The decision by the sponsor to let their business interests trump the ability of the trial to yield valid inferences about the cardiovascular safety of the drug was short sighted. The ‘fiduciary responsibility to stakeholders’ argument does not apply here because treatment estimates at interim analyses are highly unstable resulting in misleading risk-benefit ratios, misguided financial recommendations, and suboptimal regulatory decisions. For example, the false perception of MACE benefit seen at 25% interim analysis—HR 0.59 (absolute risk difference of 0.5%) regressed to HR of 0.88 (absolute risk difference of 0.3%) at 50% interim analysis and finally to HR 0.95 (absolute risk difference of 0.1%) at 64% (end-of-study) analysis.”

“The purpose of the 2-stage process for obesity (and diabetes) drug approval is to not make it overly burdensome. In my opinion, conditional approval based on interim analysis (ruling out HR >2.0) should be followed by full demonstration of pre-specified safety (ruling out HR >1.4) in a timely manner failing which the approval should be rescinded. It will be another 6-7 years, if not longer, before cardiovascular safety of naltrexone-bupropion can be fully characterized. This means naltrexone-bupropion would have enjoyed marketing authorization for nearly a decade before we can be sure of its cardiovascular safety! Is this a reasonable compromise?”

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