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The FDA Is Forcing Orexigen To Do A Second Safety Study Because Of Contrave Disclosures

This article is more than 9 years old.

Orexigen's failure to keep a lid on a key safety analysis of its obesity drug Contrave led the Food and Drug Administration to force it to do a second study in order to prove that the medicine is safe for the heart.

The FDA made the decision even before Orexigen disclosed data from the study, called LIGHT, in a patent filing earlier today because the company had allowed the data to be shared with too many people within the company. Update: To be clear, Orexigen had announced that it had to do the second study. What we are learning is why.

An FDA spokesman writes:

During the review of Contrave, FDA learned that Orexigen had shared interim, unblinded results from the Light trial with more individuals than FDA considered necessary to prepare a regulatory submission.

In order to protect the integrity of an ongoing trial, preserving confidentiality of the interim results is essential. Disclosure of such results could negatively impact the conduct of the remaining portion of the trial by contributing to unanticipated changes in recruitment and/or retention, treatment administration, other aspects of study conduct, or loss of objectivity in safety event reporting. The importance of maintaining confidentiality is well-articulated in International Conferences on Harmonisation (ICH) guidelines, FDA guidance, and the scientific literature.

The uncertainty regarding how the dissemination of interim data within Orexigen and with outside parties would affect the LIGHT trial between the interim and final analysis led FDA to determine that the LIGHT trial would not be able to serve as the primary basis to exclude the possibility that Contrave increases the risk for MACE by 40 percent or more, for regulatory purposes.

Despite the serious concerns raised by Orexigen’s dissemination of interim results, all of these activities occurred after the interim analysis was conducted. Thus, FDA approved Contrave because the interim analysis did exclude the pre-specified two-fold increased risk of MACE, yielding an acceptable benefit/risk assessment to support an approval with further characterization of the cardiovascular risk after approval.

(MACE is an acronym that stands for cardiovascular events like heart attacks and strokes.)

The FDA also said that it told Orexigen not to disclose the data and that it is "very disappointed by Orexigen's actions." However, it still approved Contrave because the improper disclosures occured after the analysis unveiled today, when the study was 25% done, were finished.

More from the FDA spokesman:

In order to protect the integrity of an ongoing trial, preserving confidentiality of the interim results is essential. Disclosure of such results could negatively impact the conduct of the remaining portion of the trial by contributing to unanticipated changes in recruitment and/or retention, treatment administration, other aspects of study conduct, or loss of objectivity in safety event reporting. The importance of maintaining confidentiality is well-articulated in International Conferences on Harmonisation (ICH) guidelines, FDA guidance, and the scientific literature.

Since Orexigen has made the interim data from the LIGHT trial public through the process of obtaining patents, FDA believes it is critical that these interim data should not be mis-interpreted given that these results only represent approximately one-quarter of the planned trial. Although FDA was reassured by the interim data that Contrave is unlikely to increase the risk of cardiovascular events by more than two-fold compared with placebo, FDA considers these preliminary data far too unreliable to conclude anything further about the cardiovascular safety of Contrave. Furthermore, these data should not be interpreted to suggest that Contrave reduces the risk for cardiovascular events.

Following approval of Contrave, FDA took steps to protect from disclosure the interim data from the LIGHT trial.  The data were redacted from the approval package that was made publicly available following the approval and the LIGHT trial data were not included in the FDA-approved labeling for Contrave.  FDA has taken similar actions to protect the integrity of ongoing trials in other similar cases where an interim analysis was used to support regulatory approval.  FDA strongly urged Orexigen to protect the interim data from public disclosure and we are very disappointed by Orexigen’s actions.

Even before FDA became aware that the interim results from the LIGHT trial would become publicly available via patent applications, the agency had determined that the LIGHT trial would not satisfy Contrave’s post-marketing requirement (PMR) related to cardiovascular safety.  Therefore, the FDA required Orexigen to complete a second cardiovascular outcomes trial and that requirement remains in effect.    While FDA concluded that the LIGHT trial would not be adequate to meet the PMR requirements for CV safety for Contrave, we strongly encouraged Orexigen to continue the Light trial to completion since it may provide complementary or supportive information, especially if a different trial design is selected for the second trial.