(Updated with statements from the FDA and Orexigen)
Earlier today
The surprising thing about the Orexigen disclosure, which was contained in a Form 8-K filed with the SEC, is that it consisted of data derived from an interim analysis of the company's ongoing Light trial. Normally, interim results are performed by an independent data monitoring committee and the results are known only to the members of the DMC. Occasionally, when important regulatory issues are at stake, the FDA may also be involved. But the detailed results of the analysis are never made public until the trial is stopped.
In this case neither the DMC nor the trial Executive Committee, headed by the Cleveland Clinic's Steve Nissen, knew about or approved the release of the data. Here's a statement Nissen sent me:
"The interim results of the Light Trial were released to a small unblinded Orexigen team by the Data Monitoring Committee under strict rules that allowed access for the purposes of regulatory filing. No public release of these data was anticipated and was not approved by the DMC or Executive Committee. It would not be appropriate for me to comment on preliminary interim data derived from an ongoing outcomes trial that is still underway."
The interim analysis was performed after the 9,000-patient trial had achieved 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. Ask any statistician: endpoints with less than 100 total events are unreliable and should be viewed with extreme caution.
One FDA consultant, cardiologist Sanjay Kaul of Cedars-Sinai medical center, explained why this sort of data release is inappropriate. Among the biggest concerns: people in the trial now have a strong incentive to drop out of the trial and take Contrave. If they believe the study drug is working why would they continue to possibly take a placebo? It now becomes unclear whether the rest of the trial will be valid. Regaining the integrity of the trial may be a bit like getting toothpaste back into the tube.
It should come as no surprise that Orexigen's stock is up nearly 50% today.
Kaul provided some additional perspective on the general issue of trial disclosure. Orexigen's action "highlights the challenging balancing act of reconciling SEC obligations with the duty to maintain data confidentiality and trial integrity." Last summer the FDA held a public hearing to address the "Confidentiality of Interim Results in Cardiovascular Outcome Safety Trials."
Although the FDA has not offered formal guidance on the issue, Kaul said that "there appeared to be general consensus among the stakeholders that disclosure of detailed analyses (such as point estimates of hazard ratios and the associated confidence intervals) could undermine the integrity of an ongoing trial and jeopardize its continuation, potentially eliminating or substantially delaying the regulatory agency’s ability to obtain needed long-term safety information. The majority position was that partial disclosure of interim findings at the time of approval, essentially disclosing only that the standard for approval has been met, might offer protection of trial integrity and also provide health care practitioners with the essential scientific information needed to inform their use of the drug."
Therefore, said Kaul, "what has happened here is in direct contravention of this position. I am disappointed at this disclosure. My hope is that it will spur the regulatory agency along with other relevant stakeholders to shine the spotlight on this vexing problem and bring some clarity to this issue."
I have asked for comments from Orexigen, FDA officials, and additional outside experts. This story will be updated as needed.
For much more on the FDA's discussions about this issue see Matt Herper's story, also on Forbes.
Update:
The FDA Response To Orexigen
The FDA has now provided detailed responses to the Orexigen disclosure. It now looks like this is a train wreck of monumental proportions. The two FDA statements-- reprinted in their entirety below-- make clear that the FDA is very unhappy with Orexigen for disclosing the data. The main piece of news from both the FDA and Orexigen, though it has not been well known, is that the company will now be required to perform a second cardiovascular outcomes trial.
Here are the key points in the FDA statement:
1. "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."
2. "FDA strongly urged Orexigen to protect the interim data from public disclosure and we are very disappointed by Orexigen’s actions."
3. "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."
4. "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."
Orexigen statement
Orexigen has sent a statement explaining its actions. As expected, the company explains that today's disclosure coincided with its patent application.
"Orexigen conducted a large cardiovascular outcomes trial in order to file for approval, with the study planned to continue after approval to serve a postmarketing regulatory requirement for additional risk exclusion. We observed an unexpected result in the interim analysis. We filed patent applications based on the results in order to preserve the potential for additional intellectual property. During the course of the study, the FDA informed us it had determined that the Light Study would not serve as the postmarketing requirement for Contrave; a new trial would be required. At this point, the company decided to continue with the patent prosecution. The second cardiovascular outcomes trial is expected to start later this year, and we look forward to the results of that study which are anticipated by 2022.
This morning the USPTO published the patent and supporting documentation, and we believed it was appropriate and necessary to make sure this information was equally available to all investors.
Orexigen has been working closely with, and is committed to continuing to work with FDA and others to support its regulatory obligations to thoroughly explore Contrave's therapeutic profile. Just as important, Orexigen is committed to its obligation to patients to fully explore the drug's profile.
Orexigen is also committed to simultaneously meeting its obligations to other regulatory authorities in the U.S., such as the SEC, and abroad, such as the EMA, which are relevant to, and have authority over, its business. The Company is similarly committed to meeting its fiduciary duties to shareholders."
Here are the full FDA statements:
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.
...
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.
Here is the statement from Orexigen:
"Orexigen conducted a large cardiovascular outcomes trial in order to file for approval, with the study planned to continue after approval to serve a postmarketing regulatory requirement for additional risk exclusion. We observed an unexpected result in the interim analysis. We filed patent applications based on the results in order to preserve the potential for additional intellectual property. During the course of the study, the FDA informed us it had determined that the Light Study would not serve as the postmarketing requirement for Contrave; a new trial would be required. At this point, the company decided to continue with the patent prosecution. The second cardiovascular outcomes trial is expected to start later this year, and we look forward to the results of that study which are anticipated by 2022.
This morning the USPTO published the patent and supporting documentation, and we believed it was appropriate and necessary to make sure this information was equally available to all investors.
Orexigen has been working closely with, and is committed to continuing to work with FDA and others to support its regulatory obligations to thoroughly explore Contrave's therapeutic profile. Just as important, Orexigen is committed to its obligation to patients to fully explore the drug's profile.
Orexigen is also committed to simultaneously meeting its obligations to other regulatory authorities in the U.S., such as the SEC, and abroad, such as the EMA, which are relevant to, and have authority over, its business. The Company is similarly committed to meeting its fiduciary duties to shareholders."
