FDA’s Dr. John Jenkins raises concerns of CVOT completion from Orexigen’s interim data disclosure – March 12, 2015

Speaking with reporters from both Forbes and the Wall Street Journal, the FDA’s head of the Office of New Drugs Dr. John Jenkins voiced a reprimand to Orexigen for its disclosure of interim data from Contrave’s (naltrexone/bupropion) 25% analysis of the Light Study (the initial CVOT) appearing to show a cardiovascular benefit – this was released in a Form 8-K last week that followed the issuance of a patent by the US Patent Office based on the same data. The FDA’s primary concern is that the disclosure of this data may compromise the ongoing Light Study and hinder enrollment for Takeda and Orexigen’s second FDA-mandated CVOT. Dr. Jenkins emphasized that providers and patients should not make any clinical decisions based on this data, acknowledging that interim data are not always reflective of the trial’s final outcomes. Voicing his personal opinion, Dr. Jenkins characterized these interim results as probably “unreliable,” “misleading,” and “likely false,” which is roughly similar to some of the uncertainty we have heard from independent scientists and clinicians of late. In Dr. Jenkins’ eyes and through his conversations with the FDA’s statisticians, the only conclusion from these interim results is that “excess cardiovascular risk is not two or greater,” but still leaves many questions unanswered. In addition, he noted that Orexigen could face fines, civil penalties, and may even be forced to withdraw Contrave from the market in the case that the drug’s second CVOT (which is a post-marketing requirement announced with Contrave’s approval) is not successfully completed. The Agency is understandably unhappy with the situation, but its lack of clarity or specific guidance on interim CVOT data disclosure itself may keep its bite from matching its bark in this case. Also, in response to a question on where this leaves the FDA, Dr. Jenkins suggested that in some future cases, the agency may have to base approval on full CVOT results rather than interim results. Right! That takes us back to 2008, when the Agency clearly thought that would be too strict – and since Avandia, the entire reason the CVOT guidance was put in place has now been exonerated, it seems a bit much that we’re moving toward pre-approval CVOTs only, if we have the implications of Dr. Jenkins’ words on target.

• As background, this is the second time Orexigen and the FDA have butted heads over interim data, although the first incident was not a case of public disclosure. Prior to Contrave’s approval, while interim data was not explicitly disclosed to the public, the company had released interim data to more employees than the FDA had expected. This prompted the Agency to ask for a post-marketing requirement of a new CVOT (its protocol is to be finalized in April). FDA’s perspective is that only a select group of Orexigen employees, excluding those involved in business or financial decisions, should have access to interim data. In this recent instance, Orexigen argued that the company sought the patent of Contrave’s cardiovascular benefit to preserve the potential for additional intellectual property. Since the US patent office disclosed this information, Orexigen then felt obligated to notify its investors of the patent to provide equal access to this development. Importantly, the Light Study does not stand as a post-marketing requirement for the company, making such decisions separate from any consequences by the FDA. Dr. Jenkins acknowledged Orexigen’s argument that as a small company, it needs access to the data to make business decisions; additionally, we wonder if the fact that Orexigen won’t have other drugs to submit to the FDA any time soon allowed investor concern to outweigh those from the FDA.
• Worryingly, in response to a question on where this leaves the FDA, Dr. Jenkins suggested that in some cases such as these, the agency may have to base approval on full CVOT results rather than interim results. We think this is a bit disingenuous to raise – it was FDA itself that felt in 2008 at the first CVOT session that this would impose unreasonable delays and financial burdens on companies. If everyone agreed in 2008 that that may disincentivize drug development, now that Avandia has been exonerated, it seems a good time to think about a day of reflection and perspective on CVOTs at FDA. Many of Dr. Jenkins’ remarks in the two interviews touched upon topics that came up during the FDA’s Public Hearing in August about interim data disclosure for diabetes CVOTs – our coverage of that meeting is a must-read for those interested in this issue. We were hoping to receive more specific guidance on interim data disclosure from the FDA following that meeting, but nothing has yet materialized. In the meantime, the lack of guidance has allowed situations like Orexigen’s that could build into more explosive situations that deprive patients of therapies.
• Although this story has generated somewhat of a media frenzy, we would note that the lack of FDA guidance on interim data confidentiality has caused problems before – just not at small, publicly traded companies. For example, CANVAS, the CVOT for J&J’s Invokana (canagliflozin), served as the basis for the drug’s approval; due to concerns about interim data there as well, the company had to initiate a second CVOT, CANVAS-R. Facing the threat of similar interim data disclosure, Sanofi ended up withdrawing its New Drug Application for Lyxumia (lixisenatide) to avoid the trouble. In addition, related scenarios are playing out in PCSK9 inhibitors, as Sanofi/Regeneron’s alirocumab disclosed positive interim data (based on very few events) at last year’s ESC even as the drug’s outcomes trial continues to progress. Therefore, while Orexigen has received significant attention and criticism regarding its recent 8-K, such a situation is not unprecedented. On the whole we believe the onus is on the FDA to provide clearer guidance on interim data disclosure and we would like for it to address CVOTs more broadly.
• According to a poll by the Wall Street Journal, the majority of respondents (60%) believed the FDA should both fine Orexigen and have Contrave withdrawn from the market. Such decisions, however, would not take place anytime in the near future as these disciplinary actions only refer to the case of a failure to complete Contrave’s second CVOT. Ultimately, difficulty in enrolling for the second CVOT seems relatively unlikely, especially because the Light Study enrolled very quickly from the start. While we are slightly wary of how such data disclosure can influence healthcare decisions and the ability to complete the trial (the last thing we want is an even slower, costlier process on this), we do not see removing Contrave from the market as a positive choice for patients. Contrave, has in fact, been doing remarkably well even before this interim data was released – see our Orexigen 4Q14 update for more.
• At the recent ENDO 2015 meeting, the FDA’s Dr. Janet Woodcock referenced the Orexigen controversy. She didn’t delve into the issue in depth, but she did reference Dr. Jenkins’ remarks in Forbes. She concluded by noting that the controversy surrounding CVOTs continues and that there remain “technical challenges” with the current process of unblinding interim data to support drug approvals. Interestingly, she also disclosed that she was one of the drivers behind the August hearing on interim data disclosure and that she recognizes the Catch-22 that currently exists for drug manufacturers regarding approvals based on interim CVOT data.
• We will be listening very closely during upcoming medical meetings for how prescribers and KOLs interpret the interim data. The most scientifically rigorous standpoint is that the signal of a potential protective effect cannot be trusted, but we have seen plenty of times that it is difficult to ignore data when it exists in the public sphere. In our eyes, the currently available data does not prove any conclusions one way or the other and we can only wait and wonder what the final CVOT data will show. Orexigen has a 50% analysis for the Light Study, and we wonder if we will be seeing that data any time soon.  
• This past Tuesday, law firm Robbins Geller Rudman and Dowd LLP also filed a complaint against Orexigen on behalf of the company’s stockholders due to the plummeting stock price after the FDA’s threats. This class action has commenced in the US District Court for the Southern District of California and is currently seeking lead plaintiff status. The complaint labels the decrease in Orexigen’s stock price as a “result of the artificial inflation caused by defendants’ misleading statements” from the company’s interim data disclosure last week. 

-- by Melissa An, Manu Venkat, and Kelly Close