Article preview from The RPM Report - July 2008 |
| Find out why July 23 was a challenging day for NexMed's lead product (Vitaros, a cream formulation of alprostadil for erectile dysfunction) and, by extension, for its platform technology (the NexACT permeation enhancer). |
Article preview from The RPM Report - July 2008
NexMed Defends Vitaros: The Candid Approach
July 23 was a challenging day for NexMed's lead product Vitaros and, by extension, for its platform technology. That was day the company had to explain an FDA "not approvable" letter. The FDA decision undercut the safety image that NexMed had been proclaiming for its new technology.
As recently as two weeks before the Food & Drug Administration sent NexMed Inc. a "not approvable" letter, the company touted its drug delivery ingredient as "powerful" and "safe" with over 100 animal studies to support it. The combination of attributes, NexMed said, would set NexACT—the platform technology used in Vitaros—apart form other drug delivery technologies.
NexMed had openly proclaimed July 19, the user fee deadline date for Vitaros, as a day of reckoning: "the day we should know the fate of this product," the company told financial analysts on July 10. The "not approvable" letter was a bitter setback and caused the company to change tack.
One thing NexMed did not do: it did not retreat into a shell and try to hide from the bad news. The company adopted a straight-talk approach for addressing the disagreements with FDA. There may be a lesson to learn from the approach, as the temptations to hide behind a wall of silence become greater as FDA rolls out a new regulatory tool for delivering bad news to sponsors: the "complete response" letter.
NexMed's strategy for addressing the "not approvable" letter with investors: face head-on the deficiencies in its new drug application; put those issues in a broader context; and provide an update on strategies to rectify the deficiencies.
The company's thorough approach helped it weather the immediate downward response to the "not approvable" headline. Nothing NexMed could say could assure a way out of "not approvable" purgatory, but its forthright approach appeared to mitigate the bad news in the short-term.
Acknowledge and Identify Deficiencies: The foundation for the candid approach is being upfront about the differences between the sponsor and the FDA on the approvability of a product. NexMed said it was disappointed by the "not approvable" decision, but acknowledged that the deficiencies the agency cited in the application were "not unexpected."
"The main stumbling block," NexMed CEO Vivian Liu said, "remains to be the results from our transgenic mouse study." NexMed says there is "evidence" that the agency has moved away from asking for that study as part of the package of information needed for a topical drug. But NexMed has been involved in a six-year debate with the agency over the significance of papillomas discovered in a transgenic mouse study in 2002. That's a good reason why the sponsor would not be surprised by the issue.
Because Vitaros is a topical erectile dysfunction product, FDA wants to make sure that the enhancer ingredient will not increase the risk of papilloma to the partner. That caution fits with FDA's recent approach for reviewing applications for products in classes where therapies already exist—especially when it comes to safety issues. NexMed says that it still unclear what information may be needed to address FDA's concerns.
Describe a Way Out of the Impasse: It's not just enough to identify any deficiencies; sponsors must also to give investors some idea of how to resolve them.
In the NexMed situation, the company explained in a lengthy conference call on the day of the rejection that there may be two ways to override the concerns from the transgenic mouse studies: (1) FDA may be ready to discount the significance of tests in the transgenic mouse strain and (2) more likely, the agency may view two, two-year follow-up studies on rats and mice as diminishing the risk.
Here's where the context comes in. Looking back six years, the company tried to show how the questions around the transgenic mice have evolved. The company also found hope in the fact that a number of sponsors had faced similar issues—"at least a dozen companies." While the ways the other companies resolved the issues with the mice are confidential, NexMed said there was solace that other companies had successfully negotiated with the agency.
NexMed has follow-up rat and mouse studies done in conjunction with Novartis AG for a separate nail fungus product that could help resolve the issue. NexMed did not have those studies in final form at the time of the "not approvable" decision. Perhaps the best interpretation of the "not approvable" letter is that FDA was sending the company a firm message: put the follow-up rat and mice studies in final form; the application goes nowhere without fully analyzed and audited data.
NexMed said that FDA specifically asked for two-year follow-up studies during the regulatory process. "At the pre-IND meeting that we had with the agency with the dermatology division of the FDA," Liu said, "they asked for two long-term studies to be done for the product."
Outline a Realistic Time Line: Sponsors should also define the events that need to happen and how long it is likely to take to get to them. Focusing only on the next step offers a short-term milestone but misrepresents the full process.
During a conference call on the day of the "not approvable" letter, NexMed identified at least three milestones it will have to pass to get to approval. First step: a meeting with FDA (up to 75 days to schedule). Second step: an effort to reach "consensus" with FDA over what data will be needed for an NDA amendment (an undetermined time frame). Third step: a six-month review after filing of the amendment. NexMed noted that FDA may also want to take the risk/benefit decision to an advisory committee.
Point out the Positive Signals: "One positive outcome," NexMed declared, is the fact that the FDA did not cite the lack of completion of our long-term open-label study as a deficiency." NexMed interpreted that to mean that the company will not have "to redo this study, which would have taken up to 18 months to complete" and would have cost $8-$10 million.
NexMed pointed to the acceptance of the Vitaros brand name as potentially auspicious. "During a call about three weeks ago with the FDA," Liu said on July 23, the agency "verbally cleared the way for our use of the name Vitaros."
That is not a major part of the process, but it does indicate that the agency takes the application seriously enough to review the marketing name. Overall, FDA avoids spending time on applications that have little likelihood of approval.
Call in the Cavalry: When the sponsor is a small company with limited financial resources and in-house regulatory skills, it can help to establish relationships with bigger partners. NexMed invoked the support of Warner Chilcott Ltd. (the partner on Vitaros) and Novartis AG (the partner on a Phase III topical terbinadine product for onychomycosis/nail fungus).
NexMed chief operating officer Hem Pandya said that the sponsor would use Warner Chilcott's regulatory expertise to respond to FDA. "We have been working with them [since] as soon as we got this letter [and] actually prior to this letter as well in terms of strategies," Pandya said.
And the Novartis relationship is even more important. Not only is the nail fungus product the prime focus of many of investors, the presence of Novartis behind the animal studies is important to NexMed. Any extra credence that Novartis can lend to rodent safety studies could be a help in NexMed's attempt to resolve the lingering concerns about the papilloma results.
By 
Cole Werble
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