Regulatory Status

We submitted our NDA for Silenor under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, an approach to seek regulatory approval for, among other things, new indications of drugs which have previously been approved by the FDA. The process allows a company to rely on published literature reports or the FDA's findings of safety and efficacy for a previously-approved drug for which the company does not have a right of reference. Filers relying on this approach may not be required to duplicate some previously conducted research, accordingly saving time and money. In addition, these filers may qualify for a period of three-year marketing exclusivity for a new condition of approval.

The FDA originally notified us that our NDA for Silenor for the treatment of insomnia was considered filed as of March 31, 2008.  Pursuant to Prescription Drug User Fee Act, or PDUFA, guidelines, the FDA was expected to complete its review and provide an action letter with respect to the NDA by December 1, 2008. However, in November 2008, the FDA indicated that its review of the NDA would be extended for up to three additional months, resulting in a new PDUFA date of February 28, 2009.

On February 25, 2009, we received a complete response letter from the FDA relating to the NDA. The FDA stated that based on its review the NDA could not be approved in its present form. In the complete response letter the FDA raised a number of issues relating to the interpretation of the efficacy data contained in the NDA and indicated that the FDA was open to a discussion of these concerns. The FDA did not specifically request us to conduct additional clinical trials of Silenor. 

With respect to safety, the FDA noted that there were no adverse events observed in the clinical studies included in the NDA that would preclude approval, but asked us to address the possibility that doxepin may prolong the cardiac QT interval. We responded by submitting to the FDA the results of our completed clinical trial of doxepin that evaluated the potential for ECG effects. The results of this clinical trial demonstrated that doxepin had no effect on QT interval prolongation when administered at 6 mg or under exaggerated exposure conditions of 50 mg. 

We held a meeting with the FDA on April 6, 2009 to discuss the issues raised in the February 2009 complete response letter. In the meeting, the FDA stated that to obtain approval of a chronic insomnia treatment, objective and subjective efficacy must be established in adult and elderly patient populations, and efficacy must be shown both at the beginning of treatment and on a persistent basis, defined as at least one month. No additional safety issues were raised in the meeting.

Based on the feedback we received at the meeting, we conducted additional analyses of our Silenor clinical data focused on the durability of subjective sleep maintenance efficacy in adults with primary insomnia. We completed these analyses and included the results in a resubmission of the NDA to the FDA which was submitted on June 4, 2009. The resubmission also included the results of our completed clinical trial of doxepin that evaluated the potential for ECG effects, which was previously submitted to the doxepin IND application. The FDA acknowledged receipt of the resubmission for review and confirmed that the review cycle would be six months, resulting in a new FDA action date of December 4, 2009.

Based on the February 2009 complete response letter and our April 2009 meeting with the FDA, we decided to no longer pursue approval of a 1mg dose of Silenor, nor approval of a statement in the indication section of the label that clinical trials of Silenor have demonstrated improvement in sleep onset.

On December 4, 2009, we received a second complete response letter relating to the Silenor NDA. In the December 2009 complete response letter, the FDA stated that the Silenor NDA did not meet the approval standard for efficacy due to a lack of robustness of sustained subjective sleep maintenance efficacy in adults with primary insomnia. With respect to safety, the December 2009 complete response letter did not raise any clinical safety issues. The FDA did state that an amended Risk Evaluation and Mitigation Strategy, or REMS, including a Medication Guide to be distributed with the product, would be required. 

We held a meeting with senior leadership of the FDA on January 20, 2010, to discuss the issues raised by the FDA in the December 2009 complete response letter. In the meeting, we discussed the remaining efficacy issue with the FDA, and the FDA instructed us to resubmit the contents of our January 20, 2010 pre-meeting briefing package to the FDA. The FDA acknowledged that this resubmission would be considered a complete response to the December 2009 complete response letter. The FDA also agreed that this would be considered a Class 1 resubmission with a two-month review cycle. No additional safety or efficacy data was required to be included in the resubmission, and we filed the resubmission with the FDA on January 21, 2010. As a result, we anticipate a decision from the FDA by March 21, 2010.

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