[removed]Transcept Pharmaceuticals[/removed] Inc received a Complete Response Letter from the US Food and Drug Administration (FDA) regarding the resubmitted New Drug Application (NDA) for Intermezzo (zolpidem tartrate sublingual tablet). In the Complete Response Letter, the FDA confirmed that Transcept has adequately demonstrated that Intermezzo is efficacious for use as needed in the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep. However, the FDA stated that it cannot conclude that Intermezzo can be used safely based on the information in the Intermezzo NDA.
The proposed label for Intermezzo indicates that Intermezzo should only be taken when patients have at least four hours of bedtime remaining before being active again. In the original, October 2009 Complete Response Letter, the FDA indicated that Transcept must demonstrate that Intermezzo, when taken as directed, would not unacceptably impair next-morning driving ability.
To address FDA concerns raised in the October 2009 Complete Response Letter, Transcept and FDA agreed that a highway driving study conducted to assess the effect of Intermezzo on subjects’ next-day driving ability would provide a reasonable approach to characterize the safety profile of Intermezzo. According to a company announcement, in the four-hour treatment condition of this highway driving study, the primary analysis used to determine the capacity of Intermezzo to impair driving showed no statistically significant difference between Intermezzo and placebo. In a secondary analysis, the mean effect on driving ability four hours after dosing was statistically different from placebo, but below the level considered in the literature to define the threshold of potential driving impairment.
In the Complete Response Letter received July 14, the FDA stated that during its review of the Intermezzo NDA resubmission it became concerned that those patients with higher zolpidem blood levels from Intermezzo could be at risk of unacceptable next-day impairment. The FDA further hypothesized that such patients may belong to distinct and identifiable demographic groups.
During the review cycle, the FDA requested, and Transcept submitted, analyses of all Intermezzo studies seeking to identify patient sub-populations that may be at risk for elevated blood levels or next-day residual effects. In these analyses, demographic groups that exhibited higher blood levels were identified, but these blood levels did not correlate with an increase in next-day residual effects as measured by Digit Symbol Substitution Test (DSST), a standard cognitive function test employed by Transcept throughout its development program. In the Complete Response Letter received July 14, the FDA expressed the opinion that DSST may not be able to adequately distinguish possible adverse effects of zolpidem on driving ability.
In its October 2009 Complete Response Letter, the FDA asked Transcept to demonstrate that inadvertent Intermezzo dosing errors could be adequately minimized, or that the potential adverse effects of such dosing errors on driving safety could be shown to be acceptable. Potential dosing errors cited by FDA as concerns include inadvertent dosing with less than four hours of bedtime remaining and inadvertent re-dosing in a single night. FDA expressed concern that such errors could lead to higher next-day blood levels that could present an unacceptable risk to next-day driving ability.
In the July 14 Complete Response Letter, the FDA confirmed that the proposed single unit dose pouch packaging adequately addressed the risk of inadvertent re-dosing of Intermezzo in a single night. However, the FDA remains concerned that some portion of patients will dose with less than four hours remaining in bed, despite proposed packaging and instructions that the FDA viewed as clearly communicating this dosing restriction.
The FDA further expressed the view that, while a patient use study to define dosing error rates might be capable of detecting high rates of misuse, such a study would not be required. To address the risk of inadvertent mis-dosing with less than four hours remaining in bed, the FDA believes that driving performance at 3 to 3.5 hours after dosing should be considered as part of the safety review of Intermezzo.
To characterize the risk profile of Intermezzo on next-day residual effects if Intermezzo were inadvertently mis-dosed, Transcept assessed subjects’ driving ability in a highway driving study beginning at three hours after dosing Intermezzo in the middle of the night. In drives that started three hours after dosing, Intermezzo was associated with statistically significant effects in the primary analysis, and one drive was discontinued due to excessive driver drowsiness. In a secondary analysis, mean effects on driving ability three hours after dosing were also statistically different from placebo, but were below the level considered in the literature to define the threshold of potential driving impairment. In the Complete Response Letter received July 14, the FDA stated that these results suggested clinically meaningful impairment.
As a possible path forward, the FDA suggested that Transcept further investigate whether body weight and demographic factors contribute to differentially elevated blood levels the morning after dosing Intermezzo, develop strategies to decrease next-morning zolpidem levels, and, after mitigation strategies are implemented, demonstrate that next-morning blood levels do not present an unacceptable risk of next-day impairment, which may include the conduct of an additional driving study.
Transcept plans to meet with the FDA to discuss the potential paths forward, and will provide further updates as appropriate.