Yesterday, 2/3/10, FDA approved under 505(b)(2) Canadian-based Labopharm’s once-daily version of trazodone HCl for the treatment of depression (as of this writing, this approval is not posted on the FDA web site). The initial PDUFA date was July 18, 2009 but this was missed because FDA found issues when inspecting the API manufacturing facility — Gruppo Angelini in Italy. A revised PDUFA date of 2/11/2010 was assigned when the API issues were addressed.
The current marketed product is an immediate release formulation, given twice per day. It is widely genericized. The drug was originally developed by BMS and approved in 1981. It was discontinued after loss of patent.
We don’t know what the complete development plan was for this drug product. Labopharm disclosed the pivotal clinical trial in a May 2009 issue of Psychiatry. The company provided the following summary:
An eight-week randomized, double-blind, two-arm, multi-centre study in patients with unipolar major depressive disorder demonstrated OLEPTROâ„¢’s efficacy as a treatment for depression. The primary efficacy endpoint of the study was to compare the change in the Hamilton Rating Scale for Depression (HAMD-17) total score from baseline to the end of the study in the OLEPTROâ„¢ group versus the placebo group.
The results of this study, which are published in the May 2009 issue of Psychiatry, include:
- Statistical significance was achieved for the primary endpoint (p value of 0.012).
- The overall discontinuation rate in the study was 25 percent with 21 percent in the placebo group and 30 percent in the OLEPTROâ„¢ group.
- In the OLEPTROâ„¢ group, four percent of patients discontinued treatment due to somnolence or sedation.
What is interesting is the Labopharm chose to use a placebo-controlled trial, showing superiority over placebo. Why wasn’t the currently marketed twice-daily comparator arm included? From a commercialization standpoint what data will the company have to assert benefit of the once-daily versus the low cost generic twice-daily? Perhaps physicians will be left to assume the same efficacy and safety and judge cost versus convenience. The company states “OLEPTROâ„¢ offers physicians another alternative in choosing therapy for their depression patients.” This might be a tough formulary sale.
Other than this trial, the company probably conducted pharmacokinetic studies to show similarity (bioequivalence) between once- and twice-daily dosing. This would involve both single- and multiple-dose studies. The FDA is concerned about dose dumping and has requested a post-approval in vitro alcohol dissolution study. Additionally, under PREA, FDA deferred a pediatric study, so the firm will have to conduct a pediatric study in the near future.