SILVER SPRING, Md. -- An FDA advisory committee will take another turn with a controversial antidepressant that has struck out three times with the agency.
On Tuesday, the the Psychopharmacologic Drugs Advisory Committee (PDAC) will discuss gepirone hydrochloride extended-release tablets (gepirone ER) for the treatment of major depressive disorder (MDD).
Back in 2007, the FDA sent its last nonapproval letter for gepirone ER to Fabre-Kramer Pharmaceuticals, citing the latter's inability to show "substantial evidence of effectiveness."
That opinion was repeated in a general advice letter sent to the Houston-based company in April 2014.
After an informal appeal, Fabre-Kramer Pharmaceuticals requested a formal dispute resolution (FDRR), which the FDA accepted earlier this year.
PDAC has been charged with weighing the results of two "positive, adequate, and well-controlled" trials and determining if the results are enough to demonstrate efficacy, in contrast to several negative and failed trials.
"Although negative or failed trials are often observed in psychiatric drug development programs, at what point does the information provided by negative/failed trials undermine the evidence of effectiveness?" asked the directors of the FDA's Division of Psychiatry Products and the FDA's Office of New Drugs, in a joint memo. The memo was included in the .
In total, there have been 13 clinical trials for gepirone ER. (Fifteen trials were submitted in 2007, but two were excluded because they used incorrect dosage.)
The agency determined the sponsor's single maintenance trial was negative "because the applicant eliminated 40 patients from the efficacy analysis several years after the blind was broken."
It categorized the remaining 12 short-term trials as follows.
- Two positive trials, deemed "adequate and well-controlled"
- Three failed trials, deemed "uninformative"
- Seven negative trials
The agency noted in the briefing documents that in trials for treatment of MDD, it is not unusual to see a test drug that does not outperform a placebo, pointing out that "even drugs with well-established efficacy fail to show a treatment effect in some trials." The agency said it encourages sponsors to use a drug whose efficacy has already been established as well as a placebo in their trials to help distinguish between ineffective drugs and ineffective assays.
Four of the seven gepirone ER short-term trials deemed "negative" by the FDA are being contested by the sponsor. All four included an active-control arm as well as a placebo.
The agency also noted in the briefing documents that "gepirone was numerically worse than placebo in three of the four studies, whereas the active comparator was numerically better than placebo in all four studies."
However, the FDA's review team reached this conclusion after re-evaluating all four trials using a commonly used depression rating scale, the , which was not the pre-specified primary endpoint, but a secondary one.
Fabre-Kramer still holds that all four trials "failed" because they lacked assay sensitivity, or a sample large enough to adequately measure efficacy. However, the company disagrees with the FDA's determination that the single maintenance trial showed a negative result.
Regardless of whether the committee agrees with the sponsor or the FDA, there are still only two trials with positive results and five with disputed results.
There appears to be little guidance on this complex issue. An amendment to The Food Drug & Cosmetics Act in 1962 defined "substantial evidence" of efficacy as "evidence consisting of adequate and well-controlled investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could be fairly and responsibly concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof."
The FDA has interpreted that provision to mean that Congress needs "at least two adequate and well-controlled trials, each convincing on its own, to establish effectiveness," according to briefing documents.
And a second piece of legislation, the FDA's Modernization Act (FDAMA) stated that " 'data from one adequate and well-controlled clinical investigation and confirmatory evidence' to constitute substantial evidence if FDA determines that such data and evidence are sufficient to establish effectiveness."
In other words, neither FDAMA or the FDA's own guidance regarding standards of clinical evidence provides clear direction on how to weigh "countervailing evidence" that may weaken the evidence from the necessary "adequate and well-controlled trials."
PDAC will likely discuss the best approach for "synthesizing evidence across positive and negative/failed trials" and whether post-hoc analyses of endpoints, other than the initial primary endpoint, can be leveraged to determine an assay's sensitivity.
Finally, the committee will vote on whether the benefit-risk profile of gepirone ER is adequate for approval.