Available data on the benefit-risk profile of gepirone (Fabre-Kramer Pharmaceuticals, Inc), an antidepressant billed as having a novel mechanism of action, do not support its approval, according to the US Food and Drug Administration (FDA) advisory committee investigating this drug.
Although the sponsor met standard approval criteria by submitting two positive well-controlled trials, the relatively high number of negative studies was an issue for members of the Psychopharmacologic Drugs Advisory Committee, who agreed there was not substantial evidence of efficacy for gepirone extended release (ER) in the treatment of major depressive disorder (MDD).
They took no real issue with the safety profile of the agent.
According to the sponsor, gepirone is a new chemical entity for short-term treatment of MDD. It is the only antidepressant whose sole mechanism of action is agonist activity at the 5- HTIA receptor.
The drug does not affect the 5-HT2A receptor or other serotonin receptors associated with adverse events. It is believed that this unique mechanism of action may explain why the drug has been linked to less sexual dysfunction, a side effect of many currently approved medications. Sexual dysfunction is also associated with depression itself.
The committee meeting was the last hurdle in a long campaign to get the drug approved. The application of the sponsor has been the subject of three review cycles; it received a "not-approvable" action on each of them.
The sponsor appealed the decision by the Division of Psychiatry Products and the Office of Drug Evaluation that the available data do not provide the substantial evidence of effectiveness required under the Food Drug and Cosmetic Act to support approval. The FDA review team was seeking input on this issue from the advisory committee.
Among other issues, committee members discussed assay sensitivity and the difference between a failed trial and a negative trial.
The FDA encourages sponsors to include known effective drugs as active controls in trials of drugs to treat MDD, which helps to provide an indication of whether the trial was adequately designed and executed in order that the trial would be capable of showing a treatment effect.
Failed vs Negative
A "failed trial" means that the active control and the test drug both failed to beat placebo.
"In other words, the trial lacked assay sensitivity; you could not detect a difference when one should have been there with a known effective drug," explained John Jenkins, MD, director, Office of New Drugs, Center for Drug Evaluation and Research (CDER), FDA. "So it may be a flaw in trial conduct or design or endpoints or power."
A "negative" trial is one in which the active control beat the placebo but the test drug did not, showing that the trial had assay sensitivity.
In general, failed trials are not counted against the drug in establishing substantial evidence of effectiveness, whereas negative trials raise concerns about whether the test drug is effective.
The advisory committee was faced with determining at what point the information provided by negative/failed trials undermines the evidence of effectiveness. They were asked to discuss the importance and interpretation of negative trials.
The gepirone development program dates back to 1999 and has been associated with three separate sponsors. It includes one maintenance trial that was considered negative by the review team and 12 short-term trials.
Of these short-term trials, the FDA and the sponsor agreed that two were well-controlled and positive, with P .05, and with treatment effects of similar magnitude to other approved antidepressants.
Three of the remaining 10 short-term trials were considered uninformative in the evaluation of efficacy. The sponsor and the review team both agreed that these studies should not be considered further.
The other seven short-term trials demonstrated no difference between gepirone ER and placebo, according to the FDA review team. Four of these were designed with an active control arm, which allows for the distinction between negative and failed trials.
According to the FDA, each of these four trials failed to demonstrate a difference between gepirone and placeb, or between active control drug and placebo, as determined on the basis of their primary endpoints, which included HAMD-25, and MADRS, (HAMD-17 and CGI were coprimary endpoints in one trial). They were thus considered failed trials.
New Analysis
To help determine how much these studies take away from the two positive trials, the FDA review team conducted a re-evaluation of these trials using the HAMD-17, which was not the primary endpoint in any of the trials. This analysis found that gepirone ER was not distinguishable from placebo; in two of the four trials, the active control was distinguishable from placebo.
In three trials, the active control was nominally statistically superior to gepirone, which suggested that these might be negative rather than failed trials.
"We believe this supports assay sensitivity, and it's almost never seen," Robert Temple, MD, deputy director for clinical science, CDER, FDA, told the committee.
"In three trials that we believe had assay sensitivity, gepirone was actually worse than placebo and statistically significantly inferior to the active control; that has to make you worry about what the effect of the drug is and creates a need for further data," said Dr. Temple.
He added that the more negative trials there are, the greater the odds that the results of the positive trials occurred by chance.
"This doesn't prove gepirone doesn't work; our concern is whether it gets in the way of concluding that there is substantial evidence that gepirone does work. We don't want to put into the world an antidepressant that doesn't work."
Interpretation of this analysis has been the subject of debate within the FDA, between the FDA and the sponsor, and now among advisory committee members.
One issue during the day-long discussion was the use of the HAMD-17, which FDA staff argued is a reasonable endpoint to use as a "common metric."
"We recognize that going from HAMD-25 to HAMD-17 raises the multiplicity question, but it's a commonly used endpoint on which the control agents are known to work in depression" and was not chosen "out of the blue," said Dr Temple.
Cherry Picking
Some members, however, felt that the HAMD-25, which includes eight items on a "reversed vegetative symptoms scale," better defines depression.
"I wish you hadn;t done the post hoc," said David Pickar, MD, adjunct professor of psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland. He pointed out that symptoms in the expanded questionnaire, such as motor retardation and hypersomnia, are "serious depression" and "are not atypical in my mind."
Some committee members used the term "cherry picking" when referring to the FDA's attempt to look at the study data after the fact.
"Post hoc analyses can contribute to what we're looking at, but it really does muddy the water," said patient representative Natalie Compagni Portis, PhysD. "You can keep looking and looking until you find what you want to find, and that's a challenge with this."
Committee Acting Chair Ralph B. D'Agostino, Sr, PhD, professor of mathematics/statistics, biostatistics, and epidemiology, Boston University, in Massachusetts, expressed concern that the review team picked an endpoint that was not the sponsor's and "chased it down" in a post hoc analysis.
"When you start finding strange things, you keep looking and finding more and more strange things."
Like some other members, Murray B. Stein, MD, Distinguished Professor of Psychiatry, Family Medicine and Public Health, University of California, San Diego, welcomed the idea of having an antidepressant with a different mechanism of action.
Excitement Over Mechanism
However, Dawn F. Ionescu, MD, Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, said she did not think the mechanism of gepirone is that different from that of serotonin reuptake inhibitors.
"There was a lot of excitement over this drug's new mechanism of action. I wish I was more positive, but at the end of the day, I see it as another serotonergic modulator. We're not necessarily looking at changing circuits or changing genetics; this is affecting the serotonin system, as many of our current medications do," said Dr Ionescu.
There was also excitement about the potential for this drug to have an impact on suicidal thinking, but there was no evidence presented on this, she added. And there was excitement over the ability of the drug to decrease sexual dysfunction.
"But I ask the question, if this medication isn't going to treat their depression, what's the point of giving patients a medicine that will also not cause as much sexual dysfunction?"
The sponsor maintains that the two positive trials met the substantial evidence standard.
Company representatives presented their own data from the five interpretable studies (two in which both primary and secondary endpoints had a "directional trend" in addition to the two positive studies), which, they said, supports the finding of "substantial evidence of effectiveness."
The company is proposing a dose of 60 to 80 mg should the drug be approved.
Committee members heard that about half of all randomized controlled trials of antidepressants fail and that there is an unmet need in the treatment of depression. Some felt that like the 18 approved antidepressants, gepirone probably works in some patients but not others.
For Dr Stein, gepirone is "squarely where other drugs that are currently marketed are," with "some performing really well and others not," which is "the state of the art" in the field of antidepressants.
Additional Studies
During a discussion of what additional research might be needed, committee members said longer studies and maintenance studies would be helpful, as would a biomarker study to identify patients who respond.
Some mentioned the usefulness of placebo lead-in trials (in which all patients are given placebo and are then randomly assigned either to continue receiving placebo or to receive active drug).
One committee member said she would like to see subgroup analyses, for example, on the elderly, in whom depression is markedly common.
If any further trials are to be conducted, Dr Stein said that one that compared a dose considered adequate, such as 60 mg, with a dose considered inadequate, for example, 20 mg, might be useful.
Dr Ionescu said she would recommend using an external rater system, which might mitigate the current problem of heterogeneity of patients.
Some members noted that if new studies are conducted, they should use "2016 standards" (the last gepirone study was carried out about a decade ago and used what many consider outdated standards ― for example, accounting for study dropouts using the last observation carried forward.
As noted by Dr D'Agonsino, "there wasn't overwhelming support for the notion of assay sensitivity being built into these studies."
In the end, the committee agreed with the FDA review team that the number of negative short-term treatment trials raised doubts about the strength of evidence provided from the two positive trials.
Members voted 4 to 9 that the sponsor provided substantial evidence of effectiveness. The vote was the same in deciding whether the available data support a favorable benefit-risk profile.
The review team did not identify any safety concerns related to gepirone. Committee members heard that dizziness, nausea, headache, insomnia, and fatigue were the most common adverse events experienced by study patients.
The committee voted 11 to 2 that the sponsor adequately characterized the safety profile of the drug.
Source: Live webinar of the meeting of the FDA Psychopharmacologic Drugs Advisory Committee, Dec. 1, 2015.
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Cite this: Novel Depression Drug Hits Regulatory Roadblock - Medscape - Dec 03, 2015.
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