SILVER SPRING, Md. -- An FDA advisory committee voted overwhelmingly to recommend approval for brexanolone, the first drug that would be specifically approved for patients with postpartum depression.
Members of the FDA's Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-0 on whether the sponsor, Sage Therapeutics, demonstrated efficacy of the drug, 16-2 on whether it had demonstrated adequate safety data (and whether concerns about certain adverse events were characterized sufficiently to enable safe use), and 17-1 on whether the benefits outweighed the risks.
At the meeting, committee members praised the treatment, calling it an "exciting breakthrough," giving "enthusiastic yes" votes, with one member saying that "probably since the approval of Prozac, this [would be] one of the greatest approvals ever." Members were mostly united on efficacy, safety, and that the benefits of brexanolone outweighed the risks for the treatment of postpartum depression, citing the intense need for therapy in this population.
The public comment portion lasted almost an hour, as the committees heard testimony from patients, mental health, and/or postpartum depression advocates, including principal investigators and patients from the brexanolone trials.
But due to concerns from the FDA and some members of the committee about adverse events -- including six patients out of 140 with observed loss of consciousness/pre-syncope during the infusion, the agency recommended implementing a Risk Evaluation and Mitigation Strategy (REMS) to improve the product's safety.
Brexanolone was described by the FDA in as a "proprietary analogue of the endogenous human hormone allopregnanolone." In the trials, it was administered as a 60-hour intravenous infusion. The sponsor, Sage Therapeutics, presented three clinical trials with a primary endpoint of a change in baseline on the Hamilton Depression Scale (HAM-D) at 60 hours. In all three trials, the agency said, brexanolone had a greater effect on HAM-D than did placebo.
"The results were consistent, the magnitude of the effect was large with a novel therapy that was, quite frankly, groundbreaking," committee member Jess G. Fiedorowicz, MD, of the University of Iowa Carver College of Medicine, said.
Questions about the safety of the product mainly centered around the six patients out of 140 patients who had lost consciousness, which FDA staff highlighted as their "major safety concern."
The two "no" votes on the safety question focused on the part that asked whether, in addition to the applicant adequately characterizing the safety profile of brexanolone, the loss-of-consciousness events have been "characterized sufficiently" to enable its safe use.
"The word characterized means understood -- do we understand why these people lost consciousness? Is it predictable? I don't feel I understand it well enough to say yes," said committee member Erick H. Turner, MD, of Oregon Health and Science University in Portland.
Agency staff outlined their proposed REMS criteria, which was "administration only in medically supervised settings." In addition, the FDA would require policies and procedures to ensure that all staff were trained on the risks, and that patients were continuously monitored "for the duration of the infusion and 12 hours after, by the healthcare provider who can intervene if the patient experiences excessive sedation or loss of consciousness."
The agency also discussed certifying that healthcare facilities are capable of doing monitoring, and that the facility must attest that only nurses, such as RNs or LPNs, will be administering the drug.
"This is a hospital-based drug," said committee member Steven B. Meisel, PharmD, of Fairview Health Services in Minneapolis. "When you say things like 'licensed care providers,' can you have a licensed audiologist? Does that count? You need somebody who can manage an IV pump, period, and someone who can provide CPR, period. So to me, that precludes any setting other than a hospital or hospital department setting."
But other committee members disagreed, arguing that perhaps availability of the drug should be extended to alternative sites, such as infusion centers, "well-equipped" pharmacies, or even sleep labs. Several members conjured up dueling images of sensational stories in the media related to accessibility of the drug.
"What if it comes out in the news that 'my wife, my mother, my sister killed herself because she had to wait 2 weeks to get a date into the infusion unit," said committee member Walter S. Dunn, MD, of University of California Los Angeles.
Kelly Besco, PharmD, of OhioHealth Pharmacy Services in Dublin, Ohio, countered that, "all you need is one adverse outcome to hit the news media," she said. "It will ruin this therapy and all the benefits we've heard today."
When considering the risks and benefits question, committee member Marie Griffin, MD, of Vanderbilt University in Nashville, Tennessee, focused on the high morbidity and mortality of postpartum depression (which is estimated to affect 400,000 women a year).
"We'd all like more safety data, but I feel better about post-marketing data," she said.
However, the one "no" vote -- consumer representative Kim O. Witczak, of Woodymatters in Minneapolis, said that when examining what might come down the line in terms of risk, "I can't rely on trust and crossing my fingers."
The committee also debated potential dosing for the drug -- 90 μg/kg/hr, with an option to decrease based on tolerability, or 60 μg/kg/hr, with an option to increase based on response. The committee concluded there was not enough evidence to make a decision, and left it to the FDA to decide, though most people with an opinion favored the initial 90 μg/kg/hr dose, based on "clinical judgment."
They also advised to further examine data in patients with psychosis, as well as an observational study in a large sample to confirm more about the safety risk, as well as which specific groups of patients could benefit from reduced hours and dosage of the drug.
The FDA does not have to follow the advice of its advisory committees, but it often does. In this case, one agency representative told the committee that, "I can't think of another meeting where we will actually leave with more to think about than when we came in."