An FDA advisory committee voted 18-6 Thursday to recommend approval for flibanserin, a drug meant to treat sexual dysfunction and loss of sexual desire in women.
The “yes” vote at the joint meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee included a requirement for “certain risk management options beyond labeling,” such as provider certification and postmarketing studies.
Flibanserin, a product of Sprout Pharmaceuticals, is proposed for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The suggested dose is a 100-mg tablet taken in the evening before bed.
Sprout Pharmaceuticals describes HSDD on its website as “a persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty.” It clarifies that diagnosis is not related to “a medical, substance-related, psychiatric (e.g., depression), or other sexual condition.”
Walid Gellad MD, MPH, of the University of Pittsburgh, voted to recommend approval of the drug, but tempered his support saying he saw its benefits as “modest” or “less than modest.” “But I think that puts it in good company with other approved drugs.”
Gellad supported a risk evaluation and management strategy (REMS) and also supported provider certification.
Michele Orza, ScD, the panel’s acting consumer representative and a senior adviser at the Patient-Centered Outcomes Research Institute, in Washington, voted against approving the drug. Orza called the treatment effect “minimal” or “marginal at best” and said she worried that as the FDA considers future products it will find that the standard is “too low and problematic.”
If You Drink, Don’t
The majority of the committee recommended a REMS strategy as well as other postmarketing studies specifically focused on use of the drug with alcohol, long-term studies to assess the drugs effects on fertility, harm to a fetus, cancer risks, and accidental injury.
In his opening statement, Hylton Joffe, MD, director of the Division of Bone, Reproductive and Urologic Products (DBRUP) acknowledged that there is an unmet need for a drug to treat HSDD. He agreed that the sponsor had met its primary endpoints in three phase III clinical trials.
Missing the Endpoint
All three trials showed “statistically significant improvement” in the number of orgasms and other satisfying sexual events (SSE) and a reduction in sex-related distress in participants taking flibanserin compared with control participants, according to FDA reviewers. The sponsor drug showed a median placebo-corrected increase of approximately 0.5-1.0 SSEs per month, from the median baseline of two to three events per month.
Neither of the first two trials demonstrated a statistically significant improvement in the secondary endpoint of sexual desire, when rated in a daily electronic diary. However, both showed a statistically significant improvement when such desire was rated using the Female Sexual Function Index (FSFI). A third trial, which used the FSFI as a co-primary endpoint for sexual desire, found the endpoint statistically significant:
“From a mean baseline of about 1.8-1.9 on the FSFI desire score, flibanserin resulted in a placebo-corrected mean increase of 0.3-0.4 (the FSFI desire score range is 1.2-6.0).”
“From a mean baseline of 3.2-3.4 on the distress score, flibanserin resulted in a placebo-corrected mean improvement of 0.3-0.4 (on a scale of 0-4).”
But the sponsor and FDA are “not in full agreement that the FSFI is optimized for assessing sexual desire,” the staff review noted. At the meeting, Ashley Slagle, MS, PhD, endpoints reviewer for FDA, said the FSFI “specifically includes multi-barrel instruction, making it unclear what components might be driving any score change, so … if one component [like fantasizing] improves but other components might not improve; it’s unclear whether a change in one single element represents meaningful change.”
Joffe also highlighted the drug’s major safety concerns: hypotension, syncope, and central nervous depression and its “sizable placebo effect.”
Some of the panel’s safety concerns centered on alcohol use while on flibanserin. The committee noted the data on alcohol use was particularly unhelpful as Sprout’s pivotal alcohol study included only two women.
Speakers for the meeting’s public hearing portion were divided on the drugs’ approval.
Lisa Larkin, MD, a women’s health internist who practices in Cincinnati, told the committee “day after day” she sees patients distressed by their sexual health concerns.
“I take real issue with those who suggest that low libido in women is always the result of relationship or situational issues, anxiety, depression, something that can always be addressed in psychotherapy or that pharma has somehow created this disorder as a niche for a drug.” She urged those who ascribe to those view to spend a day in her practice.
Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group, in Washington, D.C., questioned whether there was any new information on the drug now compared with 5 years ago, “when an FDA advisory committee voted 11-0 that the benefits did not outweigh the risks … I have concerns about exclusions in the trials and [the drug’s] minimal level of effectiveness.”
Wolfe noted that hypotension and syncope are not trivial and can result in serious, irreversible, or life-threatening injuries. “If there were clear evidence of a clinically meaningful benefit, accompanied by manageable risk, approval might be appropriate, but neither of these two is the case. I would urge the FDA to reject the drug; it isn’t ready for prime time.”