FDA Panel Votes Down Libido-Boosting Drug for Women
Published: June 18, 2010
GAITHERSBURG, Md. -- An FDA advisory committee has decided that the makers of the investigational drug flibanserin (Girosa) -- often dubbed the female Viagra -- haven't proved that the pill treats hypoactive sexual-desire disorder (HSDD) in women any better than placebo.
The agency's Advisory Committee for Reproductive Health Drugs voted 9 to 2 that Boehringer Ingelheim failed to prove efficacy of flibanserin.
It then voted 11 to 0 that the company failed to demonstrate that the benefits of flibanserin outweigh the risks, which include fainting, accidental injury, insomnia, and fatigue.
The FDA does not have to follow the advice of its advisory panels, but it usually does.
Although the committee felt the drug isn't ready for prime time, it agreed that HSDD -- the existence of which has itself been called into question -- is a legitimate medical disorder that deserves an FDA-approved treatment.
"I am convinced that women's sexual health and function is important," said Paula Hillard, MD, chief of Gynecologic Specialties in the Department of Obstetrics and Gynecology at Stanford University School of Medicine in Palo Alto, Calif. "I am not convinced of a clinically meaningful benefit of flibanserin."
HSDD is defined as the persistent or recurrent deficiency or absence of sexual thoughts, fantasies, and/or desire for sexual activity, which causes marked distress or interpersonal difficulty and may be associated with low sexual activity, sexual arousal problems, or orgasm difficulty.
The committee based its decision on data from Boehringer Ingelheim's two prospective, randomized, double-blind North American trials that compared two doses of flibanserin with placebo in premenopausal women with HSDD for 28 weeks.
Change in the number of satisfactory sexual events from a four-week baseline measure to the 28 days prior to the final clinic visit were recorded, as were sexual desire scores culled from personal electronic diaries maintained by all patients in which they recorded sexual desire, sexual activity, and orgasms.
In both trials, the groups that used flibanserin showed a significantly greater number of satisfactory sexual events than the placebo groups (a 1.6 point improvement from baseline in the flibanserin group, compared with a 0.8 point improvement in placebo; P=0.005). About 30% to 40% of women in the flibanserin group reported a greater number of satisfactory sexual events, compared with 15% to 30% in the placebo arm.
But those differences, although statistically significant, are not big enough to be "compelling," wrote FDA staff reviewers in briefing documents released in advance of Friday's hearing.
Both studies failed to demonstrate a statistically significant improvement on the coprimary endpoint of sexual desire, as measured by the e-diaries.
"Therefore, neither study met the agreed-upon criteria for success in establishing the efficacy of flibanserin for the treatment of HSDD," the FDA staff reviewers concluded.
Nine of the 11 advisory panelists agreed with the staff's assessment that the drug doesn't appear to work.
Marianne Brandon, PhD, of Wellminds Wellbodies in Annapolis, Md. disagreed.
"I work primarily with women with low desire in my therapy practice," said Brandon. "About half of [the women in the study] felt strongly the results were clinically significant. The women I deal with would be very pleased with an increase of sexual events of one time per month."
The advisory panel was also concerned with the risks of the drug.
The most common side effects seen with flibanserin were dizziness and nausea, and about 15% of women on the drug stopped taking it because of a side effect compared with 7% of women in the placebo group.
An FDA staff reviewer who spoke Friday said she also detected a signal for a possible association between flibanserin and depression, fainting, and accidental injury, including traffic accidents and concussions.
The advisory panel was also concerned that the company couldn't offer an explanation for why those 15% of women dropped out.
Panel members questioned Boehringer Ingelheim's decision to add an additional libido-measuring tool as a primary endpoint midway through the study.
Researchers originally planned on using the e-diaries to track self-reported daily intensity levels in libido and sexual activities, but the company's investigators then added what they decided was a better tool to measure sexual desire -- a questionnaire called the Female Sexual Functioning Index, which asks respondents to recall sexual desire over the previous 28 days.
The advisory panel largely agreed that drug companies can't switch their pre-established protocol midway through a study. But several members also questioned whether any accurate measure of female desire exists in the world of sexual health research.
Michael Sand, PhD, MPH, a clinical sexologist and director of general medicine for Boehringer Ingelheim explained during the hearing that many things influence desire, making it difficult to measure.
"[Desire] is influenced by our physiology, our sociology, our biology, our theology," Sand said.
Although it has been referred to as the "female Viagra," the drug works through an entirely different mechanism than the selective vasodilators now used for male erectile dysfunction. Flibanserin is a serotonin 2A receptor antagonist and an agonist of the serotonin 1A and dopamine D4 receptors.
The drug was originally developed as an antidepressant. Although animal experiments had suggested it might have a more rapid effect than serotonin reuptake inhibitors, it failed to substantially reduce depression symptoms in men and women in a clinical trial.
However, the potential to increase female sexual desire became apparent during the study. Reportedly, trial participants were reluctant to return unused pills when the study was over.
In recent weeks, critics have charged that Boehringer Ingelheim is guilty of "disease-mongering," charging that depressed sexual desire is not a pathologic condition. However, hypoactive sexual desire disorder was a recognized disorder in the fourth edition of the Diagnostic and Statistical Manual of Mental Diseases (DSM-IV), published in 1994, and a similar condition called Inhibited Sexual Desire was listed in DSM-III, published in 1980.
During the public hearing portion of the meeting, a number of the speakers accused the drug company of making up a disease in order to make money.
"Low sexual desire is not a disease," said Leonore Tiefer, PhD, professor of psychiatry at New York University School of Medicine.
Tiefer said that in a sex-obsessed culture, pharmaceutical companies are simply searching for a blockbuster sex pill to market to millions of women.
"The hunt for the pink Viagra makes this crystal clear," she said.
But Kim Whittemore, the director of the nonprofit Institute for Sexual Medicine, strongly disagreed and said that characterizing HSDD as a made-up disease is "disturbing and counterproductive to women."
"I'm someone who has suffered from this 'fake disorder' for 33 years," she told the committee.
There are no HSDD drugs approved for use in the U.S.; a transdermal testosterone patch is approved for the condition in several European countries.
Despite the negative vote, the committee agreed that HSDD patients would likely benefit from an FDA-approved drug.
"The symptom of low libido in women is real, and I certainly would accept that as a target for treatment," said panel member Matthew Rudorfer, MD, of the National Institutes of Health's intervention research department.