Flibanserin is poised for FDA approval. But why this drug? And why now?
Women with hypoactive sexual desire disorder have long sought a remedy for this common complaint. With an advisory committee recommending approval of flibanserin, their wait may be over.
Next up, BioSante Pharmaceuticals filed its NDA for LibiGel, a testosterone gel formulated specifically for postmenopausal women with HSDD. In its efficacy study, LibiGel failed to demonstrate superiority above and beyond placebo. The manufacturer, which was concurrently conducting a large, long-term safety study to satisfy the FDA’s concerns, ran out of money shortly thereafter, and that was the end of that.
Flibanserin’s focus: premenopausal women
In contrast to the 2 testosterone products, flibanserin was developed for premenopausal women. Although preliminary data on flibanserin use among postmenopausal women are available,2 the drug was studied primarily in premenopausal women with HSDD, the indication sought at this time.
In the premenopausal population, problems such as pain with intercourse or hypoestrogenism aren’t typically present, simplifying the identification of HSDD. (See the sidebar below, “What is HSDD and how is it diagnosed?”) In clinical trials of the drug, HSDD was secondary, generalized, and acquired—that is, it followed a period of normal sexual function. And it didn’t come and go but was present regardless of location and circumstance. Study participants had had a normal sex drive before their desire “turned off,” an occurrence they found distressing.3–6
What is hypoactive sexual desire disorderand how is it diagnosed?
In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), hypoactive sexual desire disorder (HSDD) is described as having the following characteristics:
- persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity
- marked distress or interpersonal difficulty in response to this deficiency
- lack of another explanation, such as another Axis I disorder or use of a substance known to affect sexual function.
In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, HSDD was folded with female sexual arousal disorder into a new diagnosis, female sexual interest and arousal disorder. This is somewhat confusing in that the physiologies of these 2 disorders are quite separate and distinct.
In clinical practice, HSDD is easily identified using the Decreased Sexual Desire Screener (DSDS), a simple screening test that asks 4 yes/no questions:
- In the past, was your level of sexual desire or interest good and satisfying to you?
- Has there been a decrease in your level of sexual desire or interest?
- Are you bothered by your decreased level of sexual desire or interest?
- Would you like your level of sexual desire or interest to increase?
A “yes” response to each of these questions is required. In addition, a fifth question asks whether a number of conditions, drugs, or circumstances might be responsible for the decreased desire or interest:
- an operation, depression, injuries, or other medical condition
- medications, drugs, or alcohol you are currently taking
- pregnancy, recent childbirth, or menopausal symptoms
- other sexual issues you may be having (pain, decreased arousal or orgasm)
- your partner’s sexual problems
- dissatisfaction with your relationship or partner
- stress or fatigue.
Boehringer Ingelheim, a German concern, developed flibanserin and filed the initial NDA in 2009. In clinical trials, that company ran into problems because the electronic diary it was using to measure desire failed to demonstrate efficacy for flibanserin. It turns out that, if you ask women who are distressed about having low desire to report their level of desire every single day, they quickly get turned off by the question and eventually stop answering altogether. Such changes in behavior play havoc with the validity of the instrument to assess desire.
After flibanserin failed the electronic diary desire domain—one of the study’s endpoints—the company substituted a different measure, the Female Sexual Function Index (FSFI) desire domain. Although the FSFI showed statistically significantly greater efficacy for flibanserin than placebo, the FDA argued that it was unreasonable for the company to change the rules to fit the outcome. For that and other reasons, it turned down the NDA.
In response, Boehringer Ingelheim went back to the drawing board and undertook a new study intended to achieve several goals:
- substitute the FSFI desire score for the electronic diary desire score
- reduce the number of restricted medications to see if the results could be more generalizable to the normal population of women with HSDD
- determine whether there were any safety signals for drug-drug interaction that weren’t apparent in the first 3 trials, in which a large number of medications had been excluded.
About the time this study was drawing to a conclusion, the company got cold feet and decided to shelve its plans for the drug.
