The FDA recently approved flibanserin (brand name Addyi) for the treatment of hypoactive sexual desire disorder (HSDD) in pre-menopausal women. The story of flibanserin illustrates several of the issues we have confronted on this blog:
- It was hyped in the media.
- Misleading headlines called it the female Viagra.
- It was initially rejected by the FDA and was approved only after extensive lobbying efforts.
- The drug is only minimally effective and has a lot of drawbacks.
- Two of the three supporting scientific studies claimed effectiveness based a surrogate measure but failed to show any measurable improvement in sexual desire.
- A campaign to support “women’s sexual health equity” pushed for approval, framing it as a step towards correcting what they perceived as gender bias (they claimed the FDA was biased because it had provided Viagra to help men have sex but hadn’t done anything to help women have sex).
- And the validity of the diagnosis of HSDD itself has been questioned.
What is HSDD?
According to the official diagnostic manual, DSM-5, the diagnosis of hypoactive sexual desire disorder requires:
lack of, or significantly reduced, sexual interest/arousal, manifesting as at least three of the following symptoms: no or little interest in sexual activity, no or few sexual thoughts, no or few attempts to initiate sexual activity or respond to partner’s initiation, no or little sexual pleasure/excitement in 75%-100% of sexual experiences, no or little sexual interest in internal or external erotic stimuli, and no or few genital/nongenital sensations in 75%-100% of sexual experiences. Symptoms must persist for at least six months, cause clinically significant distress, and not be better explained by another condition. Simply having lower desire than one’s partner is not sufficient for a diagnosis. Self-identification of a lifelong lack of sexual desire as asexuality precludes diagnosis.
Other drugs for sexual dysfunction
HSDD has been treated with testosterone and Bupropion. There is some evidence that they can be effective for some women, but they are not without drawbacks. Testosterone has been recommended to increase desire in men, but it probably only helps those whose testosterone levels are abnormally low. Drugs like Viagra are effective for erectile dysfunction in men, but they don’t increase sexual desire. They are used by men whose libido is working just fine but who are unable to sustain an erection. Viagra (sildenafil) works by increasing blood flow to the penis when there is sexual stimulation. It also increases blood flow to the genital area in women, and studies have shown increased sexual satisfaction in postmenopausal women who complained of sexual arousal disorder, but that’s not the same thing as HSDD. Other treatments for HSDD have included individual and couples counseling, education, and stress reduction.
What is flibanserin?
The new drug is the first to be approved for the treatment of HSDD. It was originally investigated for depression. The mechanism of action is not known, but it is thought to affect sexual response by increasing dopamine and norepinephrine activity and reducing serotonin activity in the central nervous system.
In two clinical trials, 45% and 39% of participants reported a meaningful benefit from the drug compared to 35% and 27% from placebo. The results suggested that ten women would need to be treated to benefit one. It increased the average number of satisfying sexual events, but only by one a month, and only after 4 weeks of daily treatment. In those trials, there was no significant difference in desire. In a subsequent third study using different questionnaires, they were able to demonstrate significant increases in desire and decreases in the distress associated with low desire.
Side effects included drowsiness, hypotension, fainting, dizziness, nausea, fatigue, insomnia, and dry mouth.
Regulatory history
The 291-page FDA Advisory Committee Briefing Document is available online.
In 2010, an FDA committee voted 11 to 0 that the overall benefit-risk balance had not been sufficiently established due in large part to failure to reach statistical significance on the pre-specified endpoint of sexual desire. Approval was denied.
In 2013, additional studies were submitted to the FDA with more data on sexual desire assessments, safety, and interactions with alcohol and other drugs. Approval was again denied. The FDA accepted that efficacy had been established; but safety questions remained, and they didn’t feel that the modest benefits justified approval. A Formal Dispute Resolution was filed, requiring further study to determine whether the drug impaired driving ability.
The FDA held a 2-day public workshop to obtain patient and expert views. They investigated “other indicators of meaningfulness.” A lobbying group was formed with the name “Even the Score: Women’s Sexual Health Equity.” A petition was sent to the FDA and letters written to congress calling for gender equity in drug approval. Lobbyists used slick PR materials. The “patient perspective” became part of the approval process.
On June 4, 2015, the FDA Advisory Committee recommended approval: 18 members voting to recommend approval but insisting on label warnings and other management measures, and 6 members voting against approval. Several members who voted “yes” said they did so with great misgivings because of the drug’s modest benefit and possible side effects.
On August 18, 2015, the FDA approved the drug for marketing. But it did so only with some extraordinary precautions. The label includes a boxed warning that users should not also consume alcohol and that the drug should be avoided by women with liver disease and by those taking drugs that are CYP3A4 inhibitors. Only prescribers and pharmacists certified through an online course will be allowed to prescribe this medication.
The FDA is requiring the company that makes Addyi (Sprout Pharmaceuticals) to conduct three well-designed studies in women to better understand the known serious risks of the interaction between Addyi and alcohol. And to top it all off, the company promised the FDA that they would not advertise the drug on radio or television for the first 18 months after it went on the market. I don’t remember hearing a similar restriction for any other drug; isn’t that an unusual provision?
Backlash
Some women’s groups criticized Even the Score as a distasteful attempt to use women’s rights as a cover to get an undeserving drug approved. One doctor said “To approve this drug will set the worst kind of precedent — that companies that spend enough money can force the F.D.A. to approve useless or dangerous drugs.” She called flibanserin “a mediocre aphrodisiac with scary side effects.” She said that the clinical trials were restricted to healthy women, but that if approved the drug would be used by a wider range of women, resulting in “an epidemic of adverse events.” The FDA was accused of having succumbed to “emotional blackmail,” valuing the comments of lobbyists and patients over the science. The satirical paper The Onion reported that the FDA had approved a new female-libido-enhancing man named Gabriel. Using him every day was shown to activate the regions of the brain associated with pleasure, increase blood flow to the genitals, and boost instance of orgasm by almost 40 percent. He was promoted as a safe, effective option, but it was noted that he became less effective when mixed with alcohol.
Questioning HSDD
The DSM diagnosis of HSDD has come under criticism. It is little more than a convenient label that serves as a starting point to investigate what are probably a number of diverse causes of the included symptoms. There is a lot of normal variation in human sexuality, and asexuality may be a normal variant rather than a mental disorder. Both the social function of the diagnosis and the scientific and clinical criteria have been questioned.
Conclusion: Controversial and questionable
The approval of flibanserin is being applauded in some quarters and censured in others. Subjectively, the drug will help some patients experience more desire and less distress from lack of desire, but objectively it can only be expected to provide 10% of the patients who try it with one additional satisfying sexual event per month (masturbation included). This raises a lot of questions. Should every drug with a similarly low effect size and a similar benefit/risk ratio be approved, particularly for conditions that are not life threatening? Was approval based on public opinion rather than on science? When is it appropriate to approve a drug that requires warning labels and other risk-reduction measures? Is the FDA doing a good job? Should the media have reported the story differently? What do you think?