In the September issue of The Journal of the American Medical Association (JAMA) three FDA advisory committee members describe the convergence of factors that made the committee’s recommendation to approve flibanserin especially challenging and politically charged. The authors of the JAMA editorial, Walid Gellad, Kathryn Flynn, and Caleb Alexander, all served on the FDA scientific advisory committee that ultimately recommended approval of flibanserin for the treatment of hypoactive sexual desire disorder (HSDD). They list all of the following factors as explanations for what made the committee’s decision so difficult in this case, but do not offer a thorough explanation as to why the drug was ultimately approved despite these issues.
Shifting Efficacy Points:
When the FDA denied the original Flibanserin application in 2009 they ruled that the phase 3 trials failed to show a significant improvement over placebo. In these trials the primary measure for assessing sexual desire was derived from a daily electronic diary completed by study participants. When the drug was brought back before the FDA in 2013 the diaries were no longer the primary outcome measure. Instead, the primary measurement was now the Female Sexual Function Index (FSFI) which showed “statistically significant but numerically small treatment differences.” For instance, at 24 weeks participants showed an increase of 0.5 satisfying sexual events per month compared with placebo. Writing for MIA ahead of the FDA’s recommendation, Emily Wheeler et al., also discussed concerns over potential conflicts of interest in the development of the FSFI scale. No new efficacy data was presented at the most recent FDA review, according to the JAMA editorial.
Tenuous Risk-Benefit Balance:
During the 2013 review, the advisory committee enumerated a list of safety concerns upon rejecting the drug application. The safety concerns included hypotension (low blood pressure), syncope (fainting), somnolence (extreme drowsiness), and “the potential for adverse effects when flibanserin is taken with alcohol or… oral contraceptives,” or with fluconazole (a common antifungal). While no new data on the drug’s efficacy was presented at the most recent FDA review, Flibanserin’s sponsors did bring some new evidence on the drug’s safety. The new safety data included a study on next-day driving impairments, a comparison of Flibanserin’s adverse effects with that of other drugs, and a study on the potential effects of taking the drug while consuming alcohol. In their review, Gellad et al. do not speak highly of the new evidence, writing:
“Although the driving study was reassuring, isolated comparisons of safety across products can be misleading because FDA product reviews are not fundamentally comparative in nature. Notably, the alcohol interaction study took place in a sample of 25 healthy volunteers, only 2 of whom were women.”
The Even the Score advocacy campaign:
Wheeler et al., also discuss in their MIA blog how the “Even the Score” marketing campaign was able to put pressure on the FDA by making powerful but dubious claims about Flibanserin and the prevalence of hypoactive sexual desire disorder. In their report, Gellad et al., acknowledge the effects of the marketing campaign. They write:
“Although flibanserin is not the first product to be supported by a consumer advocacy group in turn supported by pharmaceutical manufacturers, claims of gender bias regarding the FDA’s regulation have been particularly noteworthy, as have the extent of advocacy efforts ranging from social media campaigns to letters from members of Congress.”
Patient Reported Outcome Measures:
In their report, Gellad et al. concede that patient-reported outcomes based on study participants self-reports are increasingly becoming accepted as primary outcome measures in FDA applications. However, they draw attention to the fact that flibanserin’s sponsors switched the primary outcome measure from daily diaries, where participants recorded the intensity of their desire each day, to the FSFI, which asked participants to recall the frequency and intensity of their desires over 4 weeks. The FDA briefing memorandum, specifically states that while FSFI is commonly used, “there are continued challenges associated with its use and questions about its adequacy as an efficacy measure to support drug approval.” According to the JAMA report:
“The FDA raised some concerns about the optimization of the FSFI for assessing desire, including the content validity and recall period, but the recent advisory committee did not focus discussion on either the switch in primary end points or the validity of the FSFI.”
Potential for Off-label use:
The authors on the advisory committee understood that “there are few reliable estimates of the prevalence of HSDD” and that the product “is all but certain to be used off-label among a broader population of women than has been studied… many of whom may have conditions or concomitant medication use that increases the risk of adverse events.” They also point out that many of the women who were brought in for public comments to express the need for flibanserin, were not part of the population approved for the drug’s use. Because they reported “conditions that may have excluded them from on-label treatment, such as a cancer diagnosis or postmenopausal status,” they effectively reinforced concerns about dangerous off-label use.
According to the conflict of interest disclosures in JAMA, of the three authors, Gellad and Flynn voted to recommend approval of flibanserin with risk management strategies, and Alexander voted to not recommend approval of the drug.
To read the Wheeler et al. Op-Ed for Mad in America, which describes the ways in which “disease mongering,” conflicts of interest, and commercialization contributed to the creation and approval of Flibanserin, click here →
Gellad, W. F., Flynn, K. E., & Alexander, G. C. (2015). Evaluation of Flibanserin: Science and Advocacy at the FDA. JAMA.. (Abstract)