Behind the scenes at the FDA: Why they ultimately approved Addyi
Since its approval in October 2015, Addyi (flibanserin 100 mg) has been more a source of curiosity than a heavily sought-after drug. As of mid-November, more than one month post-launch, only 227 prescriptions for Addyi had been written and only a small percentage of OB-GYNs and 435,000 PCPs had undergone the 10-minute certification process in order to be able to prescribe Addyi.
Amidst questions about its small treatment effect and challenging safety profile, Addyi’s approval has provoked cynicism among some critics who believe that the so-called "female Viagra" should not have been approved and reinforced the notion that in the case of Addyi, politics trumped clinical science.
In this week’s “Perspective” in the New England Journal of Medicine (NEJM), Dr. Hylton V. Joffe, director of the FDA’s division of Bone, Reproductive and Urologic Products (DBRUP), attempted to clarify the history of Addyi’s review process, including the drug’s rejection by the FDA in 2010 and then again in 2013—and what finally led to Addyi’s approval last summer.
Revised endpoints, safety concerns
In 2010 , when Addyi was first reviewed by the FDA for approval consideration, one of two primary endpoints—daily sexual desire—was not achieved. Although "satisfying sexual events" was achieved and there was evidence that there was an effect on sexual desire over the previous four weeks as recalled by participants, the committee believed that an effect on daily recall of sexual desire was preferable, according to Dr. Joffe.
In addition, the FDA committee was concerned about Addyi’s side effects, particularly somnolence and drug interactions. This led to a rejection of Addyi and a request for additional studies, including a new phase 3 trial, an alcohol-interaction study, and drug-drug interaction studies.
Allegations of gender bias at the FDA
When Addyi was reviewed for a second time in 2013, Boehringer Ingelheim (which developed flibanserin and sold it to Sprout Pharma) submitted efficacy data with satisfying sexual events, sexual desire as assessed by the Female Sexual Function Index (FSFI), and reduction of distress related to low sexual desire.
All three endpoints were achieved. However, major safety concerns sidelined Addyi’s approval and led the FDA to request additional data, including a study to ensure that CNS depression would not affect next-day driving performance. At this point, allegations of gender bias started to emerge from critics citing the claim that the FDA had approved more than 20 drugs for male sexual dysfunction.
The FDA quickly clarified the erroneous claim, clarifying which products had been approved to treat male sexual dysfunction. In fact, a total of five drugs had been approved, including four phosphodiesterase type 5 inhibitors (including Viagra) and one prostaglandin E1 drug (alprostadil) available in two delivery formulations.
Joffe outlined the review committee’s full litany of safety concerns in the NEJM article. "Major safety concerns regarding flibanserin include risks of hypotension, syncope, and central nervous system (CNS) depression (e.g., somnolence)," he wrote.
"These risks increase when the drug is taken during the day, with concomitant use of any of the numerous moderate or strong cytochrome P-450 3A4 (CYP3A4) inhibitors such as some of the antiretroviral drugs, antihypertensive drugs, antibiotics, and fluconazole (which increase systemic exposure to flibanserin by a factor of 4.5 to 7), and with alcohol use."
Victory at last
When Sprout completed the studies requested by the FDA, an advisory committee to the agency voted 18 to 6 to approve Addyi. But there was considerable disagreement among the group.
Those who recommended approval acknowledged Addyi’s small treatment effect (about 10% more Addyi-treated patients than placebo-treated patients reported clinically meaningful improvements) and its worrisome safety profile. However, the general contention among Addyi supporters was that the unmet medical need for a drug for treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women needed to be addressed—and at that moment, Addyi could fill the void.
Addyi’s approval, however, came with a black-box warning highlighting the risks of severe hypotension and syncope (fainting) in patients who drink alcohol. The label recommends bedtime dosing to help reduce the risk of adverse events associated with drug-related hyptension, syncope, and central nervous system (CNS) depression. There is also a risk of accidental injuries—an event that 2.7% of Addyi-treated women experienced in clinical trials.
In addition, the FDA attached a Risk Evaluation and Mitigation Strategy (REMS) to Addyi, which requires that healthcare providers and pharmacists watch an online slide presentation and take a test before they can prescribe or dispense it. Without this boxed warning and the REMS, Addyi would have been rejected once again.
Another important factor in Addyi’s approval was that it was contingent upon Sprout agreeing to take on a considerable post-marketing surveillance (PMS) burden, including several other trials: one to test alcohol interaction in women, in addition to pharmacovigilance for hyptension, syncope, accidental injury and death. Joffe noted that, "the agency will be able to take regulatory action as needed on the basis of the resulting data."
Rancor among the clinical experts
Some at the FDA were unhappy with the decision to approve Addyi and wanted additional restrictions placed on its use. One major concern centered around alcohol.
The original alcohol-interaction studies were conducted in men (only two women were involved) in the trial. In addition, there was disturbing preclinical data demonstrating a drug-related increase in mammary tumors in female mice.
Finally, there were concerns that the presence of so many exclusion criteria in the clinical trials for Addyi made it difficult to extrapolate Addyi’s "benefits" to a broader group of women.
The approval stands
Regardless, in the final analysis, Addyi met the primary endpoints of a well-designed, placebo-controlled clinical trial—and Sprout agreed to the stipulations of the approval.
"It's impossible to know any drug's full safety profile at the time of approval," Joffe noted in his editorial.
"The agency's approach aims to ensure that patients and prescribers know about the risks so they can make informed decisions about using flibanserin. Because HSDD is symptomatic, patients can directly assess whether any improvements they experience are worth the risks. Flibanserin should be discontinued if HSDD symptoms do not improve after 8 weeks of treatment."
- New England Journal of Medicine FDA Approval of Flibanserin — Treating Hypoactive Sexual Desire Disorder