Debate Over Addyi Flares Anew – MedPage Today
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A review of eight clinical trials testing flibanserin (Addyi), the first and only drug on the market to treat hypoactive sexual desire disorder (HSDD) in women, concluded the drug performed on the low end of the clinical efficacy range used to gain FDA approval. However, women’s health experts argue that the drug earned its approval and should remain in the treatment arsenal.
“When articles that reflect opinion rather than science are published in scientific journals, they harm those meant to be aided by science and medicine resulting, in this case, in a great disservice to the millions of pre-menopausal women suffering from HSDD,” the International Society for the Study of Women’s Sexual Health (ISSWSH) wrote in a press statement.
The ISSWSH statement also took issue with JAMA Internal Medicine allowing an editorial “containing inaccuracies reflecting a strong anti-medication bias.”
“I care less about flibanserin and more about the fact that these authors have gotten away with using flawed data in a peer-review journal to promote their own agenda,” sexual medicine specialist Lauren Streicher, MD, of Northwestern University, told MedPage Today in an email. “Doctors will read this story and be misled.”
She added, “JAMA must be held accountable.” She reported no financial ties to the drug’s manufacturer.
The meta-analysis in question pooled eight randomized trials testing flibanserin effects in 5,941 women and found that satisfying sexual events increased, on average, by 0.49 per month among women in the treatment arm compared with placebo (95% CI 0.32-0.67). And, scores on the 6-point Female Sexual Function Index improved by just 0.27 points (95% CI, 0.17-0.38) on the index’s 6-point scale, Ellen T. M. Laan, PhD, of the University of Amsterdam, and colleagues, reported in JAMA Internal Medicine.
It also summarized the adverse event profile, with significant risks of dizziness and somnolence.
The overall findings from the meta-analysis were not very different from those contained in earlier reviews, including one conducted by FDA staff prior to an advisory committee meeting last June, at which panel members voted 18-6 to recommend approval.
The FDA approval for flibanserin was based on results from three phase III trials, which demonstrated placebo-corrected mean increases of about 0.5-1.0 satisfying sexual events per month with daily use, and and average increases of 0.3-0.4 points on the Female Sexual Functional Index.
In an editorial accompanying the new meta-analysis, Steven Woloshin, MD, MS, and Lisa M. Schwartz, MD, MS, of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., attacked the studies as failing to follow design recommendations from FDA’s staff, and criticized top FDA officials for then overruling staff recommendations that the drug be rejected.
“Unfortunately, companies know that they can ignore FDA [staff] suggestions and still get drugs approved,” they wrote.
Flibanserin went on the market in August 2015, and immediately thereafter Valeant Pharmaceuticals acquired Sprout for $1 billion. But, prescriptions have lagged. According to a national prescription audit by IMS Health, only 3,216 prescriptions had been filled from the time of flibanserin’s debut through January 2016. It’s unclear whether this reflects the drug’s true market, difficulties in obtaining and filling prescriptions (the FDA requires that physicians and pharmacies be specially certified), or negative buzz about the drug.
“I think this [meta-analysis] is pretty right on,” Kristen M. Carpenter, PhD, a sexual dysfunction researcher at Ohio State University, said in a phone interview with MedPage Today. “I’m happy to see that it made it’s way into JAMA. It synthesizes what a lot of us believe — the burden was not met for generating efficacy and safety prior to approval.”
“When the approval came through, I read the individual studies closely,” Carpenter said. “[I] agree with lot of the points made by the author here. I don’t know a single person, physician or psychologist, who thinks that approving [flibanserin] was a good idea.”
“We need good treatments for these women, but this is not a good answer. To have limited benefit, and fairly substantial risk of adverse events, creates a very bad situation for patients,” Carpenter said. “I would hate to see patients come through with some hope that this is there magic bullet, and be disappointed.”
Similarly, “I thought the review [by Laan et al.] was pretty compelling,” C. Neill Epperson, MD, of the University of Pennsylvania, told MedPage Today. “The effect was not large, and the side effects were not minimal, and we’ll need to see if the side effects are enhanced in the average population among people who typically aren’t as healthy as people in a randomized controlled trial.”
“I have my doubts about the medication and how effective it’s going to be, but I’m glad we have an option,” Epperson said.
Other sexual medicine specialists contacted by MedPage Today were highly critical of the meta-analysis and the journal’s decision to publish it and the editorial.
“I am surprised and disappointed that the editors of JAMA [Internal Medicine] chose to publish this manuscript,” Sheryl Kingsberg, PhD, of Case Western Reserve University, told MedPage Today in an email. “I have been involved in research for a long time and it is clear that Jasper et al. cherry picked data to use in the meta-analysis.”
Kingsberg was an investigator in one of the drug’s phase III trials and also testified on behalf of Sprout during the FDA advisory committee.
She contended that the trial data on unapproved doses and postmenopausal women should not have been included in the review, and that the conclusions by Laan’s group did not reflect the “10% of women [who] benefited above and beyond the expected improvement.”
Streicher took issue with the choice of Woloshin and Schwartz to write the editorial.
“I think the real issue is how this [article] even got accepted. The authors of the editorial are co-founders of Informulary, an anti-pharma watch group,” said Streicher, who had conferred with Kingsberg in an email exchange.
Jessica Maria Atrio, MD, MSc, of Montefiore Hospital in New York City, pointed to the polarization surrounding the drug as the real problem.
“I think it’s an issue that’s become politicized to the point that it’s hard to appreciate the scope and epidemiology of the problem as well as the quality of the evidence,” she told MedPage Today in a phone interview. “The FDA approved [flibanserin] to the best of their abilities, and [ordered] post-marketing surveys.”
“It’s wonderful to have a meta-analysis, but it’s important to interpret the findings in a dispassionate way,” Atrio said. “Unfortunately, I think this review and the editorial were subject to a certain degree of bias.”
Atrio noted that nonpharmacological therapies are expensive and often not covered by insurance. “Having more options is really important.”
“It’s [the study] really not taking the patient perspective into account,” Atrio added. “I’m not supportive of taking things away from women when they have a potential benefit, but I’m also in support of disclosure to patients.”
And Holly Thacker, MD, of the Cleveland Clinic, agreed. “The data doesn’t match their sour grapes conclusion. They conflated 50-mg data with the FDA approved 100-mg data. Flibanserin doesn’t work for all women but does work in a group of women with HSDD.”
“My patients prefer champagne and oysters over sour grapes and spilled milk,” Thacker said. “The political bias of the authors shows.”
Jaspers and Franco reported financial relationships with ErasmusAGE and Metagenics.
Woloshin and Schwartz are cofounders of Informulary.
None of the other authors reported any relevant financial relationships with industry.
Kingsberg and Streicher reported no financial relationship with Valeant or Sprout.
Debate Over Addyi Flares Anew – MedPage Today