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In a surprising vote, US Food and Drug Administration's Bone, Reproductive and Urologic Drugs Advisory Committee overwhelmingly endorsed Agile Therapeutics Inc.'s transdermal contraceptive patch Twirla, a decision that could make the agency reevaluate – and possibly even alter – its rather dim view of the application. 

The near unanimous recommendation (14-1, with one abstention) seemed like an impossible mountain for Agile to climb going into the 30 October meeting, as the FDA offered a blistering critique of the combined hormonal contraceptive (CHC) in the briefing documents. The agency went as far as to say that it does not believe Twirla's suboptimal effectiveness outweighs its risks.

Specifically worrying the FDA was Twirla's Pearl Index (PI), which measures the pregnancy rate per 100 women-years of drug exposure. In the single-arm, open-label Study 23, Twirla's PI was 5.83, while the agency has never approved a CHC for which the upper bound of the 95% confidence interval for the overall PI exceeded 5. There was a notable difference in the PIs for obese women (BMI ≥30kg/m2) and non-obese women in Study 23, which were 8.64 and 4.34, respectively. But the FDA still did not think the PI for non-obese women was acceptable.

Committee Wants Another Treatment Option 
The advisory committee, however, viewed the risk/benefit profile Twirla (levonorgestrel and ethinyl estradiol) through a largely different paradigm than the FDA did. A majority of panelists felt that Twirla, despite the less than perfect data, can be another contraceptive option for patients, so long as the limitations are communicated in labeling.

"I take care of patients who need contraceptive care, and there aren't enough choices out there," said David Eisenberg, a professor at the Washington University School of Medicine in St. Louis.

"I take care of people who are smart enough with accurate information and the counsel of their clinician, and it's our job as clinicians to distill these complicated concepts of confidence intervals and Pearl Indices to help patients understand what their personal risk is. And I think we can do that."

Sadia Haider, a professor at the University of Chicago, offered a similar assessment.

"I do think that with good information in labeling, patients and providers can really do an appropriate job of conveying this message. ... I do think that this is really a move towards patient-centered shared decision making with really good information for counseling," Haider said.

Both Eisenberg and Haider noted that they did not expect to vote in favor of approval going into the meeting.

The open public hearing portion of the meeting featured nine speakers, many of whom said they would like to have access to a more convenient, less-invasive form of contraception. The message looks to have been well-received by the panel.

"I have grown increasingly uncomfortable with a specific cut point for a Pearl Index, be it 5, be it 6," said University of California, San Francisco professor Douglas Bauer. "I don't really think that we nor the FDA is in the position to dictate what that should be. And the reason I say that is because I think it is partly because we really don't have the rigorous data on what patient preferences are and how they weigh efficacy versus convenience. ... It's difficult for me to weigh those things, but clearly we heard from women that they do weigh those things."

The FDA likely won't keep Agile waiting on a decision for too long. Twirla, which is in the middle of its third review cycle, has a user fee date of 16 November, company CEO Al Altomari told the Pink Sheet.

"We really believe in the product," Altomari said. "We just felt we hadn't told our side of the story yet. We knew it's hard to write some of the complications and thoughts down in a book. So we knew we needed to talk and have a dialogue."

Support For Limitation Of Use
The panel was largely supportive of including a limitation of use in the labeled indication to explain that the effectiveness of Twirla decreases as BMI increases. Pamela Shaw, a professor at the University of Pennsylvania School of Medicine, noted that her vote was conditioned on the inclusion of such a limitation of use.

"I think there are some more questions for the BMI over 30 group in terms of whether or not there is increased risk and how much," Shaw said. "And the efficacy, it's very underwhelming."

Most panelists explicitly opposed contraindicating the drug for obese women. Haider opined that, "Once you start limiting it, then you start closing off patients' access."

Several panelists also suggested different ways for the label to communicate the adverse relationship between BMI and effectiveness.

"I really, strongly believe that there needs to be some language about effectiveness, a suggestion that effectiveness is decreasing with increasing BMI," Shaw said. "You're not saved if your BMI is 29.9."

Sally Hunsberger, a mathematical statistician in the National Institute of Allergy and Infectious Disease's Division of Clinical Research, recommended that the label include "a curve with confidence intervals, not just cut points of obese or non-obese."

Eisenberg echoed Hunsberger's call for a curve. "BMI and decreasing efficacy needs to be displayed in a way that's more continuous than categorical," he said.

Possible Postmarketing Requirements
Another topic of discussion at the meeting focused on the prevalence of a venous thromboembolism (VTE) safety signal, which is one of the most significant safety concerns associated with CHC use. The FDA feels that Twirla does not offer any apparent VTE safety advantage over existing CHC products.

Panelists also raised concerns about the safety signal, with several suggesting that they would like to see further study of the issue in the postmarket setting. Sabrina Miller, the panel's patient representative, specifically recommended a head-to-head study to assess the VTE risk.

One Dissenter, One Abstainer
The one dissenting vote came from Virginia Leslie, a professor at Oregon Health and Science University. Leslie's primary concern was with Twirla's efficacy profile, which she felt was unacceptable given the existence of highly effective contraceptives on the US market.

"My goal in medicine is to first do no harm," Leslie said. "And I have concerns regarding the efficacy here, and giving our patients a false sense of hope when our expectations in the country are high in terms of what we can offer them."

Leslie added that she was alarmed by the 51% discontinuation rate from Study 23.

Abstaining from the vote was University of Pennsylvania professor David Margolis. While Margolis commented that the PI cap of 5 is "rigid," he admitted he did not know what the correct number should be, and was unwilling to take a side on approval as a result.

"And without having additional groups like this or studies to look at what patient preference actually is ... I think it's nearly impossible to make a decision on the efficacy, without knowing what that number should be," Margolis said.

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