Female libido drug candidate flibanserin has rekindled a debate about gender bias in the Food and Drug Administration’s drug approval process. The debate centers on that agency’s approval of 24 drugs to treat male sexual dysfunction and its failure to approve even one drug to treat female sexual dysfunction. While commentators and politicians debate alleged gender bias at a federal agency headed by a woman, the flibanserin story provides important lessons for pharmaceutical and biotech companies that run into obstacles along the path toward approval.

Lesson 1: Their Trash, Your Treasure

Flibanserin’s recent experience with the Food and Drug Administration (“FDA”) that stirred up the gender bias debate is not the compound’s first time in front of the agency. Boehringer Ingelheim originally developed the drug. After receipt of the company’s new drug application (“NDA”) and before issuing a complete response letter, the FDA sought input from the Reproductive Health Drugs Advisory Committee. In June 2010, the Advisory Committee concluded that more data was needed to support flibanserin’s efficacy and safety profile. The FDA followed the Advisory Committee’s recommendation, declined to approve the new drug application, and asked Boehringer Ingelheim to conduct additional research.

Rather than commit additional resources to flibanserin, Boehringer Ingelheim discontinued development of the drug and reported that it would focus on other products in its pipeline. That could have been the end of the flibanserin story. Instead, the smaller, agile Sprout Pharmaceuticals (“Sprout”) acquired both the compound and the opportunity to capitalize on the advanced stage of drug development.

By picking up flibanserin when it did, Sprout acquired two significant assets beyond the compound. First, Sprout acquired the benefit of extensive and costly testing of the drug. By the time Sprout entered the picture, flibanserin already had undergone the preclinical investigative phase, the investigational new drug application and approval process, and the clinical trial phase to gather safety and efficacy data. Some estimates calculate the average time for taking a drug through these phases to be 16 or more years and the average cost to bring a drug to market at more than one billion dollars1. While Sprout would need to conduct additional studies, the groundwork already had been completed.

Second, Sprout gained critical insight into the FDA’s specific concerns that the agency indicated likely must be addressed prior to approval. In fact, the FDA’s file was made even more robust because flibanserin was subjected to review by the Advisory Committee. Consequently, Sprout received a roadmap that allowed the company to target the issues most likely to impact FDA approval.

Lesson 2: Not Asking Means Not Getting

Armed with the knowledge gained during flibanserin’s first round at the FDA, Sprout resubmitted the new drug application. This time, Sprout included 14 new clinical studies and data on more than 3,000 new human subjects. All combined, Sprout has reported that the number of individuals who participated in clinical trials of the drug now has exceeded 11,000. Thus, the new submission provided additional heft to the earlier NDA.

Despite the extra support, in October 2013, the FDA issued a complete response letter, again declining to approve the NDA. This also could have ended flibanserin’s story. But Sprout would not be deterred. Instead of accepting the FDA’s position, Sprout invoked the end-of-review conference procedure under 21 CFR § 314.102(d). That provision allows an applicant to meet with the agency reviewing officials in order to discuss what other steps would have to be taken before the FDA can approve the application. An applicant is required to direct a request for an end-of- review conference to the director of the division responsible for reviewing the NDA.

The outcome of the end-of-review conference also could have concluded development of flibanserin. However, Sprout decided to take advantage of the information learned during that conference and appeal the FDA’s decision via the Formal Dispute Resolution Process. As noted in the FDA’s draft Guidance for Industry and Review Staff Formal Dispute Resolution: Appeals Above the Division Level, issued in 2013 (“Guidance”), this appellate process is designed to address a disagreement of a drug sponsor like Sprout with a decision of the CDER that involves complex scientific or procedural matters and that may be precedent-setting.

Sprout followed the right procedure, waiting to submit the appeal until after the end-of-review conference took place. Additionally, it appears that Sprout properly limited the subject of the appeal to information previously reviewed by the FDA. If a sponsor such as Sprout has new information that it would like for the FDA to consider, then the Guidance requires the appeal to be deferred until the division receives and reviews the new information.

Sprout was required to submit a request for formal dispute resolution as an amendment to its application to the review division, with a copy to the CDER Formal Dispute Resolution Project Manager. The Guidance notes that requests should include a “brief, but comprehensive statement of each issue to be resolved,” including, among other things, an account of steps already taken to resolve the issue(s), identification of possible solutions, a request for advisory committee review (if desired), and a description of the proposed outcome.

Sprout’s efforts paid off. On December 3, 2013, the FDA accepted Sprout’s formal dispute resolution request. On February 11, 2014, Sprout announced that the appellate process resulted in clear direction from the FDA. Specifically, the FDA requested completion of two additional Phase I drug interaction studies and a Phase I driving simulator study. Because Sprout availed itself of the appellate process, it does not have to go back to the drawing board. On the contrary, Sprout’s commitment was rewarded by receipt of targeted next steps along the path toward approval.

Lesson 3: Turn Crisis Into Opportunity

Allegations of gender bias tainting the FDA’s responsibility for helping to speed innovations to advance public health have gotten the attention of the public and politicians. While many purport to be aghast, the publicity arising from these allegations has not necessarily hurt Sprout or the likelihood of flibanserin’s approval. In fact, the compound now is not only championed by its sponsor, but it has received significant support in the form of pressure on the FDA.

Among others, the following have directly contacted the FDA regarding its failure to approve flibanserin: at least four congresswomen, the National Organization for Women, the Society for Women’s Health Research, the International Society for the Study of Women’s Sexual Health, the Association for Reproductive Health Professionals, the National Council of Women’s Organizations, the National Consumers League, Jewish Women International, the Center for Health and Gender Equality, the National Hispanic Medical Association, Nurse Practitioners in Women’s Health, Black Women’s Health Imperative, and the American Sexual Health Association.

Because the FDA is charged with assessing and assuring the safety and efficacy of human drugs, the notion that gender bias has eclipsed “science” may be difficult for some to fathom. However, the FDA has not been able to escape the political climate of our nation’s capital. For example, politics allegedly played a role in a different drug designed for women and girls. Specifically, in 2004, the FDA rejected its advisory committee’s recommendation that the FDA approve Barr Laboratories’ application to make Plan B emergency contraceptive available to consumers, with no age restriction mandated, without a prescription.

At the time, allegations were rampant that the White House was interfering with the FDA’s decision, driven by the political ramifications of approving the drug for over-the-counter (“OTC”) use, particularly for women below 16 years of age. Consistent with that political stance, the FDA stated that it denied OTC use because of the lack of scientific data regarding women below 16 years of age. In contrast to that position, it appears that the advisory committee believed that the company submitted sufficient data to support generalization to the population of potential users. While the FDA provided a scientific rationale, the perception of political involvement was enhanced by the FDA’s June 20, 2013, decision to approve Plan B for unrestricted sale over-the-counter.

Thus, while gender or any such bias at the FDA would be unacceptable, the potential impact that the outrage has had on the process should not be overlooked.

Conclusion

The flibanserin story provides lessons and potential paths forward for pharmaceutical and biotech  companies. By taking advantage of timing, regulatory provisions, and, even, politics, companies can better position their drugs for approval.