Flibanserin: From Bench to Bedside

Flibanserin: From Bench to Bedside Erin M. Dooley, MD, Melanie K. Miller, MD, and Anita H. Clayton, MD

ABSTRACT

Introduction: The process of approval for flibanserin (trade name Addyi) has been associated with controversy since before its approval on August 18, 2015. This argument centered on challenges to the validity of the diagnosis of hypoactive sexual desire disorder in women and the safety and efficacy of the drug. Aim: To explore the process of Food and Drug Administration (FDA) approval for flibanserin and delve further into the research, concerns, and various roadblocks to its approval. Methods: A literature review was undertaken using the terms flibanserin and hypoactive sexual desire disorder and relevant commentary from supporters and critics regarding the medication and difficulties leading up to approval. Main Outcome Measures: Review of the process of FDA approval of a medication to treat hypoactive sexual desire disorder and research published exploring the efficacy and safety of flibanserin. Results: Before flibanserin, there were no drugs approved to treat hypoactive sexual desire disorder, which has a reported estimated incidence of 10% of women. For studying the effectiveness of flibanserin, the FDA required satisfying sexual events as the primary end point, although this end point does not measure level of desire or the associated distress. The satisfying sexual event measurement was significant across all three flibanserin trials in premenopausal women, as was an increase in desire according to the Female Sexual Function Index desire domain and a decrease in distress as recorded with the Female Sexual Distress ScaleeRevised, Item 13. Safety concerns centered on the incidence of sedation, syncope, hypotension, and the interaction of flibanserin with alcohol and CYP3A4 inhibitors. Additional targeted challenge studies were mandated by the FDA. Conclusion: The process of approval of flibanserin was lengthy. This was due in part to it being the first drug in its class and one with no clear guidance on study design from the FDA or roadmap for development and approval. Dooley EM, Miller MK, Clayton AH. Flibanserin: From Bench to Bedside. Sex Med Rev 2017;X:XXXeXXX. Copyright
2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Key Words: Female Sexual Dysfunction; Hypoactive Sexual Desire Disorder; Flibanserin; Food and Drug Administration

INTRODUCTION The path to approval for flibanserin (Addyi; Sprout Pharmaceuticals, Raleigh, NC, USA) has been a controversial one, persisting even after approval by the Food and Drug Administration (FDA) on August 18, 2015.1 This was related to a confluence of factors including challenges to the diagnosis of hypoactive sexual desire disorder (HSDD), problems with required end points, the lack of other drugs in development and first in class status, and different requirements for drugs for female sexual dysfunction (FSD) than for male sexual disorders. Analysis of the safety and efficacy of a drug becomes difficult Received March 17, 2017. Accepted June 17, 2017. University of Virginia, Charlottesville, VA, USA Copyright ª 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.sxmr.2017.06.003

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when different sociocultural backgrounds and personal beliefs and values result in highly different understandings of the balance of risks and benefits. This article describes some of the relevant background for flibanserin from bench to bedside and reviews the associated processes, issues, and debate. Treatments for sexual dysfunction became a focus of interest in the mid-1990s. Sildenafil, the first FDA-approved treatment for erectile dysfunction (ED), was fast-tracked to approval in March 1998 despite deaths associated with co-administration of nitrates for cardiac disease, hypotension when used with a-blockers, and an 11-fold increase in sildenafil plasma area under the curve when taken with a CYP3A4 inhibitor.2 The primary measurement of efficacy was the International Index of Sexual Function,3 a 15-item questionnaire that assesses multiple aspects of sexual function4 including erectile function, orgasmic function, sexual desire, sexual satisfaction, and overall satisfaction. It was rapidly developed outside the requirements for a 1

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patient-reported outcome measurement5 yet was accepted by the FDA for use in ED clinical trials. The draft guidance for studies of FSD released by the FDA in 2000 (and withdrawn in 2010) did not consider such broad patient-reported outcomes acceptable efficacy measures in studies of FSD.6 In addition, the guidance required separate studies or analyses for pre- and postmenopausal women with FSD and required satisfying sexual events (SSEs) as a primary outcome measurement despite objections by sexual medicine experts. Under this guidance, proof-of-concept trials of flibanserin for treatment of HSDD in premenopausal women began.6 Soon after, in 2004, the transdermal testosterone patch, Intrinsa (Procter & Gamble, Cincinnati, OH, USA), was found efficacious and safe in 6-month clinical trials but was not approved by the FDA because of specious concerns about long-term use in postmenopausal women. In 2003, two other phosphodiesterase type 5 inhibitors, tadalafil and vardenafil, were approved for as-needed treatment of ED, with tadalafil approved for daily use (the FDA indicates there is a higher bar for safety for daily vs as-needed use) in 2008 despite an alcohol challenge test result that showed significant problems with hypotension and dizziness with “substantial amounts of alcohol (
5 units).”2 In 2009, Boehringer Ingelheim (Ingelheim am Rhein, Germany) submitted a new drug application, but the 2010 FDA Advisory Committee voted against approval of flibanserin because of problems with one of the FDArequired end points, a daily diary of desire. After years of development, Boehringer Ingelheim ended the flibanserin development program in 2010. Sprout Pharmaceuticals acquired flibanserin in 2012 and responded in 2014 to the concerns outlined in the Complete Response Letter from the FDA. Then, the FDA allowed for the use of the Female Sexual Function Index desire subdomain (FSFI-D) as the measurement of desire efficacy but also mandated additional studies. Sprout filed an appeal and the FDA withdrew the additional unwarranted requirements. In 2015, a second FDA Advisory Committee reviewed the flibanserin new drug application submission and voted 18 to 6 for approval of flibanserin for treatment of HSDD in premenopausal women. The FDA subsequently approved flibanserin in August 2015; however, a risk evaluation and mitigation strategy (REMS) was required to prohibit alcohol use with flibanserin. Figure 1 presents the regulatory timeline and details of the application cycles.

BACKGROUND FSD encompasses a wide spectrum of disorders. HSDD has been recognized as a distinct disorder of sexual function for women and men for more than 40 years; it was originally included in the psychiatric compendium, the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III), under the name “inhibited sexual desire disorder.”7 This was changed in the revised DSM-III (DSM-III-R) and included in the fourth edition of the DSM (DSM-IV) and the text revision of

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the DSM-IV (DSM-IV-TR) as HSDD.8e11 HSDD is characterized by persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity that is associated with marked distress, which can be psychological, emotional, or within the context of a relationship.12 The symptoms must not be better explained by an alternative disorder (eg, depression) or substance (eg, alcohol use, medication). HSDD can be specified as generalized or situational and acquired or lifelong.10 In the update to the fifth edition of the DSM (DSM-5) in 2013, the disorder was lumped together with “female arousal problems,” and the name was changed to “female sexual interest/arousal disorder” (FSIAD), which has the same specifiers.13e15 This change in nomenclature has been criticized by experts in the field given the physiologic differences in female sexual desire and genital arousal.16,17 Female sexual desire represents a complicated interplay of biological, psychological, and sociocultural components.18,19 The prevalence of FSD has been reported to be 40% to 43%, and most reports have indicated the prevalence of HSDD is nearly 10%.12,20e23 A recent review article reported a prevalence of 8.9% in women 18 to 22 years old.24 It is important to consider the differences between female and male sexual desire and the physiology of sex. Female sexual desire and the act of sex are not contingent on each other because women can have sex without desire. In addition, female arousal is event-dependent, whereas sexual desire is considered a general, ongoing, mental state.25 Before the approval of flibanserin, there were no FDA-approved medications for the treatment of HSDD.26,27 In 2012, FSD was listed as 1 of 20 high-priority areas of unmet medical need by the FDA under the Patient Focused Drug Development Initiative.28 Subsequently, in 2014, the FDA held a patient-focused meeting and scientific workshop in which the impact of HSDD on women’s daily lives and relationships was explored.29

FLIBANSERIN Flibanserin is a serotonin (5-hydroxytryptamine) 1A agonist and 2A antagonist; this activity was originally demonstrated in rats.30 The mechanism of action in female sexual desire is postulated to be a decrease of serotonergic inhibition of the excitatory neurotransmitters, dopamine and norepinephrine.8,21,22 Flibanserin also is a very weak partial agonist at dopamine D4 receptors, which was demonstrated in cloned cells.31 It is metabolized primarily by CYP3A4 and to a lesser extent by CYP2C19. It has a mean terminal half-life of approximately 11 hours.26 It was originally in development for treatment of depression but did not show efficacy greater than placebo in phase 2 trials. During those trials, it was noted that there was no associated sexual dysfunction and subsequently was found to show a positive effect on sexual desire using a validated measurement of sexual functioning, leading to the change in the targeted condition. The FDA-approved dose for premenopausal women with generalized, acquired HSDD is 100 mg nightly.13,26 Sex Med Rev 2017;-:1e9

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Flibanserin: From Bench to Bedside Ongoing communicaƟon between FDA and Sprout re: REMS

Type A meeƟng to discuss path forward for flibanserin November 18, 2013

Sprout resubmits NDA with proposed warning REMS

Boehringer Ingelheim sells flibanserin to Sprout

Boehringer-Ingleheim (BI) submits IND applicaƟon for flibanserin treatment of MDD to FDA

February 18, 2015

February 17, 2012

BI submits NDA for HSDD

December 2, 1996

October 27, 2009

June-August 2015

Type B pre-NDA meeƟng held April 26, 2012

FDA Approval with very restricƟve REMS

Type B meeƟng to o discuss path forward r

August 18, 2015

January 15, 2015

Sprout files appeal December 3, 2013

June 18, 2010 2002

Proof–of-Concept trials for flibanserin treatment of HSDD in premenopausal women

February 7, 2014 0

FDA Advisory CommiƩee Ʃ votes against approval v

2004-2008

Flibanserin clinical trials

FDA denies appeal p March 29, 2013 1

June 4, 2015

Advisory commiƩee meeƟng held, votes 18 - 6 to approve with a REMS

Sprout submits m March 12, 2 2014 completed requirements r Sprout wins appeal p and from CR leƩer e Type A meeƟng n held for August 27, 2010 path forward w FDA issues CR leƩer with October 27, 2014 concerns and September 27, 2013 Public paƟent-focused recommendaƟons FDA cites addiƟonal meeƟng of FDA concerns and recommendaƟons

Figure 1. Timeline to approval of flibanserin. CR ¼ Complete Response; FDA ¼ US Food and Drug Administration; HSDD ¼ hypoactive

sexual desire disorder; IND ¼ Investigational New Drug; MDD ¼ major depressive disorder; NDA ¼ New Drug Application; REMS ¼ Risk Evaluation and Mitigation Strategy.

CONTROVERSY Convenient Misnomer? Flibanserin was dubbed the “female Viagra” by the lay press, a moniker that has persisted despite the fact that it is a misnomer.20,32,33 Viagra (sildenafil; Pfizer, Mission, KS, USA) is a phosphodiesterase type 5 inhibitor administered on demand that treats ED by changing blood flow in the penis.2,34 Conversely, flibanserin is a non-hormonal, centrally acting daily medication that changes the balance of the neurotransmitters that affect sexual desire.22

The Validity of the Disorder and “Medicalizing” Human Sexuality? Some critics purport that HSDD is not a valid disorder.35,36 Because sexual desire is highly subjective, and social, interpersonal, cultural, and psychological factors play a major role in sexual desire, some detractors believe that the very act of naming it a disorder “pathologizes” a normal part of human sexuality.37 They worry that the availability of a pill for HSDD will Sex Med Rev 2017;-:1e9

de-emphasize non-pharmacologic treatments.32 Anti-pharma pundits have asserted that any pharmaceutical treatment for HSDD “medicalizes” normal sexual function and, even further, might have been created by the pharmaceutical industry.35,37,38 Conversely, numerous published studies have supported the validity of the diagnosis, and many experts in women’s sexual health believe that, like any other disorder causing distress, treatment is entirely appropriate. Patients report the negative impact of HSDD on their relationships, self-worth, and identities as sexual persons.13,36 There could be some validity to the “medicalization” argument, but in psychiatry, the persistence of extremes of many normal emotions constitutes a diagnosis that can be treated with medications. Distress, by nature, is a selfreported measurement. It does not seem appropriate for any particular agency or advocacy group to purport to know what is right and wrong for each patient and that patient’s particular array of symptoms. Each step of the process toward an intervention for a central nervous system (CNS) condition can be quite difficult. These potential hardships include recognition of a problem, ignoring or overcoming the associated stigma, opening

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up to a provider to seek treatment, making the choice of the best treatment for one’s symptoms and circumstances, and suffering the potential adverse effects and/or failures of treatment. Although the FDA attempts to limit the discomfort of the ultimate step by protecting patients from drugs that are likely to fail them or cause them harm, in conditions that rely on patient report of symptoms, because of the nature of the disorders being treated, a heavier portion of the burden must be placed on the patient and the provider. This question of whether HSDD is a valid disorder extends even to the name; some critics believe that since the DSM diagnosis was changed from HSDD in the DSM-IV-TR to FSIAD in the DSM-5, HSDD is now a discredited diagnosis.10,14 There is concern in women’s health that the change from HSDD to FSIAD was inappropriate, because sexual desire is distinct from genital arousal.39 The DSM is widely used and generally accepted in psychiatry, but it is a guide that changes over time as our understanding of mental disorders grows with research. The diagnosis of HSDD is actively used in practice and is maintained in the nomenclature of the International Consultation in Sexual Medicine, the International Society for the Study of Women’s Sexual Health, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, and the anticipated International Statistical Classification of Diseases and Related Health Problems, Eleventh Revision.12 The diagnosis of what would previously have been classified as HSDD in the DSM-IV can still be diagnosed as FSIAD in the DSM-5. In addition, the FDA has publically stated there is no question of the validity of this diagnosis.40 Hand-in-hand with the concern over the validity of HSDD as a disorder is a mistrust regarding the true burden of disease.35,37 If arguments continue over what levels of female sexual desire are normal, how to measure abnormalities, and what to call them, then it seems nearly impossible to understand, measure, and agree on the potential benefits of a treatment such as flibanserin.

Condition Overlap and Off-Label Use There is a significant level of overlap between women with HSDD and those with depression.41 What role does each disorder play in the other’s presentation? Atlantis and Sullivan42 reported a bidirectional association between sexual dysfunction and depression. Flibanserin is not currently indicated for antidepressant-induced sexual dysfunction, a common side effect of most available selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.43 However, flibanserin was found to be safe when administered concomitantly with selective serotonin reuptake inhibitors and serotoninnorepinephrine reuptake inhibitors.7,40 There is FDA concern that this could become a widespread off-label use for the drug.44 Conversely, some experts believe that given the mechanism of the drug, it should be theoretically successful in treating these side effects. It is yet to be seen what the FDA would require to add an indication or whether providers would take the liberty of

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prescribing off-label. The same issues affect the use of flibanserin in postmenopausal women, which has been found to be safe and effective, but does not yet have an FDA indication.

Flawed Study End Points? Detractors and proponents of flibanserin as a treatment for HSDD can agree that sexual desire is difficult to quantify, and perfect end points have not yet been discovered or validated.45 The co-primary prespecified end points required by the FDA in the first two trials were the daily desire diary and the number of SSEs per month, which focused on counting and very short recall periods.9 A daily measurement of sexual desire is not endorsed as meaningful by women because desire is a gestalt or state that can be recalled over weeks, rather than a construct that changes on a daily basis, and overly frequent recording can exaggerate placebo effects and cause diary fatigue.45,46 In addition, SSEs do not measure the cardinal symptoms of HSDD, but rather, are an indirect, downstream measurement that might or might not reflect changes in sexual desire and associated distress. The secondary end points used in the first two trials were sexual desire recall (frequency and intensity) during the previous 4 weeks, assessed with two items constituting the FSFI-D, and distress due to lack of desire, measured with the Female Sexual Distress ScaleeRevised, Item 13 (FSDS-R13).13 For the third trial, the daily desire diary was dropped as an end point, and sexual desire recall with the FSFI and number of SSEs were used as co-primary end points. The FDA published updated draft guidance with recommendations on changes to study end points in 2016, after approval of flibanserin.47

True Efficacy? The discussion of the efficacy flibanserin has been another matter of contention. The flibanserin phase 3 trials enrolled women with generalized, acquired HSDD of at least 6 months in duration. On the whole, statistically significant superiority over placebo for increases in sexual desire using the FSFI-D was shown consistently across the three pivotal trials, and these changes were described as meaningful by the women in the trials.13 The absolute difference between the percentage of responders, anchored to “much improved” or “very much improved,” taking flibanserin and the percentage of responders taking placebo was 7% to 13% on the three major end points in all three trials. These numbers were presumably used to imply poor efficacy. However, the percentage of responders, without subtracting the percentage of placebo responders, ranged from 21% to 48%.13 The high placebo response rates are fairly typical of CNS-active drug trials.19 The SSE measurement also was significant across all three trials, as was a decrease in distress as recorded with the FSDSR13. Comparing values for the FSFI-D, SSEs, and FSDS scores, with matching across trials, showed that 43% to 60% of subjects receiving flibanserin 100 mg daily at bedtime were Sex Med Rev 2017;-:1e9

Flibanserin: From Bench to Bedside

responders on all three end points, which essentially rules out a chance finding.13 Of note, flibanserin was reviewed by the FDA Division of Bone, Reproductive, and Urologic Products (DBRUP), despite that, in essence, it is a CNS drug acting on brain reward circuitry. It could have been evaluated by the CNS division, where similar drugs are typically reviewed, and the placebo response is characteristically 30% to 40%, higher than with other drugs.19 In addition, the typical and acceptable side effects are quite consistent across drugs that act on serotonin and are usually mild to moderate in intensity, but are not serious in nature. The expectations by the DBRUP might have been unrealistic for the mechanism of action of the drug.

Exaggerated Safety Concerns? On the other side of the coin from efficacy lies safety, a topic on which there has been extensive commentary. The most common depressive CNS adverse events in the pooled placebo-controlled phase 3 database in premenopausal women with HSDD were fatigue, somnolence, and sedation and occurred in nearly 21% of subjects receiving flibanserin 100 mg at bedtime, at a rate three times greater than placebo.7 However, most patients became tolerant, and these effects diminished or resolved after 7 to 14 days.40 The incidence of somnolence was 17% with flibanserin 50 mg twice daily, 11% with flibanserin 100 mg at bedtime, and 3% with placebo.7,13 FDA concerns initially centered on the incidence of sedation (and whether these effects would continue the day after bedtime dosing, causing cognitive impairment and/or sedation-related accidents), syncope, hypotension, and the interaction of flibanserin with alcohol and moderate or strong CYP3A4 inhibitors.13 To address these concerns, specific targeted challenge studies were required by the FDA. In phase 1 trials, there were six reports of syncope in patients who received flibanserin alone, dosed in the daytime. One was several days after the dose, ruling out the drug as a cause. One was after a dose of 200 mg (double the approved dose), and another had more than double the maximum concentration because she was in the CYP2C19 pharmacogenomic study. Medical interventions included intravenous fluids in one subject, lying down in another, and the remaining subjects did not require intervention. In the phase 3 trials, in which 60% of the women described themselves as social or moderate alcohol drinkers, syncope was reported in 6 of 1,543 subjects (0.39%) receiving flibanserin and 4 of 1,905 subjects (0.21%) treated with placebo. One event was coded as serious because the patient fell and had a concussion, but this subject had a history of autonomic dysregulation and orthostatic hypotension, so the role of flibanserin was unclear.13 A standard pharmacokinetic drug interaction study in patients who were given oral fluconazole 200 mg, a moderate CYP3A4 inhibitor, and flibanserin 100 mg resulted in large flibanserin exposure increases (area under the curve ¼ 7-fold; maximum concentration ¼ 2.24-fold). Three patients had concerning Sex Med Rev 2017;-:1e9

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decreases in blood pressure with diastolic pressures in the 40s and one was sent to the emergency room. One subject given oral ketoconazole 400 mg and flibanserin 100 mg developed orthostatic hypotension and syncope, but blood pressure was not taken and no intervention was needed. The mean flibanserin exposure increases in this case were measured at an area under the curve of 4.50-fold and a maximum concentration of 1.84-fold.13 Given the half-lives of flibanserin and fluconazole, flibanserin should be held if oral fluconazole is needed. No studies were done with vaginal fluconazole because of the low risk of systemic effects. In the required alcohol challenge study with 25 healthy subjects (23 men), patients were required to fast for 10 hours, were given a “light breakfast,” and drank 0.4 or 0.8 g/kg (weight-based dosing) of grain alcohol in 10 minutes, at 10:00 AM, with placebo or flibanserin 100 mg.13 This is the equivalent of two or four drinks, respectively, in a 70-kg person, although it seems prudent to note that the amount of alcohol in a standard size drink does not vary by the individual person’s weight, so potentially each person in this study might have had the equivalent of fewer than two or more than four standard drinks, in grain alcohol, in 10 minutes. Ten subjects who received alcohol plus flibanserin had concerning events of hypotension or syncope. The medical interventions noted included ammonia inhalants in two and lying down in five. In those who fainted, the systolic blood pressure decreased 22 to 54 mm Hg, and the diastolic blood pressure decreased 0 to 46 mm Hg. There was no effect on flibanserin serum concentrations. This study resulted in a black box warning stating that alcohol use is contraindicated with flibanserin because the combination increases the risk of severe hypotension and syncope14 and a REMS program that includes requirements that providers and pharmacies be certified to prescribe or distribute the drug. This is done by reviewing a training presentation and taking a short multiple-choice test. Patients must sign a form to be placed in their charts that they understand that they must not drink any alcohol while taking flibanserin.48 A special interest group called the National Women’s Health Network testified that they believed the REMS is not enough to keep women safe.49 They, and others, criticized this study for using 23 men of 25 total participants despite the sponsors’ statements that it was difficult to recruit women for this study.49,50 Those on the other side judged that the design of the study was highly inconsistent with alcohol use of the target demographic for this drug and with the approved flibanserin dosing (100 mg at bedtime). The sponsor believed that the phase 1 results of syncope and hypotension would be mitigated with nightly dosing, which does seem to have been the case in the phase 3 trials.13 Detractors cited concerns that this was not an appropriate resolution49; however, the drug interactions are comparable with those of other drugs on the market without a REMS. It is important to note that in the phase 3 trials, patients self-rated their alcohol use and approximately half of the flibanserin and placebo arms indicated that they drank alcohol within 30 days of filling out the

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survey and 15% reported binge drinking (more than four drinks) within the same timeframe.13 This information, in combination with the low incidence of syncope in the pivotal trials, seems to be strongly suggestive that flibanserin taken with some alcohol is not seriously dangerous. In addition, it is unlikely that patients with alcohol use disorders would receive the diagnosis of HSDD by a trained professional because the criteria specify that the symptoms cannot be due to another disorder, including substance use.11 Compared with the other available CNS-active drugs, these side effects are less severe and dangerous than other commonly used medications such as opioids, antidepressants, antiepileptic drugs, and triptans. The language used by some critics in the lay press was overly dramatic (eg, “potentially devastating complications”51). It would be reasonable to consider fainting while driving “potentially devastating,” but with bedtime dosing, and all syncopal events occurring within a few hours of dosing, there is no indication that this would occur. If the side effects with flibanserin were truly as unsafe as implied by the REMS and the drug’s critics, then should it have been approved? There were 42 patients treated with flibanserin 100 mg at bedtime (2.7%) and 47 patients treated with placebo (2.5%) who reported accidental injury.7 The FDA required that the sponsors do a simulated driving study to determine whether flibanserin had CNS effects that would result in unsafe driving the morning after dosing (9 hours later).13 In a trial of 83 premenopausal women, flibanserin performed significantly better than placebo and the required comparator hypnotic in nextmorning driving and cognitive testing.40 An interesting aside is that flibanserin was compared with placebo and a hypnotic agent that is currently unavailable in the United States. Was this a clever way to avoid developing data that currently FDA-approved hypnotic drugs do result in impaired driving? Other safety concerns noted by the FDA were an unexpected distribution of appendicitis in the flibanserin (more than expected) and placebo (fewer than expected) arms of the trials and the discovery of malignant mammary tumors in female mice at exposures 3 and 10 times those achieved with the clinical dose, although this was deemed not relevant in reference to the risk in humans.7,13,40 There was one death during the trials of a postmenopausal 54-year-old woman who was found unresponsive, lying face down on her bed, with a high blood alcohol content, 14 days after starting flibanserin.13,40 The drug’s role in her death, if any, cannot be conclusively determined. Safety concerns discussed more in the lay press than in the FDA documentation include those regarding its effects in pregnancy, given that the drug is intended to improve the sex drive of premenopausal women.40 However, it is typical that data of this kind are limited based on the ethics of studies on effects in pregnancy. Animal studies did not demonstrate fetal harm at up to 15 times the recommended human dose by weight.13,14

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Gender Bias: Sexism or Safety? There has been a great deal of debate about whether there is gender bias in the FDA and in the opponents to approval of flibanserin.13,36,38,52 Those who believe there is tout that there are currently 26 FDA-approved medications for male sexual dysfunction, whereas flibanserin was the first for women.36,53 Opponents point out that there might be 26 individual drugs, but the number of different active receptor targets is significantly smaller.53 Also, the first FDA approval for a drug to treat male sexual dysfunction (sildenafil for ED) occurred in 1998, fully 17 years before approval for the first treatment for FSD. Critics of flibanserin believe that a daily drug that alters brain chemistry is more risky than an asneeded medication such as sildenafil (Viagra).53 However, some of the listed potential side effects of sildenafil include stroke, blindness, and death.2 On-demand use is not any safer than daily use for those who have taken sildenafil and died.34 Was flibanserin held to a higher standard than other medications, particularly those for male sexual dysfunction? For example, alcohol challenge studies of another phosphodiesterase type 5 inhibitor, tadalafil (Cialis; Ely Lilly and Company, Indianapolis, IN, USA), had similar results to those of flibanserin, and the corresponding recommendation for Cialis users is to avoid drinking at least five alcoholic drinks when taking Cialis.54 Is this coming from some level of paternalism or institutionalized sexism in the FDA? It seems that it is assumed that men can choose whether the benefit is worth the risk, whereas women need help from others who can “protect” them from harm by making the decision for them. Some critics believe that the drug company sponsored a successful advocacy campaign to “shame” the FDA into approving their drug.32,52 In fact, Sprout Pharmaceuticals, among many other advocacy agencies, was a contributor to an online campaign called “Even the Score” that focuses on the differences in available treatments for male and female sexual dysfunction. Cynics wonder if the “feminist aspect” was dreamed up by the drug company out for dollars and not the idealism that they suggest.38 However, how would advocacy for another health problem such as diabetes or incontinence be perceived? In reality, their intent is less important than the opinions of experts, sexual health care providers, and those with HSDD who have compelling arguments. Nevertheless, skeptics have publicly wondered whether the experts were “bought,” an accusation unsupported by publically available data such as those reported through the Sunshine Act. In addition, there is concern that moving this debate into the forefront of public view will stigmatize something that is on the spectrum of normal and cause distress to women who were not otherwise distressed by their level of sexual desire. It is difficult to weigh this risk against the potential benefit of addressing the concerns of women who are already distressed by their hypoactive sexual desire and seeking treatment. Beyond that, it is quite notable to compare the publicity and billions of marketing dollars spent on medications for male sexual

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Flibanserin: From Bench to Bedside

dysfunction without apparent consideration for stigma in that regard.

Publications; and owns shares or restricted stock units in Euthymics and S1 Biopharma.

The FDA had the opportunity to hear and develop a better understanding of the “voice of the patient” in its 2014 meeting on women’s sexual dysfunction, one of the 20 FDA-identified high-priority unmet medical needs.29 Those on both sides of the debate might be able to agree that flibanserin is, in fact, a quality-of-life drug. This clearly necessitates a different riskbenefit analysis than drugs or devices that treat life and death medical conditions or surgical emergencies. However, it would be reasonable to argue that the side effects are quality-of-life effects, in that the risk of fainting, hypotension, dizziness, sedation, and fatigue might be bothersome, but not dangerous. They could lead some to choose to discontinue the drug, but death and ongoing disability are highly unlikely. Isn’t the choice regarding quality of life by balancing sexual well-being and side effects each woman’s to make?

Funding: None.

Questions

Category 3

A final thought to reflect on in this case concerns the perspectives and biases of the most outspoken critics on both sides of the debate. On the one hand, among the detractors of flibanserin, is there conscious or unconscious gender bias? Specifically, is there an anti-sex-in-women sentiment that isn’t present for men? Is there a general anti-pharma sentiment? Do the critics have the appropriate background and expertise to judge the efficacy and safety of this medication in its class? On the other hand, what financial stakes do the biggest proponents have? Was the result more related to effective communication than to good medicine? Do the advocacy groups on either side have their own political agendas? All these possibilities are important to consider.

CONCLUSIONS The process of approval for flibanserin was a lengthy one. This was due at least in part to it being the first drug of its class with no clear guidance on study design from the FDA and no roadmap to development and approval. Clear requirements are needed for the next drugs in development for FSD. This process is not over. Corresponding Author: Anita H. Clayton, MD, Department of Psychiatric & Neurobehaviorial Sciences, Delta Health System, 2955 Ivy Road, Northridge Suite 210, Charlottesville, VA 22903, USA; E-mail: [email protected] Conflicts of Interest: Dr Dooley and Dr Miller report no conflicts of interest. Dr Clayton has received grants from Auspex Pharmaceuticals, Axsome, Forest Research Institute, Inc, Genomind, Inc, Janssen, Palatin Technologies, and Takeda; has been on the advisory board fee or received a consultant fee from FabreKramer, Palatin Technologies, S1 Biopharma, Sprout (division of Valeant Pharmaceuticals), and Takeda; has received royalties or owns copyrights from Ballantine Books/Random House, Changes in Sexual Functioning Questionnaire, and Guilford Sex Med Rev 2017;-:1e9

STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Erin M. Dooley; Melanie K. Miller; Anita H. Clayton (b) Acquisition of Data Erin M. Dooley; Melanie K. Miller; Anita H. Clayton (c) Analysis and Interpretation of Data Erin M. Dooley; Melanie K. Miller; Anita H. Clayton Category 2 (a) Drafting the Article Erin M. Dooley; Melanie K. Miller; Anita H. Clayton (b) Revising It for Intellectual Content Erin M. Dooley; Melanie K. Miller; Anita H. Clayton

(a) Final Approval of the Completed Article Erin M. Dooley; Melanie K. Miller; Anita H. Clayton

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