FDA Decisions on Measures of Hypoactive Sexual Desire Disorder in Women: A History, With Grounds to Consider Clinical Judgment.

INTRODUCTION: In 2000, the FDA began issuing advice about treatments for hypoactive sexual desire disorder (HSDD) in women. How its recommendations have evolved has not been reviewed. Its consistent preference for self-rating by patients over evaluation by an examining clinician has not been addressed. OBJECTIVES: Recount the changes in FDA's proposals about patient-reported outcomes and diagnostics. Compare the value of patient-reported measures and clinical interviews. METHODS: Historical review is based on draft guidances, publications, meetings, and prescribing information. RESULTS: The FDA has avoided clinician input into diagnosis and evaluation of the severity of HSDD in women. It abandoned its initial (2000) insistence on counts of satisfying sexual events to define efficacy in favor of symptom-related scales to evaluate desire and distress with daily self-ratings. By 2015, the FDA accepted the self-rated Female Sexual Function Index-Desire Domain (FSFI-D) to measure desire and the most relevant item of the Female Sexual Distress Scale-Revised (FSDS-R) to measure distress; retrospection for both is one month. The FDA rejected the one clinician-rated broad measure of HSDD, the Sexual Interest and Desire Inventory (SIDI-F), although well-validated and treatment-sensitive. Since 2005, the FDA has accepted the Decreased Sexual Desire Screener (DSDS) to diagnose HSDD by non-expert clinicians using self-ratings and exploring them in more depth in a clinical interview. CONCLUSION: FDA's decisions on how to measure HSDD in women may have stabilized on accepting 2 co-primary measures: the FSFI-D and the FSDS-R item on bother about low desire, and on accepting the DSDS for diagnosis. FDA's rejection of clinician ratings of severity through interviews in clinical trials seems unsound because interviews can give broader assessments than (brief) self-ratings, although the agency's logic was to avoid diagnostic controversies and help avoid overcommercialization. Semistructured clinical interviews for diagnosis (DSDS) and severity-rating (SIDI-F) are well validated and are recommended for clinical practice. Pyke RE. FDA Decisions on Measures of Hypoactive Sexual Desire Disorder in Women: A History, With Grounds to Consider Clinical Judgment. Sex Med Rev 2021;9:186-193.

Trazodone in Sexual Medicine: Underused and Overdosed?

INTRODUCTION: Treatment of hypoactive sexual desire disorder (HSDD) remains unfulfilled. The only approved medication, flibanserin (FLI), is highly underused owing to concerns about central nervous system (CNS) depression and interactions. Trazodone (TRZ), which is not often used for sexual problems, has evidence suggesting efficacy but similar concerns. AIM: To explore whether the pharmacologic similarities between TRZ and FLI could allow treatment of HSDD without CNS depression. METHODS: A literature search on TRZ was performed for clinical effects and to facilitate pharmacologic considerations relating to doses for HSDD and CNS depression. MAIN OUTCOME MEASURE: The main measures were threshold doses for sedative-hypnotic effects, and calculated doses for occupy 20% of agonist receptors and 70% of antagonist receptors, considering 5HT1A, 5HT2A, 5HT2C, and α1 receptors for sexual benefits and 5HT2A, α1, and histamine type 1 receptors for CNS depression. RESULTS: 3.5-19.2-mg extended-release (XR) TRZ daily (bioequivalent to 1.2-6.4-mg immediate-release [IR] TRZ 3 times a day) is estimated to be the minimum effective dose for improving sexual desire and arousal; 75 mg (25-mg IR) appears to be the threshold dose for CNS depression. CONCLUSION: Although tested only in much larger dose strengths, the optimal dose of XR TRZ for HSDD according to receptor and PK data appears to be about 4-20 mg. HSDD or arousal problems might be treated without over-sedation with XR 150-mg TRZ matrix tablets quartered to 37.5 mg daily or 50-mg IR TRZ tablets quartered to 12.5 mg given 2-3 times daily or as needed for arousal problems. Interindividual sensitivity might require varying the dose. Mechanistically rational adjuncts (eg, bupropion or dopaminergics) might augment response. Pyke RE. Trazodone in Sexual Medicine: Underused and Overdosed? Sex Med Rev 2020;8:206-216.

Sexual Performance Anxiety.

INTRODUCTION: Sexual performance anxiety (SPA) is one of the most prevalent sexual complaints; yet, no diagnosis is recognized for either gender. Thus, research into treatment has been minimal. AIM: Review the prevalence of SPA and its relation to sexual dysfunctions and anxiety disorders. Compare SPA to (non-sexual) performance anxiety and social anxiety (PA/SA). Apply pharmacologic principles to the known properties of drugs and phytotherapies to hypothesize treatments for SPA. METHODS: Review SPA and PA/SA through PubMed searches for relevant literature from 2000 to 2018. MAIN OUTCOME MEASURE: Prevalence was estimated using population-representative surveys. For treatment results, controlled clinical trial results were prioritized over open-label trial results. RESULTS: SPA affects 9-25% of men and contributes to premature ejaculation and psychogenic erectile dysfunction (ED). SPA affects 6-16% of women and severely inhibits sexual desire. Cognitive behavior therapy and mindfulness meditation training have been proven effective for PA/SA and are recommended for SPA, but controlled studies are lacking. Phosphodiesterase type 5 inhibitors are effective for psychogenic ED and premature ejaculation, both of which include SPA as a major element. Drugs proven for PA/SA have adverse sexual and sedative effects, but serotonergic anxiolytics with prosexual effects (buspirone ± testosterone, trazodone ± bupropion) may have potential, and sage, passionflower, l-theanine, and bitter orange are anxiolytic. Nitric oxide boosters (l-citrulline, l-arginine, Panax ginseng) have the potential for increasing genital tumescence and lubrication, and plant-based alpha-adrenergic antagonists may aid sexual arousal (yohimbine/yohimbe, Citrus aurantium/p-synephrine). CONCLUSION: SPA causes or maintains most common sexual dysfunction. No treatments are well proven, although cognitive behavior therapy, mindfulness meditation training, and serotonergic anxiolytics (buspirone, trazodone, gepirone) have potential, and phosphodiesterase type 5 inhibitors are effective for psychogenic ED and premature ejaculation. Several phytotherapies also appear to have potential. Pyke RE. Sexual Performance Anxiety. J Sex Med 2020;8:183-190.

Dose-Finding Study of Lorexys for Hypoactive Sexual Desire Disorder in Premenopausal Women.

INTRODUCTION: Prior medication treatment for hypoactive sexual desire disorder (HSDD) in women has left about half the subjects without benefit. Lorexys (LOR), a proprietary combination of the stimulating/excitatory dopamine-norepinephrine reuptake inhibitor bupropion (BUP) and the sedating/inhibitory serotonergic agonist-antagonist trazodone (TRZ), was developed as a multifunctional solution for this problem. AIM: Test efficacy, safety, and tolerability of LOR in a range of doses in a combined phase IB/IIA study in premenopausal outpatients with HSDD. METHODS: Otherwise healthy premenopausal women from 25-50 years of age with HSDD were tested in an open-label, active-control, one-way crossover study, with three 4-week treatments of extended-release TRZ and/or sustained-release BUP. Evaluations were made before and after each treatment. A washout of at least a week followed each treatment. The order of treatments was a standard dose of BUP; a subtherapeutic dose of BUP and TRZ (LOR-low); and a threshold-therapeutic dose of BUP and TRZ (LOR-mod). A midpoint interim analysis was planned to consider adapting doses for efficacy or safety. MAIN OUTCOME MEASURE: The primary efficacy measure was the Female Sexual Function Index, Desire domain; the main secondary efficacy measures included the Female Sexual Distress Scale-Revised 13th item, on bother about low desire, and a Patient's Global Impression of Change. The main outcome comparison was the proportions of responders. Safety measures were elicited adverse events, Epworth Sleepiness Scale, Columbia Suicide Severity Rating Scale 6-item SCREEN version, vital signs, electrocardiograms, and standard laboratory tests. RESULTS: Interim analysis did not require altering doses. Most evaluable subjects responded to LOR-mod (at the standard thresholds for response based on minimum clinically relevant difference from baseline, 79% on Female Sexual Function Index, Desire domain, 87% on Female Sexual Distress Scale-Revised Item 13, and 79% on Patient's Global Impression of Change; each P < .05 vs BUP). As expected, close to half responded to BUP (38%, 45%, and 52%, respectively). Response to LOR-low was intermediate (not significant vs BUP). Sensitivity analyses to compensate for carryover effects supported the efficacy of LOR-mod. Elicited adverse events showed the expected profile of TRZ, but led to no sedative-type dropouts or worsening on the Epworth Sleepiness Scale. CLINICAL IMPLICATIONS: The open-label 1-way crossover design of this phase IB/IIA study limits conclusions, but the consistency of responder analyses showing superiority of LOR-mod dose over control, and the lack of central depressant dropouts, favor further development in double-blind placebo-control trials. STRENGTH & LIMITATIONS: Strengths include large margins of efficacy over control agent, rapid onset of action, and rigorous safety assessment. Limitations are open-label, cross-over design/lack of placebo control and 1-month duration of exposure. CONCLUSION: Moderate-dose LOR was generally well-tolerated and was significantly more effective than BUP (active control). The results seem highly favorable compared to previously tested agents. Pyke RE, Clayton AH. Dose-Finding Study of Lorexys for Hypoactive Sexual Desire Disorder in Premenopausal Women. J Sex Med 2019;16:1885-1894.

Lumping, Splitting, and Treating: Therapies Are Needed for Women With Overlapping Sexual Dysfunctions.

INTRODUCTION: Phase-specific diagnoses, such as hypoactive sexual desire disorder, are the norm in sexual medicine. Epidemiologic surveys and clinical trials show the value of this structure for understanding and treating premenopausal sexual dysfunction; however, postmenopausal women have sexual dysfunction in >1 phase, for example, in desire and arousal. OBJECTIVE: To evaluate the evidence for mixed or global sexual dysfunction in women, identify associated comorbidities, and determine the best available treatment. METHODS: Literature review of epidemiologic surveys and clinical trials to quantitate overlap in sexual dysfunction and render conclusions about treatments. MAIN OUTCOME MEASURES: The main outcome measures were the Changes in Sexual Functioning Questionnaire and the Female Sexual Function Index. RESULTS: Overlap of sexual dysfunction in women is low to moderate before menopause, but it is high after menopause. Data suggest that clinical trials of postmenopausal women diagnosed with hypoactive sexual desire disorder actually entered patients with mixed or global sexual dysfunction and that benefits were pan-phasic rather than concentrated on desire. Whether local/vaginal products for the genitourinary syndrome of menopause impact all phases of sexual dysfunction is under study. Women treated for breast or gynecologic cancer or taking antidepressants also have global sexual dysfunction. Treatment options are limited but support mindfulness-based cognitive behavioral therapy and others. Other strategies include adding or switching to a serotonin 1A receptor agonist (eg, buspirone, flibanserin), a serotonin 2A receptor antagonist (eg, flibanserin, trazodone), or a norepinephrine-dopamine reuptake inhibitor (eg, bupropion). Elimination of hormonal contraception in premenopausal women and adding hormonal therapies in postmenopausal women may be necessary. CONCLUSIONS: Practitioners should be alert to overlap of sexual dysfunction in women. Focusing diagnostics and treatment on individual phases of sexual function is appropriate in premenopausal patients, but global sexual dysfunction is more likely in women taking antidepressants or cancer chemotherapy or during and after the menopausal transition. More safe, broadly effective treatments for mixed sexual dysfunction are needed for these populations of women. Pyke RE, Clayton AH. Lumping, Splitting, and Treating: Therapies Are Needed for Women With Overlapping Sexual Dysfunctions. Sex Med Rev 2019;7:551-558.

Toward a Scientific Nutritional Supplement Combination for Prostatism and Erectile Dysfunction I: From Known Pharmacology to Clinical Testing.

Prostatism and erectile dysfunction (ED) are highly prevalent and closely comorbid. Prescription treatments are limitingly expensive but robust in mechanisms of action (MoA). Nutritional supplements (NS) are low-cost but inadequately supported by evidence. Do any NS use robust MoA? Could their efficacy be amplified via dosing, concentration of active principles, and/or use in combination? The goal is to develop an effective NS for prostatism and ED using the MoA of prescription treatments. Literature reviews were conducted on dietary supplements for prostatism or ED and MoA of relevant drugs. The most promising NS employing these MoA were chosen. A pilot study of a prototype combination was conducted. A protocol was created for an adequate dose-response trial to test the NS combination in men with ED and prostatism. The main measures were response rates, International Prostate Symptom Score, and International Index of Erectile Function. For drugs, the MoAs best proven for prostatism and ED were nitric oxide augmentation, mild androgen inhibition, and anti-inflammatory effects. The following NS best simulate these MoA and are best supported for efficacy; for prostatism: beta sitosterol; for ED: panax ginseng, arginine, and citrulline. Pilot clinical data provided support. A plan for a formal dose-response clinical trial was approved by a central institutional review board. NS using effective MoA might suffice for prostatism and ED. Pilot testing of a combination NS with the best-supported MoA supported further development. A dose-response trial should be conducted using adequate doses of L-citrulline, beta-sitosterol, ginseng, and vitamin D3.

Exo-Clinical Trials of Nutritional Supplements for Sexual Dysfunction: Precedents, Principles, and Protocols.

INTRODUCTION: Care-seeking for sexual dysfunction is limited by embarrassment, efficacy/safety concerns, and cost. Nutritional supplements (NSs) are low-cost but unproven. AIM: To provide hypotheses on whether effective NS combinations for sexual dysfunction can be created following known pharmacology principles and tested with sufficient rigor in Internet-based "exo-clinical" trials (XCTs). METHODS: PubMed and Google searches were conducted to review the feasibility of XCTs of NS combinations for sexual dysfunction. Findings were synthesized into recommendations for XCTs to treat the most common sexual problems. MAIN OUTCOME MEASURE: The hierarchy of references used for making recommendations was controlled clinical trials over uncontrolled trials. The frequency of sexual dysfunction was determined in population-representative national surveys. RESULTS: XCTs of cognitive behavioral therapy show conclusive efficacy for anxiety and depression. 5 small XCTs showed efficacy for female sexual dysfunction and erectile dysfunction (ED), and 2 XCTs of NS for other medical problems substantiated feasibility. To test the feasibility of XCTs for the most common forms of sexual dysfunction-ED, hypoactive sexual desire disorder (HSDD), and sexual performance anxiety-protocol outlines were generated for frugal XCTs; the total estimated subject time burden is ≤1 hour. CONCLUSION: An XCT is a cost-effective method of evaluating new treatments, including sexual dysfunction and common mental disorders, if compliance is maintained by regular outreach while minimizing the time burden on subjects and handling consent and privacy issues appropriately. NS combinations might expand the opportunities for relief of sexual dysfunction if formulated with pharmacologically active doses of NS with already supported efficacy and safety. The feasibility of XCTs of NS combinations for sexual dysfunction might be tested most productively in men with ED, in women with HSDD, and in men and women with sexual performance anxiety. Pyke RE. Exo-Clinical Trials of Nutritional Supplements for Sexual Dysfunction: Precedents, Principles, and Protocols. Sex Med Rev 2019;7:251-258.

Effect Size in Efficacy Trials of Women With Decreased Sexual Desire.

BACKGROUND: Regarding hypoactive sexual desire disorder (HSDD) in women, some reviewers judge the effect size small for medications vs placebo, but substantial for cognitive behavior therapy (CBT) or mindfulness meditation training (MMT) vs wait list. However, we lack comparisons of the effect sizes for the active intervention itself, for the control treatment, and for the differential between the two. AIM: For efficacy trials of HSDD in women, compare effect sizes for medications (testosterone/testosterone transdermal system, flibanserin, and bremelanotide) and placebo vs effect sizes for psychotherapy and wait-list control. METHODS: We conducted a literature search for mean changes and SD on main measures of sexual desire and associated distress in trials of medications, CBT, or MMT. Effect size was used as it measures the magnitude of the intervention without confounding by sample size. OUTCOMES: Cohen d was used to determine effect sizes. RESULTS: For medications, mean (SD) effect size was 1.0 (0.34); for CBT and MMT, 1.0 (0.36); for placebo, 0.55 (0.16); and for wait list, 0.05 (0.26). CLINICAL TRANSLATION: Recommendations of psychotherapy over medication for treatment of HSDD are premature and not supported by data on effect sizes. Active participation in treatment conveys considerable non-specific benefits. Caregivers should attend to biological and psychosocial elements, and patient preference, to optimize response. CONCLUSIONS: Few clinical trials of psychotherapies were substantial in size or utilized adequate control paradigms. Medications and psychotherapies had similar, large effect sizes. Effect size of placebo was moderate. Effect size of wait-list control was very small, about one quarter that of placebo. Thus, a substantial non-specific therapeutic effect is associated with receiving placebo plus active care and evaluation. The difference in effect size between placebo and wait-list controls distorts the value of the subtraction of effect of the control paradigms to estimate intervention effectiveness. Pyke RE, Clayton AH. Effect Size in Efficacy Trials of Women With Decreased Sexual Desire. Sex Med Rev 2018;6:358-366.

Assessment of Sexual Desire for Clinical Trials of Women With Hypoactive Sexual Desire Disorder: Measures, Desire-Related Behavior, and Assessment of Clinical Significance.

BACKGROUND: The Female Sexual Function Index-desire subscale is the standard measure for clinical trials of hypoactive sexual desire disorder (HSDD), but lacks items assessing sexually related behaviors and attitudes toward partner. Counting satisfying sexual events is criticized, but sexual behavior remains important. Mean treatment differences cannot define clinical significance; responder and remitter analyses help. We reviewed measures on sexual desire and sexual behavior relevant to HSDD, and how to assess clinical significance. METHODS: We conducted a literature review of measures of sexual desire comparing expert-proposed criteria for dysfunctional desire, expert-developed scales, and scales from patient input. Commonly recognized symptoms of HSDD were identified. Results of HSDD trials and scale validation studies were evaluated to extract responder and remitter values. The utility of distribution-based measures of responders and remitters was assessed. OUTCOMES: Symptom relevance was evaluated as the proportion of symptom sets that included the item; responder and remitter cut points were determined by distribution-based methods. RESULTS: 12 Validated rating scales, 5 scales primarily derived from expert recommendations and 7 scales initially from patient input, and 5 sets of diagnostic criteria for conditions like HSDD were compared. Content varied highly between scales despite compliance with U.S. Food and Drug Administration recommendations for patient-reported outcomes. This disunity favors an expert-recommended scale such as the Elements of Desire Questionnaire with each of the common items, plus a measure of frequency of sexual activity, eg, item in the Patient Reported Outcomes Measurement Information System. Registrational drug trials, but not psychological treatment trials, usually give responder/remitter analyses, using dichotomized global impressions or anchor-based definitions. Distribution-based methods are more uniformly applicable to define responder and remitter status. CONCLUSIONS: The Female Sexual Function Index-desire subscale measures the most relevant element of sexual desire, but it would be meaningful to include 4 or 5 more sexual symptoms as end points: sexual thoughts/fantasies, frequency of sexual activity, receptivity, initiations, and possibly avoidance of sexual situations. The Elements of Desire Questionnaire and a measure of sexual frequency may suffice. Responder and remitter analyses show the clinical relevance of a treatment and enable comparisons across trials. Pyke RE, Clayton AH. Assessment of Sexual Desire for Clinical Trials of Women With Hypoactive Sexual Desire Disorder: Measures, Desire-Related Behavior, and Assessment of Clinical Significance. Sex Med Rev 2018;6:367-383.

Flibanserin Efficacy and Safety in Premenopausal Women With Generalized Acquired Hypoactive Sexual Desire Disorder.

INTRODUCTION: Flibanserin is a postsynaptic 5-HT-1A agonist and 5-HT-2A antagonist for the treatment of generalized acquired hypoactive sexual desire disorder in premenopausal women. AIM: To review and evaluate the efficacy and safety of flibanserin. METHODS: We review and critique the appropriateness of the co-primary and secondary end points used in the flibanserin pivotal trial research program. We review the efficacy and safety parameters of this drug based on the published literature and related sources. MAIN OUTCOME MEASURES: Pivotal trial primary and secondary end points and safety profile data from the flibanserin development program. RESULTS: Our review identified instances of poor fit of two primary trial pivotal trial end points with the hypoactive sexual desire disorder construct: satisfying sexual events and electronic daily diary assessments of the most intense level of sexual desire experienced each day. Efficacy findings of the flibanserin pivotal trials program were positive for satisfying sexual events, not positive for electronic daily diary assessments of the most intense level of sexual desire experienced, and positive for secondary end points of the Female Sexual Function Index desire domain and overall measurements and the Female Sexual Distress Scale-Revised desire-specific and overall measurements. Safety data from the clinical trial program showed a reasonable safety profile. CONCLUSION: Flibanserin has demonstrated efficacy on appropriate measurements of the hallmarks of hypoactive sexual desire disorder-experience of absent or decreased sexual desire that is persistent over time and distressing-and the safety profile of flibanserin is acceptable. Fisher WA, Pyke RE. Flibanserin Efficacy and Safety in Premenopausal Women With Generalized Acquired Hypoactive Sexual Desire Disorder. Sex Med Rev 2017:5;445-460.

What Sexual Behaviors Relate to Decreased Sexual Desire in Women? A Review and Proposal for End Points in Treatment Trials for Hypoactive Sexual Desire Disorder.

INTRODUCTION: Counts of satisfying sexual events (SSEs) per month have been criticized as an end point in treatment trials of women with hypoactive sexual desire disorder (HSDD) but grounding improvement in sexual desire by assessing changes in sexual behavior remains of some importance. METHODS: We conducted a literature review to find validated measurements that are specific sexual behavioral correlates of low sexual desire. We compared expert-proposed criteria for dysfunctional desire, expert-developed sets of scale items, and self-rated scales developed before issuance of, or in accordance with, the Food and Drug Administration's guidance on developing patient-reported outcomes. Behavioral measurements of HSDD were isolated from these sets of criteria or scales. MAIN OUTCOME MEASURES: We outline a plan to evaluate such behavioral measurements of HSDD with reference to SSEs. RESULTS: Eleven rating scales, four expert-originated and seven self-rated scales mainly derived from patient input were identified as well validated and relevant to HSDD. Three recent sets of diagnostic criteria for conditions such as HSDD were compared with the scales. Twenty-four different symptoms were found in the scales. Content found relevant to HSDD during development of the rating scales varied highly among measurements, including the self-rated scales developed in conformity with current recommendations for patient-reported outcome measurements. The only item on all sets was desire for sexual activity. Four other items were in approximately at least half the sets: sexual thoughts or fantasies, frequency of sexual activity, receptivity, and initiations. Sexual thoughts or fantasies were in every expert-derived set but in only three of the seven patient-derived sets. Receptivity was in five of the seven expert-derived sets vs two of the seven patient-derived sets. Frequency of sexual activity was in one of the seven expert-derived sets but in five of the patient-derived sets. Initiation was in approximately half the two sets. All other items were on one to three sets each. We identified three sexual behaviors of validated specificity for female HSDD: frequency of sexual activity, receptivity, and initiations. Six or seven items are relevant and informative. The item on frequency of sexual activity in the Changes in Sexual Functioning-Female scale is the only item that covers frequency of dyadic and solitary sexual activity. An item in the Female Sexual Desire Questionnaire (FSDQ) covers the intuitively relevant topic of frequency of sexual activity motivated by the woman's desire. Three FSDQ items on initiations and two items on receptivity reflect expert opinion on the sexual behaviors of most relevance to HSDD, but the FSDQ has not been validated in women with HSDD. CONCLUSIONS: SSEs have been discredited as the primary measurement in clinical trials of women with HSDD, but it would be meaningful to include at least one sexual behavioral symptom specific to HSDD as an end point. Expert-recommended sexual behaviors specifically related to HSDD are irregularly represented in self-rating scales whether developed as in the Food and Drug Administration guidance on patient-reported outcomes or not. Six or seven items on sexual behavior in self-rated scales can be recommended for relevance to women with HSDD in clinical trials. Items on female sexual behavior should be tested in comparison with SSEs in women with HSDD for relevance and for treatment sensitivity, and responder and functional and dysfunctional cutoffs should be determined before incorporation into large-scale clinical trials. Pyke R and Clayton A. What Sexual Behaviors Relate to Decreased Sexual Desire in Women? A Review and Proposal for End Points in Treatment Trials for Hypoactive Sexual Desire Disorder. Sex Med 2017;5:e73-e83.

Quantitative and Qualitative Research in HSDD: The Difference Between Testing Theory and Generating New Theories.

Tiefer (2017) criticized our recent analysis of psychological treatment trials for HSDD (Pyke & Clayton, 2015) on what she claims to be scientific and "political" grounds. In the same letter, she alleged that we, and, by extension, the U.S. Food and Drug Administration, promoted drugs to the detriment of psychological treatment of female sexual problems. Such accusations require a serious response.

Standards for Clinical Trials in Male and Female Sexual Dysfunction: IV. Unique Aspects of Clinical Trials in Female Sexual Dysfunction.

The focus of this article, the fourth in the series, Standards for Clinical Trials in Male and Female Sexual Dysfunction, is on aspects of clinical trial design and measurement that are specific to clinical trials for treatments of female sexual dysfunction. Challenges in this area include the limited extent of treatment development and clinical trial research across the spectrum of female sexual dysfunctions, changing regulatory considerations, changing diagnostic criteria for female sexual dysfunction, and the need to articulate assessment procedures to these changes. Discussion focuses on approaches to addressing these challenges in clinical trials in female sexual dysfunction.

Standards for Clinical Trials in Male and Female Sexual Dysfunction: III. Unique Aspects of Clinical Trials in Male Sexual Dysfunction.

This series of articles, Standards for Clinical Trials in Male and Female Sexual Dysfunction, began with the discussion of a common expected standard for clinical trial design in male and female sexual dysfunction, a common rationale for the design of phase I to IV clinical trials, and common considerations for the selection of study population and study duration in male and female sexual dysfunction. The second article in this series discussed fundamental principles in development, validation, and selection of patient- (and partner-) reported outcome assessment. The third and present article in this series discusses selected aspects of sexual dysfunction that are that are unique to male sexual dysfunctions and relevant to the conduct of clinical trials of candidate treatments for men.