Low Sexual Interest, Desire, 
and/or Arousal in Women: 
Developing Drugs for 
Treatment 
Guidance for Industry 

 
 
 
DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852. All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Jennifer Mercier at 301-796-0957.  
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2016 

Clinical/Medical 

477695dft.doc 
 
09/16/16   
Low Sexual Interest, Desire, 
and/or Arousal in Women: 
Developing Drugs for 
Treatment 
Guidance for Industry 

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 

Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
 
Silver Spring, MD  20993-0002  

Phone: 855-543-3784 or 301-796-3400;  Fax: 301-431-6353;  Email: druginfo@fda.hhs.gov 
 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2016 

Clinical/Medical 
 
   
TABLE OF CONTENTS  
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   DEVELOPMENT PROGRAM ....................................................................................... 3
  
A.   General Considerations .................................................................................................................3
  
B.   Specific Efficacy Trial Considerations .........................................................................................4
  
C.   Trial Populations ............................................................................................................................4
  
1.  Appropriate Target Population ........................................................................................................4
  
2.  Eligibility ..........................................................................................................................................5
  
3.  Menopausal Status  ...........................................................................................................................5
  
D.   Clinical Outcome Assessment Instruments ..................................................................................6 
 
1.  Recall Period....................................................................................................................................6
  
2.  Format of Data Capture ...................................................................................................................7
  
3.  Instruments for Measuring Patient-Reported Outcomes ..................................................................7 
 
a.   Female Sexual Function Index ..................................................................................................8 
 
b.   Female Sexual Distress Scale-Revised, Item 13 .......................................................................9 
 
c.   Other scoring proposals .............................................................................................................9
  
E.   Trial Endpoints...............................................................................................................................9
  
1.  Primary and Key Secondary Endpoints .........................................................................................10 
 
2.  Other Secondary Endpoints ............................................................................................................ 11 
 
F.   Other Considerations ................................................................................................................... 11 
 
1.  Safety Considerations..................................................................................................................... 11 
 
2.  Pharmacokinetic/Pharmacodynamic Considerations ....................................................................12 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
Low Sexual Interest, Desire, and/or Arousal in Women: 

1 
Developing Drugs for Treatment 

2 
1
 
Guidance for Industry  
3 
4 
  
5 
  
6 
  
7 
  
8 
 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 

9 
 Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations. To  discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION  
18   
19  The purpose of this guidance is to assist sponsors in developing drugs for the treatment of low 
20  sexual interest, desire, and/or arousal in women.2  Specifically, this guidance addresses the Food 
21  and Drug Administrations (FDAs) current thinking regarding the overall clinical development 
22  program, with a focus on phase 3 trial designs, to support an indication for the treatment of these 
23  conditions. This draft guidance is intended to serve as a focus for continued discussions among 
24  the Division of Bone, Reproductive, and Urologic Products, pharmaceutical companies, the 
25  academic community, and the public.3    
26   
27  This guidance focuses on conditions of low sexual interest, desire, and/or arousal that cause 
28  marked distress or interpersonal difficulty in women, including female sexual interest/arousal 
29  disorder (FSIAD), hypoactive sexual desire disorder (HSDD), and female sexual arousal disorder 
30  (FSAD).4  The symptoms of these conditions are NOT considered to be caused by: 
31   
32     A coexisting medical or psychiatric condition   
33     Problems within the relationship   
34     The effects of a medication or other drug substance  
                                                 
1 This  guidance has been  prepared by the Division of Bone, Reproductive,  and Urologic Products in the Center for 
Drug Evaluation and Research at the Food and Drug Administration.   
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified.  
 
3 In addition to consulting  guidances, sponsors are encouraged to contact the division to  discuss specific issues that 
arise during drug development.  
 
4 FSIAD is a clinical entity described in the fifth edition of the Diagnostic and Statistical Manual of Mental 
Disorders (DSM) that was published  in 2013, whereas HSDD and  FSAD are conditions  described in the fourth  
edition of the DSM.  
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35   
36  The diagnostic criteria for disorders of low sexual interest, desire, and/or arousal in women were 
37  recently revised in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders 
38  (DSM). These revisions have not been universally accepted by the scientific community.  The 
39  recommendations proposed in this guidance can be applied to the diagnostic framework outlined 
40  in both the fourth and fifth editions of the DSM. 
41   
42  This guidance does not address the development of drugs to treat other forms of female sexual 
43  dysfunction such as orgasmic disorder, genito-pelvic pain/penetration disorder, or 
44  substance/medication-induced sexual dysfunction in women.  In addition, this guidance does not 
45  address the treatment of dyspareunia, which is often, but not always, related to vulvovaginal 
46  atrophy (VVA) associated with menopause.  VVA symptoms are addressed in a separate 
47  guidance.5  
48   
49  Although this guidance discusses the selection of endpoints for clinical trials, it does not address 
50  detailed design considerations for patient-reported outcome (PRO) instruments.  Those issues are 
51  addressed in the guidance for industry Patient-Reported Outcome Measures:  Use in Medical 
52  Product Development to Support Labeling Claims (PRO guidance).6  In addition, this guidance 
53  does not contain discussion of the general issues of statistical analysis or clinical trial design.  
54  Those topics are addressed in the ICH guidances for industry E9  Statistical Principles for 
55  Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical Trials, 
56  respectively. 
57   
58  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
59  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
60  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
61  the word should in Agency guidances means that something is suggested or recommended, but 
62  not required. 
63   
64   
65  II.  BACKGROUND 
66   
67  The term  female sexual dysfunction encompasses a heterogeneous group of sexual disorders, 
68  such as dyspareunia and problems related to sexual arousal, desire, interest, or orgasm.  The 
69  sexual response has a physiological basis but can be affected by interpersonal context, such as 
70  emotional and relationship dynamics.  Significant changes in any of these components can affect 
71  a womans sexual desire, response, and satisfaction.  A variety of factors can cause or contribute 
72  to sexual dysfunction, including medical conditions (such as symptoms of VVA related to 
                                                 
5 See the draft guidance for industry Estrogen and Estrogen/Progestin Drug  Products to  Treat Vasomotor Symptoms 
and Vulvar and Vaginal Atrophy Symptoms  Recommendations for Clinical Evaluation.  When final,  this guidance  
will represent the FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA 
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
6  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
2 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
73  menopause), psychiatric conditions (such as depression and anxiety), use of medications (such as 
74  selective serotonin-reuptake inhibitors), and stressors (such as fatigue or relationship 
75  difficulties).  Sexual dysfunction can adversely affect various aspects of life for a woman, 
76  including her relationship with her partner. There is a medical need for development of drugs 
77  with a favorable benefit-risk profile to treat women with sexual dysfunction.  
78   
79   
80  III.  DEVELOPMENT PROGRAM 
81   
82  A.  General Considerations  
83   
84  As with any drug development program, early clinical development should include appropriate 
85  dose-finding in the target population to ensure that the most appropriate dosing regimen(s) are 
86  selected for further study. The FDA recommends evaluating more than one dose in phase 3 
87  trials. See the following for additional information regarding dose response: 
88   
89     The Fit-for-Purpose Initiative dose-finding tool MCP-MOD (Multiple Comparison 
90  Procedure-modeling), a statistical methodology for dose response7  
91   
92     The guidance for industry Exposure-Response Relationships  Study Design, Data 
93  Analysis, and Regulatory Applications  
94   
95     The guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug 
96  and Biological Products  
97   
98     The ICH guidance for industry E4 Dose-Response Information to Support Drug 
99  Registration   
100   
101  If the investigational drug contains two or more drug components, the sponsor should address the 
102  combination drug rule by demonstrating that:  (1) each component makes a contribution to the 
103  claimed effects; and (2) the dosage of each component (amount, frequency, duration) is such that 
104  the combination is safe and effective for the intended patient population.8  
105   
106  Exploration of new PRO instruments or novel diagnostic measures in early development may 
107  allow correlation of results obtained from these modalities with dose-response findings.  We  
108  encourage early and regular discussions with the FDA regarding trial design to help ensure the 
109  use of adequate and interpretable assessments of treatment benefit.  
110   
                                                 
7 See the Drug  Development Tools:  Fit-for-Purpose Initiative Web page  at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm505485.htm. See also Bretz F, Pinheiro JC, and  
Branson M, 2005, Combining Multiple Comparisons and Modeling Techniques in  Dose-Response Studies, 
Biometrics, 61(3), 738-748.  
 
8 21 CFR 300.50(a) 
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111  B.  Specific Efficacy Trial Considerations  
112   
113  In general, support from two adequate and well-controlled trials is required to establish efficacy.9   
114  These trials should be randomized and placebo-controlled, but do not need to be identical in 
115  design. Each trial should include at least 24 weeks of blinded treatment to allow demonstration 
116  of effect onset and persistence while on treatment.  A placebo run-in period is recommended for 
117  assessing whether subjects will likely adhere to the proposed dosing regimen through the trial 
118  and for obtaining baseline data for the key efficacy measures.  
119   
120  For a drug intended for use as needed, we recommend that the sponsor determine the time period 
121  following each dose of the investigational drug when the drug is likely to exert its effect, taking 
122  into account pharmacokinetic/pharmacodynamic relationships.  This information should inform  
123  key aspects of the phase 3 trial design, such as the time interval following drug administration 
124  for assessing efficacy and the appropriate recall periods for PRO instruments. 
125   
126  If, in addition to the investigational drug, the proposed treatment involves a novel companion 
127  diagnostic procedure or device, contemporaneous development of the drug and the diagnostic is 
128  preferable such that the clinical performance and the clinical significance of the diagnostic can 
129  be established using data from the drug development program.10  The FDA encourages sponsors 
130  to seek advice on the diagnostic as early in development as possible.  The FDAs review of the 
131  investigational drug and the diagnostic procedure or device will be carried out collaboratively 
132  among relevant review staff. 
133   
134  C.  Trial Populations  
135   
136  1.  Appropriate Target Population 
137   
138  The FDA encourages sponsors to conduct trials in a well-defined patient population.  This is 
139  particularly relevant for sponsors who propose to study women with FSIAD, because patients 
140  could meet the DSM-5 criteria for this condition if they predominantly have symptoms of low 
141  sexual desire, if they predominantly have symptoms of low sexual arousal, or if they have 
142  symptoms of both low sexual desire and low sexual arousal.  Including women with these 
143  various combinations of symptoms in clinical trials is only recommended if the investigational 
144  drug is expected to have beneficial effects on both sexual desire and sexual arousal (e.g., based 
145  on the drugs mechanism of action).  For those investigational drugs that are expected to have 
146  beneficial effects on either sexual desire or sexual arousal  but not both  the FDA 
147  recommends that the enrolled population include patients with the symptoms most likely to 
148  respond to the investigational drug. Otherwise, the sponsor risks a failed study.  
149   
150  The phase 3 trials should be conducted in North America (i.e., United States and Canada) 
151  because of differences in the diagnosis, practice of medicine, and expectation of treatment effects 
                                                 
9  21 U.S.C. 355(d) 
 
10 See the guidance for industry and Food and Drug Administration staff  In  Vitro Companion Diagnostic Devices  
available on the Guidance Documents (Medical Devices and Radiation-Emitting Products) Web page at  
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm.  
4 
 Contains Nonbinding Recommendations 
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152  in different geographical regions.  These differences may affect the generalizability of efficacy 
153  data from patients outside the United States to the U.S. population.  If the development program  
154  includes trials conducted in other geographical regions, these data can be used to support safety. 
155   
156  To support efficacy, the trial population should be representative of U.S. women in whom the 
157  drug will be intended for use and should reflect the demographic characteristics of the target  
158  population with the disorder. Trial subjects should be North American patients who are sexually 
159  active and are at least 18 years of age.  They should have a documented history of personal 
160  distress related to low sexual interest, desire, and/or arousal.  Although women who are not in a 
161  stable relationship may also experience sexual dysfunction, the FDA recommends that the 
162  clinical trials limit enrollment to women who are in a stable relationship.  This approach reduces 
163  the likelihood of having changes in relationship status during the trials, which could confound 
164  the results.  Patients should be excluded if the symptoms and associated distress are related to a 
165  comorbidity, problems within the relationship, or the effects of a drug or other drug substance.  
166   
167  Female sexual dysfunction occurs in adult women.  Sponsors can request a full waiver for 
168  pediatric studies on the grounds that necessary studies would be impossible because the 
169  condition does not exist in the pediatric age group.  
170   
171  2.  Eligibility  
172   
173  The exclusion criteria (e.g., coexisting medical conditions, concomitant medications, restrictions 
174  based on body mass index, history of substance use) should be limited to ensure that the trial 
175  population is representative of North American women anticipated to use the drug, if approved.  
176  We also encourage sponsors to include patients with a broad range of severity of sexual 
177  dysfunction at baseline, provided that the dysfunction causes marked distress (see section 
178  III.D.3., Instruments for Measuring Patient-Reported Outcomes, for an assessment of distress).  
179  Furthermore, because the eligibility criteria do not need to be identical in all phase 3 trials 
180  comprising the clinical program, subsequent trial(s) can have less restrictive entry criteria than 
181  the first trial.    
182   
183  3.  Menopausal Status 
184   
185  Because conditions of low sexual interest, desire, and/or arousal occur in both pre- and 
186  postmenopausal women, both groups represent appropriate target populations.  Development 
187  programs targeting only one of these subgroups should be justified by safety concerns or other 
188  clinical grounds. 
189   
190  Sponsors can choose to study pre- and postmenopausal women in separate trials or study these 
191  populations within the same trial.  If studied in the same trial, randomization of subjects should 
192  be stratified by menopausal status.  Regardless of the approach chosen, dose-finding, safety, and 
193  efficacy should be established independently for each of these populations, because the benefit-
194  risk profile may differ and there may be differences in etiologies and treatment responses.  
195  Therefore, if both pre- and postmenopausal women are included in the same clinical trial, the 
196  trial should be powered adequately to demonstrate statistical and clinical significance for each of 
197  these subgroups. 
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198   
199  The FDA recommends subgroup analyses based on the cause of menopause (natural versus 
200  surgical) if both naturally and surgically menopausal women are enrolled in the same trial.  The 
201  FDA also recommends subgroup analyses according to baseline hormonal contraceptive use (for 
202  premenopausal women) and according to baseline hormone therapy use (for postmenopausal 
203  women, if these drugs are allowed during the trials).   
204   
205  The FDA also requires additional subgroup analyses based on age and race.11   
206   
207  D.  Clinical Outcome Assessment Instruments 
208   
209  Because decreased sexual interest, desire, and/or arousal are symptomatic conditions, a PRO is 
210  the most appropriate clinical outcome assessment for evaluating symptoms.  It is essential that  
211  sponsors use well-defined and reliable PRO instruments.12  For any PRO instrument proposed as 
212  a key study endpoint to support labeling claims, the sponsor should provide supportive 
213  information for FDA review (e.g., a copy of the assessment, the instruments conceptual 
214  framework and scoring, evidence of the instruments content validity13 and other measurement 
215  properties including reliability, construct validity, and ability to detect change).  See the PRO 
216  guidance for additional information.   
217   
218  1.  Recall Period 
219   
220  Key signs and symptoms should be recorded frequently by subjects to minimize inaccurate 
221  responses resulting  from problems with subject recall.  We recognize that shorter recall periods 
222  may be more burdensome to subjects over the course of a lengthy trial and could lead to diary 
223  fatigue, which could adversely affect compliance with diary entry over time.  However, longer 
224  recall periods (e.g., monthly) may adversely affect the ability to accurately reflect on symptoms.  
225  For example, the longer recall period may increase noise in the assessment  making it more 
226  difficult to detect or interpret change during a trial.  With a longer recall, it is also possible that 
227  subject recollection could be more heavily influenced by other experiences or by more recent 
228  experiences.   
229   
230  Because of the problems with long-term recall, we recommend using a short recall period 
231  (sponsors using a short recall period who are concerned about subject burden can propose 
232  approaches to minimizing burden).  Sponsors who wish to use a longer recall period should 
233  evaluate the accuracy of the longer recall period compared to shorter recall.  
234   
                                                 
11 21 CFR 314.50(d)(5)(v)   
 
12 21 CFR 314.126(a)(6) 
 
13  Content validity is defined as the Evidence from qualitative research demonstrating that the instrument measures 
the concept of  interest including evidence that the items and domains of an instrument are appropriate and 
comprehensive relative to its intended measurement concept, population,  and use.  Testing  other measurement 
properties will not replace or rectify problems with content validity.  See  section III.D., Content Validity, of the 
PRO guidance.   
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235  For drugs intended to be administered on an as-needed basis, the FDA recommends that 
236  symptoms be assessed following each dose of the placebo and investigational drug.  The length 
237  of time after each dose when symptoms should be assessed should be based on the 
238  investigational drugs expected duration of action, taking into account 
239  pharmacokinetic/pharmacodynamic relationships.  Including efficacy data from days when the 
240  investigational drug is not used may increase the difficulty in detecting and attributing a 
241  treatment difference to the drug, and is not recommended.  For similar reasons, the FDA does not 
242  recommend recall periods longer than 24 hours for an as-needed drug.  A longer recall period 
243  may make it more difficult for subjects to accurately reflect on symptoms because their recall 
244  may be affected by symptoms that occurred on the days when the placebo and investigational 
245  drug were not used. 
246   
247  For drugs that are administered continuously, we also recommend shorter (e.g., daily or weekly) 
248  recall periods with a 1-day lockout period for evaluation of primary endpoints such as desire or 
249  arousal. 
250   
251  2.  Format of Data Capture 
252   
253  Sponsors should specify the format used by subjects to record daily signs and symptoms, such as 
254  an interactive voice response system (IVRS), electronic tablet, smartphone, personal digital 
255  assistant, or paper diary. We prefer use of an electronic format with reminders or alarms, when 
256  appropriate and feasible, to ensure real-time data capture and limit missing data, as well as to 
257  accurately capture the timing of the assessment.  Sponsors should address lockout of delayed 
258  entry (see section III.D.1., Recall Period) and frequency of downloads.  In addition, sponsors 
259  should be able to generate, upon request, accurate and completed copies of electronic records in a 
260  form suitable for FDA review and inspection. 
261   
262  Such a diary should capture, at a minimum, whether a sexual encounter occurred, whether the 
263  investigational drug was taken, and any other information pertinent to the key efficacy endpoints.  
264  Sponsors should account for the occurrence of multiple sexual encounters on the same day or 
265  within a 24-hour period. Dosing times for drugs administered on an as-needed basis also should 
266  be captured.  The FDA recommends that the diary be submitted for review (e.g., screenshots, 
267  script for IVRS) in advance of its use. 
268   
269  3.  Instruments for Measuring Patient-Reported Outcomes 
270   
271  Phase 2 studies represent an important opportunity to evaluate measurement properties of PRO 
272  instruments.  Therefore, piloting the instrument and obtaining results from such exploratory 
273  studies can inform instrument design and the adequacy for use in the phase 3 trials.  Before use 
274  in phase 2 studies, it is important to establish that the questionnaire instructions and items are 
275  interpreted by subjects as intended and that the items adequately cover the relevant symptoms  
276  and are worded such that they do not overlap in their measurement concept.   
277   
278  We strongly recommend that sponsors discuss the selection and implementation of proposed 
279  PRO instruments with the FDA as early as possible during drug development.  Two instruments 
280  are discussed below. The FDA is open to considering other instruments to measure sexual desire 
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281  and distress.  We encourage the research and drug development community to collaborate with 
282  the FDA in development of a publicly available fit-for-purpose PRO instrument that can be used 
283  across multiple drug development programs over time.  A framework for such  collaboration is 
284  available within the FDA Development Tool Qualification program.  See the guidance for 
285  industry and FDA Staff Qualification Process for Drug Development Tools. 
286   
287  a.  Female Sexual Function Index14  
288   
289  The Female Sexual Function Index (FSFI) is a 19-item instrument that has been used in clinical 
290  trials to measure overall sexual function, although the FDA is unaware of data that adequately 
291  establish the validity of the instrument as a whole for regulatory purposes.  Individual domain 
292  questions from the FSFI have been used to measure specific components of sexual function such 
293  as sexual desire (questions 1 and 2) and sexual arousal (questions 3 through 6).  Below we focus 
294  on the FSFI sexual desire domain.  To date, the FDAs experience with the FSFI sexual arousal 
295  domain is limited.  Sponsors who wish to use that domain or other portions of the FSFI to 
296  establish efficacy for other aspects of sexual function should provide supporting data consistent  
297  with the recommendations in the PRO guidance. 
298   
299  The assessment of desire in the FSFI includes introductory instructions that define desire as 
300  being a feeling that includes wanting to have a sexual experience, feeling receptive to a 
301  partners sexual initiation, and thinking or fantasizing about having sex.  Question 1 asks How 
302  often did you feel sexual desire or interest? with response options ranging from 5 (Almost 
303  always or always) to 1 (Almost never or never).  Question 2 asks How would you rate your 
304  level (degree) of sexual desire or interest? with response options ranging from 5 (Very high) to 
305  1 (Very low or none at all). These two questions ask the subject to reflect on her symptoms over 
306  the preceding 4 weeks.  The two response scores are summed, and raw scores are multiplied by a 
307  factor of 0.6, providing a sexual desire domain score that ranges from 1.2 to 6.0. 
308   
309  The FDA has the following concerns with the content validity and response scale of the FSFI 
310  desire domain, in addition to the long recall period (28 days) as discussed in section III.D.1., 
311  Recall Period. 
312   
313     The FDAs content validity concerns for the sexual desire domain arise from the 
314  multibarreled instructions that make it unclear what is driving any change identified on 
315  the assessment (e.g., receptivity, sexual fantasies, or initiating sexual activity).  For 
316  example, if only one component (e.g., sexual fantasies) is increased with the drug, but 
317  other components (e.g., wanting, initiating, or feeling receptive to sexual activity) have 
318  not improved, a score change suggesting improvement could be shown; however, it is 
319  unclear whether this represents a meaningful benefit to patients.  
320   
321     The FDAs concerns with the response scale relate to the response option of Almost 
322  always or always feeling sexual desire or interest (question 1) and a response indicating 
323  a Very high level of sexual desire or interest (question 2).  For example, it is unclear 
                                                 
14 Rosen R, Brown C, et al., 2000, The Female Sexual  Function Index (FSFI):  A Multidimensional Self-Report 
Instrument for the Assessment of Female Sexual Function,  J Sex Marital Ther, 26(2):191-208. 
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324  whether women experiencing sexual desire all or most of the time would identify this as a 
325  benefit, or whether this could represent a different concern to women.   
326   
327  If a sponsor elects to use the FSFI, or a modified FSFI, some potential approaches for doing so 
328  are delineated below:  
329   
330  (1)  A sponsor could develop a new modified FSFI desire domain that includes individual 
331  assessment of the components of desire captured on a daily basis with subsequent 
332  validation (evaluation of measurement properties).  This approach is preferred because it 
333  addresses each of the concerns delineated above.  
334   
335  (2)  A sponsor could use the FSFI desire domain and 28-day recall as currently designed and 
336  show that this recall period does not affect conclusions by comparing these results with a 
337  subset of subjects who use a shorter recall period (e.g., daily assessment) for the 
338  individual desire items.  
339   
340  (3)  A sponsor could use the FSFI desire domain but remove the multibarreled instructions in 
341  the current instrument, and consider including secondary endpoints assessing other 
342  components of desire. 
343   
344  (4)  A sponsor could use the FSFI desire domain and 28-day recall as currently designed 
345  without any modifications. This approach carries more risk because the aforementioned 
346  issues could make it more difficult to detect or interpret changes in a trial.  
347   
348  b.  Female Sexual Distress Scale-Revised, Item 1315  
349   
350  Question 13 of the Female Sexual Distress Scale-Revised (FSDS-R) instrument is considered 
351  acceptable for measuring bother (a component of distress) related to decreased sexual desire.  
352  This question asks How often did you feel:  Bothered by low sexual desire?  Subjects assess 
353  their sexual distress over a 7-day recall period and respond on a scale of 0 (never) to 4 (always).   
354   
355  c.  Other scoring proposals 
356   
357  Total scores of the FSFI and FSDS-R are not specific to the outcome measures of interest for the 
358  conditions addressed in this guidance.  Therefore, the total scores will not be considered 
359  acceptable for any labeling claim.   
360   
361  E.  Trial Endpoints 
362   
363  Primary efficacy assessments for adequate and well-controlled trials should be well-defined and 
364  reliable to provide a basis for determining whether there is substantial evidence to support the 
365  claims of effectiveness for a new drug.16  Endpoint decisions should reflect the primary 
                                                 
15 DeRogatis L,  Clayton A, et al., 2008,  Validation of the Female Sexual  Distress Scale-Revised for Assessing  
Distress in Women With Hypoactive Sexual Desire Disorder, J Sex  Med, 5:357-364. 
 
16 21 CFR 314.126 
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366  symptoms targeted by the drug (e.g., low sexual interest, desire, and/or arousal) and should be 
367  supported by the proposed mechanism(s) of action of the drug, if known.  Sponsors are 
368  encouraged to discuss endpoint selection with the FDA early in drug development.   
369   
370  The following outcome measures can be used as primary endpoints: 
371   
372     The change from baseline in the number of satisfying sexual events (SSEs) 
373     The change from baseline in the level of sexual interest or desire  
374     The change from baseline in the level of sexual arousal 
375     The change from baseline in the level of distress  
376   
377  If a trial will use an endpoint of SSEs, the protocol and PRO instruments should define the term  
378  satisfying and what activities will be classified as a sexual encounter. 
379   
380  Baseline has been defined as a 4-week no-treatment phase or a 4-week placebo run-in period.  
381  Changes from baseline typically refer to the treatment responses obtained during the last 4 weeks 
382  of the double-blinded treatment period relative to the baseline.  With this approach, the time 
383  period used for assessing baseline status (e.g., 4 weeks) should be the same as the time period 
384  used for assessing treatment responses (e.g., 4 weeks at the end of the treatment period).  
385  However, one limitation is that this approach uses only a small portion of the efficacy data 
386  collected during the treatment period.  The FDA recommends alternative approaches that use a 
387  greater portion of the efficacy data obtained during the course of the treatment period. 
388   
389  1.  Primary and Key Secondary Endpoints 
390   
391  The primary efficacy analysis should demonstrate a clinically meaningful treatment benefit that  
392  is statistically significant. Sponsors should describe in detail what constitutes a clinically 
393  meaningful change for each of the scales used in the trials and provide justification of the 
394  selected clinically meaningful threshold to define treatment success.  In clinical programs for 
395  drugs intended to treat decreased sexual interest or desire, one approach is to assess the change 
396  from baseline in SSEs and the change from baseline in sexual interest or desire scores as  
397  coprimary endpoints,17 and associated distress as a key secondary endpoint.  Similarly, in clinical 
398  programs for drugs intended to treat decreased sexual arousal, one approach is to assess the 
399  change from baseline in SSEs and the change from baseline in sexual arousal as coprimary 
400  endpoints, and associated distress as a key secondary endpoint.  
401   
402  However, it is important to note that the definitions for disorders of low sexual interest or desire 
403  and low sexual arousal include associated distress and do not include a reduction in SSEs.  For 
404  this reason, comments received from two October 2014 public meetings have stated that 
405  associated distress should replace SSEs as a coprimary efficacy endpoint for trials of drugs 
                                                 
17 Multiple primary endpoints become coprimary endpoints when it is necessary to demonstrate an effect on each  of  
the endpoints to conclude that a drug is effective. 
 
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406  intended to treat low sexual interest, desire, and/or arousal disorders, with SSEs relegated to a 
407  secondary endpoint.18  The FDA also considers this approach acceptable.  
408   
409  2.  Other Secondary Endpoints 
410   
411  Definitions of a responder demonstrating improvement in SSEs, interest, desire, arousal, or 
412  distress also can be assessed as secondary endpoints.  Responder definitions should be 
413  prospectively described before starting the trial and should be based on actual data that establish 
414  that the change is clinically important.   
415   
416  Responder definitions should be derived using anchor-based methods.  At a minimum, a static 
417  current-state patient global impression of severity (PGI-S) should be used as the anchor to 
418  evaluate the responder definition.  The PGI-S is not subject to recall error like the patient global 
419  impression of change (PGI-C) anchor.  A PGI-C can be used in addition to the PGI-S to provide 
420  additional evidence in interpreting a clinically meaningful change.  See the PRO guidance for 
421  additional information.  The FDA is open to considering other anchor-based methods as well.  
422   
423  If the investigational drug is expected to have an effect on both sexual desire and sexual arousal, 
424  the sponsor should designate, a priori, whether all these components will be evaluated as 
425  coprimary endpoints or whether some of these components will be tested as secondary endpoints.   
426  The sponsor should include justification for the proposed approach in the protocol, including the 
427  plan for controlling type I error for endpoints the sponsor hopes will lead to labeling claims.   
428   
429  F.  Other Considerations 
430   
431  1.  Safety Considerations  
432   
433  Drugs treating conditions of low sexual interest, desire, and/or arousal are likely to be taken 
434  long-term (defined as continuous or intermittent use for at least 6 months during the course of a 
435  lifetime).  Therefore, the safety database should meet the patient exposures outlined in the ICH 
436  guidance for industry E1 The Extent of Population Exposure to Assess Clinical Safety:  For 
437  Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions. Note that these 
438  are minimum patient exposures and that larger exposures may be needed for specific drugs 
439  depending on safety concerns identified during drug development.   
440   
441  Drugs intended for as-needed use may also cumulatively lead to use of at least 6 months during 
442  the course of a lifetime, and, in this case, should meet the patient exposures outlined in ICH E1, 
443  unless the sponsor provides adequate justification for why cumulative use would not exceed 6 
444  months. 
445   
                                                 
18 See the Patient-Focused  Drug  Development Public  Meeting and Scientific  Workshop  on Female Sexual 
Dysfunction Web page at http://www.fda.gov/Drugs/NewsEvents/ucm401167.htm.  See also the public meeting 
minutes The Voice of the Patient, A series of reports from the U.S. Food and Drug  Administrations (FDAs) 
Patient-Focused  Drug Development Initiative:  Female Sexual Dysfunction, accessed at 
http://www.fda.gov/downloads/Drugs/NewsEvents/UCM453718.pdf. 
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446  The FDA may request additional studies based on specific characteristics of the drug, such as its 
447  pharmacology, signals that emerge during drug development, or the intended route of 
448  administration.  Sponsors should discuss these specifics with the FDA during drug development. 
449   
450  Development programs for all new molecular entities, including treatments for low sexual 
451  interest, desire, and/or arousal, should include an assessment of cardiac repolarization potential.19   
452  Development programs for drugs with a potential psychotropic mechanism of action should also 
453  include prospective assessment of treatment-emergent suicidal ideation and behavior.20    
454   
455  2.  Pharmacokinetic/Pharmacodynamic Considerations 
456   
457  We recommend conducting an adequately designed dose-finding study  with measurements of 
458  systemic exposure to assess the dose and exposure-response relationship.  If feasible, blood 
459  samples collected during the phase 3 trials would also be helpful in correlating efficacy or safety 
460  findings with systemic exposure. 
461   
                                                 
19 See the guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation  and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs. 
 
20 See the revised  draft guidance for industry  Suicidal Ideation and Behavior:  Prospective  Assessment  of  
Occurrence in  Clinical Trials. When  final, this guidance will represent the FDAs current thinking  on this topic.  
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