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1 Supplementary Online Content Jaspers L, Feys F, Bramer WM, Franco OH, Leusink P, Laan ETM. Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women: A Systematic Review and Meta-Analysis. JAMA Intern Med. Published online February 29, doi: /jamainternmed emethods 1. Search Strategy 17 June, efigure 1. Flowchart for Study Selection. Adapted from PRISMA Statement. emethods 2. In and Exclusion Criteria. emethod 3. Definition of adequately and inadequately blinded studies. etable 1. Linkage of the Included Registered Trials to the Retrieved Full Texts and Abstracts. etable 2. Study participant flow and number (%) per reason of dropout. etable 3. General Characteristics of the Study Participants. etable 4. Baseline Levels of the Efficacy Outcomes. etable 5. Summary of Each Assessed Risk of Bias Item Per Study. etable 6. Summary stratified per risk of bias domain. etable 7A. Support for Judgement of the Risk of Bias Assessment for study DeRogatis, 2012 (NCT ). etable 7B. Support for Judgement of the Risk of Bias Assessment for study Thorp, 2012 (NCT ). etable 7C. Support for Judgement of the Risk of Bias Assessment for study Katz, 2013 (NCT ). etable 7D. Support for Judgement of the Risk of Bias Assessment for study Simon, 2014 (NCT ). etable 7E. Support for Judgement of the Risk of Bias Assessment for Alternate Dose Study (NCT ). etable 7F. Support for Judgement of the Risk of Bias Assessment for EU Study (NCT ). etable 7G. Support for Judgement of the Risk of Bias Assessment for Terminated Study (NCT ). etable 7H. Support for Judgement of the Risk of Bias Assessment for Goldfischer, 2011 (NCT ). 1

2 etable 8. Results for Patient s Global Impression of Improvement. efigure 2A. Mean Difference for FSFI Total Score (scale 2-36) for Flibanserin 100mg versus Placebo. efigure 2B. Mean Difference for FSDS-R Item 13 (scale 0-4) for Flibanserin 100mg versus Placebo. efigure 2C. Mean Difference for FSDS-R total score (scale 0-52) for Flibanserin 100mg versus Placebo. efigure 2D. Risk Difference for PBE for Flibanserin 100mg versus Placebo. etable 9. Meta-Analysis Results Comparing Studies in All Women to Studies in Premenopausal Women Only. etable 10. Meta-Analysis Results for Studies using the Food and Drug Administration approved dose of 100 milligrams once daily at bedtime. etable 11. Meta-Analysis Results for published studies only. etable 12. Meta-Analysis Results for the Efficacy Outcomes in Flibanserin 100mg and Placebo Groups Separately. efigure 3A. Risk Ratio for Any Adverse Event for Flibanserin 100mg versus Placebo. efigure 3B. Risk Ratio for Adverse Events Leading to Discontinuation of the Study for Flibanserin 100mg versus Placebo. efigure 3C. Risk Ratio for Serious Adverse Events for Flibanserin 100mg versus Placebo. etable 13. Sensitivity analyses to check robustness of missing data imputation. This supplementary material has been provided by the authors to give readers additional information about their work American Medical Association. All rights reserved. 2

3 emethods 1. Search Strategy 17 June, Embase.com Medline (ovid) 35 6 Web-of-science Scopus Cochrane 22 2 Psycinfo (ovid) 14 1 cinahl (ebsco) 3 1 Pubmed publisher 0 0 Proquest Lilacs 0 0 Scielo 0 0 Popline 0 0 Google scholar Total Embase.com 152 (flibanserin/exp OR (bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi):ab,ti) AND ('psychosexual disorder'/exp OR 'sexual dysfunction'/exp OR 'sexual health'/exp OR 'sexual function'/exp OR sexuality/exp OR (hsdd OR fsiad OR fsad OR fsid OR sexual* OR psychosexual* OR coit* OR desire):ab,ti) NOT ([animals]/lim NOT [humans]/lim) Medline (ovid) 35 (flibanserin.nm. OR (bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi).ab,ti.) AND (exp "Sexual Dysfunctions, Psychological"/ OR exp "Sexual Dysfunction, Physiological"/ OR "Reproductive Health"/ OR "Reproductive Medicine"/ OR exp "Sexual Behavior"/ OR (hsdd OR fsiad OR fsad OR fsid OR sexual* OR psychosexual* OR coit* OR desire).ab,ti.) NOT (exp animals/ NOT humans/) Psycinfo (ovid) 14 ((bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi).ab,ti.) AND (exp "Psychosexual Behavior"/ OR (hsdd OR fsiad OR fsad OR fsid OR sexual* OR psychosexual* OR coit* OR desire).ab,ti.) NOT (exp animals/ NOT humans/) cinahl (ebsco) 3 ((bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi)) AND (MH "Sexual Dysfunction, Female+" OR MH "Sexuality+" OR (hsdd OR fsiad OR fsad OR fsid OR sexual* OR psychosexual* OR coit* OR desire)) NOT (MH animals+ NOT MH humans+) Cochrane 22 ((bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi):ab,ti) AND ((hsdd OR fsiad OR fsad OR fsid OR sexual* OR psychosexual* OR coit* OR desire):ab,ti) Web-of-science 75 3

4 TS=(((bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi)) AND ((hsdd OR fsiad OR fsad OR fsid OR sexual* OR psychosexual*)) NOT ((animal* OR rat OR rats OR mouse OR mice OR murine) NOT (human* OR woman* OR women*))) Scopus 101 TITLE-ABS-KEY(((bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi)) AND ((hsdd OR fsiad OR fsad OR fsid OR sexual* OR psychosexual*)) AND NOT ((animal* OR rat OR rats OR mouse OR mice OR murine) AND NOT (human* OR woman* OR women*))) Pubmed publisher 0 (flibanserin[nm] OR (bimt-17 OR bimt17 OR flibanserin* OR Girosa OR Addyi[tiab])) AND ("Sexual Dysfunctions, Psychological"[mh] OR "Sexual Dysfunction, Physiological"[mh] OR "Reproductive Health"[mh] OR "Reproductive Medicine"[mh] OR "Sexual Behavior"[mh] OR (hsdd OR fsiad OR fsad OR fsid OR sexual*[tiab] OR psychosexual*[tiab] OR coit*[tiab] OR desire)) NOT (animals[mh] NOT humans[mh]) AND publisher[sb] Google scholar "bimt-17" bimt17 flibanserin Girosa Addyi hsdd fsiad fsad fsid sexual psychosexual sexually psychosexually coitus coital desire Proquest 60 (ti(flibanserin) OR ab(flibanserin)) AND (ti((sexual* OR psychosexual*)) OR ab((sexual* OR psychosexual*))) Lilacs 0 Scielo 0 Popline 0 Flibanserin AND (sexual* OR psychosexual*) 4

5 efigure 1. Flowchart for Study Selection; adapted from PRISMA Statement. Records identified through database searching (n = 562) Additional records identified through other sources a (n = 30) Records after duplicates removed (n = 299) Records screened on title and abstract (n = 299) Records excluded (n = 257) Full-text articles, abstracts, and registered trials assessed for eligibility (n = 43) Studies included in qualitative synthesis (n = 8) Full-text articles, abstracts, and registered trials excluded (n = 35) Reasons: Record from excluded trial, n=5 Abstract of published study, n=21 Same abstract, other congress, n=4 Abstract or full text not found, n=4 Fulfilled inclusion criteria, but no results available, n=1 Studies included in quantitative synthesis (n = 7) a Other sources include: clinicaltrials.gov (14 records), European Medicines Agency (2 records), WHO International Clinical Trials Registry Platform (14 records), and screening of reference lists (0 new records). 5

6 emethods 2. In and Exclusion Criteria. Inclusion criteria 1. Include interventional studies (randomized trials, randomized controlled trials (RCTs), nonrandomized interventional trials). 2. Include studies focusing on women with HSDD or FSIAD. 3. Include studies evaluating flibanserin, administered orally with any type of treatment regimen. 4. Include studies with any type of outcome related to beneficial and harmful treatment effects, among others, but not exclusively restricted to: a. Change in sexual satisfaction; b. Change in sexual pleasure; c. Change from baseline in satisfying sexual events (number/month); d. Change from baseline in sexual desire (sexual desire score/month, measured using daily electronic diary or desire domain score with FSFI); e. Change from baseline in distress related to sexual desire (measured with FSDS-R, question 13 is desire, and overall score); f. Change in overall sexual function (FSFI); g. Patient global impression of improvement (PGI-I); h. Patient benefit evaluation (PBE). i. Safety assessments: i. Adverse events: syncope, hypotension, dizziness, headache, etc; ii. Amplification of harmful effects by drug interactions and concomitant alcohol use; iii. Clinical laboratory parameters (hematology, biochemistry, sex hormones, etc) iv. Vital signs (blood pressure, pulse rate); v. Physical findings; vi. Electrocardiogram; vii. Suicidality (Beck Scale for Suicide Ideation, colombia suicide severity rating scale); viii. Menstrual bleeding patterns; ix. Withdrawal symptoms. 5. No age restriction. 6. No language or date restriction. Exclusion criteria 7. Exclude the following study types: cohort, case-control, cross-sectional studies, systematic and narrative reviews, meta-analyses, letters, abstracts, and conference proceedings. 8. Exclude studies in men. 9. Exclude animal studies. 6

7 emethods 3. Definition of adequately and inadequately blinded studies. Blinding of participants: A study was qualified as low risk of bias (ROB) for blinding of participants when placebo matched flibanserin for color, size, taste, texture, and shape. Arbitrarily, at least 2 features should be reported (e.g. matching color and size). A study was qualified as high ROB when participants had prior experience with the intervention or when participants received placebo during a study run-in period. Blinding of caregivers: For blinding of caregivers, ROB was qualified as low when sequence generation, allocation concealment, and blinding of participants was assessed as low. Blinding of outcome assessors: In case participants assessed the outcome at home, blinding of outcome assessors was qualified as low risk of blinding bias, if the ROB of participants was low. If the outcome was assessed by participants with assistance in a clinical setting, low ROB was defined as low ROB in sequence generation, allocation concealment, and blinding of participants, together with the condition that the assisting outcome assessor was not the caregiver that dispensed the intervention. 7

8 etable 1. Linkage of the Included Registered Trials to the Retrieved Full Texts and Abstracts. Study Unique trial number using clinicaltrials.gov identifier Number of published peer-reviewed studies Number of published abstracts DeRogatis, 2012 NCT Thorp, 2012 NCT Katz, 2013 NCT Simon, 2014 NCT Alternate Dose Study NCT EU Study NCT Terminated Study a NCT Goldfischer, 2011 NCT Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. Abbreviations: EU, European Union. a This study was terminated early by the study sponsor due to commercial reasons, and has no published peer-reviewed study or abstract, but does have reported results on clinicaltrials.gov. The premature study termination could have resulted in inadequate power for analysis of the individual study. 8

9 Study etable 2. Study participant flow and number (%) per reason of dropout. Interve ntion N assigned to arm N total dropout N dropout AE N dropout lack of efficacy N dropout noncompliance N dropout lost to FU N dropout consent withdrawn N dropout other N completed per arm Flibanserin 100mg once daily at bedtime DeRogatis, (100) 91 (31.4) 33 (11.4) 5 (1.7) 11 (3.8) 13 (4.5) 18 (6.2) 11 (3.8) 199 (68.6) Thorp, (100) 144 (36.4) 62 (15.7) 13 (3.3) 7 (1.8) 24 (6.1) 31 (7.8) 7 (1.8) 251 (63.4) Katz, (100) 134 (24.7) 53 (9.8) 3 (0.6) 15 (2.8) 31 (5.7) 4 (0.7) 28 (5.2) 408 (75.1) Simon, (100) 102 (21.8) 3 (8.1) 7 (1.5) 14 (3.0) 9 (1.9) 0 (0) 34 (7.3) 365 (78.0) EU Study 316 (100) 114 (36.1) NR NR NR NR NR NR 202 (63.9) Terminated Study c 376 (100) 260 (69.1) NR NR NR NR NR NR 116 (30.9) Other dosing regimens DeRogatis, 2012 F 50mg 295 (100) 65 (22.0) 23 (7.8) 6 (2.0) 3 (1.0) 10 (3.4) 14 (4.7) 9 (3.1) 230 (78.0) Thorp, 2012 Alternate Dose Study F 393 (100) 133 (33.8) 67 (17.0) 13 (3.3) 9 (2.3) 16 (4.1) 24 (6.1) 4 (1.0) 259 (65.9) 50mg a F 25mg a 396 (100) 122 (30.8) 30 (7.6) 6 (1.5) 15 (3.8) 22 (5.6) 38 (9.6) 11 (2.8) 274 (69.2) F NR NR NR NR NR NR NR NR 363 (NR) 50mg a F 50mg NR NR NR NR NR NR NR NR 336 (NR) F 25mg a NR NR NR NR NR NR NR NR 337 (NR) EU Study F 50mg 311 (100) 95 (30.5) NR NR NR NR NR NR 216 (69.5) Goldfischer, 2011 F b 163 (100) 31 (19.0) 4 (2.5) 5 (3.1) 4 (2.5) 7 (4.3) 6 (3.7) 5 (3.1) 132 (81.0) Placebo DeRogatis, (100) 61 (20.7) 10 (3.4) 8 (2.7) 3 (1.0) 14 (4.7) 22 (7.5) 4 (1.4) 234 (79.3) Thorp, (100) 111 (27.8) 42 (10.8) 11 (2.8) 7 (1.8) 13 (3.3) 33 (8.3) 4 (1.0) 287 (71.9) Katz, (100) 99 (18.1) 20 (3.7) 3 (0.5) 12 (2.2) 28 (5.1) 12 (2.2) 24 (4.4) 446 (81.5) Simon, (100) 83 (17.3) 17 (3.5) 8 (1.7) 17 (3.5) 9 (1.9) 0 (0) 32 (6.7) 397 (82.5) Alternate Dose NR NR NR NR NR NR NR NR 349 (NR) Study EU Study 318 (100) 75 (23.6) NR NR NR NR NR NR 243 (76.4) Terminated Study c 372 (100) 246 (66.1) NR NR NR NR NR NR 124 (33.3) Goldfischer, (100) 24 (14.1) 7 (4.1) 0 (0) 2 (1.2) 5 (2.9) 7 (4.1) 3 (1.8) 146 (85.9) Published studies are labelled according to study author and unpublished studies according to an indicative study characteristic. Abbreviations: EU, European Union; F, flibanserin; mg, milligram; N, number; NR, not reported. a These dosages are bi-daily. b Data were provided only for three flibanserin arms combined: 100mg once daily, 50mg twice daily, and 50mg once daily. 9

10 c This study was terminated early by the study sponsor due to commercial reasons, and has no published peer-reviewed study or abstract, but does have reported results on clinicaltrials.gov. The premature study termination could have resulted in inadequate power for analysis of the individual study. 10

11 Study etable 3. General Characteristics of the Study Participants. Interventio n Age Caucasia n, N (%) Married, N (%) Duration of relationship, years Duration of HSDD, months BMI OC use, N (%) Smokers, N (%) Flibanserin 100mg once daily at bedtime DeRogatis, (7.2) 248 (85.6) 229 (79.0) 10.5 (6.4) 55.8 (43.4) 27.0 (6.0) a 239 (40.9) a 66 (11.3) a Thorp, (6.9) 358 (90.7) 294 (74.4) 10.5 (6.6) 60.0 (44.7) 26.6 (6.0) 457 (38.6) 148 (12.5) Katz, (8.0) 466 (85.9) NR 11.1 (7.5) 49.2 (40.3) 27.3 (6.4) 214 (39.5) 73 (13.5) Simon, (5.4) 425 (91.0) NR 21.6 (12.3) 59.5 (46.0) 27.7 (5.7) NA NR EU Study NR 290 (91.8) NR NR NR NR NR NR Terminated Study d NR NR NR NR NR NR NR NR Flibanserin any other dosing regimen DeRogatis, 2012 F 50mg 36.3 (7.5) 263 (89.1) 214 (72.5) 11.1 (6.9) 54.5 (40.1) 27.0 (6.0) a 239 (40.9) a 66 (11.3) a Thorp, 2012 F 50mg b 35.7 (6.9) 361 (92.1) 317 (80.9) 10.8 (6.3) 63.9 (44.2) 26.6 (6.0) 457 (38.6) 148 (12.5) F 25mg b 34.9 (7.0) 357 (90.1) 302 (76.3) 10.2 (6.5) 59.2 (44.9) 26.6 (6.0) 457 (38.6) 148 (12.5) Alternate Dose Study F 50mg b NR NR NR NR NR NR NR NR F 50mg NR NR NR NR NR NR NR NR F 25mg b NR NR NR NR NR NR NR NR EU Study F 50mg NR 282 (90.7) NR NR NR NR NR NR Goldfischer, 2011 F c 37.3 (7.0) NR 128 (78.5) 11.3 (6.8) 58.0 (49.0) 26.9 (6.5) NR NR Placebo DeRogatis, (7.0) 256 (86.8) 237 (80.3) 10.4 (6.5) 59.7 (46.0) 26.4 (6.1) 114 (38.6) 35 (11.9) Thorp, (6.6) 370 (93.0) 338 (84.9) 11.4 (6.2) 64.9 (49.6) 26.3 (5.0) 159 (39.9) 49 (12.3) Katz, (7.8) 463 (85.0) NR 10.9 (7.2) 49.5(44.7) 27.3 (7.0) 222 (40.7) 73 (13.4) Simon, (5.3) 444 (92.5) NR 20.6 (12.6) 61.6 (51.3) 27.3 (5.4) NA NR Alternate Dose Study NR NR NR NR NR NR NR NR EU Study NR 289 (90.9) NR NR NR NR NR NR Terminated Study d NR NR NR NR NR NR NR NR Goldfischer, (6.7) NR 137 (80.6) 12.4 (7.2) 63.0 (47.0) 27.5 (6.2) NR NR Continuous values are provided as mean (standard deviation). No data were provided on occupation / employment status, income, education level, socio-economic status, religion, medication use, and type and duration of prevalent chronic diseases. Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. Abbreviations: BMI, body mass index; EU, European Union; F, flibanserin; HSDD, hypoactive sexual desire disorder; mg, milligram; N, number; NA, not applicable; NR, not reported; OC, oral contraceptive. a Characteristic provided for all flibanserin participants together. b These dosages are bi-daily. c Data were provided only for three flibanserin arms combined: 100mg once daily, 50mg twice daily, and 50mg once daily. d This study was terminated early by the study sponsor due to commercial reasons, and has no published peer-reviewed study or abstract, but does have reported results on clinicaltrials.gov. The premature study termination could have resulted in inadequate power for analysis of the individual study. 11

12 etable 4. Baseline Levels of the Efficacy Outcomes. Study Interventi on SSE Number per 4 weeks e-diary desire Score per 4 weeks, 0-84 FSFI desire FSFI total FSDS-R Item 13 Score per 4 Score per 4 Score per weeks, weeks, 2-36 week, 0-4 FSDS-R total Score per week, 0-52 Flibanserin 100mg once daily at bedtime DeRogatis, (2.8) 12.9 (10.5) 1.9 (0.7) 19.5 (6.6) 3.2 (0.9) 30.7 (10.0) Thorp, (2.9) 12.0 (9.8) 1.8 (0.7) 19.1 (6.0) 3.3 (0.7) 30.6 (9.3) Katz, (2.5) NA 1.9 (0.7) 19.0 (6.0) 3.4 (0.7) 32.8 (9.0) Simon, (2.2) NA 1.8 (0.7) 15.9 (6.6) 3.3 (0.8) 30.5 (9.3) EU Study 2.3 (2.5) NR NR NR NR NR Terminated Study e NR NA NR NR NR NR Flibanserin any other dosing regimen DeRogatis, 2012 F 50mg 2.7 (2.6) 11.0 (8.9) 1.8 (0.7) 18.7 (6.5) 3.2 (0.8) 30.8 (9.6) Thorp, 2012 F 50mg a 2.9 (2.7) 11.8 (9.5) 1.8 (0.7) 19.8 (6.4) 3.3 (0.8) 31.6 (8.9) F 25mg a 3.0 (2.7) 11.4 (9.1) 1.8 (0.6) 19.8 (6.3) 3.2 (0.8) 30.3 (10.1) Alternate Dose Study F 50mg a 2.5 (2.6) c 11.4 (9.1) c NR NR NR NR F 50mg 2.5 (2.6) c 11.4 (9.1) c NR NR NR NR F 25mg a 2.5 (2.6) c 11.4 (9.1) c NR NR NR NR EU Study F 50mg 2.3 (2.5) c NR NR NR NR NR Goldfischer, 2011 F b 6.9 (5.9) 34.2 (16.2) 3.6 (1.1) 28.8 (4.9) 1.8 (1.2) 15.2 (10.4) Placebo DeRogatis, (2.8) 11.8 (9.6) 1.9 (0.7) 19.8 (7.0) 3.2 (0.8) 30.1 (9.9) Thorp, (2.8) 10.2 (8.8) 1.8 (0.7) 19.5 (6.3) 3.2 (0.8) 30.2 (9.9) Katz, (2.9) NA 1.9 (0.7) 19.0 (6.1) 3.4 (0.7) 32.5 (8.7) Simon, (2.4) NA 1.8 (0.7) 15.9 (6.4) 3.3 (0.7) 31.2 (9.1) Alternate Dose Study 2.5 (2.6) c 11.4 (9.1) c NR NR NR NR EU Study 2.3 (2.5) c NR NR NR NR NR Terminated Study e NR NA NR NR NR NR Goldfischer, (5.9) 35.5 (16.6) 3.6 (1.1) 28.6 (4.8) 1.9 (1.1) 17.1 (11.3) Weighted mean (pooled SD) d 2.5 (2.6) 11.5 (0.3) 1.8 (0.7) 18.6 (6.4) 3.3 (0.8) 31.2 (9.4) For all efficacy outcomes, a higher number means a better score (e.g. more SSE s, more desire, better sexual functioning), except for the FSDS-R (a higher score indicates higher distress). Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. The latter had missing values for most of the baseline characteristics given that no peer-reviewed full-text article were available. Abbreviations: EU, European Union; F, flibanserin; FSDS-R, Female Sexual Distress Scale-Revised; FSFI, Female Sexual Function Index; mg, milligram; N, number; NA, not applicable (measure was not listed as predefined outcome); NR, not reported (measure was listed as predefined outcome, but not reported); SD, standard deviation; SSE, satisfying sexual event. a These dosages are bi-daily. 12

13 b Data were provided only for three flibanserin arms combined: 100mg once daily, 50mg twice daily, and 50mg once daily. c Data were provided only for the intervention(s) and placebo arms combined. d The mean was calculated for all studies except Goldfischer, 2011, the withdrawal study, given its aberrant study design wherein the double-blind period was preceded by a 24 week open-label period. e This study was terminated early by the study sponsor due to commercial reasons, and has no published peer-reviewed study or abstract, but does have reported results on clinicaltrials.gov. The premature study termination could have resulted in inadequate power for analysis of the individual study. 13

14 Other bias Selective reporting (reporting bias) Incomplete outcome data (attrition bias) Blinding of outcome assessment (detection bias) Blinding of personnel (performance bias II) Blinding of participants (performance bias I) Allocation concealment (selection bias) Random sequence generation (selection bias) Unique trial number etable 5. Summary of Each Assessed Risk of Bias Item Per Study. DeRogatis, 2012?? +?? Thorp, ? +?? Katz, 2013? + +?? Simon, 2014? + +?? Alternate Dose Study?? +?? -? - EU Study?? +?? Terminated Study????? Goldfischer, 2011?? - -? -? - A + sign indicates low risk of bias, a - sign high risk of bias, and a? unclear risk of bias. Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. 14

15 etable 6. Number of studies with low, high or unclear risk of bias stratified per bias domain. 0% 100% Random sequence generation (selection bias) +??????? Allocation concealment (selection bias) + +?????? Blinding of participants (performance bias I) ? - Blinding of personnel (performance bias II)??????? - Blinding of outcome assessment (detection bias)???????? Incomplete outcome data (attrition bias) Selective reporting (reporting bias) + +?? Other bias A + sign indicates low risk of bias, a - sign high risk of bias, and a? unclear risk of bias. 15

16 etable 7A-H. Description of the Support for Judgement of the Risk of Bias Assessment per Study. etable 7A: Support for Judgement of the Risk of Bias Assessment for study DeRogatis, 2012 (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Authors' judgement Support for judgement Authors considerations Unclear risk "...sequential numbering in blocks of six" Unclear if a random number generator was used to construct the blocks. Unclear risk "...assigned to the lowest sequentially available medication kit number at randomization" Insufficient information to judge whether or not medication containers were of identical appearance. Blinding of participants and personnel (performance bias) Participants: low risk Personnel: unclear risk "...a double dummy method was used: matching placebo was used and all women took the same number of tablets at the same time." Although matching placebo was not further specified, we feel that this blinding effort, together with women taking the same number of tablets at the same time, would best be described as low risk of blinding bias for participants. Seven out of the 8 included studies were sponsored by Boehringer Ingelheim. For these 7 studies we may have the assumption that the efforts to create matching placebo would be the same. For blinding of personnel, a low risk of bias would be required in random sequence generation, allocation concealment and blinding of participants. Due to the unclear risk in the random sequence generation and allocation concealment, we have insufficient data to judge whether personnel were blinded adequately. Most of the efficacy and safety outcome were patient reported outcomes, except for some of the safety assessments such as vital signs, physical findings, etc. Blinding of outcome assessment (detection bias) Unclear risk The e-diary was a handheld electronic diary that prompted women on a daily basis to answer questions (Filled out at home, unassisted) 16

17 The FSFI and the FSDS-R were self-administered at the study center. The PGI-I was a patient evaluation completed by the patient at the study center. The PBE was a question asked upon treatment discontinuation at the study center. Safety assessments included evaluation of AE s, clinical laboratory parameters vital signs, physical findings Bias with regard to blinding of outcome assessment could have been introduced via the informed consent form which was likely to include information on the types of AE s that could be expected. Therefore, experiencing side-effects could convey the impression that the person is taking the active medication (both for the participant herself and for the personnel) and could therefore lead to higher expectations with regard to the efficacy outcomes. In all studies, both flibanserin and placebo users reported side-effects, although more side-effects were reported in the former group. Therefore, blinding of outcome assessment could be an issue in these studies. It remains difficult to assess how large this bias is exactly. Incomplete outcome data (attrition bias) High risk Around 30% of participants dropped out early in the flibanserin 100mg group. These phenomena may have introduced bias. More people withdrew due to adverse events in the treatment arms compared to the placebo arm. LOCF was used for all efficacy analyses. The number of SSE s per month was standardized to a 28-day period, based on the number of available responses: 28 x (sum of SSE/number of responses). The number of responses on which the SSE s per month was based, was not reported. Selective reporting (reporting bias) High risk The PGI-I.and was rated on a seven-point scale from 1 (very much improved) through 4 (no change) to 7 (very much worse). The PGI-I was not reported as the mean, but as the number (%) of women experiencing improvement, e.g. a score of 1, 2 or 3. From the other studies we know that the mean improvement was between for flibanserin and for placebo (e.g. minimal improvement to no 17

18 Other bias High risk Blocked randomisation with fixed block size was used. Authors had a (financial) conflict of interest with the study sponsor. Study sponsored by pharmaceutical company. change). Therefore, reporting the PGI-I as a percentage of improvement may have given the wrong impression. Given the unclear risk of bias during outcome assessment blinding, this may have made possible to predict future assignments. Systematic bias favouring flibanserin over placebo may have occurred given that this study was funded by the product owner. 18

19 etable 7B: Support for Judgement of the Risk of Bias Assessment for study Thorp, 2012 (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Authors' judgement Low risk Unclear risk Participants: low risk Personnel: unclear risk Support for judgement quoted "...using a pseudo-random number generator and sequential numbering on block sizes of 8" quoted "...women were assigned lowest available medication number at the time of randomisation" comment: unclear if medication containers were of identical appearance Authors considerations Insufficient information to judge whether or not medication containers were of identical appearance. See support for judgement of study 1. See support for judgement of study 1. For blinding of the personnel, although efforts were made to decrease observer bias by making the study coordinator and the clinician two different people, together with the unclear risk for allocation concealment, we have insufficient data to judge whether personnel was blinded adequately. Unclear risk See support for judgement of study 1. See support for judgement of study 1. High risk Around 36% of participants dropped out early in the flibanserin 100mg group. These phenomena may have introduced bias. Selective reporting (reporting bias) High risk Other support for judgement can be found under study 1, and also accounts for this study. The PGI-I.and was rated on a seven-point scale from 1 (very much improved) through 4 (no change) to 7 (very much worse). The PGI-I was not reported as the mean, but as the number (%) of women experiencing improvement, e.g. a score of 1, 2 or 3. From the other studies we know that the mean improvement was between for flibanserin and for placebo (e.g. minimal improvement to no change). Therefore, reporting the PGI-I as a percentage of improvement may give the wrong impression. 19

20 Other bias High risk Blocked randomisation with fixed block size was used. Authors had a (financial) conflict of interest with the study sponsor. Study sponsored by pharmaceutical company. Given the unclear risk of bias during outcome assessment blinding, this may have made possible to predict future assignments. Systematic bias favouring flibanserin over placebo may have occurred given that this study was funded by the product owner. 20

21 etable 7C: Support for Judgement of the Risk of Bias Assessment for study Katz, 2013 (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Authors' Support for judgement Authors considerations judgement Unclear risk No details found. No details found. Low risk "...to receive treatment using an interactive voice response system" Likely that central allocation was used. Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Participants: low risk Personnel: unclear risk See support for judgement of study 1. See support for judgement of study 1. For blinding of the personnel, although efforts were made to decrease observer bias by making the study coordinator and the clinician two different people, together with the unclear risk for random sequence generation, we have insufficient data to judge whether personnel was blinded adequately. Unclear risk See support for judgement of study 1. See support for judgement of study 1. High risk Around 25% of participants dropped out early in the flibanserin 100mg group. These phenomena may have introduced bias. Selective reporting (reporting bias) Low risk Other support for judgement can be found under study 1, and also accounts for this study. All pre-specified primary and secondary outcomes were reported. Other bias High risk Blocked randomisation with fixed block size was used. Authors had a (financial) conflict of interest with the study sponsor. It is likely that no selective reporting bias occurred. Given the unclear risk of bias during outcome assessment blinding, this may have made possible to predict future assignments. Systematic bias favouring flibanserin over placebo may 21

22 Study sponsored by pharmaceutical company. have occurred given that this study was funded by the product owner. 22

23 etable 7D: Support for Judgement of the Risk of Bias Assessment for study Simon, 2014 (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Authors' Support for judgement Authors considerations judgement Unclear risk No details found. No details found. Low risk "...to receive treatment using an interactive voice response system" Likely that central allocation was used. Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Participants: low risk Personnel: unclear risk See support for judgement of study 1. See support for judgement of study 1. For blinding of the personnel, although efforts were made to decrease observer bias by making the study coordinator and the clinician two different people, together with the unclear risk for random sequence generation, we have insufficient data to judge whether personnel was blinded adequately. Unclear risk See support for judgement of study 1. See support for judgement of study 1. Incomplete outcome data (attrition bias) High risk Around 22% of participants dropped out early in the flibanserin 100mg group. Although in this study we additionally found information about the 14-day condition, LOCF analysis is likely to introduce bias. Other support for judgement can be found under study 1, and also accounts for this study. In addition we found: Data for a visit (ie, from the 28-d period before a visit) were only evaluated if 14 days or more of data were available; otherwise, the most recent period for which 14 days of data were available was used for LOCF 23

24 Selective reporting (reporting bias) Low risk analysis. All pre-specified primary and secondary outcomes were reported. Other bias High risk Authors had a (financial) conflict of interest with the study sponsor. Study sponsored by pharmaceutical company. It is likely that no selective reporting bias occurred. Systematic bias favouring flibanserin over placebo may have occurred given that this study was funded by the product owner. 24

25 etable 7E: Support for Judgement of the Risk of Bias Assessment for Alternate Dose Study (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Authors' Support for judgement Authors considerations judgement Unclear risk No details found. No details found. Unclear risk No details found. No details found. Participants: low risk Personnel: unclear risk See support for judgement of study 1. See support for judgement of study 1. For blinding of the personnel, although efforts were made to decrease observer bias by making the study coordinator and the clinician two different people, together with the unclear risk for random sequence generation and allocation concealment, we have insufficient data to judge whether personnel was blinded adequately. Unclear risk See support for judgement of study 1. See support for judgement of study 1. High risk Unclear risk comment: no details in conference abstract or clinicaltrials.gov record. Study similar to other studies, e.g. N randomized. Not all secondary outcome measures were specified in detail at clinicaltrials.gov: and on a small number of patient-completed questions/questionnaires. Particularly, data is missing on the PGI-I and the PBE. Likely this study had large N of dropouts. Furthermore, the study is similar to the studies mentioned before. It is likely that the support for judgement of study 1 also accounts for this study. There could be a chance that the PGI-I and the PBE were administered, but not reported. Since we are unsure whether or not this was the case, we graded the risk of selecting reporting bias as unclear. Other bias High risk Study sponsored by pharmaceutical company. Publication bias: no results for this study were publicized. Systematic bias favouring flibanserin over placebo and publication bias may have occurred given that this study was funded by the product owner. 25

26 etable 7F: Support for Judgement of the Risk of Bias Assessment for EU Study (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Authors' Support for judgement Authors considerations judgement Unclear risk No details found. No details found. Unclear risk No details found. No details found. Participants: low risk Personnel: unclear risk See support for judgement of study 1. See support for judgement of study 1. For blinding of the personnel, although efforts were made to decrease observer bias by making the study coordinator and the clinician two different people, together with the unclear risk for random sequence generation and allocation concealment we have insufficient data to judge whether personnel was blinded adequately. Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Unclear risk See support for judgement of study 1. See support for judgement of study 1. High risk Around 36% of participants dropped out early in the flibanserin 100mg group. These phenomena may have introduced bias. Selective reporting (reporting bias) High risk Other support for judgement can be found under study 1, and also accounts for this study. Not all secondary outcome measures were specified in detail at clinicaltrials.gov: The first key secondary endpoint is the change from baseline in the monthly sum of responses to the e-diary daily desire question. The second key secondary endpoint in the FSDS-R. Particularly, data is missing on the PGI-I and the PBE. There could be a chance that the PGI-I and the PBE were administered, but not reported. Furthermore, it seems that there was a shift in endpoints. Therefore, we graded the risk of selective reporting bias as high risk. 26

27 From the Background Document for meeting of Advisory committee for Reproductive Health Drugs (June 18, 2010), page 34: Also as discussed in Section 2.3, the Applicant proposed modifying the analysis of ongoing Study (the European phase 3 trial, see Table 2) prior to unblinding of results, to evaluate desire using to the FSFI desire domain as the endpoint instrument. The Division was willing to consider these data, provided review of the development and validation of the FSFI indicated that it was an appropriate instrument to be used in support of labeling claims. That review is ongoing. The revised protocol for Study specified SSEs as the single primary efficacy endpoint, with FSFI desire items elevated to a key secondary endpoint. The analysis plan specified a hierarchical analysis, in which the FSFI desire would be analyzed only if the SSE endpoint for the 100 mg qhs dose had attained statistical significance. Desire as measured by the ediary was a secondary endpoint. Results are displayed in Table 13. Other bias High risk Study sponsored by pharmaceutical company. Publication bias: no results for this study were publicized. Systematic bias favouring flibanserin over placebo and publication bias may have occurred given that this study was funded by the product owner. 27

28 etable 7G: Support for Judgement of the Risk of Bias Assessment for Terminated Study (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Authors' Authors considerations Support for judgement judgement Unclear risk No details found. No details found. Unclear risk No details found. No details found. Participants: unclear Personnel: unclear risk Unclear risk "matched placebo which will be administered two tablets daily at bedtime.." Efficacy outcomes are the same as for the other studies above, and were therefore assessed by the patient at home or at the study center. Safety outcomes were either assessed by the patient or by the personnel. Unclear how the placebo matched, only matching number of tablets given. Given the unclear risk of bias for blinding of participants, random sequence generation, and allocation concealment we have insufficient data to judge whether personnel was blinded adequately. The blinding of participants and personnel has an unclear risk of bias. Assuming that the patient information / informed consent would contain information about adverse effects, the same considerations with regard to blinding of the outcome would apply to this study. Incomplete outcome data (attrition bias) High risk Around 69% of participants dropped out early in the flibanserin 100mg group and 66% in the placebo group. Reasons for discontinuation were not provided. These phenomena may have introduced bias. Selective reporting (reporting bias) High risk No peer-reviewed publication was available. These phenomena may have introduced bias. Not all secondary outcomes were precisely specified in 28

29 detail at clinicaltrials.gov, and none of the secondary outcomes were reported. Other bias High risk Study sponsored by pharmaceutical company, Boehringer Ingelheim & Sprout Pharmaceuticals, Inc Publication bias: no results for this study were publicized. Systematic bias favouring flibanserin over placebo and publication bias may have occurred given that this study was funded by the product owner. 29

30 etable 7H: Support for Judgement of the Risk of Bias Assessment for Goldfischer, 2011 (NCT ). Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Authors' Support for judgement Authors considerations judgement Unclear risk No details found. No details found. Unclear risk No details found. No details found. Participants: high risk Personnel: high risk Women who entered the study received open label flibanserin for 24 weeks At week 24, women who showed a predefined response were randomized in a double-blind manner to continued flibanserin or to placebo for a further 24 weeks. In the 24 week open label period, participants may have learnt how flibanserin felt and what side-effects it had. Therefore, it is very likely that the double-blind has been breached. For blinding of personnel, a low risk of bias would be required in random sequence generation, allocation concealment and blinding of participants. The risk for these domains in this study are unclear, unclear, and high risk of bias respectively. Therefore we considered the blinding of personnel to be high risk of bias. Blinding of outcome assessment (detection bias) Unclear risk See support for judgement of study 1. Given the high risk of blinding of participants and personnel, it is likely that also the blinding of outcome assessment has high risk of bias. Incomplete outcome data (attrition bias) High risk Around 19% of participants dropped out early in the flibanserin 100mg group. These phenomena may have introduced bias. Other support for judgement can be found under study 1, and also accounts for this study. In the publication, there is no mention of the use of the PBE. Selective reporting (reporting bias) Unclear risk It remains unclear whether or not the PBE was prespecified and was not reported, or whether it was not used at all. Therefore, we graded this domain as unclear 30

31 Other bias High risk Authors had a (financial) conflict of interest with the study sponsor. Study sponsored by pharmaceutical company. risk of bias. Systematic bias favouring flibanserin over placebo may have occurred given that this study was funded by the product owner. 31

32 etable 8. Results for Patient s Global Impression of Improvement. Study Intervention Reporting mode PGI-I DeRogatis, 2012 F 100mg / P Women answering 1, 2, or 50.0% / 30.3% 3 Thorp, 2012 F 100mg / P Women answering 1, 2, or 47.0% / 30.3% 3 Katz, 2013 F 100mg / P Mean (SE) 3.2 (NR) / 3.5 (NR) Simon, 2014 F 100mg / P Mean (SE) 3.4 (0.1) / 3.7 (0.1) Alternate Dose Study F 50mg a / P NA NA EU Study F 100mg / P NA NA Terminated Study c F 100mg / P NR NR Goldfischer, 2011 F 100mg b / P Mean change (SE) d 0.5 (0.1) / 0.8 (0.1) PGI-I was measured on a 7-point Likert scale, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. Abbreviations: EU, European Union; F, flibanserin; mg, milligram; NA, not applicable (measure was not listed as predefined outcome); NR, not reported (measure was listed as predefined outcome, but not reported); PGI-I, Patient s Global Impression of Improvement; P, placebo; SE, standard error. a These dosages are bi-daily. b Data were provided only for three flibanserin arms combined: 100mg once daily, 50mg twice daily, and 50mg once daily. c This study was terminated early by the study sponsor due to commercial reasons, and has no published peer-reviewed study or abstract, but does have reported results on clinicaltrials.gov. The premature study termination could have resulted in inadequate power for analysis of the individual study. The mean PGI-I was not reported. The values represent the mean (SE) change in PGI-I score from randomization baseline (week 24) to study end (week 48). 32

33 efigure 2A. Mean Difference for FSFI Total Score (scale 2-36) for Flibanserin 100mg versus Placebo. Legend: Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. Menopausal status: 1=premenopause, 0=postmenopause. I-V Overall represents the fixed effect model, whereas D+L Overall represents the random effects model. Abbreviations: CI, confidence interval; D-L, DerSimonian-Laird; ES, effect size; FSFI, Female Sexual Function Index; I-V, inverse-variance; N, number. 33

34 efigure 2B. Mean Difference for FSDS-R Item 13 (scale 0-4) for Flibanserin 100mg versus Placebo. Legend: Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. Menopausal status: 1=premenopause, 0=postmenopause. I-V Overall represents the fixed effect model, whereas D+L Overall represents the random effects model. Abbreviations: CI, confidence interval; D-L, DerSimonian-Laird; ES, effect size; FSDS-R, Female Sexual Distress Scale - Revised; I-V, inverse-variance; N, number. 34

35 efigure 2C. Mean Difference for FSDS-R total score (scale 0-52) for Flibanserin 100mg versus Placebo. Legend: Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. Menopausal status: 1=premenopause, 0=postmenopause. I-V Overall represents the fixed effect model, whereas D+L Overall represents the random effects model. Abbreviations: CI, confidence interval; D-L, DerSimonian-Laird; ES, effect size; FSDS-R, Female Sexual Distress Scale - Revised ; I-V, inverse-variance; N, number. 35

36 efigure 2D. Risk Difference for PBE for Flibanserin 100mg versus Placebo. Legend: Published studies are labelled according to study author and publication year; unpublished studies according to an indicative study characteristic. Menopausal status: 1=premenopause, 0=postmenopause. I-V Overall represents the fixed effect model, whereas D+L Overall represents the random effects model. Abbreviations: CI, confidence interval; D-L, DerSimonian-Laird; ES, effect size; I-V, inverse-variance; N, number; PBE, Patient Benefit Evaluation. 36

37 etable 9. Meta-Analysis Results Comparing Studies in All Women to Studies in Premenopausal Women Only. Outcome Effect size type Effect size (95% CI) Efficacy outcomes Studies in all women Studies in premenopausal women only a SSE MD 0.49 ( ) 0.65 ( ) e-diary desire b MD 1.63 ( ) 1.63 ( ) FSFI desire MD 0.27 ( ) 0.28 ( ) FSFI total score MD 1.53 ( ) 1.52 ( ) c FSDS-R Item 13 MD ( ) ( ) FSDS-R total score MD ( ) ( ) PBE RD 0.12 ( ) 0.l3 ( ) Safety outcomes Any AEs RR 1.29 ( ) d 1.28 ( ) d AEs leading to RR 2.19 ( ) c 2.21 ( ) c discontinuation of the study Dizziness RR 4.00 ( ) c 5.06 ( ) Somnolence RR 3.97 ( ) 3.85 ( ) Nausea RR 2.35 ( ) 2.71 ( ) Fatigue b RR 1.64 ( ) 1.64 ( ) Overall most common AEs RR 2.86 ( ) c 3.01 ( ) Serious AEs RR 1.48 ( ) 1.37 ( ) Scales of efficacy outcomes: SSE = number per 4 weeks; e-diary desire = score per 4 weeks, scale 0-84; FSFI desire = score per 4 weeks, scale 1.2-6; FSFI total = score per 4 weeks, scale 2-36; FSDS-R Item 13 = score per week, scale 0-4; FSDS-R total = score per week, scale 0-52; PBE, % of women reporting meaningful benefit. Fixed effect summary measures are reported, unless otherwise stated. Abbreviations: AEs, adverse events; CI, confidence interval, FSDS-R, Female Sexual Distress Scale-Revised; FSFI, Female Sexual Function Index; MD, mean difference; PBE, Patient Benefit Evaluation; RD, risk difference; RR, risk ratio; SSE, satisfying sexual event. a Two studies in postmenopausal women were excluded, Simon, 2014, and the Terminated Study. b This outcome was only reported in studies focusing on premenopausal women. c There was moderate heterogeneity. Therefore, a random effect summary measure is shown. d There was substantial heterogeneity. Therefore, a random effect summary measure is shown. 37

38 etable 10. Meta-Analysis Results for Studies using the Food and Drug Administration approved dose of 100 milligrams once daily at bedtime. Outcome Effect size type Effect size (95% CI) Efficacy outcomes All studies Studies using 100mg once daily dosing regimen a SSE MD 0.49 ( ) 0.54 ( ) e-diary desire MD 1.63 ( ) 2.05 ( ) FSFI desire MD 0.27 ( ) 0.28 ( ) FSFI total score MD 1.53 ( ) 1.66 ( ) FSDS-R Item 13 MD ( ) ( ) FSDS-R total score MD ( ) ( ) PBE RD 0.12 ( ) Not applicable b Safety outcomes Any AEs RR 1.29 ( ) d Not applicable b AEs leading to RR 2.19 ( ) c Not applicable b discontinuation of the study Dizziness RR 4.00 ( ) c Not applicable b Somnolence RR 3.97 ( ) Not applicable b Nausea RR 2.35 ( ) Not applicable b Fatigue RR 1.64 ( ) Not applicable b Overall most common AEs RR 2.86 ( ) c Not applicable b Serious AEs RR 1.48 ( ) Not applicable b Scales of efficacy outcomes: SSE = number per 4 weeks; e-diary desire = score per 4 weeks, scale 0-84; FSFI desire = score per 4 weeks, scale 1.2-6; FSFI total = score per 4 weeks, scale 2-36; FSDS-R Item 13 = score per week, scale 0-4; FSDS-R total = score per week, scale 0-52; PBE, % of women rerporting meaningful benefit. Fixed effect summary measures are reported, unless otherwise stated. Abbreviations: AEs, adverse events; CI, confidence interval; FDA; Food and Drug Administration; FSDS-R, Female Sexual Distress Scale-Revised; FSFI, Female Sexual Function Index; MD, mean difference; mg, milligram; PBE, Patient Benefit Evaluation; RD, risk difference; RR, risk ratio; SSE, satisfying sexual event. a Only 1 study included in the meta-analysis did not assess the FDA approved dosage and was therefore excluded from this subgroup analysis: the Alternate Dose study assessed 50mg of flibanserin twice daily. b This (efficacy) outcome was not reported by the Alternate Dose Study. Furthermore, it was not the objective of the study to report safety outcomes. c There was moderate heterogeneity. Therefore, a random effect summary measure is shown. d There was substantial heterogeneity. Therefore, a random effect summary measure is shown. 38