{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T20:31:31Z","timestamp":1784752291506,"version":"3.55.0"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Migraine is considered one of the most disabling diseases. Currently, there are few studies on clinical migraine treatment based on sex-related differences, despite the important role of sex in migraine. Our aim was to evaluate gender bias in published clinical trials on monoclonal antibodies (erenumab, galcanezumab, fremanezumab and eptinezumab). We performed a systematic review of controlled clinical trials of erenumab, galcanezumab, fremanezumab and eptinezumab, searching the PubMed\/MEDLINE database for articles published before December 2021. The search identified 760 articles, 25 of which met the inclusion criteria. Of all the patients included in these trials, 85.1% were women. Only one study had female lead authors. Two of the 25 studies included a sex-based analysis of the primary endpoint. None of the articles discussed the results separately for men and for women. The proportion of men recruited in trials is scarce and more studies are needed to guarantee the safety and tolerability of monoclonal antibodies used in male migraine. As observed in our study, despite the high number of women recruited, only 2 studies analysed the results separately by sex. Thus, a potential risk of gender bias was found in these clinical trials.<\/jats:p>","DOI":"10.1371\/journal.pone.0286453","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T17:30:32Z","timestamp":1685727032000},"page":"e0286453","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Gender bias in clinical trials of biological agents for migraine: A systematic review"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1200-6816","authenticated-orcid":true,"given":"Marta","family":"Alonso-Moreno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4888-3127","authenticated-orcid":true,"given":"Lupe","family":"Rodr\u00edguez-de Francisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Ciudad-Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"pone.0286453.ref001","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.maturitas.2020.12.012","article-title":"Changing levels of sex hormones and calcitonin gene-related peptide (CGRP) during a woman\u2019s life: Implications for the efficacy and safety of novel antimigraine medications","volume":"145","author":"S de Vries Lentsch","year":"2021","journal-title":"Maturitas"},{"key":"pone.0286453.ref002","doi-asserted-by":"crossref","first-page":"859","DOI":"10.2147\/NDT.S285863","article-title":"Patterns of Migraine in Postmenopausal Women: A Systematic Review","volume":"17","author":"R Ornello","year":"2021","journal-title":"Neuropsychiatr Dis Treat"},{"key":"pone.0286453.ref003","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3389\/fnins.2020.00222","article-title":"Sex-Specific Pharmacotherapy for Migraine: A Narrative Review","volume":"14","author":"P Gazerani","year":"2020","journal-title":"Front Neurosci"},{"issue":"2","key":"pone.0286453.ref004","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/head.14067","article-title":"Systematic review of outcomes and endpoints in acute migraine clinical trials","volume":"61","author":"CR Houts","year":"2021","journal-title":"Headache"},{"key":"pone.0286453.ref005","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/jnr.23903","article-title":"Sex-Related influences in Migraine","volume":"95","author":"JM Pavlovic","year":"2017","journal-title":"J neuroscience research"},{"issue":"8","key":"pone.0286453.ref006","first-page":"711","article-title":"Prevalencia de s\u00edntomas de ansiedad y de depresi\u00f3n en mujeres con migra\u00f1a","volume":"39","author":"J Pareja-Angel","year":"2004","journal-title":"Rev Neurol"},{"issue":"1","key":"pone.0286453.ref007","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s10194-021-01334-3","article-title":"Clinical symptoms of androgen deficiency in men with migraine or cluster headache: a cross-sectional cohort study","volume":"22","author":"IE Verhagen","year":"2021","journal-title":"J Headache Pain"},{"issue":"15","key":"pone.0286453.ref008","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1002\/(SICI)1097-0258(19990815)18:15<1903::AID-SIM188>3.0.CO;2-F","article-title":"Statistical principles for clinical trials (ICH E9): an introductory note on an international guideline","volume":"18","author":"JA Lewis","year":"1999","journal-title":"Stat Med"},{"key":"pone.0286453.ref009","first-page":"39409","article-title":"Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs; notice","volume":"58","author":"US Food","year":"1993","journal-title":"Fed Regist"},{"key":"pone.0286453.ref010","doi-asserted-by":"crossref","first-page":"e1001333","DOI":"10.1371\/journal.pmed.1001333","article-title":"2012 extension: reporting guidelines for systematic reviews with a focus on health equity","volume":"9","author":"NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research\u2014\u2013amended; 2001","year":"2012","journal-title":"PLoS Med"},{"issue":"1","key":"pone.0286453.ref011","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/BF03405218","article-title":"The BIAS FREE Framework: a new analytical tool for global health research","volume":"97","author":"M Eichler","year":"2006","journal-title":"Can J Public Health"},{"key":"pone.0286453.ref012","article-title":"Systematic review of gender bias in clinical trials of monoclonal antibodies for the treatment of multiple sclerosis","volume":"25","author":"M Alonso-Moreno","year":"2021","journal-title":"Neurologia (Engl Ed)"},{"issue":"9","key":"pone.0286453.ref013","doi-asserted-by":"crossref","first-page":"e0257765","DOI":"10.1371\/journal.pone.0257765","article-title":"Gender bias in clinical trials of biological agents for severe asthma: A systematic review","volume":"16","author":"P Ciudad-Guti\u00e9rrez","year":"2021","journal-title":"PLoS One"},{"key":"pone.0286453.ref014","doi-asserted-by":"crossref","first-page":"110088","DOI":"10.1016\/j.pnpbp.2020.110088","article-title":"Systematic review of gender bias in vortioxetine clinical trials","volume":"108","author":"M Santos-Casado","year":"2021","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"pone.0286453.ref015","unstructured":"Vega Casano J. Gender bias in the diagnosis of spondyloarthritis. University of Alicante. Department of Community Nursing, Preventive Medicine and Public Health and History of Science. 2021 abr."},{"key":"pone.0286453.ref016","doi-asserted-by":"crossref","first-page":"867","DOI":"10.2147\/IJGM.S291964","article-title":"Sex-Gender Differences in the Effectiveness of Treatment of Irritable Bowel Syndrome: A Systematic Review","volume":"14","author":"L Van Kessel","year":"2021","journal-title":"Int J Gen Med"},{"issue":"1","key":"pone.0286453.ref017","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s10194-020-01211-5","article-title":"Immunogenicity of biologic therapies for migraine: a review of current evidence","volume":"22","author":"JM Cohen","year":"2021","journal-title":"J Headache Pain"},{"issue":"1","key":"pone.0286453.ref018","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3892\/etm.2020.9519","article-title":"A new era for monoclonal antibodies with applications in neurology (Review)","volume":"21","author":"CA Sirbu","year":"2021","journal-title":"Exp Ther Med"},{"key":"pone.0286453.ref019","doi-asserted-by":"crossref","first-page":"e1001333","DOI":"10.1371\/journal.pmed.1001333","article-title":"PRISMA-Equity 2012 extension: reporting guidelines for systematic reviews with a focus on health equity","volume":"9","author":"PRISMA-Equity Bellagio group","year":"2012","journal-title":"PLoS Med"},{"issue":"22","key":"pone.0286453.ref020","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1056\/NEJMoa1705848","article-title":"A Controlled Trial of Erenumab for Episodic Migraine","volume":"377","author":"PJ Goadsby","year":"2017","journal-title":"N Engl J Med"},{"issue":"6","key":"pone.0286453.ref021","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S1474-4422(17)30083-2","article-title":"Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial","volume":"16","author":"S Tepper","year":"2017","journal-title":"Lancet Neurol"},{"issue":"6","key":"pone.0286453.ref022","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1177\/0333102418759786","article-title":"ARISE: A Phase 3 randomized trial of erenumab for episodic migraine","volume":"38","author":"DW Dodick","year":"2018","journal-title":"Cephalalgia"},{"issue":"10161","key":"pone.0286453.ref023","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1016\/S0140-6736(18)32534-0","article-title":"Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study","volume":"392","author":"U Reuter","year":"2018","journal-title":"Lancet"},{"issue":"4","key":"pone.0286453.ref024","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/S1474-4422(16)00019-3","article-title":"Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial","volume":"15","author":"H Sun","year":"2016","journal-title":"Lancet Neurol"},{"issue":"10","key":"pone.0286453.ref025","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1111\/head.13652","article-title":"A Randomized Phase 2 Study of Erenumab for the Prevention of Episodic Migraine in Japanese Adults","volume":"59","author":"F Sakai","year":"2019","journal-title":"Headache"},{"issue":"5","key":"pone.0286453.ref026","doi-asserted-by":"crossref","first-page":"e469","DOI":"10.1212\/WNL.0000000000010019","article-title":"One-year sustained efficacy of erenumab in episodic migraine: Results of the STRIVE study","volume":"95","author":"PJ Goadsby","year":"2020","journal-title":"Neurology"},{"issue":"6","key":"pone.0286453.ref027","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/head.14138","article-title":"Erenumab treatment for migraine prevention in Japanese patients: Efficacy and safety results from a Phase 3, randomized, double-blind, placebo-controlled study","volume":"61","author":"T Takeshima","year":"2021","journal-title":"Headache"},{"issue":"9","key":"pone.0286453.ref028","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/S1474-4422(14)70128-0","article-title":"Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study","volume":"13","author":"DW Dodick","year":"2014","journal-title":"Lancet Neurol"},{"issue":"6","key":"pone.0286453.ref029","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1177\/0333102417747230","article-title":"Safety of galcanezumab in patients with episodic migraine: A randomized placebo-controlled dose-ranging Phase 2b study","volume":"38","author":"TMM Oakes","year":"2018","journal-title":"Cephalalgia"},{"issue":"8","key":"pone.0286453.ref030","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1177\/0333102418779543","article-title":"Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial","volume":"38","author":"V Skljarevski","year":"2018","journal-title":"Cephalalgia"},{"issue":"10","key":"pone.0286453.ref031","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/S1474-4422(20)30279-9","article-title":"Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial","volume":"19","author":"WM Mulleners","year":"2020","journal-title":"Lancet Neurol"},{"key":"pone.0286453.ref032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2515816320932573","article-title":"Efficacy and safety of galcanezumab for prevention of migraine headache in Japanese patients with episodic migraine: A phase 2 randomized controlled clinical trial","volume":"3","author":"F Sakai","year":"2020","journal-title":"Cephalalgia Reports"},{"issue":"6","key":"pone.0286453.ref033","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1080\/14740338.2021.1866536","article-title":"A long-term open-label safety study of galcanezumab in Japanese patients with migraine","volume":"20","author":"K Hirata","year":"2021","journal-title":"Expert Opin Drug Saf"},{"issue":"11","key":"pone.0286453.ref034","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/S1474-4422(14)70209-1","article-title":"Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial","volume":"13","author":"DW Dodick","year":"2014","journal-title":"Lancet Neurol"},{"issue":"9","key":"pone.0286453.ref035","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1177\/0333102419858355","article-title":"Eptinezumab for prevention of chronic migraine: A randomized phase 2b clinical trial","volume":"39","author":"DW Dodick","year":"2019","journal-title":"Cephalalgia"},{"issue":"3","key":"pone.0286453.ref036","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1177\/0333102420905132","article-title":"Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1)","volume":"40","author":"M Ashina","year":"2020","journal-title":"Cephalalgia"},{"issue":"13","key":"pone.0286453.ref037","doi-asserted-by":"crossref","first-page":"e1365","DOI":"10.1212\/WNL.0000000000009169","article-title":"Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2","volume":"94","author":"RB Lipton","year":"2020","journal-title":"Neurology"},{"issue":"23","key":"pone.0286453.ref038","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1001\/jama.2021.7665","article-title":"Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial","volume":"325","author":"PK Winner","year":"2021","journal-title":"JAMA"},{"issue":"1","key":"pone.0286453.ref039","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1212\/WNL.0000000000002801","article-title":"TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points","volume":"87","author":"ME Bigal","year":"2016","journal-title":"Neurology"},{"issue":"19","key":"pone.0286453.ref040","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1001\/jama.2018.4853","article-title":"Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial","volume":"319","author":"DW Dodick","year":"2018","journal-title":"JAMA"},{"issue":"10203","key":"pone.0286453.ref041","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1016\/S0140-6736(19)31946-4","article-title":"Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial","volume":"394","author":"MD Ferrari","year":"2019","journal-title":"Lancet"},{"issue":"18","key":"pone.0286453.ref042","doi-asserted-by":"crossref","first-page":"e2487","DOI":"10.1212\/WNL.0000000000010600","article-title":"Long-term safety, tolerability, and efficacy of fremanezumab in migraine: A randomized study","volume":"95","author":"PJ Goadsby","year":"2020","journal-title":"Neurology"},{"issue":"7","key":"pone.0286453.ref043","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1111\/head.14169","article-title":"Efficacy and safety of fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients","volume":"61","author":"F Sakai","year":"2021","journal-title":"Headache"},{"issue":"7","key":"pone.0286453.ref044","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1111\/head.14178","article-title":"Efficacy and safety of fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients","volume":"61","author":"F Sakai","year":"2021","journal-title":"Headache"},{"issue":"2","key":"pone.0286453.ref045","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1177\/0333102418786266","article-title":"Epidemiology of migraine in men: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study","volume":"39","author":"AI Scher","year":"2019","journal-title":"Cephalalgia"},{"key":"pone.0286453.ref046","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.msard.2018.12.020","article-title":"Is the \u2018MS establishment\u2019 biased; the case for addressing gender inequality in the field of MS?","volume":"28","author":"G. Giovannoni","year":"2019","journal-title":"Mult Scler Relat Disord"},{"key":"pone.0286453.ref047","doi-asserted-by":"crossref","first-page":"715428","DOI":"10.3389\/fneur.2021.715428","article-title":"Gender Gap in Neurology Research Autorship (1946\u20132020)","volume":"12","author":"AX Nguyen","year":"2021","journal-title":"Front Neurol"},{"issue":"8","key":"pone.0286453.ref048","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/s41593-020-0658-y","article-title":"The extent and drivers of gender imbalance in neuroscience reference lists","volume":"23","author":"JD Dworkin","year":"2020","journal-title":"Nat Neurosci"},{"issue":"1","key":"pone.0286453.ref049","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/S1474-4422(16)30293-9","article-title":"Sex differences in the epidemiology, clinical features, and pathophysiology of migraine","volume":"16","author":"KG Vetvik","year":"2017","journal-title":"Lancet Neurol"},{"issue":"1","key":"pone.0286453.ref050","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s10194-021-01351-2","article-title":"Efficacy and safety of fremanezumab in clinical trial participants aged \u226560 years with episodic or chronic migraine: pooled results from 3 randomized, double-blind, placebo-controlled phase 3 studies","volume":"22","author":"SJ Nahas","year":"2021","journal-title":"J Headache Pain"},{"issue":"10","key":"pone.0286453.ref051","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1177\/03331024211008401","article-title":"Fremanezumab for the Preventive Treatment of Migraine: Subgroup Analysis by Number of Prior Preventive Treatments with Inadequate Response","volume":"41","author":"L Pazdera","year":"2021","journal-title":"Cephalalgia"},{"issue":"Suppl 2","key":"pone.0286453.ref052","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s10072-020-04643-8","article-title":"Gender-related differences in migraine","volume":"41","author":"G Allais","year":"2020","journal-title":"Neurol Sci"},{"issue":"1","key":"pone.0286453.ref053","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10194-010-0258-4","article-title":"Why pharmacokineticdifferences among oral triptans have little clinical importance: acomment","volume":"12","author":"A Ferrari","year":"2011","journal-title":"J Headache Pain"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286453","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T17:31:15Z","timestamp":1685727075000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286453"}},"subtitle":[],"editor":[{"given":"Alejandro","family":"Piscoya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,6,2]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0286453","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,2]]}}}