Gender bias in clinical trials of biological agents for migraine: A systematic review

Marta Alonso-Moreno; Lupe Rodríguez-de Francisco; Pablo Ciudad-Gutiérrez

doi:10.1371/journal.pone.0286453

Peer Review History

Original SubmissionJune 1, 2022
1 Dec 2022 Decision Letter - Alejandro Piscoya, Editor PONE-D-22-14914 GENDER BIAS IN CLINICAL TRIALS OF BIOLOGICAL AGENTS FOR MIGRAINE: A SYSTEMATIC REVIEW PLOS ONE Dear Dr. Rodríguez-de Francisco, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jan 08 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript' If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Alejandro Piscoya Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/fileid=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ******** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is a largely a competently executed and useful synthesis and evaluation of the literature. There are a few point that would strengthen the document. 1. The authors must distinguish more carefully in the entire document between “sex” which is an embodied, biological phenomena versus “gender” which the set of social meanings, including biases and discrimination, that are associated with sex (and which vary across place an time). It would be good to define the terms up front and then go through the paper and adjust carefully which term is being used where – the usage is currently interchangeable and imprecise. Factors such as hormones, menstruation, etc may be assumed be linked to sex. Failing to adjust for to such factors is an example of gender bias be researchers (i.e. failing to understand and account for sex-specific disease processes) Inclusion in trials and first author identity is an issue of gender bias. The failure to disaggregate the impact of drugs by sex (biological, since we are looking and biologic endpoint and pharmacodynamics) is a manifestation of gender bias (failing to recognize the importance of sex-specific data for people with different biology. 2. As regards the first authors of papers being evaluated: the relevant construct is GENDER of the first author, not sex. Please correct this. 3. Similarly: How was the gender of the first author established? Was this an assumption based on name, on-line photographs, professional acquaintanceships? All of these methods risk misclassification. If the individuals were asked to confirm their gender as of the time of publication on the manuscript, please so state. If you did not ask, please strongly consider doing so in a way that allows for the possibility that some individuals may be nonbinary, third gender, agender, etc. If you choose not to ask, the possibility of misclassification must be acknowledged as a limitation, as well as the limitation inherent in assuming that all the authors have a binary gender identity. 4. Given the very strong importance of hormones and hormonal cycles in the migraine disease process, I think the authors would do well to add an additional conclusion that failure to disaggregate these trial data by sex and supplemental hormone usage also compromises a proper understanding of the impact of these drug on women as well as men. Have men pooled in the analysis muddies the understanding of efficacy for women as well as leaving us with insufficient data for men. It’s a very important oversight across the board. 5. It is frequently reported in migraine patient forums that anti-CGRP agents impact differently on menstrual and non-menstrual migraines in patients who experience both, and that many find the prophylactic benefit to be limited to their non-menstrual migraines. This may be worth noting in reflecting on the overall biases and limitation of the literature. 6. It is worth noting in the limitations that neither the overall body of literature or this review have accounted for migraine patients who are intersex (sex category) or transgender, nonbinary, agender, etc (gender categories). The assumption that sex and gender and binary categories is common in medical literature and also inaccurate. It entirely omits the experiences of patients who take HRT as gender-affirming therapy (many of whom, regardless of their sex assigned at birth, report that such HRT impacts either positively or negatively the frequency and severity of their migraine disease). Reviewer #2: The paper is good and it initiates other researchers and practitioners to consider the gender aspects of their study and and activities. However, it is good the researcher described the characteristics of included trails and proportion of women and features of gender assessment in concise manner. ******** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: Fentahun Gebrie Mucha ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0286453.r001
Revision 1
26 Dec 2022 Author Response Reviewer #1: This is a largely a competently executed and useful synthesis and evaluation of the literature. There are a few point that would strengthen the document. 1. The authors must distinguish more carefully in the entire document between “sex” which is an embodied, biological phenomena versus “gender” which the set of social meanings, including biases and discrimination, that are associated with sex (and which vary across place an time). It would be good to define the terms up front and then go through the paper and adjust carefully which term is being used where – the usage is currently interchangeable and imprecise. Factors such as hormones, menstruation, etc may be assumed be linked to sex. Failing to adjust for to such factors is an example of gender bias be researchers (i.e. failing to understand and account for sex-specific disease processes) Inclusion in trials and first author identity is an issue of gender bias. The failure to disaggregate the impact of drugs by sex (biological, since we are looking and biologic endpoint and pharmacodynamics) is a manifestation of gender bias (failing to recognize the importance of sex-specific data for people with different biology. Author response: We agree with the reviewer’s assessment. Accordingly, throughout the manuscript, we have revised more carefully the use of both terms and we have added both definitions, line 78: “The term "sex" refers to a set of biological attributes that are associated with genetic expression, while the term "gender" refers to the socially constructed roles, attitudes and identities of individuals.” 2. As regards the first authors of papers being evaluated: the relevant construct is GENDER of the first author, not sex. Please correct this. Author response: Thank you for pointing this out. The reviewer is correct, and we have replaced the word “sex” by “gender”. The revised text reads as follows on: Line 181: “Gender of the first author” Line 253: “First author gender” 3. Similarly: How was the gender of the first author established? Was this an assumption based on name, on-line photographs, professional acquaintanceships? All of these methods risk misclassification. If the individuals were asked to confirm their gender as of the time of publication on the manuscript, please so state. If you did not ask, please strongly consider doing so in a way that allows for the possibility that some individuals may be nonbinary, third gender, agender, etc. If you choose not to ask, the possibility of misclassification must be acknowledged as a limitation, as well as the limitation inherent in assuming that all the authors have a binary gender identity. Author response: We agree that this is a potential limitation of the study. We have added this as a limitation on the discussion part, line 302: “However, a potential limitation is the possibility of misclassification of the first author's gender because it was a name-based assumption as well as the limitation in assuming that all the authors have a binary gender identity." 4. Given the very strong importance of hormones and hormonal cycles in the migraine disease process, I think the authors would do well to add an additional conclusion that failure to disaggregate these trial data by sex and supplemental hormone usage also compromises a proper understanding of the impact of these drug on women as well as men. Have men pooled in the analysis muddies the understanding of efficacy for women as well as leaving us with insufficient data for men. It’s a very important oversight across the board. Author response: We totally agree with you, and it is clear that failure to disaggregate these trial data by sex and supplemental hormone usage is one of the most interesting points to continue working on. We have tried to specify a little more final conclusions according to your comment, line 365: “In conclusion, clinical trials have become a fundamental tool to evaluate the efficacy and safety of drugs; therefore, the study population should include a well-balanced proportion of women and men. In this case, the proportion of men recruited in trials is scarce (<20%), and more studies with sufficient data are needed to guarantee the safety and tolerability of mAbs used in men with migraine. Moreover, the inclusion of variables such as the stratification of results according to sex, and the influence of hormonal contraceptives on the pharmacokinetics of the studied drug should be fundamental requirements to publish an article in high impact journals because compromises a proper understanding of the impact of these drug on women as well as men. As observed in our study, despite the high number of women recruited in clinical trials, only 2 studies analysed the results separately by sex and men were underrepresented creating a large imbalance in CTs recruitment in addition to muddy the understanding of efficacy for women. Thus, a potential risk of gender bias was found in these clinical trials.” 5. It is frequently reported in migraine patient forums that anti-CGRP agents impact differently on menstrual and non-menstrual migraines in patients who experience both, and that many find the prophylactic benefit to be limited to their non-menstrual migraines. This may be worth noting in reflecting on the overall biases and limitation of the literature. Author response: As you pointed out, the prophylactic benefit of anti-CGRP agents only on non-menstrual migraines is a reflection that we have added as a limitation of the literature, line 323: “Moreover, this issue could be a limitation of the literature due to the potential benefits of anti-CGRP agents on non-menstrual migraines in women who experience both, menstrual and non-menstrual migraines”. 6. It is worth noting in the limitations that neither the overall body of literature or this review have accounted for migraine patients who are intersex (sex category) or transgender, nonbinary, agender, etc (gender categories). The assumption that sex and gender and binary categories is common in medical literature and also inaccurate. It entirely omits the experiences of patients who take HRT as gender-affirming therapy (many of whom, regardless of their sex assigned at birth, report that such HRT impacts either positively or negatively the frequency and severity of their migraine disease). Author response: We totally agree with you that it is relevant to highlight the experiences of migraine intersex or transgender patients who are taking HRT, line 339: “However, a potential publication bias of this review is that migraine intersex or transgender patients who are taking hormone replacement therapy should be into account to assess gender-affirming therapy”. Reviewer #2: The paper is good and it initiates other researchers and practitioners to consider the gender aspects of their study and and activities. However, it is good the researcher described the characteristics of included trails and proportion of women and features of gender assessment in concise manner. Author response: Thank you very much for your positive comments towards our work. Our main goal is to encourage other researchers to consider gender aspects in their studies. However, we believe that we have concisely described the characteristics of clinical trials. As we described in materials and methods we take into account for each publication, the following variables: drug under study, year of publication, mean age patients, financing of the trial, location, trial phase, comparator, objectives of the trial and diagnosis (Table 2). In relation to the proportion of women and features of gender assessment, we have also taken into account variables that focus on the possible gender bias of each study as can be seen in Table 3 and which we have subsequently discussed and compared with other studies. If you have any suggestions for adding any more variables, we would be happy to add them to the manuscript to make it more complete. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0286453.r002
17 May 2023 Decision Letter - Alejandro Piscoya, Editor GENDER BIAS IN CLINICAL TRIALS OF BIOLOGICAL AGENTS FOR MIGRAINE: A SYSTEMATIC REVIEW PONE-D-22-14914R1 Dear Dr. Rodríguez-de Francisco, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Alejandro Piscoya Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: It will be a base for other researchers in the area and let institutions use this findings to consider. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: Yes: Fentahun Gebrie Mucha ******** https://doi.org/10.1371/journal.pone.0286453.r003
Formally Accepted
22 May 2023 Acceptance Letter - Alejandro Piscoya, Editor PONE-D-22-14914R1 Gender bias in clinical trials of biological agents for migraine: A systematic review Dear Dr. Rodríguez-de Francisco: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Alejandro Piscoya Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0286453.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .