Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial

Carolina Gomes Freitas; Michael Walsh; Enia Lucia Coutinho; Angelo Amato Vincenzo de Paola; Álvaro Nagib Atallah

doi:10.1371/journal.pone.0248567

Peer Review History

Original SubmissionAugust 27, 2020
22 Dec 2020 Decision Letter - Zhiming Zhu, Editor PONE-D-20-22114 Examining therapeutic equivalence between branded and generic warfarin in Brazil: the WARFA crossover randomized controlled trial PLOS ONE Dear Dr. Gomes Freitas, 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 Feb 05 2021 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. 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Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Zhiming Zhu 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/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere: 'Fig 1 in this manuscript has been published along with the protocol of the study. Inclusion of the figure in this submission does not constitute dual publication because the figure only depicts the design of the trial, not disclosing any results. Inclusion of the figure in this manuscript is considered necessary to help readers understand the design of the trial.' Please clarify whether this publication was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript. [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: Yes 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: Yes 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: Comments to the Author Thank you for the opportunity to review your article. The authors report therapeutic equivalence between branded and generic warfarin in a therapeutic equivalence between branded and generic warfarin. Despite the work strengths, I recommend addressing the following comments: 1. Did you monitor the concentration of branded and generic warfarin in every period? 2.S4 Table showed the clinical events in the WARFA trial, and could you record which period these clinical events first occur in? I think this table should be shown in the result section. Reviewer #2: It is refreshing to see a conclusion on a non-significant result to be presented here in terms of the width of the confidence interval and not the lack of significance. The conclusions here are entirely sound given the data. The point here is of course to rule out a difference and not detect a difference, as the positive result is a confidence interval that does not include the point of non-equivalence of 0.49. The sample size doesn't change because one assumes the drugs to be the same in efficacy. However this part of the design needs to be changed around somewhat as the trial is not a superiority trial. Given that the power calculation is for mean INR and not the new primary endpoint what were the assumptions for delta INR - and importantly what is the equivalence margin? Please explain why 0.49 is an appropriate equivalence margin here - why not 0.50? It would be helpful to note earlier that the first two treatment periods are the same to motivate the fact there are only 6 permutations where every patient gets each drug. The criteria for deciding equivalence or not could usefully be reiterated when the result is reported (i.e. CI does not include 0.49 ergo equivalent etc) ****** 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: No [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. Attachments Attachment Submitted filename: comments.docx https://doi.org/10.1371/journal.pone.0248567.r001
Revision 1
11 Feb 2021 Author Response Response to reviewers Journal 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/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf After checking my figures on PACE, I decided to improve figures 2 and 3. The new figures are uploaded. No other changes were made to the manuscript style because I believe that I have already followed the PLOS ONE's style requirements in my initial submission. In case I have missed any formatting requirement, please let me know so I can amend it accordingly. 2. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere: 'Fig 1 in this manuscript has been published along with the protocol of the study. Inclusion of the figure in this submission does not constitute dual publication because the figure only depicts the design of the trial, not disclosing any results. Inclusion of the figure in this manuscript is considered necessary to help readers understand the design of the trial.' Please clarify whether this publication was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript. Figure 1 of this manuscript has already been formally published in a peer reviewed journal as part of the article entitled "Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil". The previously published article has been provided in the submission process under the description of an "Other" file. As mentioned, the only item from this manuscript that has been published previously is the Figure 1, which was also included in this manuscript because it is deemed necessary for readers to clearly understand the design of the trial. This explanation was added to the cover letter and we added a note to the Figure 1 legend explaining that it is a reproduction from the previously published figure. Because this manuscript is not "a paper that overlaps substantially with one already published, without clear, visible reference to the previous publication" [1], it does not constitute dual publication. Reviewer #1 1. Did you monitor the concentration of branded and generic warfarin in every period? No, the concentration of warfarin in the participants' blood was not monitored. Unfortunately, for budget, time and complexity issues no pharmacokinetic parameter was measured, so, as mentioned in the manuscript, bioequivalence analyzes were not done. Also, for safety reasons, the warfarin dosage was adjusted during the trial as needed, according to the protocol in the S1 Appendix. However, knowing that the adjustment of dose could also interfere in the INR results, the primary outcomes in this trial, the doses were also recorded and analyzed in the form of two outcomes: mean dose and ∆dose. If the outcomes related to the doses suggested differences between the warfarin products, the INR results would have to be interpreted in light of this confounding factor. 2.S4 Table showed the clinical events in the WARFA trial, and could you record which period these clinical events first occur in? I think this table should be shown in the result section. The information on when the first occurrence of the clinical events happened was added to S4 Table. Given that our primary outcomes are related to the INR and that we were probably underpowered to detect any difference on the occurrence of the clinical events between warfarin products, we decided to mention S4 Table on the results section of the manuscript, but leave it as supporting information. Reviewer #2 The point here is of course to rule out a difference and not detect a difference, as the positive result is a confidence interval that does not include the point of non-equivalence of 0.49. The sample size doesn't change because one assumes the drugs to be the same in efficacy. However this part of the design needs to be changed around somewhat as the trial is not a superiority trial. Given that the power calculation is for mean INR and not the new primary endpoint what were the assumptions for delta INR - and importantly what is the equivalence margin? Please explain why 0.49 is an appropriate equivalence margin here - why not 0.50? As mentioned on the manuscript (line 148), the equivalence margin adopted for the INR variability (∆INR) was also -0.49 to +0.49. The 95% confidence interval (CI) of the difference between warfarin formulations in their ∆INR could not exceed these values. The rationale behind the equivalence margin is as follows: The therapeutic range for the INR for AF patients without a mechanical heart valve is from 2.0 to 3.0. Staying in the middle of the range, i.e., INR close to 2.5, is a goal that many healthcare providers would support, so as to avoid INRs outside of the therapeutic range. Considering a patient with an initial average INR of 2.5, a 0.5 change in their mean INR, either to an average INR of 2.0 or 3.0, would motivate a dose change. This was considered to be the minimum change in the mean INR of clinical significance, given it would motivate a dose change. Thus we considered that a reasonable equivalence margin for the mean INR would have to be immediately smaller, from -0.49 to +0.49. This was the rationale behind the equivalence margin for the mean INR outcome; however, when we decided to add the outcome of INR variability (∆INR), we decided to apply the same equivalence margin. Of note, even though we defined our equivalence margin for the INR outcomes from -0.49 to +0.49, our definition stated that for a conclusion of equivalence the 95% CI calculated for the outcomes could not exceed, i.e., could still include, these values. That is the same as an equivalence margin from -0.50 to +0.50 as defined by reviewer #2, given that according to the reviewer, these would be the points of non-equivalence and thus, 95%CI up to -0.49 or +0.49 would still be considered equivalent. It would be helpful to note earlier that the first two treatment periods are the same to motivate the fact there are only 6 permutations where every patient gets each drug. The criteria for deciding equivalence or not could usefully be reiterated when the result is reported (i.e. CI does not include 0.49 ergo equivalent etc) The interpretation of results based on the CI and its position in relation to the equivalence margin was added to the results section of the manuscript. References 1. International Committee of Medical Journal Editors. Overlapping Publications [Internet]. [place unknown]: International Committee of Medical Journal Editors; c2021 [cited 2021 Feb 03]. Available from: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/overlapping-publications.html Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0248567.r002
2 Mar 2021 Decision Letter - Zhiming Zhu, Editor Examining therapeutic equivalence between branded and generic warfarin in Brazil: the WARFA crossover randomized controlled trial PONE-D-20-22114R1 Dear Dr. Gomes Freitas, 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, Zhiming Zhu 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 #1: All comments have been addressed 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 #1: Yes Reviewer #2: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: (No Response) ****** 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 #1: (No Response) Reviewer #2: (No Response) ****** 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 #1: (No Response) Reviewer #2: (No Response) ****** 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 #1: (No Response) Reviewer #2: (No Response) ****** 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 #1: No Reviewer #2: No https://doi.org/10.1371/journal.pone.0248567.r003
Formally Accepted
16 Mar 2021 Acceptance Letter - Zhiming Zhu, Editor PONE-D-20-22114R1 Examining therapeutic equivalence between branded and generic warfarin in Brazil: the WARFA crossover randomized controlled trial Dear Dr. Gomes Freitas: 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 Dr. Zhiming Zhu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0248567.r004

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