Comparative effectiveness and safety of insulin reference biologics versus biosimilars for types 1 and 2 diabetes mellitus: Protocol for a systematic review of real-world studies

Martin K. H. Ho; Araniy Santhireswaran; Tara Gomes; Muhammad Mamdani; Mina Tadrous

doi:10.1371/journal.pone.0329299

Peer Review History

Original SubmissionMay 13, 2025
Decision Letter - Sreedhar Dharmagadda, Editor PONE-D-25-25687Comparative effectiveness and safety of insulin reference biologics versus biosimilars for types 1 and 2 diabetes mellitus: protocol for a systematic review of real-world studiesPLOS ONE Dear Dr. Ho, 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 Address the following: 1. Clarify the Scope of “Real-World Studies”: Provide explicit thresholds or examples based on the PRECIS-2 domains to support consistent judgment 2. Update and Expand Literature Coverage: While you mentioned that past systematic reviews are outdated (last up to 2019), it may be helpful to quantify the preliminary yield of the updated literature search and mention any especially recent high-impact real-world studies, if already identified. Consider including a table comparing key attributes of past reviews versus this planned review. 3. Risk of Bias Assessment and Heterogeneity: Given the inclusion of both observational and pragmatic RCTs, the heterogeneity could be substantial. Even if metal-analysis is not planned, outline how heterogeneity will be qualitatively assessed (e.g., using a matrix of study designs/outcomes). 4. Language: A few minor typographical and formatting issues could be improved. ============================== Please submit your revised manuscript by Jul 11 2025 11:59PM. 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If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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.] [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. 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Revision 1
29 May 2025 Author Response We thank Dr. Dharmagadda for taking the time to review our systematic review protocol. We genuinely appreciate Dr. Dharmagadda's thoughtful feedback and have made the suggested changes. We encourage the editor to review our detailed point-by-point response in the attached Response to Editor letter dated May 29, 2025 (note: not the cover letter). Below, we briefly highlight the changes: (1) Clarifying the scope of real-world studies: The PRECIS-2 tool was originally designed to help researchers prospectively design their randomized controlled trials (RCTs). However, the PRECIS-2 authors have recognized that it can also be used to retrospectively assess pragmatism in RCTs for literature reviews. There is no simple dichotomous threshold for distinguishing pragmatic versus explanatory RCTs. It is not recommended to sum up the domain scores, rank-order the domains by importance, or set a minimum number of domains to determine pragmatism. Consistent with these recommendations, we will not apply an explicit threshold. The decision on whether an RCT is pragmatic will be guided by PRECIS-2 scores but ultimately up to the reviewers. Nevertheless, we agree that we can be more explicit to guide reviewers on how to use PRECIS-2 to inform their judgement and discussion. Furthermore, to promote transparency and reproducibility, we will publish our PRECIS-2 scores for candidate RCTs. (2) Update and expand literature coverage: Thank you for this feedback. We agree that these changes can help highlight the novelty. We now cite several relevant studies that we came across in our feasibility search in the Introduction. However, we are cautious with the wording, as our feasibility search was only a scan of published literature and may underrepresent the growing body of evidence since 2019. Furthermore, we have added a new table to the appendix (S2 Appendix) that compares the past reviews with this planned review. (3) Heterogeneity: Thank you for this suggestion. To qualitatively assess heterogeneity, we will present our findings in a summary table (headers: author (year), insulin product, funding source, diabetes mellitus type, number of patients, follow-up duration, relevant outcomes, authors' conclusions), sorted by study design. This summary table can illustrate whether different study designs consistently report different patient characteristics and outcomes. We have added this shell table to the appendix (S7 Appendix). (4) Typographical and formatting issues: We identified some formatting issues and made the edits listed in the attached letter. Of note, “aspart” (drug name), “OAIster” (catalog name), “citationchaser” (R package), and “textword” (field-specific terminology) have been marked by Microsoft Word as spelling mistakes. We confirm that these are the correct spellings. We would like to remind the editor that the above are only excerpts from our attached Response to Editor letter dated May 29, 2025. Please view our letter for the detailed changes. Attachments Attachment Submitted filename: Response to Editor_Biosimilar Insulins.docx https://doi.org/10.1371/journal.pone.0329299.r002
Decision Letter - Sreedhar Dharmagadda, Editor Comparative effectiveness and safety of insulin reference biologics versus biosimilars for types 1 and 2 diabetes mellitus: protocol for a systematic review of real-world studies PONE-D-25-25687R1 Dear Dr. Ho, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Sreedhar Dharmagadda, Ph. D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0329299.r003
Formally Accepted
Acceptance Letter - Sreedhar Dharmagadda, Editor PONE-D-25-25687R1 PLOS ONE Dear Dr. Ho, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Sreedhar Dharmagadda Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0329299.r004

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