A code for clinical trials centralized monitoring, sharing open-science solutions to high-quality data

André Daher; Júlio Castro-Alves; Leandro Amparo; Natalia Pacheco de Moraes; Thaís Regina Araújo dos Santos; Karla Regina Gram dos Santos; Cristiane Siqueira do Valle; Maria Hermoso; Margareth Catoia Varela; Rodrigo Correa Oliveira

doi:10.1371/journal.pone.0294412

Peer Review History

Original SubmissionJune 15, 2023
14 Aug 2023 Decision Letter - Claudia Garcia Serpa Osorio-de-Castro, Editor PONE-D-23-18254A code for clinical trials centralized monitoring, sharing open-science solutions to high-quality dataPLOS ONE Dear Dr. Hermoso, 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 Sep 28 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. 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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: N/A ****** 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: The article present an enthusiastic opportunity for optimizing clinical trials timelines. Please, consider some revisions and corrections below: Line 122: Include details about the location of the study. Was it only Brazilian patients? Line 191: The sentence is indicating that all the trial CRF are available upon request. Please indicate if there are restrictions or protections on the information provideded. Line 196: Make clear if the available information will be presented only in Portuguese. Line 303: Include a rational to explain why the parameters that were chosen to be automated evaluated are representing the most critical aspects of monitoring. Are those representative to the critical aspects to be monitored? Line 313: Provide an improved explanation for this statement. Line 321: Include a discussion on how the presentation of the tool only in Portuguese represents a limitation on access? Line 326: Why and which "further statistical tests" will be needed? Reviewer #2: This is a manuscript on a relevant topic, the monitoring of clinical trials that is critical both for the protection of human subjects and for the conduct of high-quality research. It is written in a scientifically clear and adequate manner, but some minor adjustments are needed such as definitions of acronyms and some details in the discussion section. ****** 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: Yes: Gustavo Mendes Lima Santos Reviewer #2: Yes: CARLOS AUGUSTO FERREIRA DE ANDRADE ******** [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: CARLOS-SUG-PONE-D-23-18254.pdf https://doi.org/10.1371/journal.pone.0294412.r001
Revision 1
29 Sep 2023 Author Response Please see also rebuttal letter. We are grateful for the revision of publication criteria and for the reviewer’s comments and suggestions. Please find below our responses to the reviewers. Reviewer #1: The article present an enthusiastic opportunity for optimizing clinical trials timelines. Please, consider some revisions and corrections below: Line 122: Include details about the location of the study. Was it only Brazilian patients? The following text was added (line 122): The trial was performed in six clinical trial sites in Brazil, located in 5 different states (Rio de Janeiro, São Paulo, Minas Gerais, Rondônia, and Mato Grosso do Sul). Line 191: The sentence is indicating that all the trial CRF are available upon request. Please indicate if there are restrictions or protections on the information provided. The code is licensed under the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). The follow statement was inserted (line 187): “These files are licensed under a Creative commons Attribution-Non-commercial 4.0 International (CC BY-NC 4.0)” Line 196: Make clear if the available information will be presented only in Portuguese. In fact, currently the dashboard shows the information only in Portuguese. This information has been added to the text (line 205) Line 303: Include a rational to explain why the parameters that were chosen to be automated evaluated are representing the most critical aspects of monitoring. Are those representative to the critical aspects to be monitored? You are correct, the chosen parameters are critical monitoring aspects. For the sake of clarification, the following statement was inserted in line 198: “Most of the critical central monitoring aspects are evaluated. The rational of parameters election were based on the most frequent monitoring findings, i.e protocol deviations; data robustness and integrity (completeness of outcomes); and high risk aspects, as pharmacovigilance. Additionally, study sites performance metrics were included as alert signs.” Line 313: Provide an improved explanation for this statement. The statements was rephrased to: As the R script is coded as a structured language, it assures the reproducibility of these assessments across actors and trials [17]. For instance, REDCap reports are more prone to errors during the variables selection (line 324). Line 321: Include a discussion on how the presentation of the tool only in Portuguese represents a limitation on access? The following sentence was inserted at line 346: “Currently, the dashboards are presented in Portuguese, although this language barrier may be overcome by collaborative science.” Line 326: Why and which "further statistical tests" will be needed? The following reference was included (line 348): A statistical approach to central monitoring of data quality in clinical trials D Venet, E Doffagne, T Burzykowski, F Beckers, Y Tellier, E Genevois-Marlin, U Becker…Clinical Trials, 2012. Reviewer #2: This is a manuscript on a relevant topic, the monitoring of clinical trials that is critical both for the protection of human subjects and for the conduct of high-quality research. It is written in a scientifically clear and adequate manner, but some minor adjustments are needed such as definitions of acronyms and some details in the discussion section. This reviewer’s comments were included in the file named “CARLOS-SUG-PONE-D-23-18254” • Definition of acronyms have been included in the revised manuscript: o Line 27: Case Report Forms (CRFs) o Line 181: Structured Query Language (SQL) o Line 296: Good Clinical Practice (GCP) • Link to the dashboard has been checked for proper functioning (line 198): https://shiny.fiocruz.br/teste/pce0121/ • Regarding the text of figures, which the reviewer suggests to translate into English. Unfortunately translating the figures into English are not possible. The figures were extracted from the site, in order to translate the figures, we must translate the code. This is a limitation that has been highlighted in the manuscript. • In the discussion section, an explicit presentation of the strengths of the manuscript, as well as future proposals for open-science solutions was added as suggested by the reviewer: line 337. • We have included an important update on the clinical trials regulatory landscape: the new version of the Good Clinical Practice (ICH E6 R3), the first review in the last 20 years. This paper presents an open-science solution to the very edge of this new landscape of regulatory requirements. The following paragraph was inserted (line 332): “Recently, the ICH Harmonised Guideline Good Clinical Practice (GCP) E6(R3) ICH Consensus Guideline recognized that centralised monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of site monitoring or be used on its own. Use of centralised data analytics can help identify systemic or site-specific issues, including protocol non-compliance and potentially unreliable data (ref). The main strength of the manuscript is that it presents an open-science solution to push further in the centralized monitoring adoption direction, as these tools' implementation will be reinforced by this regulatory guidance soon.” Finally in order to inform future proposals for open-science solutions we added a last paragraph at the review (line 357): “A future proposal for open-science solutions includes sharing CRFs developed using CDISC for neglected tropical diseases clinical networks, allowing the use of the same centralized monitoring scripts in distinct trials. Harmonizing the data quality and datasets might promote individual data pooled metanalyses speeding up the synthesis of evidence where scarce data are generated.” Still in the discussion section, the reviewer suggests including some references in two paragraphs (lines 315 to 335 in the original manuscript). • We have included the reference: Risk-based centralized data monitoring of clinical trials at the time of COVID-19 pandemic Most Alina Afroz a, Grant Schwarber b, Mohammad Alfrad Nobel Bhuiyan b,. Barnes B, Stansbury N, Brown D, Garson L, Gerard G, Piccoli N, et al. Risk-based monitoring in clinical trials: past, present, and future. Therapeutic innovation & regulatory science. 2021;55: 899–906 Additionally, we have provided a relevant reference by the ICH Consensus Guideline (GCP E6(R3)), currently under public consultation. However, the statements are based on reported experience by using the central monitoring tool. We hope that further references will be available in the future reporting the use of similar tools. We have rephrased the two paragraphs to make this clear. https://doi.org/10.1371/journal.pone.0294412.r002
5 Oct 2023 Decision Letter - Claudia Garcia Serpa Osorio-de-Castro, Editor PONE-D-23-18254R1A code for clinical trials centralized monitoring, sharing open-science solutions to high-quality dataPLOS ONE Dear Dr. Hermoso 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. Most of the Reviewers´suggestions and recommendations were met. However, all figures and captions are in Portuguese and quality of these elements is still not adequate. Portuguese-language in Figures was highlighted by a reviewer and the answer was: "Regarding the text of figures, which the reviewer suggests to translate into English. Unfortunately translating the figures into English are not possible. The figures were extracted from the site, in order to translate the figures, we must translate the code. This is a limitation that has been highlighted in the manuscript." Publishing in English is a standard procedure and if figures are generated by code, this must be thought of in advance. It would be wise to translate the code and generate figures in English as per PlosOne policy (PlosOne Publication Criterium #5 states that "The article is presented in an intelligible fashion and is written in standard English". Although figures are intelligible, they are so only for Portuguese-Language speakers. ============================== Please submit your revised manuscript by October 30, 2023. 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, Claudia Garcia Serpa Osorio-de-Castro, Ph.D Academic Editor PLOS ONE Journal Requirements: 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.] [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.0294412.r003
Revision 2
27 Oct 2023 Author Response We are grateful for the revision of publication criteria and for the reviewer’s comments and suggestions. Please find below our responses to the reviewers. Reviewer #1: The article present an enthusiastic opportunity for optimizing clinical trials timelines. Please, consider some revisions and corrections below: Line 122: Include details about the location of the study. Was it only Brazilian patients? The following text was added (line 122): The trial was performed in six clinical trial sites in Brazil, located in 5 different states (Rio de Janeiro, São Paulo, Minas Gerais, Rondônia, and Mato Grosso do Sul). Line 191: The sentence is indicating that all the trial CRF are available upon request. Please indicate if there are restrictions or protections on the information provided. The code is licensed under the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). The follow statement was inserted (line 187): “These files are licensed under a Creative commons Attribution-Non-commercial 4.0 International (CC BY-NC 4.0)” Line 196: Make clear if the available information will be presented only in Portuguese. In fact, currently the dashboard shows the information only in Portuguese. This information has been added to the text (line 205) Line 303: Include a rational to explain why the parameters that were chosen to be automated evaluated are representing the most critical aspects of monitoring. Are those representative to the critical aspects to be monitored? You are correct, the chosen parameters are critical monitoring aspects. For the sake of clarification, the following statement was inserted in line 198: “Most of the critical central monitoring aspects are evaluated. The rational of parameters election were based on the most frequent monitoring findings, i.e protocol deviations; data robustness and integrity (completeness of outcomes); and high risk aspects, as pharmacovigilance. Additionally, study sites performance metrics were included as alert signs.” Line 313: Provide an improved explanation for this statement. The statements was rephrased to: As the R script is coded as a structured language, it assures the reproducibility of these assessments across actors and trials [17]. For instance, REDCap reports are more prone to errors during the variables selection (line 324). Line 321: Include a discussion on how the presentation of the tool only in Portuguese represents a limitation on access? The following sentence was inserted at line 346: “Currently, the dashboards are presented in Portuguese, although this language barrier may be overcome by collaborative science.” Line 326: Why and which "further statistical tests" will be needed? The following reference was included (line 348): A statistical approach to central monitoring of data quality in clinical trials D Venet, E Doffagne, T Burzykowski, F Beckers, Y Tellier, E Genevois-Marlin, U Becker…Clinical Trials, 2012. Reviewer #2: This is a manuscript on a relevant topic, the monitoring of clinical trials that is critical both for the protection of human subjects and for the conduct of high-quality research. It is written in a scientifically clear and adequate manner, but some minor adjustments are needed such as definitions of acronyms and some details in the discussion section. This reviewer’s comments were included in the file named “CARLOS-SUG-PONE-D-23-18254” • Definition of acronyms have been included in the revised manuscript: o Line 27: Case Report Forms (CRFs) o Line 181: Structured Query Language (SQL) o Line 296: Good Clinical Practice (GCP) • Link to the dashboard has been checked for proper functioning (line 198): https://shiny.fiocruz.br/teste/pce0121/ • All figures have been translated into English (figures 1 to 7). • In the discussion section, an explicit presentation of the strengths of the manuscript, as well as future proposals for open-science solutions was added as suggested by the reviewer: line 337. • We have included an important update on the clinical trials regulatory landscape: the new version of the Good Clinical Practice (ICH E6 R3), the first review in the last 20 years. This paper presents an open-science solution to the very edge of this new landscape of regulatory requirements. The following paragraph was inserted (line 332): “Recently, the ICH Harmonised Guideline Good Clinical Practice (GCP) E6(R3) ICH Consensus Guideline recognized that centralised monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of site monitoring or be used on its own. Use of centralised data analytics can help identify systemic or site-specific issues, including protocol non-compliance and potentially unreliable data (ref). The main strength of the manuscript is that it presents an open-science solution to push further in the centralized monitoring adoption direction, as these tools' implementation will be reinforced by this regulatory guidance soon.” Finally in order to inform future proposals for open-science solutions we added a last paragraph at the review (line 357): “A future proposal for open-science solutions includes sharing CRFs developed using CDISC for neglected tropical diseases clinical networks, allowing the use of the same centralized monitoring scripts in distinct trials. Harmonizing the data quality and datasets might promote individual data pooled metanalyses speeding up the synthesis of evidence where scarce data are generated.” Still in the discussion section, the reviewer suggests including some references in two paragraphs (lines 315 to 335 in the original manuscript). • We have included the reference: Risk-based centralized data monitoring of clinical trials at the time of COVID-19 pandemic Most Alina Afroz a, Grant Schwarber b, Mohammad Alfrad Nobel Bhuiyan b,. Barnes B, Stansbury N, Brown D, Garson L, Gerard G, Piccoli N, et al. Risk-based monitoring in clinical trials: past, present, and future. Therapeutic innovation & regulatory science. 2021;55: 899–906 Additionally, we have provided a relevant reference by the ICH Consensus Guideline (GCP E6(R3)), currently under public consultation. However, the statements are based on reported experience by using the central monitoring tool. We hope that further references will be available in the future reporting the use of similar tools. We have rephrased the two paragraphs to make this clear. https://doi.org/10.1371/journal.pone.0294412.r004
31 Oct 2023 Decision Letter - Claudia Garcia Serpa Osorio-de-Castro, Editor A code for clinical trials centralized monitoring, sharing open-science solutions to high-quality data PONE-D-23-18254R2 Dear Dr. Hermoso, 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, Claudia Garcia Serpa Osorio-de-Castro, Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): The graphic elements are now all in English, meeting PlosOne requirements. https://doi.org/10.1371/journal.pone.0294412.r005
Formally Accepted
7 Nov 2023 Acceptance Letter - Claudia Garcia Serpa Osorio-de-Castro, Editor PONE-D-23-18254R2 A code for clinical trials centralized monitoring, sharing open-science solutions to high-quality data Dear Dr. Hermoso: 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. Claudia Garcia Serpa Osorio-de-Castro Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0294412.r006

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