An evaluation of factors that may influence clinicians’ decisions not to enroll eligible patients into randomized trials in critical care

Mahesh Ramanan; Laurent Billot; Dorrilyn Rajbhandari; John Myburgh; Balasubramanian Venkatesh

doi:10.1371/journal.pone.0255361

Peer Review History

Original SubmissionFebruary 8, 2021
23 Apr 2021 Decision Letter - Linda L. Maerz, Editor PONE-D-21-04343 An evaluation of factors that may influence clinicians’ decisions not to enrol eligible patients into randomized trials in critical care. PLOS ONE Dear Dr. Ramanan, 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. We commend the authors for their submission. Although the manuscript has merit, several items require clarification and / or revision if the manuscript is to meet criteria for publication in PLOS ONE: - Address all queries posed by Reviewer 1 - Address all queries posed by Reviewer 2 - Address all items indicated by tracked changes in the attached Word document (PONE-D-21-04343-1 [suggested edits]) - Carefully proofread your final revised document for typos as well as errors of syntax and grammar Please submit your revised manuscript within 45 days of the date of this letter. 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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We will update your Data Availability statement on your behalf to reflect the information you provide. [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: Partly 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: The authors' question is important and relevant. It is logical to characterize the study sites as having trainees and research support to attempt to identify reasons why clinicians may not include eligible patients in a clinical trial. However, the study is a bit superficial: First - Only one trial (ADRENAL), though a large trial, was included in the analysis. Any trial specific factors cannot be isolated or assessed. In other words, it is difficult to say if the included research sites had specific protocol reasons to decline eligible patients. Including other trials would potentially provide additional clarity. Second - Additional site-level characteristics are needed. It is a big jump to say that because there is no correlation between a site being academic or having research support that the clinicians are likely concerned about a lack of equipoise. While it helps that the ADRENAL trial allowed deferred consent, the authors' conclusion is still based on speculation. For example, in how many other trials of this size did the sites participate? Were the rates of declined eligible patients similar for all studies? This manuscript will be more robust with the answers to these questions. Reviewer #2: The methods are described with adequate detail. The study is probably underpowered as indicated by the wide confidence intervals reported for many of the variables. Realizing that that the sample size was fixed by what was available in the RCT data base I did not see a description of how adequate power was estimated. Having an estimate of the sample size required to detect differences in outcome could inform future studies and place the current results in perspective. ****** 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: PONE-D-21-04343-1 [suggeted edits].docx https://doi.org/10.1371/journal.pone.0255361.r001
Revision 1
20 May 2021 Author Response Dear Prof Linda Maerz, Thank you for your thoughtful review and for giving us an opportunity to submit a revised manuscript. We have addressed all the points raised by the Reviewers and Editors. Our responses are highlighted in yellow after each query. Tracked and clean versions of the manuscript are attached to the submission as requested. We look forward to hearing the outcome of your review. Yours sincerely, Mahesh Ramanan on behalf of all authors Date: 11 May 2021 Reviewer 1 It is logical to characterize the study sites as having trainees and research support to attempt to identify reasons why clinicians may not include eligible patients in a clinical trial. However, the study is a bit superficial: First - Only one trial (ADRENAL), though a large trial, was included in the analysis. Any trial specific factors cannot be isolated or assessed. In other words, it is difficult to say if the included research sites had specific protocol reasons to decline eligible patients. Including other trials would potentially provide additional clarity. Thank you for your review and comments. It is true that trial-specific factors cannot be assessed with our study. Having access to a larger group of trials with similar data would be ideal. However, this was not the case for our study as we did not have access to such data. We have included a statement in the discussion to this effect. Second - Additional site-level characteristics are needed. It is a big jump to say that because there is no correlation between a site being academic or having research support that the clinicians are likely concerned about a lack of equipoise. While it helps that the ADRENAL trial allowed deferred consent, the authors' conclusion is still based on speculation. For example, in how many other trials of this size did the sites participate? Were the rates of declined eligible patients similar for all studies? That particular statement with regards to deferred consent and clinician equipoise is indeed speculative, as we have acknowledged in the text. We have added some further discussion to clarify this point. The data concerning other trials (‘competing trials’) and particularly the rates of CDR in these trials was not available to us. The ADRENAL trial protocol did allow for co-enrollment with several other trials, so it is possible that there were sites which were recruiting in competing trials. Reviewer 2 The methods are described with adequate detail. The study is probably underpowered as indicated by the wide confidence intervals reported for many of the variables. Realizing that that the sample size was fixed by what was available in the RCT data base I did not see a description of how adequate power was estimated. Having an estimate of the sample size required to detect differences in outcome could inform future studies and place the current results in perspective. Thank you for your review and for raising the important issue of statistical power. We did not have a baseline clinician decline rate which could be used for power calculations, hence, a priori calculations were not performed. Our results may be used to inform sample size calculations for future studies. We have elected not to perform post hoc calculations of power as there is significant controversy in the biostatistics literature regarding the validity of such calculations. A recent publication by Zhang et al (Zhang Y, Hedo R, Rivera A, et al. Post hoc power analysis: is it an informative and meaningful analysis? General Psychiatry 2019;32:e100069. doi: 10.1136/gpsych-2019-100069) had the following concluding statements: “Power analysis is an indispensable component of planning clinical research studies. However, when used to indicate power for outcomes already observed, it is not only conceptually flawed but also analytically misleading. Our simulation results show that such power analyses do not indicate true power for detecting statistical significance, since post hoc power estimates are generally variable in the range of practical interest and can be very different from the true power. In this report, we focus on the relatively simple statistical model for comparing two population means of continuous outcomes. The same considerations and conclusions also apply to non-continuous outcomes and more complex models such as regression. In general, post hoc power analyses do not provide sensible results.” Responses to Comments Page 3 What does this mean? This should be tertiary status which is defined in the Methods section. Page 4 Requires a space between “We” and “defined” This has been inserted. What is the rationale for derivation of these ICU-level variables? Wouldn’t ICU staffing also be relevant? For instance—full-versus part-time intensivist staffing; physician versus advanced practice provider staffing; trainee presence; number of patients per intensivist, etc. We selected these variables based on availability and relevance to Australia and New Zealand Intensive Care practice. All ICUs included in the trial in Australia and New Zealand are staffed by specialist Intensivists on-site during the day and on-call at night with on-site trainee presence all 24 hours. There are no advanced practice providers or nurse practitioners in ANZ ICUs. The seniority of trainee presence (i.e. basic trainee, advanced trainee, fellow) is determined by the College of Intensive Care Medicine Level as described earlier in the Methods section. The number pf patients looked after by intensivists in ANZ follow the recommended CICM guidelines as these sites are accredited by the CICM for the purpose of training. We chose volume of admissions as a marker of ICU size, and the other variables selected were resourcing variables that have a direct link to research i.e. availability of research coordinators, director of research etc. Page 5 Percentage? Yes. This has been changed. Page 6 Please provide more detail pertaining to the rationale of this speculation. Yes. We have now provided this detail in the preceding paragraph. Need a space between “of” and equipoise. This sentence has been removed. Page 7 Need space between “but” and “have” This has been inserted. If the study is underpowered, please explain why the conclusions are valid. Thanks. We have added further to the paragraph to explain that the findings are exploratory but also why they hold validity. Please define this. We have shortened the sentence for clarity. Page 8 Need a space between “on” and “enrollment” This has been inserted. Attachments Attachment Submitted filename: Responses to reviewers.docx https://doi.org/10.1371/journal.pone.0255361.r002
15 Jul 2021 Decision Letter - Linda L. Maerz, Editor An evaluation of factors that may influence clinicians’ decisions not to enrol eligible patients into randomized trials in critical care. PONE-D-21-04343R1 Dear Dr. Ramanan, 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, Linda L. Maerz, MD Academic Editor PLOS ONE Additional Editor Comments (optional): The authors are to be commended for addressing the editorial requests in the revised manuscript. Reviewers' comments: https://doi.org/10.1371/journal.pone.0255361.r003
Formally Accepted
19 Jul 2021 Acceptance Letter - Linda L. Maerz, Editor PONE-D-21-04343R1 An evaluation of factors that may influence clinicians’ decisions not to enroll eligible patients into randomized trials in critical care. Dear Dr. Ramanan: 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. Linda L. Maerz Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0255361.r004

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