Development of a conceptual framework for defining trial efficiency

Charis Xuan Xie; Anna De Simoni; Sandra Eldridge; Hilary Pinnock; Clare Relton

doi:10.1371/journal.pone.0304187

Peer Review History

Original SubmissionDecember 4, 2023
14 Feb 2024 Decision Letter - Germain Honvo, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-23-40114Development of a conceptual framework for defining trial efficiencyPLOS ONE Dear Dr. Xie, 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 Mar 30 2024 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, Germain Honvo, Ph.D. 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. 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: 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: No ****** 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 fascinating and potentially very valuable study. By deploying a Delphi e-study, the authors achieved consensus on four theoretical constructs for defining trial efficiency, and on five empirical building blocks essential for considering trial efficiency. This research will contribute to better evaluation of trial efficiency. Reviewer #2: Dear Authors, Well done on the piece of work! The authors have provided a nice framework to define efficiency in the context of trial design and conduct. However, there are a few comments/ suggestions from my end to make the paper accessible to a greater audience. 1. The most interesting question after reading the paper has been: as the authors identified four constructs and 5 building blocks of the trial efficiency concept, what is the interplay between them? As in, how each block will fall under the defined constructs? A researcher might be interested if he/she is looking for a particular kind of efficiency, which building blocks does he/she needs to consider? I would also be interested in looking at the potential overlap between these constructs (if there are any, which I think there might be). Any diagrammatic summary would be nice. 2. Please include the e-delphi questionnaire that have been used. It confuses me if Figure 1 summarise all the questions asked in the survey. As mentioned there, “Question 1. How do you define efficiency within the context of trials to improve healthcare?” How was this recorded? It will give the readers a clearer picture if the questionnaire is attached. 3. I think there might be some overlap between the identified themes from a literature review, for example: Efficient trial designs (as mentioned in the description e.g. Adaptive designs, Master protocols etc) are mostly more sophisticated statistical trial designs instead of a simple RCT (where the paradigm looks like design -> conduct -> analysis). In that case why it is not different from statistical efficiency or operational/economical efficiency (which the designs typically target to optimise)? Why can’t it not fall under them? 4. Please include some description of the figures in the text/caption of the figure. I am still unsure of what figure 2 describes. It is not clear whether it reports some sort of frequency or ranking or percentage. 5. A quick clarification: what do the authors mean by member of public? Are they trial participants? A small typo in the appendix, all the inter-percentile ranges in IPRAS are mentioned as intercentile ranges. Hope this helps! Good luck! ****** 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: Dr Sarah Markham 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. https://doi.org/10.1371/journal.pone.0304187.r001
Revision 1
22 Mar 2024 Author Response Review Comments to the Author Reviewer #1: This is a fascinating and potentially very valuable study. By deploying a Delphi e-study, the authors achieved consensus on four theoretical constructs for defining trial efficiency, and on five empirical building blocks essential for considering trial efficiency. This research will contribute to better evaluation of trial efficiency. We appreciate your recognition of our study's value and its potential impact on the field. Reviewer #2: Dear Authors, Well done on the piece of work! The authors have provided a nice framework to define efficiency in the context of trial design and conduct. However, there are a few comments/ suggestions from my end to make the paper accessible to a greater audience. 1. The most interesting question after reading the paper has been: as the authors identified four constructs and 5 building blocks of the trial efficiency concept, what is the interplay between them? As in, how each block will fall under the defined constructs? A researcher might be interested if he/she is looking for a particular kind of efficiency, which building blocks does he/she needs to consider? I would also be interested in looking at the potential overlap between these constructs (if there are any, which I think there might be). Any diagrammatic summary would be nice Thank you for highlighting this crucial aspect of our study. The potential overlaps between the constructs have been discussed in the original manuscript in the discussion section, on pages 21 and 22. Regarding the relationships between the constructs and the building blocks, we initially distinguish between the constructs and the building blocks to illustrate a layered understanding of trial efficiency. The four constructs were conceptualised to provide a broad, overarching view of efficiency within healthcare trials. In contrast, the five building blocks were identified as the essential, practical components that operationalise efficiency in real-world settings. However, recognising the relationships among these identified themes is indeed essential in the theory-building process. As such, we have added the following descriptions in the revised discussion, on page 23. “There is a layered connection between the constructs and the building blocks: the four constructs were conceptualised to provide a broad, overarching view of efficiency within healthcare trials. In contrast, the five building blocks were identified as the essential, practical components that operationalise efficiency in real-world settings. In addition to this relationship, we suggest that for a comprehensive understanding, each efficiency construct takes into account all five building blocks. For instance, while it may seem apparent that scientific efficiency is closely linked with trial design, focusing on how the study is conceptualised to ensure methodological soundness; it also intersects with stakeholder involvement, where patient and public engagement can improve the trial design and thus the trial outcomes' relevance and applicability. Figure 5 illustrates the potential interplay between the theoretical constructs and the empirical building blocks.” And in light of your suggestion, we have included an updated conceptual framework of trial efficiency (figure 4 on page 21) to visually outline the theoretical constructs, building blocks and their relationship. This diagrammatic representation is part of our ongoing effort to refine our conceptual framework and enhance its applicability and understanding: Figure 4. The conceptual framework of trial efficiency. Footnote: The outer blue circle outlines four theoretical constructs of trial efficiency, which are Scientific Efficiency, Statistical Efficiency, Operational Efficiency and Economic Efficiency. At its core, the inner pentagon outlines five empirical building blocks: Superstructure, Stakeholders, Infrastructure, Trial Process, and Trial Design. The cyclical arrows indicate the necessity for a balanced consideration of each building block within each construct to optimise trial efficiency. 2. Please include the e-delphi questionnaire that have been used. It confuses me if Figure 1 summarise all the questions asked in the survey. As mentioned there, “Question 1. How do you define efficiency within the context of trials to improve healthcare?” How was this recorded? It will give the readers a clearer picture if the questionnaire is attached. The e-Delphi questionnaire has been added to the supplementary file 1. Question one was recorded in free text. The following changes have been made to the manuscript on page 8, method section: “In the open round, we invited panellists to share their thoughts on 1) their understanding of trial efficiency and 2) the most efficient or inefficient aspects they have encountered in the trials they have conducted or in which they have participated. These questions were designed as free text to encourage detailed, narrative responses. (see S1 File 1 for the questionnaire).” 3. I think there might be some overlap between the identified themes from a literature review, for example: Efficient trial designs (as mentioned in the description e.g. Adaptive designs, Master protocols etc) are mostly more sophisticated statistical trial designs instead of a simple RCT (where the paradigm looks like design -> conduct -> analysis). In that case why it is not different from statistical efficiency or operational/economical efficiency (which the designs typically target to optimise)? Why can’t it not fall under them? Thank you for raising the point about the overlaps among the four constructs. We provide the following rationale for categorising trial design into scientific efficiency: The theme synthesis was partially based on the previous discussions about scientific efficiency and operational efficiency [1], in which the authors argued that innovative clinical trial designs (such as adaptive studies) are integral to scientific efficiency. [1] Kelly D, Spreafico A, Siu LL. Increasing operational and scientific efficiency in clinical trials. Br J Cancer. 2020;123(8):1207-8. While these designs inherently enhance statistical efficiency through sophisticated design features, they are considered distinct due to their broader impact on the scientific process. They extend beyond statistical considerations to influence the trial's methodological soundness, ethical conduct, and the potential for quicker patient benefit. Additionally, operational efficiency, as addressed in our review, involves the effective management and organisation of trial processes and procedures. Sophisticated trial designs aim to improve these aspects but do not encapsulate the entirety of operational considerations. Economic efficiency, distinct yet linked, focuses on the cost implications of conducting a trial. Innovative trial designs can influence costs but are one of many factors that contribute to the overall economic efficiency of a trial. By delineating these designs as a separate entity, we aim to emphasise their unique contribution to trial efficiency. They are a part of the broader constructs but deserve individual recognition for their specific impacts. As such, we clarified this interplay in the discussion section of the original manuscript, on page 22: “Overall there was no disagreement over the four constructs ……thus offering a nuanced theoretical framework for its comprehension.” Nonetheless, we recognise that interpretations of qualitative data can vary, and to account for this, we have included the following statement in the limitations section: “While we have sought to delineate each construct and building block distinctly, we acknowledge the potential for different interpretations of qualitative data. The interplay between the identified themes is likely to be more intricate, reflecting the complex nature of trial efficiency. Future research could delve deeper into this interplay to unravel the connections.” 4. Please include some description of the figures in the text/caption of the figure. I am still unsure of what figure 2 describes. It is not clear whether it reports some sort of frequency or ranking or percentage. Thank you, we have added the following note to figure 2: “Figure footnote: The x-axis represents the frequency of responses.” 5. A quick clarification: what do the authors mean by member of public? Are they trial participants? Thank you for seeking further clarification. In our study, 'trial participants' are referred to as individuals who have directly participated in clinical trials (e.g. receiving interventions or being part of control groups), offering invaluable insights from their lived experiences. This is to separate the role of 'members of the public', who may not have personally participated in clinical trials, but may have helped in patient engagement and/or assisted in developing study designs. In light of this comment, we have clarified it in the revised manuscript under the section of “Patient and public involvement” on page 9: “In this study, members of the public (n=4) (including two who had participated in trials) were invited to share their thoughts, participate in the ranking process, provided with the outcomes of each round upon completion.” 6. A small typo in the appendix, all the inter-percentile ranges in IPRAS are mentioned as intercentile ranges. Thank you for spotting this typo. They have been corrected accordingly. Attachments Attachment Submitted filename: Delphi study_rebuttal letter.docx https://doi.org/10.1371/journal.pone.0304187.r002
8 May 2024 Decision Letter - Germain Honvo, Editor Development of a conceptual framework for defining trial efficiency PONE-D-23-40114R1 Dear Dr. Xie, 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, Germain Honvo, Ph.D. 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: (No Response) ******** 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: Yes 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: Yes 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: I am happy with the revisions made by the authors. This conceptual paper will make a positive contribution to the literature. 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.0304187.r003
Formally Accepted
14 May 2024 Acceptance Letter - Germain Honvo, Editor PONE-D-23-40114R1 PLOS ONE Dear Dr. Xie, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks 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. Germain Honvo Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0304187.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 .