Ethical acceptability of human challenge trials: Consultation with the US public and with research personnel

James William Benjamin Elsey; David Manheim; Abigail Marsh; Virginia Schmit; David Moss

doi:10.1371/journal.pone.0307808

Peer Review History

Original SubmissionOctober 3, 2023
14 May 2024 Decision Letter - Isha Amatya, Editor PONE-D-23-31643Ethical Acceptability of Human Challenge Trials: Consultation with the US public and with research personnelPLOS ONE Dear Dr. Elsey, 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 Jun 28 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. 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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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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: 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 paper overall is well-presented. Many doubts were explained in the limitations. However, I would recommend that the authors include a socio-demographic table summarizing the characteristics of the public participants surveyed, either in the main manuscript or as extended data. Reviewer #2: The manuscript is technically sound and the data supports the conclusion along with appropriate statistical analysis. However, I have few points for minor review of the manuscript. They are mentioned below. 1) Please mention how the general participants were fielded in male and female, what was the sampling method used and how they were equally distributed? [article line number 148] 2) It has been mentioned that non binary population were excluded but sensitivity analysis was done to check any major differences by assigning them as male/ female. What method was used to assign them as male/female. And were they also equally assigned as male and female (in numbers)? what method was used for equal distribution? [Article line number 154] 3) The 3rd inclusion criteria for research personnel as mentioned in the manuscript and information sheet in the supplementary data does not match with the research personnel actually involved in the study. Please specify the reason for including participants who do not fall under the mentioned inclusion criteria. [ Article line number 159,160 and 171] 4) The study shows two different groups. It is advisable to mention them by their group name rather than respondents as it would sound less confusing for readers. 5) Please mention the full form of MCMC sampling in the text. [Article line number 272] 6) The total number of participants (N) should be mentioned in the table number 1 provided in the supplementary data with heading "sample information for research personnel across different outcomes" for different outcomes category. ****** 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: Sushila Paudel Reviewer #2: Yes: Dr. Shruti Shah ******** [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.0307808.r001
Revision 1
2 Jul 2024 Author Response Dear Editor, Dr Shruti Shah, and Sushila Paudel Thank you for your positive review of our work. We appreciate the time and effort you took to evaluate our manuscript. In the following pages, we have provided responses to any outstanding questions and comments you had, highlighting where any edits have been made in the manuscript. Editor notes/comments: 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 manuscript has now been updated to match the style requirements of PLOS ONE. 2. Note from Emily Chenette, Editor in Chief of PLOS ONE, and Iain Hrynaszkiewicz, Director of Open Research Solutions at PLOS: Did you know that depositing data in a repository is associated with up to a 25% citation advantage (https://doi.org/10.1371/journal.pone.0230416)? If you’ve not already done so, consider depositing your raw data in a repository to ensure your work is read, appreciated and cited by the largest possible audience. You’ll also earn an Accessible Data icon on your published paper if you deposit your data in any participating repository (https://plos.org/open-science/open-data/#accessible-data). Data and analysis files are available via the Open Science Framework (https://osf.io/u2ev9/) and is referred to in the manuscript. 3. Thank you for stating the following financial disclosure: [Astral Codex 10 Grant]. Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. We’ve now updated our funding statement at the end of the manuscript and cover letter: “ACX had no role in study design, analysis, decision to publish, or preparation of the manuscript. As noted in the manuscript, ACX played a minor role in data collection by increasing awareness of the study among potential research personnel via a mention in a blog post.” 4. Thank you for stating the following in the Competing Interests section: [This work was supported by an ACX Grant to 1Day Sooner, a 501(c)(3) non-profit organization that advocates for people who participate and want to participate in high-impact medical studies, including HCTs. Rethink Priorities was contracted by 1Day Sooner to execute this research project and collected and analyzed data independently of 1Day Sooner.]. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. We’ve now added this to our COI statement. In full, the COI is now: “This work was supported by an ACX Grant to 1Day Sooner, a 501(c)(3) non-profit organization that advocates for people who participate and want to participate in high-impact medical studies, including HCTs. Rethink Priorities was contracted by 1Day Sooner to execute this research project and collected and analyzed data independently of 1Day Sooner. This does not alter our adherence to PLOS ONE policies on sharing data and materials. ACX had no role in study design, analysis, decision to publish, or preparation of the manuscript. As noted in the manuscript, ACX played a minor role in data collection by increasing awareness of the study among potential research personnel via a mention in a blog post.” 4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. I’ve now generated an ORCID id and linked it to the submission. 5. Please remove your figures from within your manuscript file, leaving only the individual TIFF/EPS image files, uploaded separately. These will be automatically included in the reviewers’ PDF. We’ve removed the Figures from the file itself, and now generated and uploaded TIFF files (including putting them through the PACE system). 6. Please review your reference list to ensure that it is complete and correct The reference list has been updated and checked for including all the appropriate articles. Reviewers' comments: Reviewer #1: The paper overall is well-presented. Many doubts were explained in the limitations. However, I would recommend that the authors include a socio-demographic table summarizing the characteristics of the public participants surveyed, either in the main manuscript or as extended data. Thank you for this suggestion, including the raw demographics can add to the transparency of information regarding the sample. We’ve now included a demographics table titled ‘Sample information for general population’ in our appendix/supplementary materials. We also highlight that this table is available in the demographics section of the main manuscript. Reviewer #2: The manuscript is technically sound and the data supports the conclusion along with appropriate statistical analysis. However, I have few points for minor review of the manuscript. They are mentioned below. 1) Please mention how the general participants were fielded in male and female, what was the sampling method used and how they were equally distributed? [article line number 148] We’ve now slightly modified the sentence here – the participants were recruited via the survey platform called Prolific. In order to ensure an equal number of male and female respondents, you can set a quota to specifically ask for certain percentages on some demographic features, and so we set it to field to 50-50 male and female respondents. On p7, we now say: “Data were collected from US residents aged 18 or above using the Prolific platform, and fielded to equal numbers of men and women through quotaing on the platform.” 2) It has been mentioned that non binary population were excluded but sensitivity analysis was done to check any major differences by assigning them as male/ female. What method was used to assign them as male/female. And were they also equally assigned as male and female (in numbers)? what method was used for equal distribution? [Article line number 154] In order to do this, we avoided splitting the respondents between male or female identifications and just ran different regression models either with them all assigned to male, or all assigned to female. Essentially what we found is that this small amount of respondents did not perceptibly or significantly change any of the outcome metrics. The same would be the case if we had tried splitting them in some way across male or female, as then the sample changes would be even smaller. We’ve tried to clarify the nature of the sensitivity analyses with some minor edits on page 8: “Sensitivity analyses in which these respondents were included in analyses and assigned as either all male or all female respondents are presented in the Supplementary Materials, and indicate that the inclusion or exclusion of these respondents would not shift any outcomes” 3) The 3rd inclusion criteria for research personnel as mentioned in the manuscript and information sheet in the supplementary data does not match with the research personnel actually involved in the study. Please specify the reason for including participants who do not fall under the mentioned inclusion criteria. [ Article line number 159,160 and 171] We think there may be a slight misunderstanding here – if I understand correctly then what is being referred to here is that we conducted some follow-up analyses in which personnel who had vs. had not conducted human challenge trials were either included or excluded, and this varied for some of the different outcomes. However, our key eligibility criterion was to do with whether respondents had been involved in Phase III clinical trials, rather than HCTs specifically. Accordingly, there is some variation as to whether or not respondents were involved in HCTs specifically. We chose not to include those who had conducted HCTs themselves in assessments of whether they thought HCTs were ethically acceptable as these respondents would presumably be heavily biased in favor of HCTs being acceptable. 4) The study shows two different groups. It is advisable to mention them by their group name rather than respondents as it would sound less confusing for readers. Thank you for pointing out this possible source of confusion, especially in the methods. When introducing and talking about research personnel in the methods section, we know replaced the terms ‘respondents’ with ‘research personnel’. We also made similar edits throughout the manuscript where we thought there might be confusion about who was being referred to. 5) Please mention the full form of MCMC sampling in the text. [Article line number 272] Thank you for highlighting this – we’ve now added on Page 13 that: “The sampling for the Bayesian regression models used Hamiltonian Monte Carlo (HMC) No-U-Turn samplings (NUTS).” 6) The total number of participants (N) should be mentioned in the table number 1 provided in the supplementary data with heading "sample information for research personnel across different outcomes" for different outcomes category. We’ve now added a short sentence above the table indicating the total number of eligible research personnel. Additional note: On page 22 of the manuscript, we made one additional minor change from stating that the first three factors of importance were all to do with risk to participants, to state that the first two are to do with risk, and the third relates to risk: “Foremost among the items in importance for both the general public and research personnel were two factors that directly related to the risks posed to participants: the level of risk exposure and that participants fully understand those risks, and a third item that may be seen to relate to the risks participants face: the availability of rescue treatments.” Attachments Attachment Submitted filename: Response to Reviewers.pdf https://doi.org/10.1371/journal.pone.0307808.r002
12 Jul 2024 Decision Letter - Isha Amatya, Editor Ethical Acceptability of Human Challenge Trials: Consultation with the US public and with research personnel PONE-D-23-31643R1 Dear Dr. Elsey, 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, Isha Amatya, M.D. Guest Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0307808.r003
Formally Accepted
21 Aug 2024 Acceptance Letter - Isha Amatya, Editor PONE-D-23-31643R1 PLOS ONE Dear Dr. Elsey, 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. Isha Amatya %CORR_ED_EDITOR_ROLE% PLOS ONE https://doi.org/10.1371/journal.pone.0307808.r004

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