PONE-D-21-13952

Patient and retina specialists’ preferences in neovascular age-related macular degeneration

PLOS ONE

Dear Dr. Blanch,

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.

This study considers preferences for treatment for neovascular age-related macular degeneration (nAMD) from both a patient and retinal practitioner perspective, using .This involved a series of hypothetical options for treatment, followed by focus groups. This does provide good background for expectations in ongoing personalised nAMD treatment but there are several areas that require further details and clarification.

1. For the selection of retinal specialists, please provide a brief description of the AMD-MANAGE study and criteria for this study, and how specialists for the current study were selected.

2. Informed consent is noted but was a Human Ethics Committee aproval involved? Please provide further details, thank you. Please also provide full details on patient and specialist demographics (e.g. patterns of treatment and monitoring, how long receiving treatment etc). Thank you,

3. In the Abstract and Conclusions, the authors indicate that "these results suggest that the use of more efficacious anti-VEGF agents with a longer duration of action.." are required. Please note that this aspect was not assessed in the study and should be amended.

4. Please provide more details on the focus group aspects, including overall M:F for the group. All patients were females and age range 45 to 75 - were these new patients to anti-VEGF therapies, what were their experiences? Same for the retina specialists and pharmacists. Thank you.

5. Please address all the comments provided by the reviewers.

Please submit your revised manuscript by Oct 22 2021 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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We look forward to receiving your revised manuscript.

Kind regards,

Michele Madigan

Academic Editor

PLOS ONE

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2. Please provide additional details regarding the retina specialists participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was suitably informed and (2) what type you obtained (for instance, written or verbal). If your study included minors under age 18, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

3. Please include in your Methods section (or in Supplementary Information files) the participating hospitals/institutions.

4. Thank you for stating the following in the Competing Interests/Financial Disclosure* (delete as necessary) section:

“I have read the journal's policy and the authors of this manuscript have the following competing interests: LGB and CB are paid employees of Novartis.”

We note that one or more of the authors are employed by a commercial company:  Novartis

a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

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We will update your Data Availability statement to reflect the information you provide in your cover letter.

6. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://linkinghub.elsevier.com/retrieve/pii/S0161642020300415

- https://www.dovepress.com/the-emotional-and-physical-impact-of-wet-age-related-macular-degenerat-peer-reviewed-fulltext-article-OPTH

- https://linkinghub.elsevier.com/retrieve/pii/S1098301520342388

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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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: No

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

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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

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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: No

Reviewer #2: Yes

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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: Patient and retinal specialist preferences for nAMD treatment is an interesting and relevant study. The authors should state earlier in the manuscript how this study stands apart from other patient preference studies. Also becareful of concluding that better visual & anatomical outcomes would be achieved with longer acting anti-VEGF agents. This is not what you analysed.

Abstract:

line 29 define VEGF

line34 Methods: include who the participants are ?nAMD patients on anti-VEGF treatment, previous treatment?

Abstract Results

line 40 need to say aged 79 or 79 years old

line 42 insert 'their' in front of 'visual function'

line 45 improvements of visual function (instead of improving)

line 45 agree on instead of 'for delaying'

line 46 when is the frequency delayed? with or without treatment

line 47 Conclusion : first sentence does not make sense

line 50 FInal line of conclusion is wrong: These results do not suggest that more efficacious anti-VEGF agents with a longer duration of action would facilitate better disease management. This study is about patient and doctor preference.

Introduction

line 2 age-related not 'aged-related'

line 6 'by' instead in 2040

line 8 ameliorate isn't quite the correct word to describe this means 'make better'

line 14 In this study, prior to 'the most commonly reported diseae'

line 18 insert 'their' prior to vision impairment

line 22 treatment should be inserted after anti-VEGF

line 22 visual decline not 'visual damage'

line 24 last line does not make sense

line 31,32 and 33 is not clear

line 22 new paragraph in front of Conjoint analysis

You need to explain in the introduction why this analysis is different/better than others nAMD studies completed in this area

line 43 who are the stakeholders'? Pharma companies?

METHODOLOGY

Methods need to define what is ment by treatment regimen and monitoring frequency and how they differ. For instance if fix regimen then is monitoring the same time as treatment? more detail required here

Line 54 aret the retinal specialists independent or do they treat the patients in the study?

I would mention ethics approval in first paragraph of methods

line 72 define the acronyms

Table 2 needs to be translated into English

line 116 RI is used earlier in the manuscript and should be abbreviated defined when first used

line 120 MRS previously defined

Results

line 137 79.0 uears

line 138 2.3 years

line 140 has SNHS been defined

line 150 sentence not clear

line 160 ? in contrast to cost and treatment regimen

line 165 is the cost to the patient or to the retinal specialist or both not defined

line 177 monitoring frequency, is this increasing or decreasing?

Line 180 who is 'we'? Your centre, your country? international retinal specialist?

line 181 their instead of 'a' treatment plan

line 198 insert 'patient's' before independence

line 200 remove 'therefore, the main treatment decision driver.'

Other bias is patients that started treatment but couldn't continue due to cost or other. Not included in the group.

The conclusions again are to clear. How can a study on patient and treating specialist's preference concluded that longer acting anti-VEGF agents would facilitate better disease management (visual function and anatomical outcomes). That may be true but not what the authors have studied here.

Reviewer #2: A unique, well-written study that contrasts the differing priorities of patients and retinal specialists with respects to anti-VEGF treatment in neovascular AMD. Certainly, a key strength of the work is the juxtaposition of findings from different stakeholder groups.

Lines 19-21: Treatment accessibility (distance to treatment, time spent in the clinic, caregiver demands) and patient understanding of the benefits of treatment are also important barriers that should be considered, either here or elsewhere.

Lines 48-51: Can the authors justify their 2 year inclusion criteria? Acknowledged in part on lines 238-242, patients on treatment for 2 years may have quite different preferences compared to patients newer to treatment and arguably, it is the second population group with lower adherence, which requires more study. On this point, it is also worth commenting on the participant characteristics in more detail generally.

All patients were recruited from tertiary care so presumably proceeding with anti-VEGF treatment, which again, would lead them to have significantly different preferences to treatment naïve patients or patients considering treatment discontinuation. How might retinal specialists working in the Spanish National Healthcare System compare to retinal specialists in other countries?

Line 71: What search terms were used?

Line 76-77: Further detail on the composition and conduct of these focus groups is important to include. Was it a single focus group with 10 participants total? How were the participants identified? How was data collected? Was there an interview guide? And how was the data analysed? Did all participants agree on the final list of attributes? And if so, how was consensus reached? Interesting that access (distance to the treating clinic) was not considered an important attribute to include.

Line 82: How were the attribute levels determined? E.g., the levels for the attribute effect on visual function seem very limited. Presumably, they refer to high contrast visual acuity but as we know, late AMD also causes central scotomas, the size and severity of these scotomas might have also been considered. For patients, the impact on activities of daily living would rate quite differently, especially depending on how the activity is framed. This seems essential information to include as it forms the basis of the options presented. Other considerations include how fluid reduction/resolution was communicated. Does the latter mean zero fluid tolerance? Cost level options were defined relative to current cost. This is discussed in part in the manuscript discussion but any attempts to minimize bias should be presented in the methods.

Line 99: How long did the survey take to complete and how was it administered? In hard copy? What is the likelihood of satisficing, response bias or the Hawthorne effect?

Is an English version of Table 2 available? The wording used to ask participants about their preferences is very important.

Line 209: Do you have any data on how the participants attended their treatment or monitoring appointments? Patients more reliant on their carers might have expressed different preferences relative to more independent patients.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-13952R1Patient and retina specialists’ preferences in neovascular age-related macular degenerationPLOS ONE

Dear Dr. Blanch,

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 .Thank you for the revised manuscript and fr addressing the reviewers comments. A few minor comments below;

p.58 (track changes copy): please explain what a 'naive' adult patient refers to in the context of the current study. The term is used in several places throughout the manuscript.

The reviewer also noted minor typographical errors that should be edited

The Supporting Information data provided could also presented with Column titles in English if possible. Thank you.

Please submit your revised manuscript by Jan 13 2022 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,

Michele Madigan

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.

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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 #2: All comments have been addressed

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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 #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

********** 

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 #2: Yes

********** 

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 #2: Yes

********** 

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 #2: All comments have been addressed and the manuscript improved.

Some minor outstanding notes:

Line 58 (track changes copy): What is an "adult naive" patient? Have the authors included the word naive here by mistake?

There is a repeating typographical error (ADM should be AMD) e.g. on lines 82, 97 and elsewhere

The authors have included their data in the supporting information but it is not in English

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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 #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.

Patient and retina specialists' preferences in neovascular age-related macular degeneration treatment. A discrete Choice Experiment.

PONE-D-21-13952R2

Dear Dr. Blanch,

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.

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Kind regards,

Michele Madigan

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for addressing the reviewer comments.

Reviewers' comments: