PONE-D-24-19336

Application of observational research methods to real-world studies for rare disease drugs: a scoping review protocol

PLOS ONE

Dear Dr. Patel,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

The protocol is not within the scope of the journal. PLOS ONE only considers protocols for systematic reviews and meta-analyses.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Kind regards,

Tim Mathes

Academic Editor

PLOS ONE

[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.]

- - - - -

For journal use only: PONEDEC3

PONE-D-24-19336R1Application of observational research methods to real-world studies for rare disease treatments: a scoping review protocolPLOS ONE

Dear Dr. Patel,

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 Feb 28 2025 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,

Kiyan Heybati

Academic Editor

PLOS ONE

Journal Requirements:

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 provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement.

3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager.

4. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:

A numbered table of all studies identified in the literature search, including those that were excluded from the analyses.

For every excluded study, the table should list the reason(s) for exclusion.

If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed.

A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study:

Name of data extractors and date of data extraction

Confirmation that the study was eligible to be included in the review.

All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses.

If data or supporting information were obtained from another source (e.g. correspondence with the author of the original research article), please provide the source of data and dates on which the data/information were obtained by your research group.

If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome. Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome.

An explanation of how missing data were handled.

This information can be included in the main text, supplementary information, or relevant data repository. Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected.

5. We note that your manuscript is not formatted using one of PLOS ONE’s accepted file types. Please reattach your manuscript as one of the following file types: .doc, .docx, .rtf, or .tex (accompanied by a .pdf).

If your submission was prepared in LaTex, please submit your manuscript file in PDF format and attach your .tex file as “other.

6. Please amend the title either on the online submission form or in your so that they are identical.

"Application of observational research methods to real-world studies for rare disease treatments: a scoping review protocol

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In the study protocol “Application of observational research methods to real-world studies for rare disease

treatments: a scoping review protocol,” the authors outline a methodology to identify observational research methods used over the past 5 years and evaluate their application. This work is relevant to those closely related to their field.

Minor revision suggestions:

• In the introduction, please place references 1 – 4 with the respective piece of information rather than all together at the end.

• Under exclusion criteria the authors state English as a language restriction. A scoping review should not technically have a language restriction. If this is appropriate in this case, it should be justified.

• Under exclusion criteria the authors mention that case reports and series will be excluded, however these are often also observational in nature; please clarify.

• Consider adding the use of a medical librarian to assist in setting up key words and concepts.

Reviewer #2: Title: Looks interesting and identifies the report as a scoping review protocol

Short title: Observational research methods for rare disease treatments (suggestion)

Abstract:

7000 different conditions looks like a huge number of diseases, are the authors looking at any specific diseases (it might be good to keep the diseases to one condition or specialty) for better results (suggestion).

Can the authors change their search duration till 2024?

Languages?

Will they consider implementation studies?

MEDLINE and EMBASE looks very narrow for this research question? Please consider adding subject specific databases, if none exist – please mention

Some terms like – observational research methods, rare disease would be helpful for readers and standardizing the terminology.

Competing interests:

Looks like MT has some conflicts of interests reported in a paper, this can be mentioned here in this paper as well?

“M. T. received financial support from the Canadian Agency for Drugs and Technologies in Health. M. T., T. A., and K. N. H. report a relationship with Canadian Agency for Drugs and Technologies in Health that includes consulting or advisory.”

(ref: Development of a Canadian Guidance for reporting real-world evidence for regulatory and health-technology assessment (HTA) decision-making., https://doi.org/10.1016/j.jclinepi.2024.111545. Journal pre proof)

If there are concerns with conventional RCTs it might be helpful to look at concerns related to efficacy, safety evidence too?

Can they address concerns with real world studies as well? They aren’t planning to look at RCTs.

Introduction:

Nice introduction.

It might be helpful to mention how observational studies may contribute to effectiveness in real world drug (line 97,98)

Can a reference be added for statement 107,108 please?

Imperative sounds too strong – can this very be changed to ‘might be helpful’. If its imperative, might as well perform RCTs?

Rare diseases – looks very broad, can the authors consider narrowing the participants?

Can they also explain and add some detail on the existing research methods for better understanding. And expand on the ‘information sources’ please. Add a note on grey literature search as well. Can they also add a note on how they will conduct their supplementary search (line 151-153) especially in relation to relevant literature searches.

Data management: How they will manage data using Excel is unclear, if they could explain which data will be managed it might be helpful.

The inclusion criteria need to be bit more robust and detailed to prevent any future concerns during the screening phase- hope the authors will consider the suggestion to make the criteria a bit more detailed.

Regarding missing data – line 219 to 220, is there are a time frame the authors will wait while they contact the study authors, any time frames for sending reminders?

Will they use Covidence for data extraction as well? Might be good to mention it here.

Data analysis and presentation:

It might be good to mention the type of quantitative and qualitative analysis that will be performed please?

Inclusion criteria: please explain the concept in detail to prevent ambiguity, like conditions or please consider adding an appendix

Context: the term ‘health administrative data’ sounds confusing please explain.

I am not sure how the authors are planning to search unpublished studies? Please expand the types of sources.

Others: Please consider updating the PRISMA ScR checklist based on the revision 1 protocol.

A few questions:

Not sure how they might be able to generate evidence on drug effectiveness or safety?

It might be good to explain real world effectiveness methods

Rare disease drugs and evaluation.

**********

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

**********

[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.

Application of observational research methods to real-world studies for rare disease drugs: a scoping review protocol

PONE-D-24-19336R2

Dear Dr. Patel,

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,

Kiyan Heybati

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: