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PONE-D-21-08607Guidance for pediatric use in prescription information of novel therapeutics in the EU and the USPLOS ONE

Dear Dr. Christiansen,

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: Yes

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: Dear Authors,

I have read your manuscript and I think that t is very well written, and references are well reported. The limitations of the study have been also described.

Therefore I have not comments regarding it

Reviewer #2: The comparison of the pediatric information provided in drug labels across the EU and the US covered in this paper is an incredibly valuable contribution given differences in pediatric regulations and incentives across these two regions. The findings of the paper are fascinating – it seems reasonable to begin with a prior that because of the broader scope of drugs and conditions covered by EMA regulations relative to FDA regulations, more information and more guidance would be provided in the EU. However, the authors find differences in information provided across the two regions, with an equal share of indications having more guidance in one region relative to the other. I would also like to applaud the authors for what must have been an extensive and careful data collection exercise. I have listed below a few major suggestions that I believe will strengthen the conclusions of the paper and a few more minor comments after that (mostly stylistic comments and suggestions related to clarity).

Major comments

• I find the three possible levels at which statistics are reported in this paper slightly disorienting, especially since the authors discuss in the data section that they map indications to disease/conditions, which makes it seem that the level of analysis is disease/condition. This is also the level of analysis that the authors state in their analysis section, and yet we only see statistics for drugs and indications. It would be helpful to use consistent terminology across the paper and in the results. Even when reporting both statistics for drugs and indications (or diseases/conditions), the emphasis should be on indications (or diseases/conditions) since that appears to be the main level of analysis.

• While I broadly agree with the tiered categories used for pediatric guidance, I also recommend adding a category on dosage or pharmacokinetic/pharmacodynamic studies. Many pediatric studies in the US may not focus on determining safety/efficacy but rather dosage or pharmacokinetics and pharmacodynamics, making it an important dimension of information to consider for comparing drug labels across the two regions.

• It’s not clear to me that the mandate covers more drugs/indications in the EU relative to the US and that we should expect differences in guidance across the two regions because of the BPCA. The authors do point out that the BPCA in the U.S. is designed so that studies can be requested for orphan drugs and other indications that are exempt under PREA. It is worth investigating the BPCA role further.

o First, to assess differences in guidance resulting from factors outside of the scope of PREA vs. PIP, please report the level of discrepancies and where discrepancies lie when excluding orphan drugs and pediatric indications outside of the adult indication. This would directly inform how much of the observed discrepancies are due to regulatory agency interpretation or approach, level of information provided, etc. rather than differences in where studies are requested across the two regions.

o How many of the drugs with more guidance in US were covered under PREA but have more information because of BPCA? The authors can add information on issued written requests under BPCA (which are publicly reported by the FDA) and how much of the observed discrepancies between EU and the US are reduced due to the BPCA.

• Are there any systematic differences in which types of drugs have more info in EU vs. which drugs have more info in the US? I would move Table 2 to appendix and add a table summarizing drug categories, disease categories, or sponsors where there seem to be differences.

Minor comments

• The quality of images for Figures 1 and 2 is low, making the figures illegible. It would be great if the authors could provide better quality images or figures.

• Please list in the data section the ages used for each pediatric group.

• Within each pediatric age group, I assume that the authors considered a given level of guidance as present in that age group if guidance was provided for any age within that group. For example, if guidance was provided for ages 15-17, then this would count as having adolescent use guidance, even if only providing guidance for a partial age range of the full adolescent age range. If I have understood this methodology correctly, it would be great to have this information included in the data section.

• A stylistic suggestion – in the abstract, a “broader mandate” sounds ambiguous because it is not obvious what the breadth refers to. “Mandate of a broader scope” or a version of this wording to indicate that the EMA can require pediatric assessments in more cases than the FDA might be clearer.

• In the abstract, it takes a few reads to understand that the focus is on indications listed as of March 2020 for products approved 2010-2018. Please make the wording clearer.

• Throughout the paper, “higher level of guidance” is slightly odd to use because guidance is either provided or not, but the level of information in the guidance can differ. I would recommend using terminology referring to the information levels rather than guidance levels (e.g., “more information” or “higher level of information”).

• Throughout the paper, the authors should use “an equal share” instead of “an equal distribution” for simplicity and clarity.

• Line 77 typo: Cross jurisdiction investigations is important � Cross jurisdiction investigations are important.

• I would recommend either moving to appendix or fully excluding the analysis, comparison, and discussion of withdrawn products since it detracts from the main point of the paper (unless these are products who were withdrawn due to issues in the pediatric population, in which case please discuss these).

• To tie the results in directly to the motivation on different regulations across the two regulations, it would be great to mention in the abstract that only 21% of discrepancies in pediatric information can be explained by differences in regulations.

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Reviewer #1: No

Reviewer #2: No

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Guidance for pediatric use in prescription information for novel medicinal products in the EU and the US

PONE-D-21-08607R1

Dear Dr. Christiansen,

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,

Carlo Torti

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 #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: (No Response)

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

Reviewer #2: (No Response)

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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: (No Response)

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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: (No Response)

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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: (No Response)

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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