PONE-D-22-27576Creation of an ustekinumab external control arm for Crohn’s disease using electronic health records data: a pilot studyPLOS ONE

Dear Dr. Rudrapatna,

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VR received funding from the UCSF Division of Gastroenterology (gastroenterology.ucsf.edu).

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"NS, NE, CC, SR, DA, MC, NSK, CO, NT, and BDM are employees of Janssen Pharmaceuticals, a for-profit entity that owns all rights to the drug ustekinumab. UM is a consultant for Janssen Pharmaceuticals. AJB is a co-founder and consultant to Personalis and NuMedii; consultant to Mango Tree Corporation, and in the recent past, Samsung, 10x Genomics, Helix, Pathway Genomics, and Verinata (Illumina); has served on paid advisory panels or boards for Geisinger Health, Regenstrief Institute, Gerson Lehman Group, AlphaSights, Covance, Novartis, Genentech, and Merck, and Roche; is a shareholder in Personalis and NuMedii; is a minor shareholder in Apple, Meta (Facebook), Alphabet (Google), Microsoft, Amazon, Snap, 10x Genomics, Illumina, Regeneron, Sanofi, Pfizer, Royalty Pharma, Moderna, Sutro, Doximity, BioNtech, Invitae, Pacific Biosciences, Editas Medicine, Nuna Health, Assay Depot, and Vet24seven, and several other non-health related companies and mutual funds; and has received honoraria and travel reimbursement for invited talks from Johnson and Johnson, Roche, Genentech, Pfizer, Merck, Lilly, Takeda, Varian, Mars, Siemens, Optum, Abbott, Celgene, AstraZeneca, AbbVie, Westat, and many academic institutions, medical or disease specific foundations and associations, and health systems.  Atul Butte receives royalty payments through Stanford University, for several patents and other disclosures licensed to NuMedii and Personalis.  Atul Butte’s research has been funded by NIH, Peraton (as the prime on an NIH contract), Genentech, Johnson and Johnson, FDA, Robert Wood Johnson Foundation, Leon Lowenstein Foundation, Intervalien Foundation, Priscilla Chan and Mark Zuckerberg, the Barbara and Gerson Bakar Foundation, and in the recent past, the March of Dimes, Juvenile Diabetes Research Foundation, California Governor’s Office of Planning and Research, California Institute for Regenerative Medicine, L’Oreal, and Progenity. The authors have declared that no competing interests exist."

  

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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: Partly

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

Reviewer #1: 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

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: 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: The authors made an effort to emulate the control arm of a clinical trial in Crohn's disease. I have two major concerns with this manuscript.

First, the concept behind is either contentious or not clear. Starting with the growing accepted concept that external control arms are needed in many situations like for example rare disease and many oncology settings, the paper's motivation appears to be that this concept should be extended to more common diseases because of the cost and complexity of running trials. I think this is very contentious. Randomization still has a value and should be pursued as much as possible. It does not seem justified that external control arms where clinical trials are feasible are justified. But the authors also appear to deviate from this concept in some other parts of the paper, as the concept of running this feasibility exercise is more loosely justified in terms of replacing "prospective" studies, and in some other places their rationale is about "complementing" other types of research. There should be clarity on the place where the authors see this. If the main justification is about replacing a phase III RCT for this kind of approach, I do not think it is a good scientific approach. If the idea is about post laungh evidence generation, or about adding to the totality of the evidence regarding new comparators, I think it will be more justitiable.

Analytically. the authors made a good effort but it falls short on many elements.

First, they did not fully replicate the arm in question, two exclusion criteria were left out. I do not know how the control arms can be emulated. It is not clear if this was an a priori or ex-post decision. Did they try first with all the criteria and numbers were too low or was this an a priori plan? And if it is an a priory plan, how can it emulate the control arm of the trial if these criteria were left out. If the interest was about emulating the control arm, we do not know if a full emulation is possible. Second, to show empirically that the emulation was close, they should present results comparing versus the trial. Actually they should have matched patients using trial data. But all these comparisons or analytical approaches are not in scope and are important. Finally, this is a single center attempt, we do not know if this approach would work for other centers. How dependent on the data quality of the center was this approach? How would it vary if attempting to do a multi-center emulation.

In conclusion, my advice is to deeply clarify the conceptual intent about the role of this exercise and provide more analyses that use the trial baseline information. In addition, generalizability should be explored. The paper, as is, minimally needs to clarify its conceptual intent and recognize analytical limitations. And in that case, it may be a better fit for a medical informatics journal.

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Reviewer #1: No

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Creation of an ustekinumab external control arm for Crohn’s disease using electronic health records data: a pilot study

PONE-D-22-27576R1

Dear Dr. Rudrapatna,

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,

Sreeram V. Ramagopalan

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

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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 #1: Yes

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

Reviewer #1: Yes

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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 #1: Yes

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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 #1: Yes

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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 #1: The authors addressed the comments transparently and the points in question are communicated clearly to the readers. The manuscript is in my opinion suitable for publication.

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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: Gerardo Machnicki

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