PONE-D-21-06687

A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

PLOS ONE

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PLOS ONE

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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: Yes

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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: The authors highlighted the important topic of treatment switching in clinical trials which makes conclusions about treatment effects difficult and should therefore be addressed more often. I thank the authors for bringing up a new possibility to handle this iusse.

I have only minor comments:

- How about an adaptive design ? (to i.e. assume another underlying distribution or amount of treatment swichtching)

- What about the robustness against the assumed underlying distribution (i.e. exponential distribution might often not be given) did you consider Weibull, Gompertz, log-lormal distributed data?

- What about a situation of crossing hazards?

- Which effect measure is best to go along with your test? What (time-dependent? ) effect measure would you propose?

- Did you consider what estimand framework the in the your paper described setting/test would refer to?

- In formula (1) (test hypothesis): Where is S0(t)>S1(t) included? (Not clear whether you have a one or two-sided hypothesis)

Reviewer #2: It is well-written paper and topic is also very important. The authors proposed an alternative weight method for WLR and showed the advantage over existing methods by simulation study. A motivative example is re-analyzed and demonstrate the potential usefulness of the new proposed method. The idea is clearly explained.

The simulations are done only with the case matching to the motivation example. I am not sure if the method is still working better for other situations. Maybe additional simulation can help to identify when the mWLR has more advantage.

The efficiency measure in formula (21) is the squared ratio between two statistics. Is there a reason/literature to choose this efficiency (why squared)? Is the ration of two powers more natural?

Minor points:

The asymptotic property of WLR is fine with fixed weights while mWLR used the weights related to the outcome, the asymptotic property still holds true?

Figure 1, it is better to put sample sizes for plot A, B, C in figure’s caption.

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Reviewer #1: No

Reviewer #2: No

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A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

PONE-D-21-06687R1

Dear Dr. Jiménez,

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,

Farzad Taghizadeh-Hesary

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

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 #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #2: 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

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 #1: I thank the authors for their detailed response. All comments were adequatley addressed and I have no further comments.

Reviewer #2: The revision well addressed reviewer's comments, statistical methods are explained clearly. It is an interesting topic and potential useful method in real application, especially with open source code included in the article (link).

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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 #1: No

Reviewer #2: Yes: Changxing Ma