PONE-D-20-02492

Hidden duplicates: At least 3 dozen Indian trials, registered with ClinicalTrials.gov, have not been registered in India, as required by law

PLOS ONE

Dear Dr. Saberwal,

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.

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Omid Beiki, M.D., Ph.D.

Academic Editor

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: Partly

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

Reviewer #1: Yes

Reviewer #2: N/A

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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: No

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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 aim of this study was to investigate whether all such trials registered with CTG, that included India as a location, also been registered with CTRI or not. The author reported three dozen of the 581 relevant CTG trials were not registered with CTRI.

The strength of this study was to investigate the theme extensively. However, there were some weakness in this study.

First, the authors had better to add references to the following sentences in Introduction: “The biggest public repository is that of the United States of America (US), ClinicalTrials.gov (CTG), which holds over 320,000 records. The International Clinical Trials Registry Platform (ICTRP), established by the World Health Organization (WHO), enables users to search 18 open-access registries, including CTG. These registries cumulatively hold over 550,000 records.”

Second, they had better to add references to the following recommendations in Conclusions: “Going forward, registries should make it compulsory to provide the Universal Trial Number. Alternatively, they should require trialists to provide the relevant ID if the study is registered elsewhere, or to confirm that it is not, and is unlikely to be, registered elsewhere. Further, the registry could coordinate with the drug regulator to compel trialists to provide this information, even retrospectively. If all registries enforce this, then it will go a long way in reducing the number of hidden duplicates, which inter alia will make it easier to identify whether or not the law has been broken in this manner.”

Third, they had better to add description about penalties if the law about trial registration in India is broken.

Reviewer #2: The manuscript by Kumari et al. “Hidden duplicates: At least 3 dozen Indian trials, registered with ClinicalTrials.gov, have not been registered in India, as required by law” uses an informatics approach to identify clinical trials with India as location that are registered with the US federal register ClinicalTrials.gov (CTG in the manuscript) but not the Indian Clinical Trials Registry (CTRI). The manuscript is written in a rather convoluted way and the significance of the findings is not quite evident.

Major concerns

1) The authors describe exclusion of what they call “Phase 1” from their analysis (Page 22, Line 316) but then they say they have included “Early Phase 1” (Page 22, Line 319). The difference is not clear and should be further explained.

2) The authors used 1) a training set of clinical trials for their algorithms and 2) several exclusion/inclusion criteria (e.g. studies posted to CTG after 2009) to come up with 581 studies registered in CTG with India as location and tried to determine the number so these trials that were also registered with CTRI. It is intriguing and worrisome that common hits from their two different algorithms were only 304 (52.3%). Although they claim “at least 3 dozen Indian trials” do not conform with the law, this number is not at all informative. Did they try to manually identify the 293 cases that are not common hits of their algorithms? They keep repeating in the discussion that 37-38 trials predicted to be registered only in CTG is a significant underestimate but no effort has been made to come up with a more precise number.

Minor concerns

1) Page 12, Lines 96-98: The sentence “57 records were common to the two searches, leaving 1013 unique trials that were registered in both databases (S1 Table)” should read “57 records were common to the two searches, leaving 1013 unique trials that were registered in either database (S1 Table)”.

2) Page 13, Line 114: Status should read “Recruitment status”

3) Several of the subheadings in the Results and Discussion sections are not informative (e.g. “The Year 2009”) and should be re-written.

3) The bibliography is sloppily written and I would suggest the authors make sure it is presented in a uniform style. Additionally, I would suggest the following substitutions/changes/additions.

Page 10, Line 63: Add reference (Zarin DA, Tse T, Williams RJ, Carr S. Trial Reporting in ClinicalTrials.gov - The Final Rule. N Engl J Med. 2016;375(20):1998-2004. doi: 10.1056/NEJMsr1611785. PubMed PMID: WOS:000387856100015) after the sentence “In the US, it is mandatory that the results of most trials be deposited in CTG within one year of completion of the trial.”

Reference 6: Substitute reference (Turner L. ClinicalTrials.gov, stem cells and 'pay-to-participate' clinical studies. Regen Med. 2017;12(6):705-19. doi: 10.2217/rme-2017-0015. PubMed PMID: WOS:000417040900014) for the “Washington Post” article.

Reference 7: This is a book by the National Academies Press (https://www.nap.edu/catalog/12900/transforming-clinical-research-in-the-united-states-challenges-and-opportunities), cite appropriately.

Reference 10: Add complete reference.

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Reviewer #1: Yes: Masahiro Banno

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 to be viewed.]

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PONE-D-20-02492R1

Hidden duplicates: 10s or 100s of Indian trials, registered with ClinicalTrials.gov, have not been registered in India, as required by law

PLOS ONE

Dear Dr. Saberwal,

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 Jul 17 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Omid Beiki, M.D., Ph.D.

Academic Editor

PLOS ONE

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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 #1: (No Response)

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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: No

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

Reviewer #1: 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

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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

**********

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 revised the manuscript extensively. However, I have some comments.

First, The authors had better to clarify when they visited the website in the following sentence of Introduction: “We have visited the websites of each of these registries, and determined that they cumulatively hold 598,746 records, with CTG holding 335,963 (56%).”

Second, they had better to add reference to the following sentence of Introduction: “We have visited the websites of each of these registries, and determined that they cumulatively hold 598,746 records, with CTG holding 335,963 (56%).” I consider the sentence need reference about the web site they visited. The example of reference is as follows: World Health Organization. International Clinical Trials Registry Platform (ICTRP): About the WHO ICTRP. 2019. Available at https://www.who.int/ictrp/about/en/. Accessed August 4, 2019.

Third, they had better to add justifications or references about the following each sentence (one by one) in Conclusions: “Alternatively, they should require trialists to provide the relevant ID if the study is registered elsewhere. If it is not, we suggest that trialists should explicitly confirm that the trial is not, and is unlikely to be, registered elsewhere. Further, the registry could coordinate with the drug regulator to compel trialists to provide this information, even retrospectively. If all registries enforce this, then it will go a long way in reducing the number of hidden duplicates, which, inter alia, will make it easier to identify whether or not the law has been broken in this manner.” They had better to add explanation or references to connect Discussion with these recommendations in Conclusions. I think these recommendations in Conclusions appeared abruptly.

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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: Yes: Masahiro Banno, MD, PhD

[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.

Hidden duplicates: 10s or 100s of Indian trials, registered with ClinicalTrials.gov, have not been registered in India, as required by law

PONE-D-20-02492R2

Dear Dr. Saberwal,

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.

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Kind regards,

Omid Beiki, M.D., Ph.D.

Academic Editor

PLOS ONE

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