Peer Review History
| Original SubmissionJune 1, 2022 |
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PONE-D-22-15922Information about confirmatory studies required for new drugs conditionally approved by Health Canada: a cross-sectional studyPLOS ONE Dear Dr. Lexchin, 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. First of all, I would like to thank the two reviewers for their important feedback. I'm following their opinion and suggest major revisions. as both agree on this recommandation. Please also note that one reviewer was very critical about the study. I agree that more details are needed, especially concerning the methods and the results. Of course, you are expected to take all the comments from the 2 reviewers into consideration in your revised manuscript but please have a very strong focus on the methods and the results, in order to make sure that all important aspects for reproducibility purpose are present. The use of one or more reporting guideline may help (see on the EQUATOR NETWORK). In case more material needs to be share, it can be attached as a supplement or posted on the Open Science Framework. Please also note that without an appropriate consideration of the major edits that are required, I cannot guarantee publication. Please also make it explicit if a protocol was registered for this study (and where) and in case, no, please add a few words about that in the limitation section. Please also write a few words about the main limitation in the abstract to avoid any spin. Please submit your revised manuscript by Sep 04 2022 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:
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, Florian Naudet, M.D., M.P.H., Ph.D. Academic Editor PLOS ONE 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 2. Thank you for stating the following in the Competing Interests section: In 2019-2021, Joel Lexchin received payments for writing a brief on the role of promotion in generating prescriptions for Goodmans LLP and from the Canadian Institutes of Health Research for presenting at a workshop on conflict-of-interest in clinical practice guidelines. He is a member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare. He receives royalties from University of Toronto Press and James Lorimer & Co. Ltd. for books he has written. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. 3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. [Note: HTML markup is below. Please do not edit.] 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 Reviewer #2: No ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ********** 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 ********** 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 ********** 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: This study is a cross-sectional study assessing the quality of the reporting of data regarding the design of confirmatory studies that were requested after a conditonal approval granted by Health Canada (under the Notice of Compliance with condition (NOC/c) policy). Information (patient demographics, design, outcomes, expected date of completion, record of information for allowing the retrival of published data of the completed confirmatory studies) at the drug and study level are supposed to be provided under the Qualifying Notices policy. Data were retrieved for drugs for which a NOC/c was granted since the begining of the program until May 2022 (with request for filling a Qualifying Notice (QN) starting in 2003 and the primary outcome for approving new drugs recorded since 2005). The study also compares the type of primary outcome (i.e., clinical, surrogate) between the study that led to NOC/c and the expected outcome in the confirmatory studies. The main result is the fact that information are frequently lacking regarding most aspects of confirmatory studies (patient demographics, study designs, outcomes) and confirmatory studies are frequently eexpected to be conducted on surrogate outcomes. In its current stage, the reported information hampers the possibility for clinicians and patients to understand if confirmatory studies will alleviate or not uncertainties regarding treatment efficacy. The conclusion is the need for a standardized reporting of these aspects by Health Canada. Overall, the methodology of the study seems sound, but I had troubles understanding what is the specific definition of the sample of drugs that were analyzed and I had troubles to understand if the info that were analyzed were info about what the confirmatory studies were expected to be before completion, or info about how confirmatory studies were indeed conducted. I'm confident the confusion I've experienced is just a matter of clarification withhin the text and not due to design flaws, so I'm confident it will be easily resolved. However, currently, I was not able to fully understand what truly the findings of the study are about. I will try to pinpoint below why I've experienced this confusion. The study analyzes 78 drugs with NOC/c that were granteds since the begining of the program. It is specified it is ddivided into 39 drugs for which the condition of the program were "fullfilled", 34 were "unfulfilled" and 5 drugs were discontinued from the market before fullfilling their conditions. But what does "fullfilled" and "unfullfilled" really mean? At first, I was under the impression "fullfilled" means the confirmatory study was completed AND the drug was granted a full NOC. Thus, "unfullfilled" means the confirmatory study was completed AND the drug failed to obtain a full NOC. But, tha data analysis section indicates "the median number of days from granting the NOC/c until fullfillment or until May 18, 2022 (date of database lock) for drugs that had not fullfilled their conditions was estimated". Therefore, does it means "fullfilled" only describes drugs for which confirmatory studies were completed whether the results were positive or not, and "unfullfilled" only describes drugs for which the confirmatory study is still under conduct? This aspect needs to be clarified for understanding what is the definition of the "population" analyzed in the study. Of note: I have looked reference nuimber 6 of the paper which indicates a sample of 89 new drugs and new indications with NOC/c untile May 2017. I understand the present study does not analyze new indications, but still why only 78 drugs if this study covers a period untile May 2022? Moreover, I was confused about the nature of the info that are recorded under under the Qualifying Notices policy. Does those info are only about what will be the confirmatory studies as provided by the health technology manufacturer when granted a NOC/c (therefore prospective info about what will be done) or is it retrospective info on how the confirmatory studies were indeed conducted, or is it a mix of both? Indeed, the study tackles data such as expected date of completion (therefore info about what the confirmatory study will be conducted), but also compares outcomes of the initial study leading to NOC/c and outcomes expected in confirmatory studies (the word expected seems to imply the info for confirmatory studies are info about what will be expected and not what has been done, but I was not sure which one it really was). But, the study also tackles info about patient demographics and sample size. Here, I was under the impression the study is about info on how the confirmatory studies were really conducted and collected after completion. In the end, I think the paper needs to clarify what's what in order to be fully able to understand the results. I will now discuss more specific details. I/INTRODUCTION The date of the begining of the NOC/c program could be clearly specified. Page 5. After the first paragraph, I think the eligibility criteria a drug needs to fullfill for the NOC/c program could be specified in accordance with the Health Canada website in addition to the goal of the program. Page 5. It is specified that before February 2003 QN did not exist and info were provided into a letter of understanding. Therefore, does it makes sense to analyze drugs since the begining of the NOC/c program instead of the begining of the request for a QN? Was it expected the same info were requested under the letter of understanding policy? Page 6. Please, specify why QNs for new indications were excluded from the study. II/ METHODS What was the criteria for deciding an outcome was a clinical or surrogate one? On a related note, the method should clearly states data were only retrieved and analyze by one person, therefore there were no methods for reducing measurement biases such as inter-rater agreement. III/ RESULTS In general, does "undetermined" characteristics (such as study outcome, randomization) corresponds to missing data, or data that were not reported with sufficient clarity for understanding the info, or a mix of both? I think the paper could benefit from a little more detail about this aspect. Reviewer #2: The paper authored by Joel Lexchin throws a glance on regulatory decisions and requirements following conditional or accelerated approval of drugs in Canada. In a cursory approach, 78 conditional approval decisions by Health Canada were retrieved from the regulator’s website and other sources, which are not detailed. Names of the specific drugs, year of conditional approval, or the manufacturer are not provided. This article does not contribute new insights to the scientific debate on how shifting clinically important efficacy and safety assessments from before to after authorization affects our ability to obtain an unbiased assessment of the risk-benefit ratio and safety of newly developed drugs (1-4). Meanwhile, there are many reports that post-authorisation studies often fail to deliver—lots of studies are never started, many take years longer than planned, and some fail to confirm pre-authorisation results. Evidence on relevant outcomes often remains inconclusive for several years, (5-7) and post-authorisation safety events are seen more frequently for drugs with expedited approval.(8) The sketchy findings presented by Lexchin suggest that Health Canada seems to accept that the manufacturers are not adhering to post-authorisation study requirements, and drugs are only rarely withdrawn, as was described before.(2) The paper has major limitations. Methods, results and conclusions are not well founded. It is unclear how drugs approved under the NOC/c policy were identified and how exactly the information on QNs was retrieved and compiled in which time period. The tables are not clear and uninformative to the reader, totals are missing. In table 1, the calculation of total study numbers is N=70 for “Outcome” and “Randomization” but 69 for “Blinding”. A descriptive table of availability of main characteristics for each of the 78 QNs (e.g. number of studies, study identification, duration of conditional approval procedures, drug name and class, number, age and sex of participants, date of conditional approval, and outcome measures in NOCs and QN) is not provided. The result section is vague and does not attempt to look for potential associations, e.g. between missing information and drug class or duration of conditional approval. The conclusion to call for a regulatory template for “confirmatory studies” is weak. Does the author think that manufacturers would better adhere to regulatory templates than to QNs and why should they? Would regulators be more restrictive by using the templates instead the QNs and why should they? Rather, the integrity of accelerated/conditional approval should be discussed. Is there really a justification for curtailing or totally omitting Phase III trials ? Take Covid-19 mRNA vaccines as an example: After a median of only 2 months follow-up, the pivotal Phase III studies were unblinded and placebo-group participants were offered vaccination, thereby introducing bias which may severely impair the comparability of vaccinated and non-vaccinated participants in the remaining observation time of the study. In light of the many unknowns of Covid-19 mRNA vaccine efficacy and safety, stopping the randomized trials at the time of conditional/ emergency approval violates basic principles of good medical practice. (9) A very recent independent analysis of adverse events summary tables submitted to the FDA for emergency use approval shows that the risk of severe adverse events of special interest after mRNA vaccination exceeds the benefit risk reduction of hospitalization due to Covid-19. The authors call for a “systematic review and meta-analysis using individual participant to address questions of harm-benefit in various demographic subgroups. Full transparency of the COVID-19 vaccine clinical trial data is needed to properly evaluate these questions. Unfortunately, well over a year after widespread use of COVID-19 vaccines, participant level data remain inaccessible.” (10) Therefore, my conclusion is to omit conditional approval wherever possible. Access to Individual participant data (IPD) should be granted for independent scrutiny for all drug approval pathways. 1) Dawoud D, Naci H, Ciani O, Bujkiewicz S. Raising the bar for using surrogate endpoints in drug regulation and health technology assessment. BMJ2021;374:n2191. doi:10.1136/bmj.n2191 2) Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA2017;318:626-36. doi:10.1001/jama.2017.9415 3) Moore TJ, Furberg CD. Development times, clinical testing, postmarket follow-up, and safety risks for the new drugs approved by the US food and drug administration: the class of 2008. JAMA Intern Med2014;174:90-5. doi:10.1001/jamainternmed.2013.11813 4) Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA2020;323:164-76. doi:10.1001/jama.2019.20288 5) Davis C, Naci H, Gurpinar E, Poplavska E, Pinto A, Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ2017;359:j4530. doi:10.1136/bmj.j4530 6) Beaver JA, Howie LJ, Pelosof L, et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol2018;4:849-56. doi:10.1001/jamaoncol.2017.5618 7) Gyawali B, Hey SP, Kesselheim AS. Assessment of the clinical benefit of cancer drugs receiving accelerated approval. JAMA Intern Med2019;179:906-13. doi:10.1001/jamainternmed.2019.0462 8) Downing NS,Shah ND, Aminawung JA, et al. Postmarket safety events among novel therapeutics approved by the US Food and Drug Administration Between 2001 and 2010. JAMA2017;317:1854-63. doi:10.1001/jama.2017.5150 9) Prugger, C., Spelsberg A., Keil U. et al. Evaluating covid-19 vaccine efficacy and safety in the post-authorisation phase. BMJ 2021;375:e067570 10) Fraiman, J. Erviti J, Jones M. et al. Serious adverse events of special interest following mRNA vaccination in randomized trials. https://ssrn.com/abstract=4125239 ********** 6. 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: Angela Spelsberg ********** [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. |
| Revision 1 |
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PONE-D-22-15922R1Information about confirmatory studies required for new drugs conditionally approved by Health Canada: a cross-sectional studyPLOS ONE Dear Dr. Lexchin, 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. Sorry for the delay in answering, but -as I have answered to your information request to PLOS One last month- one of the reviewer required more time to perform his review for personal reasons that I totally understand. In addition, I needed the feedback from this reviewer to arbitrate as the other reviewer was quite unhappy with your revisions and asked to reject the paper. The second reviewer who has just answered, as promised, asked for minor revisions. I am also satisfied with the changes made in response to my own comments. However I wanted to discuss the case with PLOS One staff before making my final decision, facing those 2 divergent reviews. It took a few additional extra days. After this process, and considering the comments of the 2 reviewers, I ask you a new round of major revisions. Indeed, I do think that the comments by the 2 reviewers can be fixed by a new round of revisions and that the points raised by the critical reviewer can be addressed. I would be therefore very happy to consider a new version of this manuscript. I will likely invite a new reviewer for the next round. I agree that it is a long journey for a paper but, I also think that it will make it even better. Importantly, I would like to thank both reviewers for their comments. Please submit your revised manuscript by Nov 12 2022 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:
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, Florian Naudet, M.D., M.P.H., Ph.D. Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] 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) Reviewer #2: (No Response) ********** 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: No ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ********** 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: (No Response) 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. 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: Overall, the revised version of the draft has alleviated the issues that I have raised in my previous review. Minor remarks: Introduction: I suggest to reword the sentence "Most approvals are based on promising surrogate outcomes" by "Most approvales are based on surrogate outcomes assumed to be validated for surrogacy". Indeed, it is discussed later that the validity of numerous surrogate outcomes can be doubtfull. However, the current version of the sentence seems to imply all surrogate outcomes are promising. Results section: There are still occurence within the manuscript and tables of the term "undetermined" instead of "unknown". Discussion page 17: There may be a typo in the sentence "whereas 14 were being tested in studies with further surrogate outcomes". Should it be 44 instead of 14? Conclusion: The new begining of the conclusion could be modified a little to be more accurate regarding the findings. Indeed, the findings are striking regarding the lack of information in the QNs, but maybe the conclusion is not as strong as "virtually no one... has any knowledge...." because sometimes there are information. Reviewer #2: Thank you for revising the manuscript and addressing critical points, particularly providing the supplementary table with key information on the 78 drugs conditionally approved between 1998 and 2022 . From this table follows that: 1. The -use of conditional approval pathways is increasing There were only 34 NOCs issued during the first 17 years between 1998 and 2014, i.e. roughly 2 per year. In contrast, between 2015 and 2021, 43 drugs were conditionally approved, about 6 drugs per year 2. Conditionally approved drugs are increasingly focusing on lucrative cancer treatment From 1998 through 2014 there were 6 NOC/c on drugs for HIV treatment, 19 for cancer, and 9 for the treatment of mixed conditions. During 2015-2021, all 43 except one were oncology drugs. 3. Drug withdrawals in conditionally approved pathways decrease Four of 34 conditionally approved drugs between 1998 and 2014 were withdrawn, among them the prominent example natrecor ®, an expensive „innovative“ drug for acute congestive heart failure which was shown to be a killer of patients by independent scientific evaluation of primary trial reports to the FDA and from the manufacturer (Sackner-Bernstein JD et al. JAMA 2005;293:1900-1905). After 2015, only one drug out of 43 was withdrawn by the manufacturer. From the perspective of clinicians, it would be more informative to describe which 8 drugs had missing QNs, which drugs or drug class had no information on outcome (38), randomization (33) and blinding (39), for which drugs or drug class the number of patients and their ages (23) and surrogate outcomes were available(52) and for which drugs or drug class outcomes could not be determined (30). According to the author, the aim of the paper is “to resolve uncertainties about the benefits of drugs with a NOC/c”. I do not see how the proposed templates can basically improve the sobering reality of conditional/expedited approval pathways. The rationale for ommitting phase III pivotal trials i.e. to provide innovative treatments faster to patients with life-threatening illnesses must be questioned. Innovation does not automatically imply more good than harm. The conditional approval pathway puts patients, doctors, and society at high risks of no or marginal benefit and severe undiscovered adverse events at extremely high costs. In my opinion, scientists have to speak up against this bad clinical practice jointly committed by regulators and manufacturers. ********** 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: Angela Spelsberg ********** [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. |
| Revision 2 |
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PONE-D-22-15922R2Information about confirmatory studies required for new drugs conditionally approved by Health Canada: a cross-sectional studyPLOS ONE Dear Dr. Lexchin, 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. As I have said previously, I have invited a new reviewer to assess the manuscript because of the discrepancies between the 2 previous reviewers. I really would like to tank the reviewer for being so fast in reviewing the manuscript. He made a few comments that can be easily addressed in a round of revisions. I look forward to reading your manuscript. Please submit your revised manuscript by Nov 24 2022 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:
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, Florian Naudet, M.D., M.P.H., Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] 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 #3: (No Response) ********** 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 #3: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: N/A ********** 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 #3: 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 #3: 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 #3: Thank you for the opportunity to review this manuscript on the information about confirmatory studies required for new drugs conditionally approved by Health Canada. Overall, this manuscript is methodologically sound, easy to read and understand, and suitable for publication. However, I have a few comments that will further increase clarity: Abstract Methods: “A list of drugs approved under the NOC/c policy and their QNs were sourced” .. please report from where? Abstract Results - Provide time-frame for 78 drugs approved using NOC/c (dates) - Provide median number of studies per drug with IQR - Should say proportion of men and women? - Where is information about other aspects of methodology that are considered primary endpoints? Abstract Discussion “Confirmatory studies with surrogate outcomes were often used to validate efficacy in drugs initially approved using surrogate outcomes” – often may not be the right word, considering it is <30%. Introduction: - Missing reference for “provide patients suffering from serious….” - The author mentions that prior to 2/2003 the QN did not exist? The abstract and results section of the manuscript can be improved by more transparent reporting of dates - Some of the objectives in the introduction are not discussed in the abstract – when will the studies be completed and is there enough information about the studies that will enable them to search for and read the studies - The final paragraph of the introduction seems like a methods section paragraph Results: - The reporting of characteristics at the QN level is rather confusing. I think the following reporting system could improve clarity: � At least one study randomized vs. no studies randomized � At least one study blinded vs. no studies blinded � At least one clinical outcome vs. no clinical outcomes - Table 1 is a little difficult to follow. Please see suggestion above. Methodology in individual studies - Please report %’s (e.g. 99 (X%)) for the numerators - Table 2, please report %’s Patient demographics - What about race/ethnicity or age? Other information - Please report %’s Discussion - In the opening of the discussion, please recap study design, time, and sample. E.g.. In this cross-section study of XXXXX…..between XXX and XXXXX, - The opening of the discussion highlights an outcome that was not included in the abstract and therefore does not appear to be a major finding – the information to identify studies. - What are SBD documents? - The author could consider referencing https://www.bmj.com/content/361/bmj.k2031 , which focuses on the lack of information including in descriptions of postmarketing requirements for FDA-approved drugs. (disclosure: I am an author on this manuscript, so please do not feel any pressure to reference this paper. I just thought it had some similar and interesting findings). ********** 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 #3: 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. |
| Revision 3 |
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Information about confirmatory studies required for new drugs conditionally approved by Health Canada: a cross-sectional study PONE-D-22-15922R3 Dear Dr. Lexchin, 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. Thank you for taking the time to address all the reviewer's comments. Please note a typo in table 1 that you will have to correct at the proof stages (a parenthesis ")" is missing after 20%). 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Florian Naudet, M.D., M.P.H., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: |
| Formally Accepted |
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PONE-D-22-15922R3 Information about confirmatory studies required for new drugs conditionally approved by Health Canada: a cross-sectional study Dear Dr. Lexchin: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Pr. Florian Naudet Academic Editor PLOS ONE |
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