Immunoglobulin Replacement Therapy is critical and cost-effective in increasing life expectancy and quality of life in patients suffering from Common Variable Immunodeficiency Disorders (CVID): A health-economic assessment

Philippe van Wilder; Irina Odnoletkova; Mehdi Mouline; Esther de Vries

doi:10.1371/journal.pone.0247941

Peer Review History

Original SubmissionAugust 12, 2020
24 Nov 2020 Decision Letter - Kednapa Thavorn, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-20-23871 Immunoglobulin Replacement Therapy is critical and cost-effective in increasing life expectancy and quality of life in patients suffering from Common Variable Immunodeficiency Disorders (CVID): A health-economic assessment PLOS ONE Dear Dr. de Vries, 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 Jan 08 2021 11:59PM. 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Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 3. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 2 in your text; if accepted, production will need this reference to link the reader to the Table. [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: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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 manuscript is very good writing. Here are my concern and comments as follow; 1. I was wondering why you chose 5 years for study delayed in diagnostic? Because you mentioned that CVID-patients would face a median diagnostic delay of 4 years. 2. The mortality was derived from the studies those are quite old. I was wondering if there is the mortality from recent study available that would be better. 3.Reference No. 16 Line 434 "Accessed June 9th, ... via"Please specify the year you accessed the reference. Reviewer #2: This is a well written paper that aims to provide new information in an under-researched area: cost-effectiveness and cost-utility of immunoglobulin replacement therapy in patients with common variable immunodefiency disorder. Minor revision only is recommended. Abstract: Line 44: ‘imput’ should be spelt ‘input.’ General comment on mathematical model vs economic model. Given this paper is about cost utility/cost effectiveness, please use health economic model and delete ‘mathematical’ model. It is confusing to the reader, as it appears they are different models, but it’s just an inconsistency in language. Methods/Results: Line 189: please provide justification for the assignment of distributions selected (gamma, beta etc). It is unclear what software was used to undertake the modelling, please state. It is unclear if the same patient numbers started in each health state for the delayed intervention model. Please clarify. The analysis was undertaken from a health care system perspective, but it is unclear which healthcare system (ie: the country), please state. It is unclear if any adjustments were made to costs (inflation or conversion), please provide this information in Table S2 and/or S4. ****** 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. 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Revision 1
7 Dec 2020 Author Response Journal Requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. We have checked our manuscript and adapted it according to the ‘manuscript body formatting guidelines’ and the ‘title, author, affiliations formatting guidelines’. 2.Thank you for stating the following in the Competing Interests section: [I have read the journal's policy and the authors of this manuscript have the following competing interests: both EdV and PvW received funding from PPTA to perform the work. EdV has received a research grant from Shire/Takeda for performing independent research on unclassified antibody deficiency.]. "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” Please include your updated Competing Interests statement in your cover letter. We have complied with these requests. 3. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 2 in your text; if accepted, production will need this reference to link the reader to the Table. We have corrected this omission. Reviewer #1: This manuscript is very good writing. We thank the reviewer for his/her positive evaluation of our manuscript. Here are my concern and comments as follow; 1. I was wondering why you chose 5 years for study delayed in diagnostic? Because you mentioned that CVID-patients would face a median diagnostic delay of 4 years. We are grateful to the reviewer to mention this apparent inconsistency. In the source that we used for estimating the diagnostic delay (ESID Registry study (2018)), it is indeed mentioned that the median delay was 4 years. Accordingly, in the text we corrected and replaced all the results obtained for a delay of 5 years by the results obtained for a delay of 4 years. The conclusion may remain as formulated because, as we mentioned in the manuscript, the ICER/ICUR was fairly robust when we changed the duration of the diagnostic delay in a univariate sensitivity analysis. 2. The mortality was derived from the studies those are quite old. I was wondering if there is the mortality from recent study available that would be better. The mortality data for the control group (< 100mg/kg of IgG) were derived from the MRC-study which was indeed published more than 4 decades ago; in our literature study we did not find a more recent study describing mortality for untreated CVID-patients. We assume that the widespread use of IgG became standard practice for CVID-patients in the years after the MRC-study, making more recent randomized trials with an ‘untreated’ control group unethical. For the IgGRT-group we used the Cunningham-Rundles study published in 1999; more recently, the ESID Registry study (2018) also provided estimates of mortality on IgGRT (with a lower mortality risk than in the Cunningham study). In our manuscript we have chosen to keep the Cunningham reference and to use the ESID-data in a sensitivity analysis. To correct and update the old mortality estimates, we reduced the CVID treatment specific mortality rates (MR) by comparing the mortality rates of the general population (gen pop) in the distinct time periods: new MRCVID = old published MRCVID x (recent MR gen pop / old MR gen pop) We have added this last sentence to the manuscript. 3.Reference No. 16 Line 434 "Accessed June 9th, ... via"Please specify the year you accessed the reference. The year we accessed reference 16 was 2020: we corrected the reference accordingly. Reviewer #2: This is a well written paper that aims to provide new information in an under-researched area: cost-effectiveness and cost-utility of immunoglobulin replacement therapy in patients with common variable immunodefiency disorder. Minor revision only is recommended. We thank the reviewer for his/her positive evaluation of our manuscript. Abstract: Line 44: ‘imput’ should be spelt ‘input.’ We have corrected this. (NB: because of other adjustments, the line numbers have changed somewhat.) General comment on mathematical model vs economic model. Given this paper is about cost utility/cost effectiveness, please use health economic model and delete ‘mathematical’ model. It is confusing to the reader, as it appears they are different models, but it’s just an inconsistency in language. We have complied with this request. Methods/Results: Line 189: please provide justification for the assignment of distributions selected (gamma, beta etc). The specific distributions linked to transition probabilities, to cost elements and to utilities have been selected based on the modeling methods described in: Richard Edlin, Christopher McCabe, Claire Hulme, Peter Hall, Judy Wright. Cost Effectiveness Modelling for Health Technology Assessment. A Practical Course. Adis (2014) ISBN 978-3-319-15743-6 ISBN 978-3-319-15744-3 (eBook) DOI 10.1007/978-3-319-15744-3. This document is available in the public domain and we have now provided it in S1 Appendix. We used bèta distributions for transition probabilities, as proposed in chapter six, gamma distributions for cost estimates, as described in chapter seven, and bèta distributions for utilities (or disutility if utility should encompass 0), see chapter seven. We have included this information in the Methods section. It is unclear what software was used to undertake the modelling, please state. The data used in the health economic model were managed in 2 software programs. Basic data manipulations, e.g., converting probabilities to rates, in Microsoft Excel 2016; advanced data management, Boolean logic, algorithm for Monte Carlo simulations, and programming documentation in IBM SPSS Statistics 26. The base-case ICER-computations were done in parallel in both software programs to check the calculation accuracy. We have included this information in the Methods section. It is unclear if the same patient numbers started in each health state for the delayed intervention model. Please clarify. The distribution at start across the distinct health states for the delayed intervention group is identical to the distribution in the other control groups; we did not find relevant data to decide otherwise. We have added this information to Table 2. We assume this is a conservative assumption because more patients may be in a more severe health state due to the delay. Thus, our results might underestimate the value of IgGRT. The analysis was undertaken from a health care system perspective, but it is unclear which healthcare system (ie: the country), please state. The study is based on data from the literature, originating in many different countries. We used estimates of direct medical costs from the literature, mostly from various countries in the Western European region but also from other geographic regions. Thus, the supporting data mainly originate from countries with a well-developed public healthcare funding in the healthcare system. This is mentioned in the Discussion section. It is unclear if any adjustments were made to costs (inflation or conversion), please provide this information in Table S2 and/or S4. The cost estimates came from various geographic sources. Considering the regional diversity in cost estimates, we built a core health economic model, in which the published cost data were used and converted to actual value in Euro, rounded to the upper 100 Euro level. We believe more accurate estimates per health state are needed in country-specific analyses for country-specific use; but a country-specific health economic analysis would require checking the country-specific databases and tariffs which goes beyond the purpose of our study. We compensated the uncertainty in our estimates by performing sensitivity analyses on the efficiency impact of changing the cost estimates of: - the immunoglobulin G replacement therapy - the health state ‘major infections’ - the health state ‘auto-immune disease’ - the health state ‘chronic lung disease’ - the health state ‘cancer’ In our analyses, the cost parameter estimates were varied as follows: Results from Monte Carlo simulations on cost estimates IgGRT Infection Major Auto-immune disease Chronic Lung Disease Cancer Mean 1.663 8.991 329 453 600 Median 1.656 8.976 328 452 599 Minimum 1.065 6.520 234 303 448 Maximum 2.227 12.079 453 584 818 We believe the range used in our estimates should compensate for the relative lack of precision of the cost estimates per health states, due to geographical variation. This information was added to S4 Table. Attachments Attachment Submitted filename: CVID_PlosONE_HTA_ResponseToReviewers_DEF.pdf https://doi.org/10.1371/journal.pone.0247941.r002
17 Feb 2021 Decision Letter - Kevin Lu, Editor Immunoglobulin Replacement Therapy is critical and cost-effective in increasing life expectancy and quality of life in patients suffering from Common Variable Immunodeficiency Disorders (CVID): A health-economic assessment PONE-D-20-23871R1 Dear Dr. de Vries, 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. 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, Kevin Lu, PhD 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 ******** 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 ****** 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 ****** 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: (No Response) ****** 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 https://doi.org/10.1371/journal.pone.0247941.r003
Formally Accepted
24 Feb 2021 Acceptance Letter - Kevin Lu, Editor PONE-D-20-23871R1 Immunoglobulin Replacement Therapy is critical and cost-effective in increasing life expectancy and quality of life in patients suffering from Common Variable Immunodeficiency Disorders (CVID): A health-economic assessment Dear Dr. de Vries: 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 Professor Kevin Lu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0247941.r004

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