Medicine manipulation: An alternative to mitigate therapeutic gaps in the Brazilian Unified Health System?

Gabriel Gonçalves Okamoto; Kathiely Martins dos Santos; Luma de Lira Nogueira; Guilherme Martins Gelfuso; Rafael Santos Santana

doi:10.1371/journal.pone.0276785

Peer Review History

Original SubmissionMay 28, 2022
1 Sep 2022 Decision Letter - Paola Brusa, Editor PONE-D-22-14777Medicine manipulation: an alternative to mitigate therapeutic gaps in the Brazilian Unified Health System?PLOS ONE Dear Dr. Santana, 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 Oct 06 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. 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We will update your Data Availability statement to reflect the information you provide in your cover letter 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): I thank the authors for reading their paper: masgistral preparations are still very necessary in many countries. The paper need minor revisions before to be publish. [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: 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: 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: The manuscript is acceptable in the current form. The authors have used multiple methods to provide an detailed methodology, analysis, and results on medical manipulation for mitigating gaps in therapeutic provision in the Brazilian Health System. Reviewer #2: This is a novel, important breakthrough paper. The objective is honorable in securing treatments needed for many diseases of poverty and in children. The abstract does not define the SUS acronym and it would be better referred to in general as the Brazil health system in the abstract. When the abstract describes “national production” it should specify Brazil as the nation. The abstract is missing some of the most exciting motivations and results of the paper. You could add for example "The study prioritized candidate drugs for cost-effective local manufacturing in a Brazil laboratory to fill unmet needs in the population... We found the absence of a standard formula for production was most often in indications for poverty-related diseases." The terminology of “magistral medicines”, “magistral production”, and “manipulation” need to be defined early in the introduction. Do the authors refer to production at a central facility or does this also include manipulation at the pharmacy level? The abstract should also provide a short definition before using these terms. This sentence from the results/discussion should be moved to the beginning of the introduction section. “In Brazil, the National Health Surveillance Agency (ANVISA) is the agency responsible for authorizing drug registration in the national territory. However, so far there is no specific regulation for medications intended for the pediatric population, nor are there any evidence-based guidelines on the transformation of pharmaceutical forms for the administration of adequate doses.” Results lines 226-228 should be closer to the beginning of the introduction because they are very motivating for readers. The use for kids, tube users, swallowing difficulties for “therapeutic orphans” is a good explanation right after you define the concepts of magistral production. Add citation of other papers that provide examples of magistral production in middle-income countries, such as this one from Colombia: Vaca González, C.P., Arteaga, L. & Delgado López, N.E. Magistral drug production in Colombia and other middle-income countries. Nat Biotechnol 37, 216–217 (2019). https://doi.org/10.1038/s41587-019-0044-z. https://www.nature.com/articles/s41587-019-0044-z It is confusing when the authors refer to availability “in Brazil and in SUS” and could be more clear to readers rephrased as “available in the country and covered by the health system.” This applies in at least lines 72, 80, 98, 101-105. The section on categorization of preparations by low vs high complexity and by active ingredients commercially available vs not available in Brazil can reference this prior work establishing those concepts as dimensions to evaluate to achieve the objectives of this paper: Zimmermann M, Adamson B, Lam-Hine T, Rennie T, Stergachis A. Assessment tool for establishing local pharmaceutical manufacturing in low- and middle-income countries. Int J Pharm Pract. 2018 Aug;26(4):364-368. doi: 10.1111/ijpp.12455. Epub 2018 May 6. PMID: 29732641. Consider working with the editor or layout designer to create a “call-out” or “highlighted box” titled “Therapeutic Gaps Considered” with three bullet points from manuscript lines 101-105 in the methods section. This is key to understanding the paper and readers may want to refer to it when interpreting each section of the paper. Can you separate the results section from the discussion section? The results should contain only new information that was learned in the study and the discussion can include the interpretation of the results, examples from other countries, and discuss the implications for policy and manufacturing in Brazil. Results line 203 would be clearer rephrased “Among the essential medicines needed to fill treatment gaps in Brazil, we identified 56 drug products that could be locally manufactured.” Consider a new title for Table 1 as “Summary of medicine types with potential for manufacturing in Brazil, according to ATC type.” Define ATC acronym in the footnote of the table. Be more specific in the table column headers (quantity of what? percentage of what?) How were the 56 drugs in Table 2 selected from the total number that the authors say were found to be eligible 56% of 253? How were the drugs in Table 3 selected from the longer list in Table 2? It would assist readers if the results section about costs could include a conversion of the total amount into USD $ for easier interpretation globally. The manuscript methods description of costing used in the study was clear but it was not clear in Table 3 how to interpret the total costs for each drug. Is this the estimated value or budget impact if locally manufactured? The phrase “susceptible to manipulation” makes sense to pharmacists but I fear will be misunderstood by the general audience reading the manuscript. Is there an alternative way to describe this attribute using other words that will be more effective for clear communication? For example, “drug products that are plausible candidates for local manufacturing given low complexity of formulations using active ingredients commercially available in Brazil.” The text inside Figures need to be translated into English. Please copyedit the decimal and comma notation for numbers within tables so they align with PLOS ONE style guidelines. ****** 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: Yes: Denny John 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.] 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. https://doi.org/10.1371/journal.pone.0276785.r001
Revision 1
10 Oct 2022 Author Response Reviewer #1: 1) The manuscript is acceptable in the current form. The authors have used multiple methods to provide an detailed methodology, analysis, and results on medical manipulation for mitigating gaps in therapeutic provision in the Brazilian Health System. R: We thank the reviewer for positively evaluating our manuscript. Reviewer #2: 1) This is a novel, important breakthrough paper. The objective is honorable in securing treatments needed for many diseases of poverty and in children. R: We thank the reviewer for the positive evaluation of our manuscript. Your suggestions were considered in the elaboration of the revised manuscript, which we believe have contributed to the improvement of its quality. 2) The abstract does not define the SUS acronym and it would be better referred to in general as the Brazil health system in the abstract. When the abstract describes “national production” it should specify Brazil as the nation. R: In response to this recommendation, the definition of the SUS acronym is now included in line 20. We also included the explanation that the study was carried out considering the Brazilian sanitary context (line 22). 3) The abstract is missing some of the most exciting motivations and results of the paper. You could add for example "The study prioritized candidate drugs for cost-effective local manufacturing in a Brazil laboratory to fill unmet needs in the population... We found the absence of a standard formula for production was most often in indications for poverty-related diseases." R: The abstract was properly reviewed and the main motivations for the study were included in lines 20-23 and 27-29. In addition, we added information regarding candidate drugs for local manufacture that were prioritized in the evaluation of production costs, considering the Brazilian health context. We reiterate the fact that the absence of studies to develop a standard formula was, in this study, related to drugs that had therapeutic indications for poverty-related diseases. 4) The terminology of “magistral medicines”, “magistral production”, and “manipulation” need to be defined early in the introduction. Do the authors refer to production at a central facility or does this also include manipulation at the pharmacy level? The abstract should also provide a short definition before using these terms. R: We thank the reviewer for the suggestion. We have changed the term to "magistral drug production" throughout the manuscript. 5) This sentence from the results/discussion should be moved to the beginning of the introduction section. “In Brazil, the National Health Surveillance Agency (ANVISA) is the agency responsible for authorizing drug registration in the national territory. However, so far there is no specific regulation for medications intended for the pediatric population, nor are there any evidence-based guidelines on the transformation of pharmaceutical forms for the administration of adequate doses.” R: We thank you for your contribution. The sentence is now included in the introduction section (lines 49-54) in the revised version of the manuscript. 6) Results lines 226-228 should be closer to the beginning of the introduction because they are very motivating for readers. The use for kids, tube users, swallowing difficulties for “therapeutic orphans” is a good explanation right after you define the concepts of magistral production. R: The introduction was properly altered. Please, check lines 41-45. 7) Add citation of other papers that provide examples of magistral production in middle-income countries, such as this one from Colombia: Vaca González, C.P., Arteaga, L. & Delgado López, N.E. Magistral drug production in Colombia and other middle-income countries. Nat Biotechnol 37, 216–217 (2019). https://doi.org/10.1038/s41587-019-0044-z. https://www.nature.com/articles/s41587-019-0044-z R: The experience carried out in Colombia was included in this revised version of the manuscript, between lines 423 and 430. 8) It is confusing when the authors refer to availability “in Brazil and in SUS” and could be more clear to readers rephrased as “available in the country and covered by the health system.” This applies in at least lines 72, 80, 98, 101-105. R: We appreciate this contribution. The terminology “medicines covered by SUS”. Such adjustments can be found in lines 79,106, 108, 113-116. 9) The section on categorization of preparations by low vs high complexity and by active ingredients commercially available vs not available in Brazil can reference this prior work establishing those concepts as dimensions to evaluate to achieve the objectives of this paper: Zimmermann M, Adamson B, Lam-Hine T, Rennie T, Stergachis A. Assessment tool for establishing local pharmaceutical manufacturing in low- and middle-income countries. Int J Pharm Pract. 2018 Aug;26(4):364-368. doi: 10.1111/ijpp.12455. Epub 2018 May 6. PMID: 29732641. R: We appreciate the contribution. The experience carried out in the Zimmermann et al. study was referenced in lines 480-482. 10) Consider working with the editor or layout designer to create a “call-out” or “highlighted box” titled “Therapeutic Gaps Considered” with three bullet points from manuscript lines 101-105 in the methods section. This is key to understanding the paper and readers may want to refer to it when interpreting each section of the paper. R: In response to the suggestion, we decided instead of including a figure in the manuscript, to make a subdivision in the methods to improve the understanding of the readers (lines 90 - 124). 11) Can you separate the results section from the discussion section? The results should contain only new information that was learned in the study and the discussion can include the interpretation of the results, examples from other countries, and discuss the implications for policy and manufacturing in Brazil. R: Given the suggestion, we divided the sections: the results are now available between lines 218 and 318 and the between lines 319 and 482. 12) Results line 203 would be clearer rephrased “Among the essential medicines needed to fill treatment gaps in Brazil, we identified 56 drug products that could be locally manufactured.” R: Aiming at improving the quality of the manuscript, we adjusted the text between lines 293 and 296, making it clearer that the medicines would be produced locally, and in which structures these medicines could be produced. 13) Consider a new title for Table 1 as “Summary of medicine types with potential for manufacturing in Brazil, according to ATC type.” Define ATC acronym in the footnote of the table. Be more specific in the table column headers (quantity of what? percentage of what?) R: We appreciate the suggestion. A new title was included in Table 1, available in lines 234-235. In addition, the table header was also altered, and the acronym ATC was defined in a footnote following the table, as suggested. 14) How were the 56 drugs in Table 2 selected from the total number that the authors say were found to be eligible 56% of 253? How were the drugs in Table 3 selected from the longer list in Table 2? R: As described in the methods section, after the identification of drugs that could be produced via manipulation, SUS demands were prioritized, where of the 235 drugs identified as feasible to be produced via manipulation, 30% were identified as a priority, i.e., 70 drug products. Based on the priority drugs (n=70), a theoretical assessment of the feasibility of producing these drugs via manipulation was carried out, considering that drugs that had both the standard formula described in the literature and the availability of the active principle or of a finished product available in the Brazilian market were considered viable for production by manipulation. Thus, table 2 presents the list of 56 drugs that were considered feasible, making them suitable for the cost estimate evaluation. In relation to Table 3, the prioritized drugs, which presented theoretical and production feasibility (n=56), had their cost survey for local production estimated. To estimate demand, data on prevalence, incidence or when unavailable, number of cases in 2019, of diseases and conditions for which the prioritized presentations have a main indication were considered, according to the age group of the target audience. However, as described in the study, one of the main limitations found was the survey of the demand estimate, which made it impossible to present the demand estimate for some drugs. Table 3 presents the annual cost estimate of local production, through the handling of medicines whose study carried out the survey of the cost estimate, when it identified the demand estimate. 15) It would assist readers if the results section about costs could include a conversion of the total amount into USD $ for easier interpretation globally. R: We thank the reviewer for the suggestion. The conversion of all values in Brazilian Real to US Dollars was carried out. 16) The manuscript methods description of costing used in the study was clear but it was not clear in Table 3 how to interpret the total costs for each drug. Is this the estimated value or budget impact IF locally manufactured? R: New wording was included between lines 293 and 296 to improve the interpretation of the data from the Table 3. 17) The phrase “susceptible to manipulation” makes sense to pharmacists but I fear will be misunderstood by the general audience reading the manuscript. Is there an alternative way to describe this attribute using other words that will be more effective for clear communication? For example, “drug products that are plausible candidates for local manufacturing given low complexity of formulations using active ingredients commercially available in Brazil.” R: Firstly, we thank you for your contribution. Aiming at a better understanding by the general public, the adaptation suggested was carried out in lines 237-238, changing the terminology to ¨drugs identified as plausible candidates for local manufacture by manipulation¨. 18) The text inside Figures need to be translated into English. R: Firstly, the text into the Figures were translated. We are sorry for the mistake. 19) Please copyedit the decimal and comma notation for numbers within tables so they align with PLOS ONE style guidelines. R: We performed the suggested change in Table 3. Attachments Attachment Submitted filename: Response to reviewers manipulated medicines eng 0510g.pdf https://doi.org/10.1371/journal.pone.0276785.r002
14 Oct 2022 Decision Letter - Paola Brusa, Editor Medicine manipulation: an alternative to mitigate therapeutic gaps in the Brazilian Unified Health System? PONE-D-22-14777R1 Dear Dr. Santana, 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, Paola Brusa Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276785.r003
Formally Accepted
18 Oct 2022 Acceptance Letter - Paola Brusa, Editor PONE-D-22-14777R1 Medicine manipulation: an alternative to mitigate therapeutic gaps in the Brazilian Unified Health System?Medicine manipulation: an alternative to mitigate therapeutic gaps in the Brazilian Unified Health System? Dear Dr. Santana: 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 Paola Brusa Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276785.r004

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