Ten Years after the Implementation of the Risk Management Plan in Japan: The Impact of Risk Management Plan on Package Insert Revision

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However, the impact of the Japanese RMP (J-RMP) system on drug safety measures is unclear. Herein, we investigated the impact of the J-RMP system on package insert (PI) revision, focusing on the rapidity of identification of clinically significant adverse reactions (ARs) as an effect indicator of the J-RMP system in drug safety measures. We created an original database from public information of the Pharmaceuticals and Medical Devices Agency and investigated the speed of adding clinically significant ARs to PIs. Comparing the time lapse from drug approvals to PI revisions after the implementation of the J-RMP system to that before implementation, the median value was 32 months vs. 32 months (149 vs. 318 cases), and no significant difference was observed. We also compared the time lapse from drug approvals to PI revisions when additional ARs had been included as safety specifications at the time of drug approvals and when they had not been included, and the median value was 35 months vs. 32 months (14 cases vs. 126 cases, p = 0.7820), and no statistically significant difference was observed. Therefore, it was suggested that the J-RMP system did not affect PI revision and its speed. It should be considered how to effectively utilize J-RMP for safety measures in Japan. RMP risk management plan package insert revision adverse reaction drug safety pharmacovigilance Introduction The Japanese Risk Management Plan (J-RMP) is a document that shows the risk management of drugs from the development phase to the postmarketing phase. It aims for the risks of drugs to be evaluated to minimize their risks and for postmarketing safety measures to be ensured by publishing J-RMP and sharing the information on risk management among healthcare professionals [ 1 ]. It comprises the following three elements for individual drugs: safety specification, pharmacovigilance activities, and risk minimization activities [ 2 ]. “Risk Management Plan Guidance,” which was issued in 2012, is applicable to new drugs for which approval applications were submitted on or after April 1, 2013, and requires the creation of J-RMPs [ 3 ]. The effect of the J-RMP system (which is a relatively new system) on safety measures is still unclear. Given that it has been 10 years since J-RMP was implemented in 2013, we believe it is meaningful to investigate the impact of J-RMP on safety measures and evaluate its effectiveness. A study to evaluate the impact of Pharmacovigilance Planning (PVP) regulatory reforms, which included the publication of the revised Good Post-marketing Study Practice (GPSP) in 2017 [ 4 , 5 ] and the procedure for developing Post Marketing Surveillance (PMS) plans in 2018 [ 6 ], demonstrated that the regulatory renovation had a clear impact on PVP shown in J-RMP; the proportion of drugs with efficacy issues decreased, safety issues with additional activity also decreased, and database studies increased in contrast. [ 7 ]. However, to the best of our knowledge, no study has been conducted to find the impact of regulatory reform in 2013, the implementation of J-RMP. This study aimed to investigate the impact of the J-RMP system implemented in 2013 on drug safety management, focusing on PI revision, especially for the speed of identifying clinically significant ARs. Suzuki et al. published the results of their analysis of the factors influencing the addition of clinically significant ARs to PIs in 2017 [ 8 ]. Per their findings, domestic information was the main factor influencing the addition of clinically significant ARs, and external information (research papers, overseas information, etc.) influenced the amount of domestic side-effect information required for revising PIs. In addition, when the causal relationship between the AR and the drug was difficult to establish based on domestic case reports, external information was often used as evidence to support the revision of the PI. In the absence of external information, more domestic side-effect information was required for this revision. However, the impact of J-RMP on the addition of clinically significant ARs to PIs was not examined in Suzuki’s study. We considered that if risks and missing information are predefined in J-RMP and shared with medical professionals, postmarket AR information may be quickly accumulated, which may affect the speed at which it is reflected in PI. Therefore, we investigated the influence of the J-RMP system on PI revision and speed, additionally examining other factors influenced by J-RMP, and evaluated its effectiveness. Methods In this study, we investigated the “Summary of Investigation Results” attached to the “Notice of Revision of Precautions” on the website of Pharmaceuticals and Medical Devices Agency (PMDA) [ 9 ], following the methods outlined in Suzuki’s previous research [ 8 ]. “Notice of Revision of Precautions” is a list of notification based on which manufacturers revise their package inserts. We targeted PI revisions with the addition of clinically significant ARs. The PI revisions from April 2013 to March 2023 were included as PI revisions after RMP implementation, and PI revisions of drugs with no RMP at the time of approval were excluded from the analysis. The PI revisions from April 2003 to March 2013 were included as PI revisions before RMP implementation. We created an original database and first checked the background characteristics of package insert revisions for additional clinically significant adverse reactions and therapeutic category of drugs. Next, we compared the speed of adding clinically significant ARs to PIs with respect to 1) before and after RMP implementation, 2) listed and unlisted ARs as the safety specifications at the time of approval. Also, 3) the number of cases for which a causal relationship between the drug and the event was reasonably possible were compared when the additional ARs were listed and unlisted as the safety specifications at the time of approval, and 4) the number of PI revisions based on overseas information, such as overseas PI revisions, were compared in the same way. Lastly, 5) the current RMP description of the additional ARs (as of May 28, 2023) was also investigated. The speed of adding the AR to the PI was defined as the time from the initial approval for new active ingredients of the drug (s) to the date of issuance of the “Notice of Revision of Precautions [ 9 ].” When comparing such speed of PI revisions, “After RMP implementation” refers to PI revisions from April 2013 to March 2023) for products first approved after April 2013 and for which RMP was created at the time of approval, and “Before RMP implementation” refers to PI revisions from April 2003 to March 2013 for products first approved after April 2003. If “Draft drug risk management plan” was included in the review report at the time of approval [ 10 ], it was determined that the RMP was created at the time of approval, and whether or not the ARs were listed as the safety specifications was checked by “Draft drug risk management plan” in the review reports. Also, to determine the number of cases for which a causal relationship between the drug and the additional AR was reasonably possible, we checked” the number of cases in which a causal relationship between the drug and event was reasonably possible” in “Summary of Investigation Results 6 .” When this number was 0 or 1, it was determined that the number of cases was small, and the number of additional ARs with a small number of cases was compared when the ARs (or medically relevant contents) were listed and unlisted as safety specifications at the time of approvals. The assessment of medically relevant contents was conducted by a total of two medical professionals, including a physician. Regarding the current RMP description, additional ARs were determined to be described in the RMP as long as noted somewhere in the RMP, such as in the details. This study was conducted per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines [ 11 ] for cross-sectional studies. All statistical analyses were performed using the analytical tools of JMP Pro 15, with two-sided p-values less than 0.05 being considered statistically significant. The Wilcoxon rank sum test was used to perform comparisons between quantitative data while the Chi-square test was used to perform comparisons between categorical data. ARs were coded using MedDRA [ 12 ] ver. 26.0 and classified by System Organ Class. Results and Discussion The most common ARs after RMP implementation were “Infections and infestations,” “Skin and subcutaneous tissue disorders,” and “Hepatobiliary disorders.” As for ARs before RMP implementation, “Hepatobiliary disorders,” “Nervous system disorders,” and “Skin and subcutaneous tissue disorders” were the most common. Regarding the therapeutic category of the drugs, “Other oncology drugs,” “Diabetic drugs,” and “Metabolic drugs not elsewhere classified,” were the most common after RMP implementation, and “Other oncology drugs,” “Metabolic drugs not classified elsewhere” and “Antiviral agents” were the most common before RMP implementation. Table 1 shows the background characteristics of the PI revisions for the addition of clinically significant ARs. Table 1 Background characteristics of package insert revisions for adding clinically significant adverse reactions After RMP implementation 1) Before RMP implementation 2) Additional Adverse Reactions Total ( N ) 149 318 Additional Adverse Reactions (SOC) Infections and infestations 19 14 Skin and subcutaneous tissue disorders 18 32 Hepatobiliary disorders 17 33 Immune system disorders 14 22 Metabolism and nutrition disorders 14 15 Gastrointestinal disorders 10 25 Blood and lymphatic system disorders 9 29 Respiratory, thoracic and mediastinal disorders 8 29 Nervous system disorders 3 33 Others 39 99 Therapeutic Category of Drugs Other oncology drugs 66 72 Diabetic drugs 28 16 Metabolic drugs not classified elsewhere 15 31 Antiviral agent 12 27 Synthetic antibacterial agent 0 20 Psychoneurotic agent 1 18 Vaccines 2 17 Others 25 120 1) package insert revision for 10 years (from April 2013 to March 2023) for products first approved after April 2013 and for which the RMP was published at the time of approval 2) package insert revision for 10 years (from April 2003 to March 2013) for products first approved after April 2003 Comparing the revisions after RMP implementation with before implementation, the number of clinically significant ARs added to the revised PIs was 149 vs. 318, and the median time from approvals to PI revisions was 32 months for both, respectively. In addition, for 140 of the 149 cases after RMP implementation, excluding nine cases having no information on safety specifications at the time of approvals, we investigated the speed of PI revisions, comparing when the additional ARs were listed and unlisted as safety specifications at the time of approvals. The number of clinically significant ARs which had been listed or unlisted as safety specifications was 14 vs. 126, and the median time from approvals to PI revisions was 35 months vs. 32 months (p = 0.7820), and these variables did not differ significantly from each other. A comparison of the speed at which clinically significant ARs were added to the PI is shown in Table 2 . Table 2 Comparisons of the time lapse from drug approval to the addition of adverse reactions in package insert revisions Addition of Adverse Reactions N Median time (month) After RMP implementation 1) total 149 32 listed as safety specifications at the time of approval 14 35 unlisted as safety specifications at the time of approval 126 32 no information 9 Before RMP implementation 2) total 318 32 1) package insert revision for 10 years (from April 2013 to March 2023) for products first approved after April 2013 and for which the RMP was published at the time of approval 2) package insert revision for 10 years (from April 2003 to March 2013) for products first approved after April 2003 Regarding the proportion of additional ARs with a small number of cases for which a causal relationship between the drug and an event was reasonably possible (0/1 case), it was compared based on its being listed or unlisted as a safety specification at the time of approval. The result was 42.86% (6/14) when listed, and 34.40% (43/126) when unlisted; however, the difference was not statistically significant (p = 0.5299). Comparisons were also made based on the presence or absence of medically relevant contents as safety specifications at the time of approval, revealing 40.85% (29/71) vs. 28.99% (20/69) for those with and without medically relevant content, respectively; however, the difference was still not statistically significant (p = 0.1413, Table 3 ). Thus, if there were descriptions of the additional ARs or medically relevant contents to the safety specifications at the time of approval, the PIs tended to be more revised than when there was no description, even if there were only a few cases with the ARs, although there were no statistically significant differences. Furthermore, we investigated the number of PI revisions based on overseas information, compared that when additional ARs had been listed and unlisted as safety specifications at the time of approvals, and the result was 21.43% (3/14) vs. 32.54% (41/126). Although it was slightly higher when unlisted, the difference was not statistically significant (p = 0.3956). As for medically relevant contents, the result was 26.76% (19/71) vs. 36.23% (25/69). Although it was slightly higher when unlisted, the difference was not statistically significant (p = 0.2275, Table 3 ). From the above, if there were descriptions of the additional ARs or medically relevant contents to the safety specifications at the time of approval, the PIs tended to be more revised than when there was no description, using domestic information without relying on overseas information; however, there were no statistically significant differences. Table 3 Number of addition of adverse reactions with 0/1 accumulated cases / based on overseas information AR additions N AR additions with 0/1 cases*( N /%) p AR additions based on overseas information(N/%) p Listed as safety specifications at the time of approval 14 6/42.86 0.5299 3/21.43 0.3956 Unlisted as safety specifications at the time of approval 126 43/34.40 41/32.54 Listed as safety specifications at the time of approval (including medically relevant contents) 71 29/40.85 0.1413 19/26.76 0.2275 Unlisted as safety specifications at the time of approval (not including medically relevant contents) 69 20/28.99 25/36.23 AR : Adverse Reaction *a causal relationship between the drug and the event was reasonably possible Of the 140 clinically significant ARs added to the PIs after the implementation of RMP, 71 had been listed as safety specifications at the time of approval, and 69 had not been listed. Of the 69 cases that had not been listed, 66 were listed after the revision of PIs as important identified risks, two were listed as important potential risks, and only one was not listed (Table 4 ). Regarding the case that was not listed, only three months had passed since the “Notice of Revision of Precautions” was issued, when the investigation was performed. Table 4 Subsequent RMP descriptions regarding clinically significant adverse reactions added to package inserts At the time of approval Listed as safety specifications Identified risks Potential risks Unlisted as safety specifications No disclosed document 71 36 35 69 9 After package insert revisions Identified risks* Potential risks* Identified risks* Potential risks* Identified risks* Potential risks* Identified risks* Potential risks* Unlisted as safety specifications* 65 6 36 0 29 6 66 2 1 *As of May 28, 2023 The speed of PI revisions is instrumental in the identification of risks as ARs without delay to improve awareness and patient safety. In this study, we investigated the impact of the J-RMP system on the revisions of PIs, focusing on the speed of PI revisions. This is because we expected that if risks were appropriately managed using J-RMPs, they could be identified as ARs more rapidly, and PI revisions could be faster. However, the results revealed that the implementation of the J-RMP system or description as safety specifications at the time of approvals did not affect the speed of PI revisions regarding the addition of clinically significant ARs, which means that J-RMP did not affect the rapidity of risk identification as ARs. As a side note, in the study examining the relationship between the revision of the information in the clinically significant adverse reactions section in PI and the description in J-RMP at the time of drug approval, the median time from drug approval to PI revisions was 29.5 months [ 13 ], which was almost the same as that in our study (32 months). Alternatively, when there were descriptions of the additional ARs to the safety specifications at the time of approval, the PIs tended to be more revised than when there was no description, even if there were only a few cases with the ARs for which a causal relationship between the drug and the event was reasonably possible. Nevertheless, the speed of PI revision was unaffected. This was considered to be because additional ARs with a few cases have a low incidence of events themselves, or it was difficult to evaluate the causal relationship by case reports such as the ARs classified as Meyboom’s type C [ 14 ]. In such cases, the companies and PMDA can jointly recognize and manage risks as safety specifications before the evidence for PI revisions is accumulated, which is useful for risk management. Additionally, when there were descriptions of the additional ARs to the safety specifications at the time of approvals, the PIs tended to be more revised than when there was no description by using domestic information without relying on overseas information. From now on, if more pharmaceuticals are developed in Japan ahead of other countries, it will be harder to obtain overseas information, and more domestic information will be needed, potentially delaying PI revisions [ 8 ]. However, even in such cases, it might be possible to revise the PIs without delay by managing risks in advance to include them in safety specifications. The J-RMP contains more information than PI; it contains not only the risks that have already been confirmed but also potential risks and missing information, and may also be useful in sharing the possibility of risks with healthcare professionals before PI revisions. However, per the findings of a survey, 61.2% of hospitals and 44.3% of pharmacies used J-RMP documents, indicating a low rate of utilization [ 15 ]. It may be cumbersome to refer to multiple documents such as PIs, interview forms, and J-RMPs in medical settings. Therefore, even without J-RMPs, referring to the other documents such as PIs may be sufficient to confirm risks. Additionally, although the Ministry of Health, Labor and Welfare indicated in 2019 that J-RMP would be used as a criterion for determining the cases of side effects to be reported from the medical field to the PMDA [ 16 ], our study demonstrated that the speed of PI revisions to add clinically significant ARs did not change significantly, with or without J-RMPs. Therefore, although the use of J-RMP documents in medical settings is not yet widespread, there may not be a need to raise awareness about the use of J-RMP documents in medical settings from the perspective that there are alternatives as a risk confirmation document and that it does not have an effect on the speed of risk identification. However, if safety specifications such as potential risks are added to the J-RMPs before PI revisions, it would be preferable to include that information somewhere in the PIs, since it is known that there is a strong relationship between ARs listed as safety specifications at the time of approval and those being added to the PIs as clinically significant ARs postapproval, indicating that safety specifications could potentially induce severe ARs [ 17 ]. Conversely, according to a questionnaire-based survey, there was an opinion that risk minimization materials could be checked on the PMDA website, which was convenient for medical professionals [ 18 ]. Since risk minimization materials are created and distributed based on risk minimization activities, the J-RMP is useful for risk awareness among medical professionals through risk minimization materials. Additionally, the same survey pointed out the inconvenience of not being able to view risk minimization materials on the PMDA website after removing the J-RMP from the approval conditions at the end of the reexamination period [ 19 ], which should be considered an issue. Almost all clinically significant ARs added to PIs were listed in the J-RMPs after PI revisions. Since the J-RMP is a document that shows the consistent risk management of drugs from the development phase to the postmarketing phase [ 1 ], almost all clinically significant ARs are outlined in it. However, regarding RMPs in EU (EU-RMPs) [ 19 – 21 ], additional pharmacovigilance activities and risk minimization activities are set on a one-to-one basis with risks, and risks that do not require special attention are not listed [ 22 ]. A survey of pharmaceutical companies also pointed out the problematic existence of discrepancies between Japanese policies and global ones regarding standards for listing risks in RMPs [ 18 ]. For example, an AR listed in the PI for the same product is listed in the J-RMP but not in the EU-RMP, which highlights the need to establish a common standard. Nevertheless, our study has some limitations. First, since most of the initial J-RMPs are unknown from published materials, this study focused on the safety specifications in the review reports available at the time of approvals. Review reports, unlike J-RMP documents, do not include details of safety specifications. Therefore, it is unknown whether additional ARs were included in the details of safety specifications at the time of approvals, which may have influenced the results of the study. However, ARs listed in PIs are often outlined in the safety specifications themselves rather than in detail; therefore, the impact on the results seems to be small. Second, since the entire revision history of J-RMP is not disclosed in public materials, it was not included in the analysis. In some cases, J-RMPs were revised with additional safety specifications before PI revisions, which may have skewed the results of this study. Third, regarding the comparison between findings before and after J-RMP implementation, there may be differences in the drug safety system or the procedure for PI revisions between the target periods, which may have affected the speed of the PI revision process. To minimize this effect, we also compared the speed of PI revisions only after J-RMP implementation between when additional ARs had been included as safety specifications at the time of drug approvals and when they had not been included. Conclusions In conclusion, the implementation of J-RMP and safety specifications did not affect PI revision and its speed. Strategies for the effective utilization of the J-RMP for safety measures in Japan should be considered. Declarations Funding statement: This study was partly supported by a grant from Japan Health and Labour Sciences Research Grant (grant number 21KC2006). Conflicts of Interest statement: NK is an employee of CMIC Holdings Co., Ltd. The other authors have no conflict of interest to declare. Author Contributions: NK designed the study, main conceptual ideas, and proof outline. NK and AH collected the data. All authors contributed to data analysis and interpretation. NK wrote the manuscript with support from HM. HM supervised the conduct of this study. All authors critically reviewed and revised the manuscript draft and approved the final version for submission. References Pharmaceuticals and Medical Devices Agency. Risk Management Plan (RMP). https://www.pmda.go.jp/english/safety/info-services/drugs/rmp/0001.html. Accessed 03 October 2023. Pharmaceuticals and Medical Devices Agency. Pharmaceuticals and medical devices safety information. https://www.pmda.go.jp/files/000153064.pdf. Accessed 28 May 2023. Ministry of Health, Labour and Welfare. Risk Management Plan Guidance (PFSB/SD Notification No. 0411-1, PFSB/ELD Notification No. 0411-2). Pharmaceuticals and Medical Devices Agency. https://www.pmda.go.jp/files/000153333.pdf. Accessed 28 May 2023. Ministry of Health, Labour and Welfare. Ministerial Ordinance Partially Revising the Ministerial Ordinance. https://www.pmda.go.jp/files/000220720.pdf. Accessed 28 May 2023. Ministry of Health, Labour and Welfare. Partially Revising the Ministerial Ordinance No.116 (PSEHB Notification No.1026–1). https://www.pmda.go.jp/files/000220721.pdf. Accessed 28 May 2023. Ministry of Health, Labour and Welfare. Procedures for developing postmarking study plan (PSEHB/PED Notification No.0314-4, PSEHB/PSD Notification No.03414-4). https://www.pmda.go.jp/files/000228612.pdf. Accessed 28 May 2023. Kohama M, Nonaka T, Uyama Y, et al. Descriptive analysis for the trend of pharmacovigilance planning in risk management plans on new drugs approved during 2016–2019. Ther Innov Regul Sci. 2023;57:37–47. https://doi.org/10.1007/s43441-022-00437-6. Suzuki Y, Kishi T, Nakamura M, et al. Evaluation of factors influencing addition of clinically significant adverse reactions section in drug package inserts. Jpn. J. Drug Inform. 2017;19:17–23. https://doi.org/10.11256/jjdi.19.17. Pharmaceuticals and Medical Devices Agency. Notice of Revision of Precautions (Pharmaceuticals). https://www.pmda.go.jp/safety/info-services/drugs/calling-attention/revision-of-precautions/0001.html. Accessed 28 May 2023. Pharmaceuticals and Medical Devices Agency. Information Search for Prescription Drugs. https://www.pmda.go.jp/PmdaSearch/iyakuSearch/. Accessed 28 May 2023. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Epidemiology. 2007;18:805–835. https://doi.org/10.1097/EDE.0b013e3181577511. MedDRA/J. Medical Dictionary for Regulatory Activities. https://www.jmo.pmrj.jp/english. Accessed 28 May 2023. Kakutani Y, Murayama T, Kobayashi E, et al. Research on the utilization of risk management plan. Regul Sci Med Prod. 2023;13:51–61. https://doi.org/10.14982/rsmp.13.51. Meyboom RH, Egberts AC, Edwards IR, et al. Principles of signal detection in pharmacovigilance. Drug Saf. 1997;16:355–365. https://doi.org/10.2165/00002018-199716060-00002. Pharmaceuticals and Medical Devices Agency. Pharmaceuticals and Medical Devices Safety Information, No. 401. 2023. https://www.pmda.go.jp/files/000252814.pdf. Accessed 28 May 2023. Ministry of Health, Labour and Welfare. Draft standards for side effect information to be reported by medical personnel. https://www.mhlw.go.jp/content/11121000/000529048.pdf. Accessed 7 February 2024. Saito R, Miyazaki S. Analysis of safety specifications in risk management plan at the time of drug approval and addition of clinically significant adverse reactions in the package insert post-approval in Japan. Pharmacol Res Perspect. 2023;11:e01110. https://doi.org/10.1002/prp2.1110. Maintenance of Japanese risk management plan seen from company cases-suggestions for appropriate pharmaceutical risk management. https://www.jpma.or.jp/information/evaluation/results/allotment/rfcmr000000010il-att/rfcmr000000010s9.pdf. Accessed 5 September 2023. European Medicines Agency. Risk management plans. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/pharmacovigilance/risk-management/risk-management-plans. Accessed 6 November 2023. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module V-Risk management systems (Rev 2). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf. Accessed 5 September 2023. Butler D, Vucic K, Straus S, et al. Regulatory experience of handling risk management plans (RMPs) for medicinal products in the EU. Expert Opin Drug Saf. 2021;20:815–826. https://doi.org/10.1080/14740338.2021.1909569. Nakamura Y, Maeda H. International comparison of risk management plans for drugs approved under the pioneer drug designation system. Ministry of Health, Labour and Welfare (MHLW) Research on rebuilding post-marketing drug safety measures for the next system revision. 2021. https://mhlw-grants.niph.go.jp/system/files/download_pdf/2021/202125035A.pdf. Accessed 5 September 2023. Additional Declarations Competing interest reported. NK is an employee of CMIC Holdings Co., Ltd. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3958424","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":273117771,"identity":"9e9f6170-4ab6-4f07-8f21-21895f4fee4d","order_by":0,"name":"Natsuko Kameyama","email":"","orcid":"","institution":"Meiji Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Natsuko","middleName":"","lastName":"Kameyama","suffix":""},{"id":273117772,"identity":"2d84e7c6-92ca-4ae6-b4d4-a62563cd9c4b","order_by":1,"name":"Aoi Hosaka","email":"","orcid":"","institution":"Meiji Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Aoi","middleName":"","lastName":"Hosaka","suffix":""},{"id":273117773,"identity":"e43a771f-2a7d-4081-a3fe-80f5eb0a0fd6","order_by":2,"name":"Hideki Maeda","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYJACCYYKEMUDF0ggQssZkrUwtqFqwQ902w8fvPFz3rbEBuneg58rcxjk+RsYnj3Ap8XsTFqyZe+224kNMueSJc9uYzCccYAh3QCvlgM5ZhK8QC37b+QYSDZuY2DcwMCQJoFXy/n33yT/zgHaIpFj/BOoxZ6wlhs5bNK8DWAtZiBbEonQ8szYWubYbeMGmTNmlo3bJJJnHCbkl/PJD2++qbkt2yDdY3yzcZuNbX97T9oDfFpgwLEB4hggycyTRowOBnsGhPvZjxGlZRSMglEwCkYMAACZCUwlWCwaiAAAAABJRU5ErkJggg==","orcid":"","institution":"Meiji Pharmaceutical University","correspondingAuthor":true,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Maeda","suffix":""}],"badges":[],"createdAt":"2024-02-15 10:59:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3958424/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3958424/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54438667,"identity":"b5052615-9b2d-4e87-9824-4fb268068cdf","added_by":"auto","created_at":"2024-04-10 14:23:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":251278,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3958424/v1/e866ed78-0c56-47f5-973a-7a1f64896860.pdf"}],"financialInterests":"Competing interest reported. NK is an employee of CMIC Holdings Co., Ltd. The other authors have no conflict of interest to declare.","formattedTitle":"Ten Years after the Implementation of the Risk Management Plan in Japan: The Impact of Risk Management Plan on Package Insert Revision","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe Japanese Risk Management Plan (J-RMP) is a document that shows the risk management of drugs from the development phase to the postmarketing phase. It aims for the risks of drugs to be evaluated to minimize their risks and for postmarketing safety measures to be ensured by publishing J-RMP and sharing the information on risk management among healthcare professionals [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. It comprises the following three elements for individual drugs: safety specification, pharmacovigilance activities, and risk minimization activities [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. \u0026ldquo;Risk Management Plan Guidance,\u0026rdquo; which was issued in 2012, is applicable to new drugs for which approval applications were submitted on or after April 1, 2013, and requires the creation of J-RMPs [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. The effect of the J-RMP system (which is a relatively new system) on safety measures is still unclear. Given that it has been 10 years since J-RMP was implemented in 2013, we believe it is meaningful to investigate the impact of J-RMP on safety measures and evaluate its effectiveness. A study to evaluate the impact of Pharmacovigilance Planning (PVP) regulatory reforms, which included the publication of the revised Good Post-marketing Study Practice (GPSP) in 2017 [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e] and the procedure for developing Post Marketing Surveillance (PMS) plans in 2018 [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e], demonstrated that the regulatory renovation had a clear impact on PVP shown in J-RMP; the proportion of drugs with efficacy issues decreased, safety issues with additional activity also decreased, and database studies increased in contrast. [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, to the best of our knowledge, no study has been conducted to find the impact of regulatory reform in 2013, the implementation of J-RMP. This study aimed to investigate the impact of the J-RMP system implemented in 2013 on drug safety management, focusing on PI revision, especially for the speed of identifying clinically significant ARs.\u003c/p\u003e\n\u003cp\u003eSuzuki et al. published the results of their analysis of the factors influencing the addition of clinically significant ARs to PIs in 2017 [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Per their findings, domestic information was the main factor influencing the addition of clinically significant ARs, and external information (research papers, overseas information, etc.) influenced the amount of domestic side-effect information required for revising PIs. In addition, when the causal relationship between the AR and the drug was difficult to establish based on domestic case reports, external information was often used as evidence to support the revision of the PI. In the absence of external information, more domestic side-effect information was required for this revision. However, the impact of J-RMP on the addition of clinically significant ARs to PIs was not examined in Suzuki\u0026rsquo;s study. We considered that if risks and missing information are predefined in J-RMP and shared with medical professionals, postmarket AR information may be quickly accumulated, which may affect the speed at which it is reflected in PI. Therefore, we investigated the influence of the J-RMP system on PI revision and speed, additionally examining other factors influenced by J-RMP, and evaluated its effectiveness.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eIn this study, we investigated the \u0026ldquo;Summary of Investigation Results\u0026rdquo; attached to the \u0026ldquo;Notice of Revision of Precautions\u0026rdquo; on the website of Pharmaceuticals and Medical Devices Agency (PMDA) [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e], following the methods outlined in Suzuki\u0026rsquo;s previous research [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. \u0026ldquo;Notice of Revision of Precautions\u0026rdquo; is a list of notification based on which manufacturers revise their package inserts. We targeted PI revisions with the addition of clinically significant ARs. The PI revisions from April 2013 to March 2023 were included as PI revisions after RMP implementation, and PI revisions of drugs with no RMP at the time of approval were excluded from the analysis. The PI revisions from April 2003 to March 2013 were included as PI revisions before RMP implementation. We created an original database and first checked the background characteristics of package insert revisions for additional clinically significant adverse reactions and therapeutic category of drugs. Next, we compared the speed of adding clinically significant ARs to PIs with respect to 1) before and after RMP implementation, 2) listed and unlisted ARs as the safety specifications at the time of approval. Also, 3) the number of cases for which a causal relationship between the drug and the event was reasonably possible were compared when the additional ARs were listed and unlisted as the safety specifications at the time of approval, and 4) the number of PI revisions based on overseas information, such as overseas PI revisions, were compared in the same way. Lastly, 5) the current RMP description of the additional ARs (as of May 28, 2023) was also investigated.\u003c/p\u003e\n\u003cp\u003eThe speed of adding the AR to the PI was defined as the time from the initial approval for new active ingredients of the drug (s) to the date of issuance of the \u0026ldquo;Notice of Revision of Precautions [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e].\u0026rdquo; When comparing such speed of PI revisions, \u0026ldquo;After RMP implementation\u0026rdquo; refers to PI revisions from April 2013 to March 2023) for products first approved after April 2013 and for which RMP was created at the time of approval, and \u0026ldquo;Before RMP implementation\u0026rdquo; refers to PI revisions from April 2003 to March 2013 for products first approved after April 2003. If \u0026ldquo;Draft drug risk management plan\u0026rdquo; was included in the review report at the time of approval [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e], it was determined that the RMP was created at the time of approval, and whether or not the ARs were listed as the safety specifications was checked by \u0026ldquo;Draft drug risk management plan\u0026rdquo; in the review reports. Also, to determine the number of cases for which a causal relationship between the drug and the additional AR was reasonably possible, we checked\u0026rdquo; the number of cases in which a causal relationship between the drug and event was reasonably possible\u0026rdquo; in \u0026ldquo;Summary of Investigation Results\u003csup\u003e6\u003c/sup\u003e.\u0026rdquo; When this number was 0 or 1, it was determined that the number of cases was small, and the number of additional ARs with a small number of cases was compared when the ARs (or medically relevant contents) were listed and unlisted as safety specifications at the time of approvals. The assessment of medically relevant contents was conducted by a total of two medical professionals, including a physician. Regarding the current RMP description, additional ARs were determined to be described in the RMP as long as noted somewhere in the RMP, such as in the details.\u003c/p\u003e\n\u003cp\u003eThis study was conducted per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e] for cross-sectional studies. All statistical analyses were performed using the analytical tools of JMP Pro 15, with two-sided p-values less than 0.05 being considered statistically significant. The Wilcoxon rank sum test was used to perform comparisons between quantitative data while the Chi-square test was used to perform comparisons between categorical data. ARs were coded using MedDRA [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e] ver. 26.0 and classified by System Organ Class.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eThe most common ARs after RMP implementation were \u0026ldquo;Infections and infestations,\u0026rdquo; \u0026ldquo;Skin and subcutaneous tissue disorders,\u0026rdquo; and \u0026ldquo;Hepatobiliary disorders.\u0026rdquo; As for ARs before RMP implementation, \u0026ldquo;Hepatobiliary disorders,\u0026rdquo; \u0026ldquo;Nervous system disorders,\u0026rdquo; and \u0026ldquo;Skin and subcutaneous tissue disorders\u0026rdquo; were the most common. Regarding the therapeutic category of the drugs, \u0026ldquo;Other oncology drugs,\u0026rdquo; \u0026ldquo;Diabetic drugs,\u0026rdquo; and \u0026ldquo;Metabolic drugs not elsewhere classified,\u0026rdquo; were the most common after RMP implementation, and \u0026ldquo;Other oncology drugs,\u0026rdquo; \u0026ldquo;Metabolic drugs not classified elsewhere\u0026rdquo; and \u0026ldquo;Antiviral agents\u0026rdquo; were the most common before RMP implementation. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the background characteristics of the PI revisions for the addition of clinically significant ARs.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBackground characteristics of package insert revisions for adding clinically significant adverse reactions\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter\u003c/p\u003e\n \u003cp\u003eRMP implementation 1)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore\u003c/p\u003e\n \u003cp\u003eRMP implementation 2)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdditional Adverse Reactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal (\u003cem\u003eN\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e318\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdditional Adverse Reactions (SOC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfections and infestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHepatobiliary disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImmune system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNervous system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTherapeutic Category of Drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther oncology drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetic drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetabolic drugs not classified elsewhere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAntiviral agent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSynthetic antibacterial agent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePsychoneurotic agent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaccines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003e1) package insert revision for 10 years (from April 2013 to March 2023) for products first approved after April 2013\u003c/p\u003e\n \u003cp\u003eand for which the RMP was published at the time of approval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003e2) package insert revision for 10 years (from April 2003 to March 2013) for products first approved after April 2003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eComparing the revisions after RMP implementation with before implementation, the number of clinically significant ARs added to the revised PIs was 149 vs. 318, and the median time from approvals to PI revisions was 32 months for both, respectively. In addition, for 140 of the 149 cases after RMP implementation, excluding nine cases having no information on safety specifications at the time of approvals, we investigated the speed of PI revisions, comparing when the additional ARs were listed and unlisted as safety specifications at the time of approvals. The number of clinically significant ARs which had been listed or unlisted as safety specifications was 14 vs. 126, and the median time from approvals to PI revisions was 35 months vs. 32 months (p\u0026thinsp;=\u0026thinsp;0.7820), and these variables did not differ significantly from each other. A comparison of the speed at which clinically significant ARs were added to the PI is shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparisons of the time lapse from drug approval to the addition of adverse reactions in package insert revisions\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAddition of Adverse Reactions\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMedian time\u003c/p\u003e\n \u003cp\u003e(month)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter RMP implementation 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elisted as safety specifications at the time of approval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eunlisted as safety specifications at the time of approval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno information\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBefore RMP implementation 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e318\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003e1) package insert revision for 10 years (from April 2013 to March 2023) for products first approved after April 2013\u003c/p\u003e\n \u003cp\u003eand for which the RMP was published at the time of approval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003e2) package insert revision for 10 years (from April 2003 to March 2013) for products first approved after April 2003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eRegarding the proportion of additional ARs with a small number of cases for which a causal relationship between the drug and an event was reasonably possible (0/1 case), it was compared based on its being listed or unlisted as a safety specification at the time of approval. The result was 42.86% (6/14) when listed, and 34.40% (43/126) when unlisted; however, the difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.5299). Comparisons were also made based on the presence or absence of medically relevant contents as safety specifications at the time of approval, revealing 40.85% (29/71) vs. 28.99% (20/69) for those with and without medically relevant content, respectively; however, the difference was still not statistically significant (p\u0026thinsp;=\u0026thinsp;0.1413, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Thus, if there were descriptions of the additional ARs or medically relevant contents to the safety specifications at the time of approval, the PIs tended to be more revised than when there was no description, even if there were only a few cases with the ARs, although there were no statistically significant differences. Furthermore, we investigated the number of PI revisions based on overseas information, compared that when additional ARs had been listed and unlisted as safety specifications at the time of approvals, and the result was 21.43% (3/14) vs. 32.54% (41/126). Although it was slightly higher when unlisted, the difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.3956). As for medically relevant contents, the result was 26.76% (19/71) vs. 36.23% (25/69). Although it was slightly higher when unlisted, the difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.2275, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). From the above, if there were descriptions of the additional ARs or medically relevant contents to the safety specifications at the time of approval, the PIs tended to be more revised than when there was no description, using domestic information without relying on overseas information; however, there were no statistically significant differences.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eNumber of addition of adverse reactions with 0/1 accumulated cases / based on overseas information\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAR additions\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAR additions\u003c/p\u003e\n \u003cp\u003ewith 0/1 cases*(\u003cem\u003eN\u003c/em\u003e/%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAR additions\u003c/p\u003e\n \u003cp\u003ebased on overseas information(N/%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eListed as safety specifications at the time of approval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/42.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3/21.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.3956\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnlisted as safety specifications at the time of approval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43/34.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41/32.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eListed as safety specifications at the time of approval (including medically relevant contents)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29/40.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1413\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19/26.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2275\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnlisted as safety specifications at the time of approval (not including medically relevant contents)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20/28.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25/36.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAR : Adverse Reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" align=\"left\"\u003e\n \u003cp\u003e*a causal relationship between the drug and the event was reasonably possible\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eOf the 140 clinically significant ARs added to the PIs after the implementation of RMP, 71 had been listed as safety specifications at the time of approval, and 69 had not been listed. Of the 69 cases that had not been listed, 66 were listed after the revision of PIs as important identified risks, two were listed as important potential risks, and only one was not listed (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Regarding the case that was not listed, only three months had passed since the \u0026ldquo;Notice of Revision of Precautions\u0026rdquo; was issued, when the investigation was performed.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSubsequent RMP descriptions regarding clinically significant adverse reactions added to package inserts\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAt the time of approval\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eListed as safety specifications\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eIdentified risks\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003ePotential risks\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"3\" align=\"left\"\u003e\n \u003cp\u003eUnlisted as safety specifications\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo disclosed document\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" align=\"left\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter package insert revisions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIdentified risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePotential risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIdentified risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePotential risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIdentified risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePotential risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIdentified risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePotential risks*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnlisted as safety specifications*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"11\" align=\"left\"\u003e\n \u003cp\u003e*As of May 28, 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe speed of PI revisions is instrumental in the identification of risks as ARs without delay to improve awareness and patient safety. In this study, we investigated the impact of the J-RMP system on the revisions of PIs, focusing on the speed of PI revisions. This is because we expected that if risks were appropriately managed using J-RMPs, they could be identified as ARs more rapidly, and PI revisions could be faster. However, the results revealed that the implementation of the J-RMP system or description as safety specifications at the time of approvals did not affect the speed of PI revisions regarding the addition of clinically significant ARs, which means that J-RMP did not affect the rapidity of risk identification as ARs. As a side note, in the study examining the relationship between the revision of the information in the clinically significant adverse reactions section in PI and the description in J-RMP at the time of drug approval, the median time from drug approval to PI revisions was 29.5 months [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e], which was almost the same as that in our study (32 months).\u003c/p\u003e\n\u003cp\u003eAlternatively, when there were descriptions of the additional ARs to the safety specifications at the time of approval, the PIs tended to be more revised than when there was no description, even if there were only a few cases with the ARs for which a causal relationship between the drug and the event was reasonably possible. Nevertheless, the speed of PI revision was unaffected. This was considered to be because additional ARs with a few cases have a low incidence of events themselves, or it was difficult to evaluate the causal relationship by case reports such as the ARs classified as Meyboom\u0026rsquo;s type C [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. In such cases, the companies and PMDA can jointly recognize and manage risks as safety specifications before the evidence for PI revisions is accumulated, which is useful for risk management. Additionally, when there were descriptions of the additional ARs to the safety specifications at the time of approvals, the PIs tended to be more revised than when there was no description by using domestic information without relying on overseas information. From now on, if more pharmaceuticals are developed in Japan ahead of other countries, it will be harder to obtain overseas information, and more domestic information will be needed, potentially delaying PI revisions [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, even in such cases, it might be possible to revise the PIs without delay by managing risks in advance to include them in safety specifications.\u003c/p\u003e\n\u003cp\u003eThe J-RMP contains more information than PI; it contains not only the risks that have already been confirmed but also potential risks and missing information, and may also be useful in sharing the possibility of risks with healthcare professionals before PI revisions. However, per the findings of a survey, 61.2% of hospitals and 44.3% of pharmacies used J-RMP documents, indicating a low rate of utilization [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. It may be cumbersome to refer to multiple documents such as PIs, interview forms, and J-RMPs in medical settings. Therefore, even without J-RMPs, referring to the other documents such as PIs may be sufficient to confirm risks. Additionally, although the Ministry of Health, Labor and Welfare indicated in 2019 that J-RMP would be used as a criterion for determining the cases of side effects to be reported from the medical field to the PMDA [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e], our study demonstrated that the speed of PI revisions to add clinically significant ARs did not change significantly, with or without J-RMPs. Therefore, although the use of J-RMP documents in medical settings is not yet widespread, there may not be a need to raise awareness about the use of J-RMP documents in medical settings from the perspective that there are alternatives as a risk confirmation document and that it does not have an effect on the speed of risk identification. However, if safety specifications such as potential risks are added to the J-RMPs before PI revisions, it would be preferable to include that information somewhere in the PIs, since it is known that there is a strong relationship between ARs listed as safety specifications at the time of approval and those being added to the PIs as clinically significant ARs postapproval, indicating that safety specifications could potentially induce severe ARs [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Conversely, according to a questionnaire-based survey, there was an opinion that risk minimization materials could be checked on the PMDA website, which was convenient for medical professionals [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. Since risk minimization materials are created and distributed based on risk minimization activities, the J-RMP is useful for risk awareness among medical professionals through risk minimization materials. Additionally, the same survey pointed out the inconvenience of not being able to view risk minimization materials on the PMDA website after removing the J-RMP from the approval conditions at the end of the reexamination period [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e], which should be considered an issue.\u003c/p\u003e\n\u003cp\u003eAlmost all clinically significant ARs added to PIs were listed in the J-RMPs after PI revisions. Since the J-RMP is a document that shows the consistent risk management of drugs from the development phase to the postmarketing phase [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e], almost all clinically significant ARs are outlined in it. However, regarding RMPs in EU (EU-RMPs) [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e], additional pharmacovigilance activities and risk minimization activities are set on a one-to-one basis with risks, and risks that do not require special attention are not listed [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. A survey of pharmaceutical companies also pointed out the problematic existence of discrepancies between Japanese policies and global ones regarding standards for listing risks in RMPs [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. For example, an AR listed in the PI for the same product is listed in the J-RMP but not in the EU-RMP, which highlights the need to establish a common standard.\u003c/p\u003e\n\u003cp\u003eNevertheless, our study has some limitations. First, since most of the initial J-RMPs are unknown from published materials, this study focused on the safety specifications in the review reports available at the time of approvals. Review reports, unlike J-RMP documents, do not include details of safety specifications. Therefore, it is unknown whether additional ARs were included in the details of safety specifications at the time of approvals, which may have influenced the results of the study. However, ARs listed in PIs are often outlined in the safety specifications themselves rather than in detail; therefore, the impact on the results seems to be small. Second, since the entire revision history of J-RMP is not disclosed in public materials, it was not included in the analysis. In some cases, J-RMPs were revised with additional safety specifications before PI revisions, which may have skewed the results of this study. Third, regarding the comparison between findings before and after J-RMP implementation, there may be differences in the drug safety system or the procedure for PI revisions between the target periods, which may have affected the speed of the PI revision process. To minimize this effect, we also compared the speed of PI revisions only after J-RMP implementation between when additional ARs had been included as safety specifications at the time of drug approvals and when they had not been included.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, the implementation of J-RMP and safety specifications did not affect PI revision and its speed. Strategies for the effective utilization of the J-RMP for safety measures in Japan should be considered.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding statement:\u0026nbsp;\u003c/strong\u003eThis study was partly supported by a grant from Japan Health and Labour Sciences Research Grant (grant number 21KC2006).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest statement:\u0026nbsp;\u003c/strong\u003eNK is an employee of CMIC Holdings Co., Ltd. The other authors have no conflict of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eNK designed the study, main conceptual ideas, and proof outline. NK and AH collected the data. All authors contributed to data analysis and interpretation. NK wrote the manuscript with support from HM. HM supervised the conduct of this study. All authors critically reviewed and revised the manuscript draft and approved the final version for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePharmaceuticals and Medical Devices Agency. Risk Management Plan (RMP). https://www.pmda.go.jp/english/safety/info-services/drugs/rmp/0001.html. Accessed 03 October 2023.\u003c/li\u003e\n\u003cli\u003ePharmaceuticals and Medical Devices Agency. Pharmaceuticals and medical devices safety information. https://www.pmda.go.jp/files/000153064.pdf. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. Risk Management Plan Guidance (PFSB/SD Notification No. 0411-1, PFSB/ELD Notification No. 0411-2). Pharmaceuticals and Medical Devices Agency. https://www.pmda.go.jp/files/000153333.pdf. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. Ministerial Ordinance Partially Revising the Ministerial Ordinance. https://www.pmda.go.jp/files/000220720.pdf. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. Partially Revising the Ministerial Ordinance No.116 (PSEHB Notification No.1026\u0026ndash;1). https://www.pmda.go.jp/files/000220721.pdf. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. Procedures for developing postmarking study plan (PSEHB/PED Notification No.0314-4, PSEHB/PSD Notification No.03414-4). https://www.pmda.go.jp/files/000228612.pdf. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eKohama M, Nonaka T, Uyama Y, et al. Descriptive analysis for the trend of pharmacovigilance planning in risk management plans on new drugs approved during 2016\u0026ndash;2019. Ther Innov Regul Sci. 2023;57:37\u0026ndash;47. https://doi.org/10.1007/s43441-022-00437-6.\u003c/li\u003e\n\u003cli\u003eSuzuki Y, Kishi T, Nakamura M, et al. Evaluation of factors influencing addition of clinically significant adverse reactions section in drug package inserts. Jpn. J. Drug Inform. 2017;19:17\u0026ndash;23. https://doi.org/10.11256/jjdi.19.17.\u003c/li\u003e\n\u003cli\u003ePharmaceuticals and Medical Devices Agency. Notice of Revision of Precautions (Pharmaceuticals). https://www.pmda.go.jp/safety/info-services/drugs/calling-attention/revision-of-precautions/0001.html. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003ePharmaceuticals and Medical Devices Agency. Information Search for Prescription Drugs. https://www.pmda.go.jp/PmdaSearch/iyakuSearch/. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eVandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Epidemiology. 2007;18:805\u0026ndash;835. https://doi.org/10.1097/EDE.0b013e3181577511.\u003c/li\u003e\n\u003cli\u003eMedDRA/J. Medical Dictionary for Regulatory Activities. https://www.jmo.pmrj.jp/english. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eKakutani Y, Murayama T, Kobayashi E, et al. Research on the utilization of risk management plan. Regul Sci Med Prod. 2023;13:51\u0026ndash;61. https://doi.org/10.14982/rsmp.13.51.\u003c/li\u003e\n\u003cli\u003eMeyboom RH, Egberts AC, Edwards IR, et al. Principles of signal detection in pharmacovigilance. Drug Saf. 1997;16:355\u0026ndash;365. https://doi.org/10.2165/00002018-199716060-00002.\u003c/li\u003e\n\u003cli\u003ePharmaceuticals and Medical Devices Agency. Pharmaceuticals and Medical Devices Safety Information, No. 401. 2023. https://www.pmda.go.jp/files/000252814.pdf. Accessed 28 May 2023.\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. Draft standards for side effect information to be reported by medical personnel. https://www.mhlw.go.jp/content/11121000/000529048.pdf. Accessed 7 February 2024.\u003c/li\u003e\n\u003cli\u003eSaito R, Miyazaki S. Analysis of safety specifications in risk management plan at the time of drug approval and addition of clinically significant adverse reactions in the package insert post-approval in Japan. Pharmacol Res Perspect. 2023;11:e01110. https://doi.org/10.1002/prp2.1110.\u003c/li\u003e\n\u003cli\u003eMaintenance of Japanese risk management plan seen from company cases-suggestions for appropriate pharmaceutical risk management. https://www.jpma.or.jp/information/evaluation/results/allotment/rfcmr000000010il-att/rfcmr000000010s9.pdf. Accessed 5 September 2023.\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency. Risk management plans. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/pharmacovigilance/risk-management/risk-management-plans. Accessed 6 November 2023.\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module V-Risk management systems (Rev 2). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf. Accessed 5 September 2023.\u003c/li\u003e\n\u003cli\u003eButler D, Vucic K, Straus S, et al. Regulatory experience of handling risk management plans (RMPs) for medicinal products in the EU. Expert Opin Drug Saf. 2021;20:815\u0026ndash;826. https://doi.org/10.1080/14740338.2021.1909569.\u003c/li\u003e\n\u003cli\u003eNakamura Y, Maeda H. International comparison of risk management plans for drugs approved under the pioneer drug designation system. Ministry of Health, Labour and Welfare (MHLW) Research on rebuilding post-marketing drug safety measures for the next system revision. 2021. https://mhlw-grants.niph.go.jp/system/files/download_pdf/2021/202125035A.pdf. Accessed 5 September 2023.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"RMP, risk management plan, package insert revision, adverse reaction, drug safety, pharmacovigilance","lastPublishedDoi":"10.21203/rs.3.rs-3958424/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3958424/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"It has been 10 years since the Japanese Risk Management Plan (RMP) was implemented in 2013. However, the impact of the Japanese RMP (J-RMP) system on drug safety measures is unclear. Herein, we investigated the impact of the J-RMP system on package insert (PI) revision, focusing on the rapidity of identification of clinically significant adverse reactions (ARs) as an effect indicator of the J-RMP system in drug safety measures. We created an original database from public information of the Pharmaceuticals and Medical Devices Agency and investigated the speed of adding clinically significant ARs to PIs. Comparing the time lapse from drug approvals to PI revisions after the implementation of the J-RMP system to that before implementation, the median value was 32 months vs. 32 months (149 vs. 318 cases), and no significant difference was observed. We also compared the time lapse from drug approvals to PI revisions when additional ARs had been included as safety specifications at the time of drug approvals and when they had not been included, and the median value was 35 months vs. 32 months (14 cases vs. 126 cases, p = 0.7820), and no statistically significant difference was observed. Therefore, it was suggested that the J-RMP system did not affect PI revision and its speed. It should be considered how to effectively utilize J-RMP for safety measures in Japan.","manuscriptTitle":"Ten Years after the Implementation of the Risk Management Plan in Japan: The Impact of Risk Management Plan on Package Insert Revision","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-19 06:19:01","doi":"10.21203/rs.3.rs-3958424/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b7eb5f53-4c5f-436b-a752-314f0a33d7cf","owner":[],"postedDate":"February 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-10T14:15:17+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-19 06:19:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3958424","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3958424","identity":"rs-3958424","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}