Introduction: Limited data exist regarding the prevalence and clinical practice involving generic drugs and biosimilars for treating ulcerative colitis (UC) in Japan. We aimed to clarify the clinical usage of these generic drugs and biosimilars for UC treatment in Japan using a nationwide database. Methods: We collected data from 30,675 UC cases, along with their prescriptions for both generic drugs or biosimilars and their original counterparts, using a medical claim database provided by DeSC Healthcare, Inc. We calculated the prescription and penetration rates of generic drugs and biosimilars and demonstrated the transition of these rates. Additionally, the cumulative retention rates between infliximab originator and biosimilar were compared using the Kaplan-Meier method. Results: The prescription rate of generic mesalazine increased from approximately 10% in 2015 to over 30% in 2021. Although the prescription rate of generic molecular targeting drugs (MTDs) also increased from approximately 0.15% in 2014 to 2.5% in 2021, the increment was lower than that of generic mesalazine. The penetration rates of generic 5-aminosalicylic acid and tacrolimus ranged from over 30% to approximately 50%. Infliximab biosimilar achieved an approximate 20% penetration rate, whereas adalimumab achieved <5%. The cumulative retention rates did not differ between infliximab originator and biosimilar. Conclusions: The penetration rates of generics and biosimilars for UC treatment are relatively low compared with those for treatment in other fields and the goal of the Ministry of Health, Labor, and Welfare. Several countermeasures are necessary for the widespread use of generics and biosimilars, ultimately contributing to cost-effective and sustainable healthcare delivery.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent periods of remission and exacerbation, the cause of which remains unknown [1, 2]. UC treatment with 5-aminosalicylic acid (5ASA), molecular targeting drugs (MTDs) including biologics (infliximab [IFX], adalimumab [ADA], golimumab [GLM], ustekinumab [UST], and vedolizumab [VDZ]), and small molecular agents (tacrolimus [TAC], tofacitinib, and upadacitinib) is approved for insurance coverage and widely used in daily practice in Japan. Several drugs have reached their patent expiration, leading to the development and availability of generic drugs or biosimilars. Generic drugs are pharmaceutical products with the same ingredients, dosage form, quality, administration route, efficacy, and safety as the original proprietary drugs [3‒5].

The increase in healthcare costs is a serious issue in many countries. One advantage of generic drugs is their low cost. Generic drugs, especially biosimilars, are expected to reduce medical expenses [3, 5]. In Japan, the volume share of generic drugs in relation to the total amount of pharmaceuticals (including original and its counterpart generic drugs) increased from 32.5% in 2005 to 78.3% in 2020 [6, 7]. However, limited data exist on the proportion and clinical use of generic drugs and biosimilars for UC treatment in Japan. Clarifying these points is essential to ensure efficient clinical practice with limited medical resources.

Previously, we conducted clinical research on lower gastrointestinal diseases using big data analytics on a national scale [8‒15]. We herein contracted DeSC Healthcare, Inc. to use their dataset of national claim database. In the present study, we aimed to clarify the clinical use of generic drugs and biosimilars for UC treatment in Japan using a nationwide database.

Data Source

We contracted DeSC Healthcare, Inc. (https://desc-hc.co.jp/en), a joint company that provides various healthcare services, and obtained permission to use their dataset for this study. Their dataset contains anonymized records of inpatient and outpatient prescription claims for UC patients. These records included demographic information (birth year and month, and sex), medical treatments, surgeries, and clinical diagnoses based on the International Classification of Diseases 10th version (ICD-10) between April 2014 and February 2022 from a Japanese health insurance association.

Selection of Eligible Patients and Data Collection

Eligible patients were selected from the dataset, as shown in the flowchart in Figure 1. UC cases were identified using the ICD-10 code K51, and cases with the term “suspicious” were excluded. Patients with Crohn’s disease were also excluded from the study. The validity of ICD-10 code has been confirmed [12].

Fig. 1.

Flowchart of eligible patient selection and analysis process. Eligible patients were meticulously selected, and data on the prescription and retention rates of IFX were analyzed.

Fig. 1.

Flowchart of eligible patient selection and analysis process. Eligible patients were meticulously selected, and data on the prescription and retention rates of IFX were analyzed.

Close modal

We collected the following patient data from the dataset: sex, birth year and month, observational period start and end dates, and surgery information. Details of prescribed medications, including 5ASA (mesalazine); MTDs including biologics (IFX, ADA, GLM, UST, and VDZ); and small-molecule agents (tofacitinib, TAC, and cyclosporine) were also collected. The commercial name of each drug was collected to distinguish original drugs from generic drugs.

Data Analysis

We compared the prescription rates and usage trends between original drugs and generics and biosimilars. The prescription rate analysis encompassed all UC cases in the DeSC dataset. The calculation was performed as follows: (number of patients prescribed each drug in each quarter) × 100/(total number of patients prescribed any drug in each quarter). The calculation was conducted for each quarter of the year. Duplicates within the same quarter were excluded. The penetration rate of generics and biosimilars was calculated as follows: (prescription rate of generics and biosimilars in each quarter) × 100/(sum of the prescription rates of generics and biosimilars and their original counterparts).

Furthermore, we compared the cumulative retention rates between new prescriptions of IFX originator and biosimilar using the Kaplan-Meier method. New prescriptions of IFX were defined as those with no prescription of the drug within 26 weeks before the initial prescription date during the observation period. The other types of prescriptions were defined as “old” prescriptions. Prescription discontinuation was defined as no prescription for >13 weeks from the next scheduled prescription date (8 weeks after the last prescription date). Patients who switched between IFX originator and biosimilar during the observation period were excluded from this analysis.

We categorized newly diagnosed UC patients into different age groups: <15 years, 15–24 years, 25–34 years, 35–44 years, 45–54 years, 55–64 years, 65–74 years, and ≥75 years. Subsequently, we examined their utilization of generic drugs and IFX biosimilars during the observation period. To evaluate which demographic groups exhibited lower rates of generic and biosimilar usage, we conducted age-stratified analyses using the χ2 test.

Additionally, we classified eligible patients who were prescribed mesalazine into two groups: the mesalazine monotherapy group and the non-monotherapy group (comprising patients who received systemic steroid treatment, immunomodulators, or MTDs, including biologics). We then compared the rates of generic and biosimilar utilization between these two groups using the χ2 test. Use of generics or biosimilars was defined as one or more prescription of generics or biosimilars during the observation period.

Statistical significance was set at p < 0.05. All analyses were performed using JMP Pro17 software (SAS Institute, Tokyo, Japan) or R software, version 4.3.2 [http://www.r-project.org/].

Patient Selection

As depicted in Figure 1, 30,675 patients with UC were included in the prescription rate analysis. Among them, 420 cases with new prescriptions of IFX originator or biosimilars were selected for further analysis: 348 were assigned to the IFX originator group, and the remaining 72 were assigned to the IFX biosimilar group. As described above, cases with an exchange of IFX originator and biosimilar during the observation period were excluded from this analysis.

Transition of Prescription Rate of Generics Compared with Original Drugs in Mesalazine and MTDs

Figure 2a shows the transition of prescription rate of generic mesalazine compared with that of the original one. The prescription rate of generic mesalazine increased over time and plateaued at over 30%, whereas the prescription rate of the original mesalazine remained stable at approximately 80% during the study period. The total prescription rate of mesalazine increased along with the increase in prescription rate of generic mesalazine.

Fig. 2.

Transitions of prescription rates for different drugs. a The prescription rate of generic mesalazine exhibited a continuous increase, eventually plateauing above 30%. Conversely, the prescription rate of original mesalazine remained constant at approximately 80% during the study period. b Prescription dynamics of original and generic mesalazine. The prescription rate of original PENTASA remained steady at 30% during the study period. The prescription rate of generic PENTASA peaked by approximately 16–17% in 2020 and slightly decreased to approximately 10% in 2021. The prescription rate of original ASACOL decreased in response to the introduction of its generic counterpart and LIALDA. c The transition of prescription rate of original and generic molecular targeting drugs (MTDs). The overall prescription rate of MTD increased during the observation period. d Details of prescribed MTD. Although the prescription rates of biosimilars of IFX and ADA increased during the observation period, their prescription rates remained below 1%. PENTASA, original mesalazine with time-dependent solubility; ASACOL, original mesalazine with pH-dependent solubility; LIALDA, original mesalazine with multi-matrix system formulation; IFX, infliximab; ADA, adalimumab; GLM, golimumab; UST, ustekinumab; VDZ, vedolizumab; TOF, tofacitinib; TAC, tacrolimus; CyA, cyclosporine; iv, intravenous injection; po, per os.

Fig. 2.

Transitions of prescription rates for different drugs. a The prescription rate of generic mesalazine exhibited a continuous increase, eventually plateauing above 30%. Conversely, the prescription rate of original mesalazine remained constant at approximately 80% during the study period. b Prescription dynamics of original and generic mesalazine. The prescription rate of original PENTASA remained steady at 30% during the study period. The prescription rate of generic PENTASA peaked by approximately 16–17% in 2020 and slightly decreased to approximately 10% in 2021. The prescription rate of original ASACOL decreased in response to the introduction of its generic counterpart and LIALDA. c The transition of prescription rate of original and generic molecular targeting drugs (MTDs). The overall prescription rate of MTD increased during the observation period. d Details of prescribed MTD. Although the prescription rates of biosimilars of IFX and ADA increased during the observation period, their prescription rates remained below 1%. PENTASA, original mesalazine with time-dependent solubility; ASACOL, original mesalazine with pH-dependent solubility; LIALDA, original mesalazine with multi-matrix system formulation; IFX, infliximab; ADA, adalimumab; GLM, golimumab; UST, ustekinumab; VDZ, vedolizumab; TOF, tofacitinib; TAC, tacrolimus; CyA, cyclosporine; iv, intravenous injection; po, per os.

Close modal

Details of the prescribed mesalazine are shown in Figure 2b. The proportion of original mesalazine with time-dependent solubility (PENTASA) use remained 30% during the study period, whereas that of generic mesalazine with time-dependent solubility peaked at 16–17% in 2020 and slightly decreased to approximately 10% in 2021. The proportion of original mesalazine with pH-dependent solubility (ASACOL) use decreased from approximately 40% in 2015 to 20% in 2021 after the availability of its generic counterpart and original mesalazine with multi-matrix system formulation (LIALDA). The proportion of generic ASACOL use plateaued at approximately 15% in 2021.

The transition of the proportion between original and generic MTD counterparts or biosimilar use is depicted in Figure 2c. The overall prescription rate of MTD increased from 6% in 2014 to >14% in 2021. The prescription rates of both original and generic MTD also increased.

The details of the prescription rates for each MTD are shown in Figure 2d. Original biologics (IFX, ADA, GLM, and VDZ) accounted for approximately 2%, whereas UST accounted for ≤1%. Although the prescription rate of IFX and ADA biosimilars increased during the observation period, the rate remained very low (<1%). In contrast, TAC had a higher prescription rate than IFX in 2014. However, the prescription rate of TAC decreased with the availability of new agencies and generic drugs.

Comparison between Generic and Biosimilar and Original Drugs

Figure 3 shows the changes in the penetration rate of each generic drug (IFX, ADA, mesalazine with time-dependent solubility, mesalazine with pH-dependent solubility, and TAC). The penetration rates of all generic drugs increased after becoming available in the Japanese market. The penetration rates of generic ASACOL and TAC increased to >40% and approximately 60%, respectively (Fig. 3d, e). The proportion of IFX biosimilar use increased to >20% compared with that of IFX originator (Fig. 3a). ADA generics constituted only a few percent of all ADA prescriptions (Fig. 3b).

Fig. 3.

Comparisons of penetration rates between original and generic drugs. a Comparison of the penetration rate between original and generic PENTASA. The penetration rate of generic PENTASA reached approximately 30%. b The penetration rate of generic ASACOL increased during the observation period and reached over 40%. c The penetration rate of generic TAC increased and reached over 50%. d The penetration rate of IFX biosimilar increased after its approval. However, the penetration rate of IFX biosimilar was approximately only 20%. e The penetration rate of ADA biosimilar was approximately only 5% in the first financial quarter of 2022. PENTASA, original mesalazine with time-dependent solubility; ASACOL, original mesalazine with pH-dependent solubility; LIALDA, original mesalazine with multi-matrix system formulation; TAC, tacrolimus; IFX, infliximab; ADA, adalimumab.

Fig. 3.

Comparisons of penetration rates between original and generic drugs. a Comparison of the penetration rate between original and generic PENTASA. The penetration rate of generic PENTASA reached approximately 30%. b The penetration rate of generic ASACOL increased during the observation period and reached over 40%. c The penetration rate of generic TAC increased and reached over 50%. d The penetration rate of IFX biosimilar increased after its approval. However, the penetration rate of IFX biosimilar was approximately only 20%. e The penetration rate of ADA biosimilar was approximately only 5% in the first financial quarter of 2022. PENTASA, original mesalazine with time-dependent solubility; ASACOL, original mesalazine with pH-dependent solubility; LIALDA, original mesalazine with multi-matrix system formulation; TAC, tacrolimus; IFX, infliximab; ADA, adalimumab.

Close modal

Comparison of Retention Rate between IFX Originator and Biosimilar

Table 1 shows the comparisons of backgrounds between IFX originator and biosimilar groups. Although the disease duration of IFX originator group was shorter than that of IFX biosimilar group, the majority of background characteristics showed no significant differences. Figure 4 presents a comparison of the cumulative retention rates between the IFX originator and biosimilar using the Kaplan-Meier curve. There was no significant difference in the cumulative retention rate between the IFX originator and biosimilar groups (p = 0.51, log-rank test).

Table 1.

Comparisons of backgrounds between patients newly administered IFX originator and biosimilar

IFX originatorIFX biosimilarp value
Sex (male/female) 228/120 50/22 0.59* 
Average onset age (SD) 49.7 years (21.9) 51.2 years (21.6) 0.67** 
Average disease duration at induction of IFX (SD) 0.90 years (1.1) 1.3 years (1.1) 0.012** 
Previous history of MTDs 
 ADA 41 0.54* 
 GLM 12 0.49* 
 UST 0.051* 
 Vedolizumab 21 0.13* 
 Tofacitinib 0.054* 
 TAC 31 0.82* 
 Cyclosporin A po 0.66* 
 Cyclosporin A iv 0.43* 
IFX originatorIFX biosimilarp value
Sex (male/female) 228/120 50/22 0.59* 
Average onset age (SD) 49.7 years (21.9) 51.2 years (21.6) 0.67** 
Average disease duration at induction of IFX (SD) 0.90 years (1.1) 1.3 years (1.1) 0.012** 
Previous history of MTDs 
 ADA 41 0.54* 
 GLM 12 0.49* 
 UST 0.051* 
 Vedolizumab 21 0.13* 
 Tofacitinib 0.054* 
 TAC 31 0.82* 
 Cyclosporin A po 0.66* 
 Cyclosporin A iv 0.43* 

IFX, infliximab; SD, standard difference; MTD, molecular targeting drug; po, per os; iv, intravenous injection.

2 test.

**Wilcoxon rank sum test.

Fig. 4.

The cumulative retention rates of IFX originator and biosimilar. There was no significant difference in the cumulative retention rate between IFX originator and biosimilar (p = 0.51).

Fig. 4.

The cumulative retention rates of IFX originator and biosimilar. There was no significant difference in the cumulative retention rate between IFX originator and biosimilar (p = 0.51).

Close modal

Stratified Age-Based Analysis Comparing the Rates of Generics and Biosimilar

Figure 5a and b depict the results of the stratified age-based analysis. The category of 75 years or older demonstrated a tendency of lower rates of generic PENTASA and generic ASACOL utilization compared to the other age categories. The penetration rates of generic PENTASA in each category are as follows: 75 years or older, 33.3%; 65–74 years, 40.1%; 55–64 years, 40.4%; 45–54 years, 40.7%; 35–44 years, 38.5%; 25–34 years, 37.4%; 15–24 years, 34.4%; under 15 years, 40.0% (p = 0.29). Similarly, the penetration rates of generic ASACOL in each category are as follows: 75 years or older, 47.7%; 65–74 years, 55.1%; 55–64 years, 58.2%; 45–54 years, 57.9%; 35–44 years, 59.4%; 25–34 years, 57.6%; 15–24 years, 51.6%; under 15 years, 63.6% (p = 0.068).

Fig. 5.

Stratified age-based analysis comparing the rates of generics and biosimilar. a Although no statistical significance was observed, use of generic PENTASA in the category aged ≥75 was lower compared with other age categories. b A similar trend was observed in the utilization of generic ASACOL. c There was no tendency in the use of IFX.

Fig. 5.

Stratified age-based analysis comparing the rates of generics and biosimilar. a Although no statistical significance was observed, use of generic PENTASA in the category aged ≥75 was lower compared with other age categories. b A similar trend was observed in the utilization of generic ASACOL. c There was no tendency in the use of IFX.

Close modal

However, this trend was not observed in the case of IFX usage, as shown in Figure 5c. The penetration rates of IFX biosimilar in each category are as follows: 75 years or older, 24.0%; 65–74 years, 20.0%; 55–64 years, 26.7%; 45–54 years, 16.0%; 35–44 years, 25.5%; 25–34 years, 27.6%; 15–24 years, 22.2%; under 15 years, 14.3% (p = 0.96).

Differences in the Frequency of Generic Utilization between Mesalazine Monotherapy and Non-Monotherapy Groups

The frequency of generic PENTASA utilization in the monotherapy group tended to be higher than that in the non-monotherapy group (40.7% vs. 38.9%, p = 0.0069) (Fig. 6a). Regarding ASACOL, the frequency of generic ASACOL utilization in the mesalazine monotherapy group was significantly higher than that in the non-monotherapy group (47.8% vs. 43.4%, p < 0.0001) (Fig. 6b).

Fig. 6.

Differences in the frequency of generics utilization between mesalazine monotherapy and non-monotherapy groups. a Although use of generic PENTASA in mesalazine monotherapy group was higher than that of non-monotherapy group, statistical significance was not observed (40.7% vs. 38.9%, p = 0.069). b Use of generic ASACOL in mesalazine monotherapy group was statistically higher than that in non-monotherapy group (47.8% vs. 43.4%, p < 0.0001).

Fig. 6.

Differences in the frequency of generics utilization between mesalazine monotherapy and non-monotherapy groups. a Although use of generic PENTASA in mesalazine monotherapy group was higher than that of non-monotherapy group, statistical significance was not observed (40.7% vs. 38.9%, p = 0.069). b Use of generic ASACOL in mesalazine monotherapy group was statistically higher than that in non-monotherapy group (47.8% vs. 43.4%, p < 0.0001).

Close modal

In this study, we investigated the clinical use of generics and biosimilars in patients with UC using a nationwide database. The prescription rate of generic mesalazine increased from approximately 10% in 2015 to >30% in 2021. Although the prescription rate of generic MTD also increased from approximately 0.15% in 2014 to approximately 2.5% in 2021, the increase was less than that for generic mesalazine. The penetration rates of generic 5ASA and TAC ranged from >30% to approximately 50%, whereas the proportion of IFX biosimilar use remained approximately 20% and that of ADA was <5%. The cumulative retention rates did not differ between the IFX originator and biosimilar.

In Japan, where healthcare costs are a growing concern in an aging population, using or substituting original drugs with generic drugs is the most effective measure for reducing medical costs [3, 5]. Generic drugs are expected to impose lower financial burdens on patients. Therefore, the Ministry of Health, Labor, and Welfare (MHLW) in Japan has been promoting the use of generic drugs [6]. The penetration rate of generic drugs (not limited to UC treatment) in Japan scored approximately 80% [6]. Our analysis demonstrated that the prescription rate of generic drugs increased during the observational period. Additionally, we found that the penetration rates of generic mesalazine and TAC were approximately 35–45% and up to 60%, respectively. Notably, the penetration rate of generic drugs for UC treatment is lower than that in other fields. Regarding biologics, the MHLW aims to achieve 60% in the proportion of biosimilars whose penetration rate reaches 80% to all biologics used by the end of fiscal year 2029 [16]. This shift is expected to reduce medical expenses and patients’ financial burdens [17]. Similar to our findings, another retrospective study using a different database also reported a lower penetration rate (22.5%) for IFX biosimilar in 2018 [18].

Several factors may contribute to these results. First, the rarity of UC may contribute to the low penetration rate of generics and biosimilars. Despite the increasing prevalence of UC in Japan, it remains a rare disease compared with more common conditions such as hypertension, hyperlipidemia, and diabetes mellitus, the penetration rate of which is >80% [6]. This rarity of UC potentially limits the market for UC medication, resulting in lower proportion of generics and biosimilars being used compared with those in other fields. Second, perceptions and familiarity among physicians and patients may impact these low penetration rates. A survey revealed that almost 50% of physicians expressed negative perceptions on the quality of generic drugs, and >25% were reluctant to use generic drugs for themselves or their families [19]. Moreover, an online survey revealed that approximately 50% of respondents believed that biosimilars were less effective than originators and concluded that many patients with inflammatory bowel disease were unfamiliar with biosimilars [20]. These negative perceptions among both physicians and patients likely contribute to the underutilization of generics and biosimilars.

Efforts to enhance the use of generics and biosimilars include patient education and stabilizing the supply chain. Correct information provision to patients with inflammatory bowel disease was shown to increase acceptance of biosimilars [21]. Several studies have demonstrated equivalent efficacy and safety between generics and biosimilars and their originators [22‒25]. Our results revealed the same cumulative retention rate between IFX originator and biosimilar, indicating similar efficacy and safety between the two drugs. Addressing patient anxieties regarding the effectiveness of generics and biosimilars by providing them with accurate information could foster greater acceptance. Furthermore, stabilizing the supply chain of generics and biosimilars is crucial to inspire confidence among physicians and patients, mitigating concerns on supply shortages. In 2020, there were generic drug shortages in Japan owing to manufacturing violence and quality problems caused by several generic pharmaceutical companies [7]. Other factors including the supply-and-demand balance, shortage of ingredients, and management decisions could also contribute to an unstable supply or shortage of generics and biosimilars [26]. Such unstable supply and shortage could cause anxiety in physicians and patients, resulting in the loss of confidence in generics and biosimilars. Thus, stabilizing the supply chain is essential for widespread use of generics and biosimilars.

The Japanese insurance system and the Intractable Disease Registry may have an impact on the utilization of generics and biosimilars. The results of age-stratified analysis suggest that variations in out-of-pocket expenses, linked to the insurance system, contribute to a reduced prevalence of generic drugs among individuals aged 75 and older, while younger individuals may have a higher likelihood of having a broader array of generic drug options. Similarly, the Japanese Intractable Disease Registry primarily enrolls patients with moderate or severe disease activity, providing financial support to UC patients. However, patients with mild activity are not registered in the Intractable Disease Registry. Therefore, eligibility for healthcare cost assistance programs may lead to our results that mesalazine monotherapy group, expected to have mild disease activity, exhibited higher use rate of generic mesalazine compared with non-monotherapy group.

This study had several limitations. First, owing to the nature of the DeSC database, there was no clinical patient information, including blood tests, endoscopic findings, and computed tomography, which are necessary to determine the disease severity. Therefore, the evaluation of IFX retention rate may contain several biases. The DeSC dataset does not contain the healthcare facility size and the number of available beds. Second, this was a retrospective study. To comprehensively evaluate the clinical application of generics and biosimilars, a nationwide prospective study is imperative. Third, although the DeSC database contains data from a large patient cohort, the representativeness of the dataset is not guaranteed because the DeSC database has relatively high proportion of elderly patients aged 75 years or older (approximately over 30%). Fourth, although the ICD-10 code is valid for detecting patients with IBD [12], its accuracy is not perfect. Despite these limitations, our analysis revealed the clinical use of generics and biosimilars in a large dataset of UC patients. Our findings are expected to enhance daily clinical practice in managing UC and inform future investigations.

In conclusion, despite the MHLW’s goal of increasing the penetration rate of generic drugs, our findings indicate that their utilization in UC treatment remains relatively low, reflecting challenges associated with the rare nature of the disease and negative perceptions among physicians and patients. Addressing these barriers through several countermeasures including patient education and supply chain stabilization could bolster the adoption of generics and biosimilars, ultimately contributing to cost-effective and sustainable healthcare delivery.

We would like to thank Honyaku Center Inc. for the English language editing.

The study protocol was reviewed and approved by the Ethics Committee of Tohoku University Graduate School of Medicine (2022-1-412). The requirement for informed consent was waived owing to the anonymity of the patient’s data. The need for informed consent was waived by the Ethics Committee of the Tohoku University Graduate School of Medicine (2022-1-412).

The authors have no conflicts of interest to declare.

The study was self-funded.

R.M., Y. Kakuta, H.N., Y.S., T.N., and H.S. contributed to the study’s conception and design. Y. Kakuta performed data extraction and collection. R.M. and Y. Kakuta performed data analysis. R.M. wrote the first draft of the manuscript and R.M., Y. Kinouchi, and A.M. critically revised it. All authors have read and approved the final version of this manuscript.

The corresponding author opted not to share the data because of a contract with DeSC Healthcare, Inc. Further inquiries can be directed to the corresponding author.

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