Simultaneous Global Drug Development and Multiregional Clinical Trials (MRCT): 5 Years After Implementation of ICH E17 Guidelines.

The ICH E17 guidelines (2014-2017) on Multiregional Clinical Trials (MRCT) was a joint effort by the regulators and industry to facilitate simultaneous global drug development and registration through taking a strategic approach for clinical trials. In other words, the objective was to reduce the time it takes to bringing medications to patients around the world through minimizing unnecessary duplication of local or regional studies, which may add the regulatory burden to cost and time of bringing new therapies to patients. Under the auspices of ICH, training materials were created and provided to various stakeholders. Despite the successful promotion of the benefits of ICH E17 MRCT guidelines across the different regions, the uptake of some concepts (e.g., pooling strategy) in the ICH E17 guidelines has been slow. This paper describes various factors which could affect the conduct of MRCT at a global level, including ambiguity in definition of "region" (in MRCT), new regulatory requirements to enroll a diverse patient population, the use of decentralized clinical trials, use of data sources other than randomized clinical trials (e.g., use of Real Word Data), and the impact of the COVID-19 pandemic on the conduct of MRCT.

Different Development Strategies Affecting Japan's Drug lag between Japan-Based and Foreign-Based Companies.

We examined the development strategies of new molecular entities approved during a 10-year period (fiscal years of 2012-2021) in Japan to determine the differences in drug lag between Japan and foreign companies. The results demonstrated a clear difference in development strategies. For example, products were usually developed through a "only-Japan" strategy by Japan companies (51.1% of products), compared to a "MRCT (multi-regional clinical trials)" strategy by foreign companies (54.9% of products). Regarding types of licenses, for Japan companies, the percentage of original products was higher in the category of less drug lag, such as "no approval in the US and EU" (59.1%), whereas the percentage of "license-in" products was markedly higher in the "drug lag ≥ 5 years" category (52.5%). Such differences were not observed for products developed by foreign companies. Of 64 license-in products developed by Japan companies with a drug lag > 5 years, 51 (79.7%) had already been approved in the US or EU at initiation of clinical development in Japan. The origin of approximately half (34) of the products was from the emerging companies (non-member foreign companies of the Japan Pharmaceutical Manufacture Association). These results suggest that more global cooperation of Japan companies, particularly with emerging foreign companies, is necessary in terms of the earlier timing of license-in and development strategies of products to promote drug development without drug lag or drug loss in Japan.

Detection Algorithms for Gastrointestinal Perforation Cases in the Medical Information Database Network (MID-NET®) in Japan.

BACKGROUND: The Medical Information Database Network (MID-NET®) in Japan is a vast repository providing an essential pharmacovigilance tool. Gastrointestinal perforation (GIP) is a critical adverse drug event, yet no well-established GIP identification algorithm exists in MID-NET®. METHODS: This study evaluated 12 identification algorithms by combining ICD-10 codes with GIP therapeutic procedures. Two sites contributed 200 inpatients with GIP-suggestive ICD-10 codes (100 inpatients each), while a third site contributed 165 inpatients with GIP-suggestive ICD-10 codes and antimicrobial prescriptions. The positive predictive values (PPVs) of the algorithms were determined, and the relative sensitivity (rSn) among the 165 inpatients at the third institution was evaluated. RESULTS: A trade-off between PPV and rSn was observed. For instance, ICD-10 code-based definitions yielded PPVs of 59.5%, whereas ICD-10 codes with CT scan and antimicrobial information gave PPVs of 56.0% and an rSn of 97.0%, and ICD-10 codes with CT scan and antimicrobial information as well as three types of operation codes produced PPVs of 84.2% and an rSn of 24.2%. The same algorithms produced statistically significant differences in PPVs among the three institutions. Combining diagnostic and procedure codes improved the PPVs. The algorithm combining ICD-10 codes with CT scan and antimicrobial information and 80 different operation codes offered the optimal balance (PPV: 61.6%, rSn: 92.4%). CONCLUSION: This study developed valuable GIP identification algorithms for MID-NET®, revealing the trade-offs between accuracy and sensitivity. The algorithm with the most reasonable balance was determined. These findings enhance pharmacovigilance efforts and facilitate further research to optimize adverse event detection algorithms.

Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET® in Japan: a new-user cohort study.

BACKGROUND: In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function. METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group). RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period. CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.

Real-world prescription of anti-COVID-19 drugs in hospitalized patients with COVID-19 in Japan.

OBJECTIVE: Prescription trends and patterns of anti-COVID-19 drugs in hospitalized patients were examined based on real world data to understand the use of anti-COVID-19 drugs in clinical practice in Japan. DESIGN: The longitudinal and cross-sectional study was conducted utilizing data from January 1, 2019 to December 31, 2021 of the MID-NET® medical information database, which stored the electronic medical records, administrative claim data, and diagnosis procedure combination data of patients in Japan. PARTICIPANTS: Hospitalized patients with a COVID-19-related diagnosis who received at least one anti-COVID-19 drug between April 1, 2020 and December 31, 2021. EXPOSURES: The following 14 drugs were included in this study: remdesivir, baricitinib, combination product of casirivimab and imdevimab, favipiravir, dexamethasone, ivermectin, azithromycin, nafamostat mesylate, camostat mesylate, ciclesonide, tocilizumab, sarilumab, combination product of lopinavir and ritonavir, and hydroxychloroquine. RESULTS: We identified 5,717 patients hospitalized with COVID-19 and prescribed at least one anti-COVID-19 drug. The entire cohort generally included patients over 41-50 years and more males. The most common prescription pattern was dexamethasone monotherapy (22.9%), followed by the concomitant use of remdesivir and dexamethasone (15.0%), azithromycin monotherapy (15.0%), remdesivir monotherapy (10.2%), and nafamostat mesylate monotherapy (8.5%). However, an often prescribed anti-COVID-19 drug differed depending on the period. CONCLUSIONS AND RELEVANCE: This study revealed the real-world situation of anti-COVID-19 drug prescriptions in hospitalized COVID-19 patients in Japan. A prescribed drug would depend on the latest scientific evidence, such as efficacy, safety, and approval status, at the time of prescription. Understanding the prescription of anti-COVID-19 drugs will be important for providing the most up-to-date treatments to patients and evaluating the benefit and/or risk of anti-COVID-19 drugs based on the utilization of an electronic medical record database.

Lower Risks of Gastrointestinal Perforation and Intestinal Obstruction in Patients with Atypical Antipsychotics in Comparison with Typical Antipsychotics Based on Real-World Data from the MID-NET® in Japan.

Intestinal perforation and obstruction are known to be one of the adverse events caused by antipsychotics; however, warning information on package inserts varies among antipsychotics. To investigate the risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics compared with those in patients prescribed typical antipsychotics, a nested case-control study was conducted utilizing real-world data from the MID-NET® medical information database in Japan. The study period spanned from January 1, 2009, to December 31, 2018. We found that the risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics were significantly lower than those in patients prescribed typical antipsychotics (adjusted odds ratio, 0.48; 95% confidence interval, 0.29-0.80). This finding was supported with prolonged periods for the exposure definition in the sensitivity analyses. In addition, no major differences in the risks of atypical antipsychotics, such as risperidone, quetiapine, olanzapine, and aripiprazole, were identified in this study. The safety profile regarding the lower risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics should be considered when choosing antipsychotics in clinical practice in terms of the proper use of such drugs.

Characteristics of Asian Participation in Multi-regional Clinical Trials Reviewed for Drug Approval in Japan: Opportunities for Collaboration Between South-East Asia, East Asia, and Japan.

Although the percentage of multi-regional clinical trials (MRCTs) submitted for drug approval in Japan increased significantly since the 2007 publication of the regulatory guideline, "Basic principles on global clinical trials", strategic collaborations between Asian countries will be important to promote MRCTs in accordance with the ICH E17 guideline published in 2017. In this study, characteristics of MRCTs reviewed for drug approval in Japan, especially those with participation by South-East Asia and East Asia, were investigated to explore opportunities for collaborations on global drug development in Asia. More than 90% of reviewed trials were conducted as global MRCTs. In addition to Japan, South-East Asia has participated in various types of MRCTs in terms of total numbers of subjects and countries. However, South-East Asia participation was lower in large-size MRCTs (total sample size ≥ 1000) than in middle- (500 ≤ total sample size < 1000) and small-size MRCTs (total sample size < 500). Furthermore, similar clinical trials for the same indications to the MRCTs without South-East Asia were rarely conducted separately in South-East Asia. Participation of other Asian countries did not affect the percentage of Japanese subjects enrolled in an MRCT, but did significantly increase the percentage of participating Asian subjects. These results suggest that additional opportunities for collaboration on MRCTs may be possible between Japan and other Asian countries, especially more collaborations with South-East Asia in the large-size MRCTs. More data of Asian populations from MRCTs will be useful for exploring an important ethnic factor affecting drug response, and will provide a sound scientific basis in considering the application of the pooled data concept in Asia, as described in the ICH E17 guideline.

Use of National Database of Health Insurance Claims and Specific Health Checkups for examining practical utilization and safety signal of a drug to support regulatory assessment on postmarketing drug safety in Japan.

The Pharmaceuticals and Medical Devices Agency (PMDA) has conducted many pharmacoepidemiological studies for postmarketing drug safety assessments based on real-world data from medical information databases. One of these databases is the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), containing health insurance claims of almost all Japanese individuals (over 100 million) since April 2009. This article describes the PMDA's regulatory experiences in utilizing the NDB for postmarketing drug safety assessment, especially focusing on the recent cases of use of the NDB to examine the practical utilization and safety signal of a drug. The studies helped support regulatory decision-making for postmarketing drug safety, such as considering a revision of prescribing information of a drug, confirming the appropriateness of safety measures, and checking safety signals in real-world situations. Different characteristics between the NDB and the MID-NET® (another database in Japan) were also discussed for appropriate selection of data source for drug safety assessment. Accumulated experiences of pharmacoepidemiological studies based on real-world data for postmarketing drug safety assessment will contribute to evolving regulatory decision-making based on real-world data in Japan.

Characterizing Granulocytopenia Associated with Thiamazole in Patients with Hyperthyroidism Based on Real-World Data from the MID-NET in Japan.

Despite the requirement of routine blood tests during thiamazole treatment in Japan, granulocytopenia among patients treated with thiamazole has been occasionally reported to the Pharmaceuticals and Medical Devices Agency (PMDA). To characterize granulocytopenia in patients with thiamazole in Japan, the effects of routine blood tests were examined in a cohort of new users of thiamazole or propylthiouracil utilizing the MID-NET. The occurrence of granulocytopenia (neutrophil count ≤ 1,500/µL) in a given period was compared between patients with and without blood test results prior to the period. The trend in neutrophil count during thiamazole treatment was also compared between patients with and without granulocytopenia. A nested case-control study based on the cohort was conducted to identify potential risk factors for granulocytopenia during thiamazole treatment. In the new user cohort including 4,371 patients treated with thiamazole, the occurrence of granulocytopenia in patients who had undergone blood tests at all previous periods was similar or higher than that among those who had not undergone blood test in all previous periods (e.g., adjusted odds ratio in period 2 was 1.63). The neutrophil count was relatively lower in the group of patients with granulocytopenia even before the occurrence of granulocytopenia. In a nested case-control study, an upward tendency of the risk was observed when a patient was co-prescribed anti-arrhythmic drugs or antiulcer drugs with thiamazole. The characteristics of granulocytopenia during thiamazole treatment elucidated in this study should be recognized in clinical practice for the proper use of thiamazole.

Cardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

In the present study, we aimed to investigate the association between urate-lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate-lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate-lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95-0.98) for febuxostat and 0.84 (95% CI: 0.78-0.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real-world evidence regarding the cardiovascular risk associated with urate-lowering drugs, indicating that no additional safety-related regulatory actions are warranted in Japan.

Descriptive Analysis for the Trend of Pharmacovigilance Planning in Risk Management Plans on New Drugs Approved During 2016-2019.

BACKGROUND: Japanese pharmaceutical authorities have conducted regulatory renovations of pharmacovigilance planning (PVP) since implementing new procedures for developing post-marketing study plans in 2018 in order to promote more focused and scientific approaches. This study aimed to descriptively assess the effects of those regulatory renovations on PVP for new drugs in Japan. METHODS: We identified PVP information (drug characteristics, efficacy and safety issues, and additional activities) from the first version of risk management plans for new drugs approved between 2016 and 2019. The following indicators were analyzed: (1) proportion of the number of drugs with at least one efficacy issue among all the drugs, (2) proportion of the number of safety issues with additional activity among all the safety issues, and (3) proportion of database studies among all additional activities. RESULTS: In total, 168 drugs, 1212 safety issues, and 301 additional activities were identified. The proportion of drugs with at least one efficacy issue decreased from 91.4% in 2016 to 27.3% in 2019, and the proportion of safety issues with additional activity also decreased from 93.9% in 2016 to 53.7% in 2019. In contrast, the proportion of database studies increased from 0 to 19.2%. The percentages of additional activities targeting important identified and potential risks also gradually decreased during the 4-year period. CONCLUSION: Notable changes in the three indicators during 2016-2019 were observed, which suggests that regulatory renovation has affected PVP in Japan.

Prescription trend and lactic acidosis in patients prescribed metformin before and after the revision of package insert for allowing metformin administration to patients with moderately decreased kidney function based on real-world data from MID-NET® in Japan.

Introduction: This study was conducted to understand the impact of package insert (PI) revision in Japan on 18 June 2019 to allow metformin use for patients with moderately decreased kidney function (30 ≤ estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2). Methods: A new user cohort design was employed to examine the prescription trend and the occurrence of lactic acidosis in patients prescribed metformin before and after PI revision using the Medical Information Database Network (MID-NET®). Results: From 12 May 2016 to 31 March 2020, 5,874 patients (before, n = 4,702; after, n = 1,172) were identified as new metformin users, including 1,145 patients (before, n = 914; after, n = 231) with moderately decreased kidney function. Although no marked changes in metformin prescription were observed before and after PI revision, the daily metformin dose at the first prescription decreased after PI revision. For both before and after PI revision, less than 10 cases of lactic acidosis occurred in all patients prescribed metformin, and no lactic acidosis was observed in patients with moderately decreased kidney function. Conclusion: The results of this study are useful for understanding the safety of metformin use in patients with decreased kidney function and suggest no worse impacts of PI revision in Japan, indicating no further safety concerns on metformin use in patients with moderately decreased kidney function under the situation with careful use and safety monitoring of metformin.

Assessing the Risk of Decrease in Kidney Function in Patients Prescribed Direct-Acting Antivirals for Hepatitis C Utilizing the MID-NET® Medical Information Database Network in Japan.

An association between kidney disease and direct-acting antivirals against hepatitis C (DAAs) has been suggested, however the warning on the package insert (PI) of the drug varies among DAAs. In this study, the risk of decreased kidney function associated with DAAs marketed in Japan was investigated to determine whether the risk of kidney disease is a common adverse event and class effect of DAAs. Data for patients who were new users of DAAs marketed in Japan, with eGFR ≥ 45 mL/min/1.73 m2 and without specific risk factors, were extracted from the MID-NET® medical information database network in Japan. Changes from the baseline on estimated glomerular filtration rate (eGFR) categories (eGFR ≥ 90, 90 > eGFR ≥ 60, 60 > eGFR ≥ 45, 45 > eGFR ≥ 30, 30 > eGFR ≥ 15, 15 > eGFR; unit: mL/min/1.73 m2) were used for evaluating the risk of decreased kidney function. Exposure groups for DAAs and relevant concomitant drugs were categorized into 10 patterns based on the PI. Among the 10 patterns, a significant increase in the incidence rate ratio (P < 0.01) was observed in the prescription patterns of concomitant use of telaprevir with peginterferon alpha and ribavirin, concomitant use of daclatasvir hydrochloride with asunaprevir, and ombitasvir hydrate combined with paritaprevir hydrate and ritonavir, which were concomitantly used with ribavirin; such an increase was not observed in the other prescription patterns. The effects of DAAs on kidney function may differ among drugs, suggesting the possibility that the risk of kidney disease is not a class effect of DAAs and should be evaluated individually for each DAA.

Validity of identification algorithms combining diagnostic codes with other measures for acute ischemic stroke in MID-NET®.

PURPOSE: We aimed to develop a reliable identification algorithm combining diagnostic codes with several treatment factors for inpatients with acute ischemic stroke (AIS) to conduct pharmacoepidemiological studies using the administrative database MID-NET® in Japan. METHODS: We validated 11 identification algorithms based on 56 different diagnostic codes (International Classification of Diseases, Tenth Revision; ICD-10) using Diagnosis Procedure Combination (DPC) data combined with information on AIS therapeutic procedures added as "AND" condition or "OR" condition. The target population for this study was 366 randomly selected hospitalized patients with possible cases of AIS, defined as relevant ICD-10 codes and diagnostic imaging and prescription or surgical procedure, in three institutions between April 1, 2015 and March 31, 2017. We determined the positive predictive values (PPVs) of these identification algorithms based on comparisons with a gold standard consisting of chart reviews by experienced specialist physicians. Additionally, the sensitivities of them among 166 patients with the possible cases of AIS at a single institution were evaluated. RESULTS: The PPVs were 0.618 (95% confidence interval [CI]: 0.566-0.667) to 0.909 (95% CI: 0.708-0.989) and progressively increased with adding or limiting information on AIS therapeutic procedures as "AND" condition in the identification algorithms. The PPVs for identification algorithms based on diagnostic codes I63.x were >0.8. However, the sensitivities progressively decreased to a maximum of ~0.2 after adding information on AIS therapeutic procedures as "AND" condition. CONCLUSIONS: The identification algorithms based on the combination of appropriate ICD-10 diagnostic codes in DPC data and other AIS treatment factors may be useful to studies for AIS at a national level using MID-NET®.

Potential Future Drug Development Lag in Japan Based on an Analysis of Multiregional Clinical Trials in the US, Europe, and East Asia.

Although the "drug lag"-namely, the delay in drug approval time in Japan relative to the United States and/or European Union (US/EU)-has been shortened for drugs approved in Japan, there remain many new drugs that have been approved in the US/EU, but not in Japan. To assess the possibility of a future drug lag, this study has examined the current lag in drug development in Japan based on "ClinicalTrials.gov" data from multiregional clinical trials (MRCTs) conducted in the US/EU and East Asia. Among 828 MRCTs registered as of April 5th, 2021, the percentage of MRCTs in which Japan participated (jMRCTs) was 57.1%. jMRCTs were common for some diseases such as "nervous system" and "visual system" disorders, but less common for "neoplasm," infection," "mental," and "circulatory" disorders. Regarding the investigational drugs in non-jMRCTs (i.e., MRCTs without Japanese participation) in the latter four therapeutic areas (i.e., neoplasm, infection, mental and circulatory disorders), approximately 80% (313/399) of drugs were not being developed in Japan. Furthermore, many of these drugs were being developed by the top 50 pharmaceutical companies by sales, and the majority would be recognized as a new active ingredient with a new mode of action in Japan. This study has highlighted the possibility of a future drug lag in Japan, especially in the therapeutic areas of neoplasm, infection, mental, and circulatory disorders. Such a lag may arise not only between Japan and the US/EU, but also between Japan and other countries in the East Asian region.

Evolving Acceptance and Use of RWE for Regulatory Decision Making on the Benefit/Risk Assessment of a Drug in Japan.

There is growing interest in the utilization of real-world data (RWD) and real-world evidence (RWE) for regulatory purposes. However, there are challenges in the practical utilization of RWD to provide RWE as a basis for regulatory decision making. This article presents the regulatory initiatives in Japan and efforts taken to promote the utilization of RWD/RWE for regulatory decision making at the pre- and postapproval stages of a drug. There has been a rapid increase in the number of RWD cases evaluated for drug safety assessment in Japan. Nevertheless, more regulatory experiences and considerations are necessary for the utilization of RWD in the efficacy evaluation of a drug. Based on past experiences, data reliability and appropriateness of the methodology for analysis are the major discussion points in utilizing RWD and RWE for regulatory decision making. International harmonization of regulatory requirements is another important area in utilizing RWD and sharing the RWE globally. We describe our perspective on providing RWE, which is useful for regulatory decision making throughout a drug's life cycle.

Factors Influencing Classifications of Safety Specifications in a Risk Management Plan for Antineoplastic Agents Approved in Japan: A Review and Descriptive Analysis.

A risk management plan (RMP) has an important role in assuring the optimal benefit-risk balance of a drug throughout its life cycle. However, no clear standards have been established for differentiating risk classification between "important identified risks" and "important potential risks". This study was a review and descriptive analysis for Japanese RMPs with a focus on antineoplastic agents to identify effective factors to discriminate an important identified risk from an important potential risk. Analysis based on 51 RMPs, reporting 310 important identified risks and 72 important potential risks, revealed significant associations between selection of the risk classification and several factors, including severe cases, actual cases in the Japanese population, availability of confirmatory trial data, and incidence of adverse events. Trend of the association was also found for discontinuation cases and immune-oncology agents [IO (drug type)]. These results suggest that consideration of these factors may be useful for coherent risk classification in creating a RMP.

Nested Case-Control Study Utilizing MID-NET® on Thrombocytopenia Associated With Pegfilgrastim in Patients Treated With Antineoplastic Agents.

Although several spontaneous case reports on the occurrence of thrombocytopenia in patients treated with human granulocyte colony-stimulating factor (G-CSF) preparations have been accumulated, its actual causality is still unclear. To investigate the association between G-CSF preparations (filgrastim, nartograstim, lenograstim, and pegfilgrastim) available in Japan and thrombocytopenia in patients treated with antineoplastic agents, a nested case-control study was conducted using the Medical Information Database NETwork (MID-NET®) with the cohort of the Japanese population taking antineoplastic agents between 2009 and 2018. A case of thrombocytopenia was defined as a patient who had decreased platelet counts (< 50,000/mm3 ). We identified a maximum of 10 controls for each case matched on the index date. Adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) of thrombocytopenia for the use of G-CSF preparations compared with nonuse were estimated using conditional logistic regression. From the cohort in which 33,124 patients were included, 733 cases and 5,592 controls were identified. Compared with the nonuse of G-CSF preparations, the use of any G-CSF preparations increased the risk of thrombocytopenia (aOR: 5.7, 95% CI: 4.3-7.5). More detailed analysis showed that a distinctive increased risk was observed when pegfilgrastim was prescribed at 2-7 days before the index date (aOR: 7.4 95% CI: 2.0-28.1). Associations of the other G-CSF preparations with thrombocytopenia were unclear due to the inconsistent results among different analyses. A significantly increased risk of thrombocytopenia associated with pegfilgrastim was identified, leading to a revision of precautions in the package inserts of pegfilgrastim as a regulatory safety action.