Estimation of a Suitable Number of Patients for Selective Safety Data Collection (ICH E19 Draft Guideline): When is the Safety Profile of a Drug Well Characterized?

PURPOSE: We propose methods to estimate a suitable number of patients for implementing selective safety data collection (SSDC) in clinical investigations based on a confidence interval of the incidence rate or risk difference using Monte Carlo simulation. METHODS: The incidence rates and risk differences of adverse events (AEs) were based on the safety outcome measures. A suitable number of patients for implementing SSDC was estimated based on the probability that the half-width of the two-sided 95% confidence interval of incidence rate or risk difference was equal to or less than a pre-specified cut-off value (0.5-3.0%). Monte Carlo simulation was used to estimate the suitable number of patients at probabilities of 70%, 80%, and 90%. The applicability of our proposed method for estimating a suitable number of patients for SSDC implementation was confirmed based on the incidence rates or risk differences from actual clinical trial data for panitumumab. RESULTS: We demonstrated the performance of our proposed method in estimating a suitable number of patients to implement SSDC in several situations. Furthermore, according to the safety datasets of three phase III clinical trials, the number of suitable patients for implementing SSDC using incidence rates or risk differences of common AEs with panitumumab could confirm the applicability of our proposed method. CONCLUSION: A suitable number of patients estimated based on our proposed method may be one of the foundations for implementing SSDC, as additional data accrual may not impact the precision of the estimates of the frequency of common AEs.

Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims database in Japan.

PURPOSE: Alerts for bleeding events are included in the Japanese package inserts of some anti-influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti-influenza drugs. This large-scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti-influenza drugs and in untreated patients. METHODS: This retrospective cohort study used a large-scale Japanese employment-based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders. RESULTS: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti-influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti-influenza treatments (odds ratios for baloxavir were 0.90-0.99 compared to other therapies). CONCLUSIONS: Based on real-world observation using a large-scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti-influenza drugs.

Comparison of Household Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors. METHODS: Using a Japanese claims database, the first family members with influenza diagnosis during the 2018-2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3-8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs. RESULTS: The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05-1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI, .89-.97) and 0.99 (95% CI, .96-1.02), respectively. CONCLUSIONS: Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences.

Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. METHODS: In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2-14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. RESULTS: Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00-2.00]; risk difference [RD] and 95% CI, 0.06 [.01-.12]) and zanamivir group (RR, 1.85 [1.23-2.78]; RD, 0.11 [.02-.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82-.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21-2.38]) or antibacterial injection (RR, 1.67 [1.17-2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05-2.18], 2.84 [2.04-3.96], and 1.68 [1.35-2.10], respectively). CONCLUSIONS: Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir. CLINICAL TRIALS REGISTRATION: University hospital Medical Information Network Clinical Trials Registry (UMIN000038159).