Comparison of Addition of Indications for Antineoplastic Agents Approved in the United States and Japan from 2001 to 2020.

The indications for antineoplastic agents are limited in Japan compared with those in the United States. This may be because it takes longer to add indications and the number of additions of indications is lower in Japan than in the United States. To clarify the differences in the timing and number of additions of indications for antineoplastic agents, the agents approved from 2001 to 2020 and sold as of the end of 2020 in Japan and the United States were identified and their additions of indications were compared. Of the 81 antineoplastic agents analyzed, the proportion of agents with additional indications was 71.6 and 63.0%, and the number of additions of indications (median/average per agent) was 2/3.52 and 1/2.43, for the United States and Japan, respectively. The median date of approval for addition of indications was August 10, 2017 and July 3, 2018 for the United States and Japan (p = 0.015), indicating that the indications were added earlier in the United States. The proportion of priority review and orphan drug designation for addition of indications was lower in Japan (55.6 and 34.7%) than in the United States (80.9 and 57.8%) (p < 0.001). When indications were developed with global clinical trials or designated as orphan drugs in the United States, delays in application and approval in Japan against the United States were small (p < 0.020). New indications for antineoplastic agents should be added promptly for Japanese patients because malignancy is the leading cause of death in Japan.

Comparison of New Drug Indications Approved in the United States, Europe, and Japan from 2001 to 2020.

In Japan, there have been many requests for off-label drugs from academic societies or patient groups to the "Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs." Thus, drug indications in Japan may be limited compared to those in other countries. To clarify whether drug indications in Japan are limited, the drugs containing new active ingredients approved in Japan, the United States, and Europe from 2001 to 2020 and sold in these three regions as of the end of 2020 were identified and their indications were compared. The indications of antineoplastic agents, psycholeptics, drugs from non-Japanese companies, and drugs approved in Japan from 2011 to 2020 were limited in Japan and Europe compared to the United States. These trends were more notable among antineoplastic agents. Thirty-seven indications for 19 antineoplastic agents were approved in the United States but not in Japan, and the most common indications were urothelial carcinoma (4), hepatocellular carcinoma (3), and thyroid cancer (3). The numbers of indications and drugs with different indications in Japan and Europe were generally comparable, and no specific imbalance was observed. The same indications of antineoplastic agents should be made promptly available in Japan and Europe as in the United States, as malignancy is one of the leading causes of death.

The efficacy and safety of tazobactam/ceftolozane in combination with metronidazole in Japanese patients with complicated intra-abdominal infections.

Tazobactam/ceftolozane, a novel antimicrobial therapy, is active against Pseudomonas aeruginosa and most extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. We report the results of the efficacy and safety of tazobactam/ceftolozane in Japanese patients with complicated intra-abdominal infections (cIAI). A multicenter, open-label, noncomparative study (MK-7625A Protocol 013, ClinicalTrials.gov Identifier: NCT02739997) to investigate the efficacy and safety of tazobactam/ceftolozane used in combination with metronidazole in Japanese patients with cIAI was conducted. One hundred Japanese patients with cIAI received tazobactam/ceftolozane 1.5 g (tazobactam 0.5 g/ceftolozane 1 g) plus metronidazole 500 mg intravenously every 8 h for 60 min for 4-14 days. The clinical response rate at the Test-of-Cure visit (TOC; Day 28 ± 2 days) was 92.0% (81/88 subjects). By disease type, the clinical response rates were 92.3% (24/26) for cholecystitis, 100% (6/6) for liver abscess, 93.5% (58/62) for intra-abdominal abscess and 90.2% (55/61) for peritonitis. The per-subject microbiological response rate at the TOC was 90.2% (55/61). Per-pathogen microbiological response rates in the most common baseline pathogens were Escherichia coli 90.2% (37/41), Kebsiella pneumoniae 91.7% (11/12), Streptococcus anginosus 100% (11/11), Streptococcus constellatus 90.0% (9/10) and Bacteroides fragilis 95.2% (20/21). The most common drug-related AEs were aspartate aminotransferase increased (11.0%) and alanine aminotransferase increased (9.0%). No serious drug-related AE was reported during the study. The favorable effect of tazobactam/ceftolozane in the treatment of cIAI suggests that the agent will be useful in clinical practice in Japan.

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine in Japanese healthy infants: A phase III study (V114-033).

BACKGROUND: This phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in Japanese infants. V114 contains all 13 serotypes in PCV13 plus additional serotypes 22F and 33F. METHODS: Healthy Japanese infants were randomized to receive three primary doses of V114 or PCV13 (dose 1 at 2-6 months of age; doses 2 and 3 ≥ 27 days after prior dose), plus a toddler dose at 12-15 months of age. Adverse events (AEs) were collected on Days 1-14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-dose 3, pre-dose 4, and 30 days post-dose 4. Primary objectives included non-inferiority of V114 to PCV13 for the 13 shared serotypes based on serotype-specific IgG response rates (IgG ≥ 0.35 µg/mL) and geometric mean concentration (GMC) ratios, and for serotypes 22F and 33F based on IgG response rates and compared with the lowest response of any serotype in the PCV13 group, at 30 days post-dose 3. RESULTS: Overall, 694 infants were randomized to V114 (n = 347) or PCV13 (n = 347). Proportions of participants with solicited and serious AEs were comparable between vaccination groups. V114 met non-inferiority criteria for all 13shared serotypes, based on difference in proportion of responders (lower bound of two-sided 95 % confidence interval [CI] > -10.0) and IgG GMC ratios (V114/PCV13, lower bound of two-sided 95 % CI > 0.5) at 30 days post-dose 3. The non-inferiority criterion based on IgG response rates was met for serotype 22F, but narrowly missed for serotype 33F (90.9 %, lower bound of two-sided 95 % CI -10.6). CONCLUSION: In Japanese infants, a four-dose series of V114 was generally well tolerated. Compared with PCV13, V114 provided non-inferior immune responses to the 13 shared serotypes and higher immune responses to serotype 22F and 33F post-primary series. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04384107; EudraCT 2019-003644-68.

Efficacy and safety of pentavalent rotavirus vaccine in Japan: a randomized, double-blind, placebo-controlled, multicenter trial.

Rotavirus is the most common cause of severe gastroenteritis in children under 5 y of age. Estimates of disease burden in Japan suggest that between 26,500 and 78,000 children in this age group need hospitalization each year, resulting in a direct medical cost of 10 to 24 billion Yen. Since being introduced in routine infant immunization schedules in the United States in 2006, the oral live pentavalent rotavirus vaccine RV5 (RotaTeq™) has contributed to dramatic reductions in the incidence of rotavirus gastroenteritis (RVGE) and in health care resource utilization. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of a 3-dose regimen of RV5 in healthy infants, age 6 to 12 weeks, at 32 sites across Japan. The results indicate that RV5 was significantly efficacious in preventing any severity [74.5% (95% confidence interval [CI]: 39.9%, 90.6%; p<0.001)], moderate-to-severe [80.2% (95% CI: 47.4%, 94.1%)], and severe [100% (95% CI: 55.4%, 100%)] RVGE caused by viruses with serotypes contained in the vaccine. The observed cases of RVGE included rotavirus types G1 (n=19), G3 (n=9), G9 (n=5) and one unspecified G serotype with P1A[8]. No G2 or G4 RVGE cases were observed, and this study was not powered to evaluate efficacy against individual serotypes. RV5 was generally safe and well tolerated in Japanese infants. These results are comparable to those observed in clinical studies conducted in other developed countries. Introduction of the vaccine in Japan may reduce disease burden and associated health care costs.