US FDA-accelerated approvals and subsequent withdrawals: influence on Japanese clinical oncology practice guidelines.

Abstract

The US (US) Food and Drug Administration (FDA)-accelerated approval pathway facilitates early access to oncology drugs based on surrogate endpoints, with required confirmatory post-marketing trials. However, regulatory decisions vary globally, with some drugs withdrawn in the US remaining approved in Japan. We conducted a cross-sectional analysis of Japanese professional society guidelines, evaluating recommendations for seven accelerated approval cancer drugs withdrawn from the US market but retained in Japan. We assessed for level of evidence and level of treatment preference ratings with consensus across guidelines issued by the corresponding Japanese professional societies. Four of the seven drugs (57%) were recommended as highly or moderately preferred treatment options in Japanese guidelines: gemtuzumab ozogamicin for acute myeloid leukemia, gefitinib for EGFR-positive non-small cell lung cancer, bevacizumab for HER2-negative metastatic breast cancer, and atezolizumab with nab-paclitaxel for PD-L1-positive triple-negative breast cancer. Detailed analysis of regulatory history and background of guideline recommendation revealed discrepancies in the assessment of clinical benefits: gemtuzumab ozogamicin failed to demonstrate benefits amid safety concerns, while gefitinib, bevacizumab, and atezolizumab were more controversial, although they did not demonstrate improved overall survival in post-marketing trials. Despite regulatory withdrawal in the US due to unproven clinical benefits, drugs retained in Japan received positive guideline recommendations. This finding highlights regional variations in regulatory decisions and different approaches to benefit-risk assessments, suggesting a need for improved transparency in Japan's regulatory decisions and guideline recommendations, with clearer justifications for endorsing drugs that are considered to have unproven clinical benefits in the US.