Document Detail

Japanese Regulatory System for Approval of Off-Label Drug Use: Evaluation of Safety and Effectiveness in Literature-Based Applications.
MedLine Citation:
PMID:  23036337     Owner:  NLM     Status:  Publisher    
BACKGROUND: Although approved elsewhere, many drug indications remain unapproved in Japan. Many of these unapproved indications are off-label, which, despite strong supporting evidence, are not covered by the Japanese health insurance system. To address this situation, the Ministry of Health, Labour and Welfare of Japan announced in 1999 that, under certain conditions, it would approve a new supplement for a drug indication without clinical trials. This approval scheme involved application evaluation using literature-based evidence; however, the type of indications and the kind of evidence used in practical applications remain to be clarified. OBJECTIVE: This commentary sought to investigate the factors that contribute to the approval of individual applications through an analysis of review reports and to assess the outcome of efforts to facilitate the approval of off-label drugs by this approval system that has been used for over a decade in Japan. METHODS: Data from 80 approvals granted under this scheme were obtained from the official review reports of the Japanese regulatory agency. The following criteria were selected for the analysis of individual applications: review time, therapeutic class, application category under Japanese regulations, international approval status, postapproval monitoring plan, and variety and quantity of literature evidence. The literature used as a source of evidence was categorized into 4 types: (I) standard textbooks, (II) standard guidelines, (III) reviews, and (IV) application dossier submitted to the foreign regulatory authorities. RESULTS: The number of approvals and applications per year showed no consistent trend. The median (SD) review time was 16.4 (9.0) months, which was not affected by the international approval status or the literature evidence. This approval scheme was applied to not only a new indication (56 applications [70%]) or dosage (9 [11%]) but also a new route of administration (13 [16%]). Of the 80 applications, 46 (58%) had been approved in the United States, the United Kingdom, or both; 11 (14%), in other countries; and 23 (29%), in no country. For 2 approvals, the review reports were not released; the other 78 were based on either standard textbooks or guidelines, while 67 (84%) were based on both. The variety and quantity of literature evidence provided in the application showed no consistent trend with respect to international approval status. CONCLUSIONS: Prior approval by foreign authorities, although important, did not appear to be essential for approval in Japan. However, substantiating safety and effectiveness of agents by means of standard textbooks or guidelines was used consistently to obtain approval for off-label use.
Rumiko Shimazawa; Masayuki Ikeda
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-2
Journal Detail:
Title:  Clinical therapeutics     Volume:  -     ISSN:  1879-114X     ISO Abbreviation:  Clin Ther     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7706726     Medline TA:  Clin Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. Electronic address:
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