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Cited by 27Pharmaceutical Economics and PolicyPharmaceutical studies and practicesPharmaceutical industry and healthcare

Japanese Regulatory System for Approval of Off-Label Drug Use: Evaluation of Safety and Effectiveness in Literature-Based Applications

Shimazawa, Rumiko, Ikeda, Masayuki·2012·Clinical Therapeutics
DOI 10.1016/j.clinthera.2012.09.004
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Abstract

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.

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  • The Japanese Ministry of Health has created a mechanism that allows the approval of new indications based on international scientific literature, even in the absence of additional domestic clinical trials.

    “To address this, the Japanese Ministry of Health has created a mechanism that allows the approval of new indications based on international scientific literature, even in the absence of additional domestic clinical trials.160”

    From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [160]

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Authors
Shimazawa, R., & Ikeda, M.
Affiliations
Nagasaki University (JP)
Corresponding author
Shimazawa, Rumiko
ORCID
Venue
Clinical Therapeutics
Publisher
Elsevier BV
Published
2012-10
Volume
34
Issue
10
Pages
2104-2116
ISSN
0149-2918 (ISSN-L)
DOI
10.1016/j.clinthera.2012.09.004
OpenAlex
W2005763656
Cited by
27
References
20
Citations by year
2026: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 1
FWCI
4.59
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Clinical Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Funders
JSPS KAKENHI (24590619, 23590603)
Topics
  • Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmaceutical industry and healthcare
Keywords
off-label drug use, review time, post-approval monitoring, safety and effectiveness, route of administration, health insurance coverage, drug regulation, Japan, United States, United Kingdom
MeSH terms
Clinical Trials as Topic, Humans, Japan, National Health Programs, Publications, Time Factors, Drug Approval, Insurance Coverage, Off-Label Use

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