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.
Key words
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Article info
Publication history
Published online: October 04, 2012
Accepted:
September 6,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
