contract-out PMS works, and store the informa-
tion records properly.
ADR and Infections Reporting System are
following ICH rules for reporting within 15
and 30 days. From October 2003, it became
mandatory to use MedRA for individual adverse
event report.
Specific guidelines for drug development
In addition to the Law and Quality Standards,
specific guidelines have been notified for both
preclinical and clinical studies. They regulate the
preparation of the data to be submitted for approval
by the authorities and they should generally be
strictly followed. These guidelines explain what
kind of data have to be produced and indicate the
methodology to generate these data; many of these
guidelines were discussed at the ICH, and most of
them are already harmonized and implemented on
Japanese territory.
Other guidelines or recommendations regulate
the administrative procedures surrounding devel-
opment works, such as the import or labeling of the
study drug. The PAL directly describes the proce-
dures for notifying clinical trials in its section
‘handling of clinical trials’. These regulations
will be reviewed with the next section.
35.4 Drug development
procedures
After the chemical research and screening test
periods, the development of a new chemical entity
(NCE) follows preclinical and clinical steps similar
to Western ones. It takes 8–10 years to establish the
efficacy and safety for a new drug and to prepare
the documentation required for a NDA.
Regarding the development of a new drug in
Japan that is already approved in a foreign country,
even if preclinical data were harmonized up to
95%, six to eight years are still necessary in order
to conduct clinical development on the Japanese
territory on Japanese subjects and patients from
phase I to phase III. New regulations, such as
‘ICH E5’ implementation in Japan, offer potential
strategies to reduce the development time, using
foreign data; however, in practice, acceptable cases
are rather limited.
Preclinical studies
Physicochemical properties, specifications
and test methods
Basic chemical data, identification, purity and test
methods should follow the Guidelines ‘Setting
Specifications and Test Methods of New Drugs’,
notified in May 2001. Several others dealing with
analytical validation, impurities or residual sol-
vents were established on the basis of ICH agree-
ments. When available, standards published in the
JP or other quality standards (cf. section on ‘Qual-
ity standards’) represent the references for specifi-
cations and test methods.
Stability studies
Stability data on the active principle and on the
formulation(s) are required on three batches,
according to the Stability Test Guidelines issued
in April 1994. These guidelines are now harmo-
nized between the three ICH regions, implemented
in Japan with the New Stability Test Guidelines,
June 2003. Long-term data and tortured conditions
test data should be submitted for new drug applica-
tion; accelerated conditions tests only are neces-
sary for applications regarding new dosages or new
indications of a drug already registered.
Animal safety data
In May 1980, Notification 698 from the MHLW
specified the type of data required for the evalua-
tion of safety in animals and Guidelines for Toxi-
city Studies were subsequently established in
- It is necessary to generate data on acute,
sub-acute and chronic toxicity, effect on reproduc-
tion, dependence, antigenicity, mutagenicity, car-
cinogenicity and local irritation.
498 CH35 JAPANESE REGULATIONS