However, Japanese clinical trials show some dif-
ferences in their organization and methodological
approaches, which are still in practice in spite of
regulations requesting the application of interna-
tionally validated standards.
Clinical trials regulations
The PAL and its Enforcement Regulationsestab-
lishes some basic rules for clinical trials, that is, in
summary, it is necessary
to conduct preclinical tests (toxicity, pharmacol-
ogy, etc.) before starting human administration;
to request in writing to an adequate medical
institution to conduct a clinical trial;
to inform the patient before his/her enrollment
into the trial;
to submit to the MHLW information regarding
the clinical protocol for each study, with infor-
mation regarding the study drug and a summary
of the preclinical tests.
Each change in the study course should be notified
to the authorities by filling specific administration
forms (protocol modification, study suspension,
study completion).
Notification 698 of May 1980does not provide
much more information regarding clinical trials,
requesting to submit ‘at least 150 cases in at least
five institutions’ for a new ethical drug application
for approval.
Two guidelines notified in 1992brought more
detailed guidance on the purpose, methodology
and assessment of the three clinical development
phases:
Guidelines for the Statistical Analysis of Clin-
ical Study Results (May 1992)
General Considerations for the Clinical Evalua-
tion of New Drugs (June 1992)
And, including ICH standards, the General Con-
siderations for Clinical Studies (April 1998)
Phase Ishould estimate a range of safe dose levels
up to a maximum tolerated dose, and characterize
the PK profile of the study drug in humans. Gen-
erally, a single-dose study and a one-week
repeated-dose study are conducted in a small num-
ber (six to eight) of healthy male volunteers. Food
effects, drug interactions and bioequivalence stu-
dies nowadays belong to this clinical pharma-
cology phase, as well as PK in the elderly and
studies in subjects with poor kidney or hepatic
function.
Phase II is traditionally divided in two
sequences: Phase IIa or early Phase II; and Phase
IIb or late Phase II. Phase IIa is generally an open
study with three or four arms, performed to explore
efficacy and safety of three or four doses in
patients, and it should also bring supplementary
information regarding PK parameters. This is dif-
ferent from conventional phase IIa, which is Proof
of Concept Study (POC). Phase IIb is a double-
blind study comparing the effects of two or three
doses to placebo effects, aiming at the determina-
tion of the optimal dose and dose regimen for a
specific indication. It should be noticed that pla-
cebo use is not mandatory, but is used ‘if neces-
sary’. The final galenic formulation and dosage
forms of the study drug is required for the conduct
of phase IIb.
Phase IIIshould confirm the efficacy and safety
of the optimal dose and dose regimen in a large
group of patients under the usual therapeutic con-
ditions. A large randomized double-blind trial
should be conducted versus a reference drug (tra-
ditionally, a reference drug in Japan has been mar-
keted for at least six years, and its efficacy and
safety has been confirmed through the reexamina-
tion procedure).
Long-term trials have now to be conducted and
meet international standards, the Extent of Popula-
tion Exposure to Assess Clinical Safety (it was
difficult in the past to obtain long-term data).
Some open phase III trials might be added to
study particular patient subgroups, for example
the elderly, or a specific subgroup of the disease.
The guidelines on statistics indicate how to ana-
lyze the study results properly and introduce inter-
national and validated standards for the statistical
evaluation.500 CH35 JAPANESE REGULATIONS