Specific guidelines. With regard to certain phar-
macological or therapeutic classes, several specific
guidelines have been published since 1980,
describing the type of data necessary for a NDA
and how to generate these data. Twelve guidelines
have been published, in different clinical fields;
guidelines for clinical trials on urinary tract infec-
tions and on dysuria are to be announced soon;
other therapeutic fields should be covered in the
coming years.
ICH guidelines. In addition to these Japanese
original guidelines for clinical development, inter-
nationally harmonized guidelines are now imple-
mented in Japan:
Clinical Trials in Special Population (Geriatrics)
Dose–Response Information to Support Drug
Registration
The Extent of Population Exposure to Assess
Clinical Safety
Clinical Safety Data Management (Definition
and Standard for Expedited Reporting)
Clinical Study Reports: Structure and Content
Clinical investigation in Pediatric population
Choice of Control Group and Related Issues in
Conducting Clinical Studies
International Good Clinical Practices. Finally, all
clinical studies supporting a drug registration
should comply with the harmonizedGood Clinical
Practices, which were enforced in April 1997.
Other development rules and practices
- Regarding the clinical development organiza-
tion, some aspects were unique to Japan (Labbe ́,
1995). Traditionally, an investigators’ commit-
tee will take full charge of the clinical develop-
ment from Phase I or Phase IIa through Phase
III. The committee consisted of a chairman, a
senior leader in his specialty, chosen by the
pharmaceutical company. The chairman recom-
mended key investigators and well-known
experts to the sponsor (See fig. 35.5).
Each of the five or eight key investigators
recommend several medical institutions, public
or private, where the investigators performed the
clinical trial. The investigators’ committee was
supposed to write the clinical protocol, to follow
the study progress and to propose action when
something wrong happen (serious adverse events
for instance), to decide whether to keep or reject a
case report form before statistical analysis, and to
write the clinical study report. They met and
worked under the supervision of a government
controller (often a clinical pharmacologist).
There is usually, for one indication, one study
per phase from phase IIa, and all trials are multi-
center studies. Regulations required around 100
patients for phase II and 200 for phase III; how-
ever, 1000–1500 cases are commonly submitted
to date in the NDA; as one investigator may
produce only one, two or three case reports, 30,
80 or more investigators may consequently be
involved in a phase II or III trial.
Clinical development has to progress step by
step, according to the general guidelines; after
each phase, the steering committee of investiga-
tors decided whether the study results justified
whether or not to proceed to the next step. It was
surprising to notice that the placebo was not
considered as mandatory in dose determination
studies (always mentioned in the protocols as
‘placebo if necessary’), and it was never used
in phase III studies, for ethical reasons, unless no
reference treatment is available. This is still true
today.
These specificities and many others are chan-
ging with the implementation ICH guidelines,
for example, the enforcement of the new GCP
abolishes the traditional Steering Committee of
Investigators, the ‘controller’ is only responsible
towarrant the ‘blindness’ of the trial. However, it
generally takes a long time in Japan to modify
suchstrong traditions, andthey willprobablystill
be in practice for some years more.- Foreign data could be helpful to reduce the six to
eight years necessary for clinical development
35.4 DRUG DEVELOPMENT PROCEDURES 501