Principles and Practice of Pharmaceutical Medicine

Reexamination aims at confirming the conclu-
sions from the drug approval and particularly
the daily recommended dose, treatment duration,
safety in long-term use, and so on. The manufac-
turer should apply a reexamination file three
months before expiration of the six-year period
for a new drug.
The dossier contains data from case report forms
collected from hospitals. The number of cases is
around 3000–4000 observations, reporting pre-
scriptions on a routine basis (survey of use). Safety
information comes from this particular survey and
from spontaneous ADR reporting (serious events
reports and the synthesis of the periodic safety
update reports). Of course, information on mea-
sures taken during the period should be added
(modification of the data sheet, etc.), as well as
updated information regarding approval of the
drug in foreign countries.
The Safety Division is in charge of reviewing
the application; subcommittees and committees
of the PAFSC will carry out the scientific assess-
ment of the data and will either confirm the useful-
ness of the drug or ask for modification of the
data sheet.

Reevaluation

The spirit of the Reevaluation system is different
from that of reexamination. Here, the efficacy
and safety are reconsidered in the light of the
evolution of medical sciences and regulatory pro-
gress. The reevaluation is nowadays periodical,
that is, every five years after the reexamination
(Figure 35.8); however,ad hocreevaluation can
occur at any time upon request of the MHLW,
when efficacy or safety is questioned for some

therapeutic groups. Reevaluation is done for

each drug designated by the MHLW; drugs are

usually grouped by therapeutic categories for ree-

valuation; consequently, it may happen that for a

given drug, reevaluation is performed just before

the reexamination, as reevaluation is not directly

dependent on the approval date. Additional stu-

dies might be requested by the MHLW to keep the

drug on the market if the available data are not

consistent with the present regulations and/or

medical knowledge. If a drug designed by the

MHLW does not undergo reevaluation or does

not show evidence of usefulness, the drug

approval is cancelled.

So, from approval to market withdrawal, the

drug dossier is a ‘living substance’, regularly com-

pleted by the pharmaceutical company and peri-

odically revised by the health authorities.

35.7 Conclusion

Japanese regulations regarding drug development

and PMS were recently amended, because of the

progress of the ICH program, and for other rea-

sons, such as recent incidents related to contami-

nated blood infusion and a fatal interaction

between an antiviral and an anticancer drug,

which most probably prompted the changes.

However, there is a strong will from the Japanese

authorities to apply international standards to

drug development, particularly in the clinical

field. The introduction of new GCP and GPMSP

rules deeply modifies the background of the tradi-

tional Japanese R&D: the industry has to modify

its structure and take over new responsibilities,

hiring medical doctors in order to organize

New drug

application

24 months

tox years

New drug

approval

2 or 3

months

NHI price

listing

Launch

6 years

(4–10) Re-examination 5 years Re-evaluation Re-evaluation 5 years

Figure 35.8 Flow chart of the regulatory process after new drug application

506 CH35 JAPANESE REGULATIONS