Principles and Practice of Pharmaceutical Medicine

After several revisions, including ICH agree-
ments in 1993 and 1999, the present Guidelines
for Toxicity Studies cover almost all these items,
describing the tests methods to be conducted for

single-dose toxicity study;

repeated-dose toxicity study, 1 or 3 months and
6 or 12 months administration, and guidance
for toxicokinetics;

reproductive and developmental toxicity studies;

drug dependence studies were notified in 1975
by the Narcotic Division (for drugs having a
pharmacological effect on the central nervous
system);

antigenicity studies;

skin sensitization and skin photosensitization for
dermatological preparations;

genotoxicity studies;

carcinogenicity studies (requirements and dose
selection for carcinogenicity study has been
harmonized).

All toxicity studies supporting a new drug applica-
tion should comply with GLP standards.

Pharmacology

Pharmacological data should include two different
types of data:

‘Specific pharmacology’ data provide informa-
tion regarding the main effects on the target
disease in animal models and try to clarify the
mechanism of action as far as possible. There are
no guidelines for specific pharmacology.

‘General pharmacology’ studies are conducted
to assess the overall pharmacological profile and
to obtain information about the effects on the
main physiological functions and potential
adverse events. Three dose levels are studied

(low, intermediate and high or very high doses)

in a battery of tests exploring the main body

functions. General pharmacology studies are

regulated by guidelines notified in January 1991.

In 2001, general pharmacology data have been

classified in ‘efficacy pharmacology, secondary/

safety pharmacology, and other pharmacology’.

All pharmacological studies should also comply

with the GLP standards.

Animal PK

Data on absorption, distribution, metabolism and

excretion in animal are necessary to clarify the

drug’s biological fate in the body and to establish

an appropriate dose regimen in animal studies, and

ultimately in man.

The guidelines for nonclinical PK studies were

notified in January 1991. They request those stu-

dies to be performed after single and repeated

administration. Japan was traditionally the only

country to systematically conduct a two- or three-

week administration test in order to detect tissue

accumulation.

Recently, the ICH-harmonized tripartite guide-

line, Guidance for Repeated Dose Tissue Distribu-

tion Studies, opened the door for such repeated-

dose studies, but recognized that there was no

consistent justification to conduct these tests sys-

tematically. In June 2001, new guidelines on non-

clinical PK studies were notified.

Clinical development

Efficacy and safety data supporting a NDA

approval does not differ fundamentally from the

Western clinical data package. They are generated

through similar phases, which are

human pharmacology studies (phase I)

therapeutic exploratory studies (dose determina-

tion studies, phase II)

therapeutic confirmatory studies (safety and effi-

cacy studies vs. a reference drug, phase III)

35.4 DRUG DEVELOPMENT PROCEDURES 499