Principles and Practice of Pharmaceutical Medicine

Acute toxicity studies

Single-dose studies in animals are an important
first step in establishing a safety profile, with the
general aim of exploring a feasible dose range.
Note that finding the LD 50 (the acute dose of a
test material causing a 50 % mortality in the test
animals) is no longer required or scientifically
necessary. Identification of an upper dose without
drug-related effects, the dose that produces some
level of exaggerated pharmacological effect (not
necessarily death) that helps identify potential
side effects, and other doses in between helps all
further toxicological (and clinical) tolerability
assessments. These studies can be designed using

‘up-and-down’ (Dixon) protocol designs or other

tactics to reduce the time and number of animals

required. These studies may then guide dose selec-

tion for the first repeated-dose studies. Various

guidelines for the performance of these studies

are available, and the ICH has also published its

own guideline (Federal Register, 26 August 1996).

Repeated-dose toxicity studies

Repeated-dose studies are designed to identify safe

levels of the drug following treatment regimens

that are designed to provide continuous exposure

of the animals to the test drug. Ideally, the route of

Table 6.1 Duration of repeated-dose toxicity studies to support phase I and phase II clinical

trials in the EU and phase I, II and III clinical trials in the United States and Japana

Duration of clinical trial

Minimum duration of repeated-dose toxicity studies

Rodents Non-rodents

Single dose 2–4 weeksb 2 weeks

2 weeks 2–4 weeksb 2 weeks

1 month 1 month 1 month

3 months 3 months 3 months

6 months 6 months 6 monthsc

>6 months 6 months Chronicc

aIn Japan, if there are no phase II clinical trials of equivalent duration to the proposed phase III trials, then

nonclinical toxicology studies of the durations shown in Table 6.2 should be considered.

bIn the EU and the United States, two-week studies are the minimum duration. In Japan, two-week non-rodent

and four-week rodent studies are needed. In the United States, with FDA concurrence, single-dose toxicity

studies with extended examinations can support single-dose human exposures.c

Data from six months of administration in non-rodents should be available before clinical exposures of more

than three months. Alternatively, if applicable, data from a nine-month non-rodent study should be available

before clinical treatment duration exceeds that supported by other toxicology studies.

Table 6.2 Duration of repeated-dose toxicity studies to support phase III clinical trials

in the EU, and product marketing in all jurisdictionsa

Duration of clinical trial

Minimum duration of repeated-dose toxicity studies

Rodents Non-rodents

2 weeks 1 month 1 month

1 month 3 months 3 months

3 months 6 months 3 months

>3 months 6 months Chronic

aThe table reflects the marketing recommendations in all three ICH regions, except that a chronic non-rodent

study is recommended for clinical use>1 month in Japan.

6.6 TOXICOLOGICAL SUPPORT PRE-IND AND FOR PHASE I CLINICAL STUDIES 67