6 Nonclinical Toxicology

Frederick Reno

Testing new pharmaceutical agents for tolerability
in nonclinical studies is a critical aspect of any
development program. Usually, in the ‘discovery’
stage,in vivoorin vitrostudies establish the phar-
macological profile of the new drug and a rationale
for its potential clinical efficacy. At this stage, the
potential agent can be considered a new chemical
entity (NCE) or perhaps an analog or metabolite of
an existing one. Preliminary studies are also made
with respect to drug absorption, metabolism and
excretion. In many companies, drug metabolism is
a separate entity from the toxicology function but,
for the sake of completeness of this chapter, a
discussion of this important research area will be
included. At some point, a decision is made to
move the agent into the ‘development’ phase, and
the initiation of nonclinical toxicology studies
necessary to establish safety for initial clinical
trials is started.

6.1 International harmonization

Initially, over a period of four decades or so, indi-
vidual regulatory authorities in the United States,
Japan and across Europe established their own

guidelines for the types and extent of preclinical

studies required prior to various types of human

exposure to investigational products. Although

often providing detailed guidances, these jurisdic-

tions rarely said the same thing, and designing a

single nonclinical toxicology program that would

be universally accepted was difficult, if not impos-

sible. The International Conference on Harmoni-

zation (ICH), a tripartite group that consists of

regulators and pharmaceutical company represen-

tatives from the three geographical areas, has now

been meeting for several years with the aim of

harmonizing many aspects of the drug develop-

ment process including preclinical toxicology.

The ICH guidelines (in either draft or final form)

for nonclinical studies are now applicable in all

three geographical areas and will be identified

throughout this chapter.

6.2 Good laboratory practices

In addition, all nonclinical toxicology studies that

are intended to support clinical trials or marketing

applications must be conducted in compliance

with Good Laboratory Practices guidelines

Principles and Practice of Pharmaceutical Medicine, 2nd Edition Edited by L. D. Edwards, A. J. Fletcher, A. W. Fox and P. D. Stonier
#2007 John Wiley & Sons, Ltd ISBN: 978-0-470-09313-9