(and possible major metabolites) in solvents and
plasma. Such assays need to be separately vali-
dated for each nonclinical species, as well as for
each biological substrate (blood, urine, cerebros-
pinal fluid, etc.).
Appropriate species
The selection of the animal species for the non-
clinical program is often not straightforward, espe-
cially in the early stages of development. At this
stage, there is often little, if any, information on
which to make a scientific judgment about which
species might be the most appropriate, i.e. which
species will best predict response in humans. In
these cases, regulatory agencies have a default
position requiring the use of both a rodent and a
non-rodent species. The typical approach would be
to use a rat and a dog for the general toxicity
studies, and mice or rabbits (the latter are now
classed as lagomorphs and not as rodents) for
other more specialized studies. Topical formula-
tions are another special case, and the rabbit is
commonly employed.
Primates may be needed when it becomes
clearer that the parameters of interest (hematology,
blood chemistry, histopathology, etc.) can only be
studied in species that are phylogenetically closer
toH. sapiens. This is often the case when candidate
drugs are proteins (e.g. animal-derivedmonoclonal
antibodies), and antibody formation may be major
issue and may dictate the choice of species. For
example, it may be known that only the chimpan-
zee does not develop neutralizing antibodies to the
drug, which would lead one to select that species as
the nonclinical model.
6.6 Toxicological support pre-IND
and for phase I clinical
studiesThe preliminary evaluation of the safety assess-
ment of any new drug requires multiple studies,
some of which evaluate general and multiple end
points (such as general toxicity studies). Other
studies evaluate more specific and defined end
points (such as mutagenicity studies and safety
pharmacology studies). Drugs that are derived
from a biological origin, such as proteins, mono-
clonal antibodies or drugs produced by biological
vectors (or what are generally referred to as ‘bio-
technology products’), present additional problems
that require a significantly modified approach. The
ICH guidelines recognize that unique approaches
may be needed, and it has addressed this in a
further guideline (Terrell and Green, 1994; ICH,
1997). This section will elaborate on those studies
that are needed to support the safety of a typical
xenobiotic agent; the same general principles fol-
low for biotechnology products, although they are
usually necessary but not sufficient.
There are two types of guidelines that must be
considered in initiating the nonclinical program.
The first relates to the types of studies required; the
second relates to protocol requirements for the
studies themselves.Types of study
The types of studies needed are dictated bynational
regulatory requirement, although ICH has promul-
gated an international guideline (Federal Register,
25 November 1997) that is progressing through the
final review stage at present. These studies, out-
lined in Tables 6.1 and 6.2, vary somewhat by the
phase of the clinical trial and may still vary among
countries where the trial is being conducted. The
US Food and Drug Administration (FDA) has also
published guidelines that outline the requirements
necessary to initiate initial clinical studies (FDA,
1995). This latter document focuses more on the
extent of study documentation required than on the
study types and allows for data to be submitted that
is not in final report form.
The following sections briefly describe the stu-
dies that would typically be performed to support
initial studies in humans. Additional specialized
studies might be needed to study the potential for
an effect that might be characteristic of drugs in the
particular class in question (e.g. antibody determi-
nations for some biological products, neurotoxicity
studies for drugs acting on the central nervous
system, etc.).66 CH6 NONCLINICAL TOXICOLOGY