(GLP;Federal Register, December 1978; also see
Williams and Hottendorf, 1997). These define
technical matters such as laboratory methods,
documentation, data handling, instrument cali-
bration and much more connected with the
actual conduct of toxicology testing at the bench
level.
6.3 Considerations related to
the clinical development planThe nature, timing and extent of the initial non-
clinical toxicology program depend on the clinical
development plan that it must support. The ICH
guidelines further specify the extent and duration
of nonclinical studies that are required to initiate
or continue clinical studies (Federal Register,
November 1997, and see below). Therefore, it is
important that the clinical development plan, at
least the initial stages, be clearly delineated.
Initial clinical studies
Usually, the initial clinical goals are to study toler-
ability and to provide initial pharmacokinetic
assessments. These studies may only involve sin-
gle doses of the drug administered to normal volun-
teers. Such a clinical study would require a
restricted set of toxicity studies to support safe
use of drug in this situation. On the contrary,
some companies achieve economies by having
the initial toxicology program to be sufficient
to support not only initial clinical studies but also
phase II. The toxicology studies may then involve
repeated doses over a period of weeks. Thus,
the initial clinical studies must be determined
before the nonclinical program can be designed.
One small exception to this is that recent guidances
provide a certain amount of relief from standar-
dized toxicological testing, when the clinical expo-
sure is a ‘microdose’, usually defined as less than
100 mg in absolute mass or less than 30 nanomoles
of a polypeptide, and without the use of any exci-
pient that is not on the ‘generally recognized as safe
(GRAS)’ list.
Initial proof of principle
In most cases, a proof of principle (i.e. initial
indication of clinical efficacy) during early phase
II clinical studies will require clinical treatment for
some period of time, ranging from days (diagnostic
agents, etc.) to weeks or months (for other types of
drug). As exposure of patients in clinical trials (in
most cases) cannot last beyond the duration of the
animal studies, careful consideration of the devel-
opment schedule must be made so that no delays
are caused through lack of toxicological coverage.
This requires that the appropriate preclinical
reports are available prior to the planned initiation
of the clinical trial.Enrollment of women
Most regulatory agencies now request that women
be enrolled into the clinical studies as early in
phase II as possible. Since thalidomide, reproduc-
tion and teratology studies havebeen required prior
to enrollment of large numbers of women in clin-
ical studies, in some cases, depending on the pro-
posed indication for the drug, postmenopausal or
otherwise reproductively incapable women can be
enrolled. However, the timing of the enrollment of
women needs to be understood well in advance so
that the lack of appropriate nonclinical reports does
not hinder clinical development.6.4 Consideration of regulatory
strategyThe European Clinical Trials Directive has now
standardized the submissions to regulatory authori-
ties needed for phase I studies within the
European Community. The data in support of
such submissions are now more or less the same
as for an IND in the United States, and there is
comparable institutional review board/ethics com-
mittee review and oversight on both sides of the
North Atlantic. The preclinical manager must keep
a close eye on the pace of such studies so that the
preclinical testing for phase I in humans, which
is usually rate limiting, causes as little delay as
possible.64 CH6 NONCLINICAL TOXICOLOGY