studies are required. Table 6.3 lists the guidelines
from major countries. As can be seen from these
guidelines, it is not always clear when such
studies are required. All of the major organ
systems need to be evaluated, and therefore
studies need to be performed that would identify
potential effects on the central nervous, cardiovas-
cular and gastrointestinal systems, as well as
an evaluation of renal function and possibly
immunogenicity.
Like many other disciplines, there are a multi-
tude of protocols and procedures that can be fol-
lowed for each safety pharmacology study. A
detailed review of each available procedure is out-
side the purview of this discussion.
Nonclinical summary documents
Prior to the initiation of initial studies in humans, it
is important that all of the nonclinical information
available is made into an integrated summary. This
information must be included in the clinical inves-
tigators’ brochure so that the clinical protocol can
be modified to include relevant biochemical or
other markers to minimize human risk. The regu-
latory authority and ethics committees are
further target audiences, and the company may
wish to use this for formal, internal proceedings
to justify the decision to proceed with initial human
exposure.6.7 Toxicological support
for phase II and III studiesNonclinical toxicology studies required to support
phase II and phase III stages of the program depend
on a variety of factors. First, as shown in Tables 6.1
and 6.2, the ultimate clinical regimen, that is the
duration of therapy or treatment, determines the
ultimate duration of the animal studies. For exam-
ple, a diagnostic agent or a drug with a three- to
four-day exposure (such as an anesthetic agent)
may require little in the way of additional
repeated-dose toxicity studies beyond what is
already conducted prior to phase I. But drugs
intended for chronic therapy, for example a new
antihypertensive agent, may require much more.
As the longer term studies take time, they must
begin well in advance in the phase II clinical pro-
gram if toxicology testing is not to introduce delay
into the development process.Table 6.3 International regulatory guidelines for safety pharmacology studies (excerpts from international
regulatory documents)
USA: ‘Studies that otherwise define the pharmacological properties of the drug or are pertinent to possible
adverse effects’ (21CFR, part 314.50, para 2)
EU: ‘A general pharmacological characterization of the substance, with special reference to collateral effects’
(EC Directive 91/507/EEC)
UK: ‘A general pharmacological profile of the substance is required, with special reference to collateral
effects...the aim should be to establish a pattern of pharmacological activity within major physiological
systems using a variety of experimental models’ (MAL2, p. A3F-1)
Canada: ‘Secondary actions studies related to secondary pharmacological actions of the new drug which
may be relevant to expected use or to adverse effects of the new drug’ (Canada RA5, exhibit 2, p. 21).
Australia: ‘Studies should reveal potentially useful and harmful properties of the drug in a quantitative manner,
which will permit an assessment of the therapeutic risk...Investigations of the general pharmacological profile
should be carried out’ (Guidelines under the Clinical Trial Exemption Scheme, pp. 12, 15)
Nordic countries: ‘New drugs should be studied in a biological screening program so as to define any action over
and above that which is desirable for the therapeutic use of the product’
Japan: ‘The objective of general pharmacological studies is to examine extensively the kind and potency of
actions other than the primary pharmacological actions, predict potential adverse effects likely to manifest in
clinical practice...’ (Japanese Guidelines, 29 January 1991)
70 CH6 NONCLINICAL TOXICOLOGY