The Drug development process - Pharmaceutical Biotechnology: Concepts and Aapplications - page 86

The indicator molecule serves to assess the state of health of the cultured cells. The dye neutral
red is often used (healthy cells assimilate the dye, dead cells do not). The major drawback to such
systems is that they do not refl ect the complexities of living animals and, hence, may not accu-
rately refl ect likely results of whole-body toxicity studies. Regulatory authorities are (rightly) slow
to allow replacement of animal-based test protocols until the replacement system is proven to be
reliable and is fully validated.
The exact range of preclinical tests that regulatory authorities suggest be undertaken for bi-
opharmaceutical substances remains fl exible. (Generally, only a subgroup of the standard tests
for chemical-based drugs is appropriate. Biopharmaceuticals pose several particular diffi culties,
especially in relation to preclinical toxicological assessment. These diffi culties stem from several
factors (some of which have already been mentioned). These include:

• the species specifi city exhibited by some biopharmaceuticals, e.g. GH and several cytokines,

means that the biological activity they induce in man is not mirrored in test animals;

• for biopharmaceuticals, greater batch-to-batch variability exists compared with equivalent

chemical-based products;

• induction of an immunological response is likely during long-term toxicological studies;

• lack of appropriate analytical methodologies in some cases.

In addition, tests for mutagenicity and carcinogenicity are not likely required for most biopharma-
ceutical substances. The regulatory guidelines and industrial practices relating to biopharmaceuti-
cal preclinical trials thus remain in an evolutionary mode, and each product is taken on a case-by-
case basis. An overview of the main preclinical tests undertaken for a sample biopharmaceutical
(Myozyme) is provided in Box 4.2.

4.13.3 Clinical trials

Clinical trials serve to assess the safety and effi cacy of any potential new therapeutic 'interven-
tion' in its intended target species. In our context, an intervention represents the use of a new
biopharmaceutical. Examples of other interventions could be, for example, a new surgical proce-
dure or a novel medical device. Veterinary clinical trials are based upon the same principles, but
this discussion is restricted to investigations in humans. Clinical trials are also prospective rather
than retrospective in nature, i.e. participants receiving the intervention are followed forward with
time.
Clinical trials may be divided into three consecutive phases (Table 4.4). During phase I trials,
the drug is normally administered to a small group of healthy volunteers. The aims of these stud-
ies are largely to establish:

• the pharmacological properties of the drug in humans (including pharmacokinetic and pharma-

codynamic considerations);