alter biological activity. The potential for the repli-
cation of viruses or bacteria in fermenters, and their
persistence in finished drug product raise addi-
tional safety concerns arising from the manufactur-
ing process for such compounds. For the clinical
trialist, this leads to a generality: when studying
biologicals there is usually a greater need for early-
stage test medications to be as similar as possible to
the eventual marketed product than for ‘orthodox’
small chemicals. The same reasoning is the current
concern of regulators when trying to understand
and approve ‘generic’ biologicals that have not
been subjected to large-scale clinical trials demon-
strating bioequivalence.
22.6 Product classes
and resultant clinical trial
issuesMany of the principles outlined in other chapters
for phase I and II studies of these compounds
are equally applicable to the testing of most
biotechnology products. The same basic principle
of demonstrating clinical tolerability as a priority
over proving efficacy must apply. Other chapters
also discuss some specific toxicology and drug
discovery aspects of biotechnology products.
The general design of a development program
for a biological product has the same principles as
for ordinary drugs, and this should be familiar to
the competent clinical trialist. The development
program should be determined by the nature and
needs of the disease; often the pharmacological
activity of a biological product is likely to be
very precise. For example, an antibody will bind
to a previously identified narrow range of antigens,
and the pathogenesis or source of antigen presenta-
tion will have a fixed relationship to a well-
described disease or set of diseases. Equally useful
in the case of biologics is to begin development
with an agreed, desirable package insert or product
information leaflet. That document can then be
used to define the development strategy. Only
those tactics (i.e. clinical trial designs, milestones
and product-killing findings) that are justified or
validated by that strategy should be implemented.
The nature and seriousness of the disease being
treated is just as important as in more orthodox
clinical trials. The degree of lethality or morbidity
associated with the disease treated with existing
therapies is correlated positively with the degree of
intolerability of the test agent that may be accepted.
The trialist’s first general concern, of course, is
tolerability. Most biological products carry a
higher probability of antigenic immune response,
compared with small molecules, because of their
large size. However, the range of target-organ toxi-
cities is usually narrower, and directly related to the
specific receptors (using that term in a loose sense),
to which the product is targeted. Clinical trialists
should also be careful not to ignore the toxicologi-
cal potential of the often large amounts of vehicle,
with unusual ionic strengths, buffering materials,
nonphysiological pH or unusual preservatives (e.g.
cresols for insulin) which may be required to main-
tain complex peptides in a stable form. These
‘inactive’ product ingredients can have their own
nephrotoxic, hepatotoxic and allergenic properties.
The clinical trialist who switches to a biological
product will nonetheless use familiar tactics to
prove efficacy. With ‘breakthrough’ agents that
offer the potential for a new type of therapy, clinical
trialscan beconductedcomparing thetrialagenttoa
placebo. The central ethical consideration will
usually be about whether standard treatment
(if any) can be withheld, and the debate is not
about the use of placebo in an absolute sense.
Dose–response relationships need to be evaluated
forbiologicalagentspriortoapprovalevenwhenthe
biological response is an ‘all or nothing’ type of
response (e.g. serological conversion, when the pro-
portion of responding patients may be the end point
of interest). It should be remembered that dose–
responserelationships must beunderstood forpopu-
lations, as well as for the range among individuals.
Therapies like vaccines need also to be evaluated in
different racial populations, and in other types of
special populations, such as the elderly.22.7 Peptides
For a long time, interest in biotechnology centered
on the production and properties of administered282 CH22 BIOTECHNOLOGY PRODUCTS AND DEVELOPMENT