Drug Development

Drug Development
This process starts with the synthesis of
novel chemical compounds. Substances
with complex structures may be obtained
from various sources, e.g., plants
(cardiac glycosides), animal tissues
(heparin), microbial cultures (penicillin
G), or human cells (urokinase), or by
means of gene technology (human insulin).
As more insight is gained into structure-
activity relationships, the search
for new agents becomes more clearly
focused.
Preclinical testing yields information
on the biological effects of new substances.
Initial screening may employ
biochemical-pharmacological investigations
(e.g., receptor-binding assays
p. 56) or experiments on cell cultures,
isolated cells, and isolated organs. Since
these models invariably fall short of
replicating complex biological processes
in the intact organism, any potential
drug must be tested in the whole animal.
Only animal experiments can reveal
whether the desired effects will actually
occur at dosages that produce little
or no toxicity. Toxicological investigations
serve to evaluate the potential for:
(1) toxicity associated with acute or
chronic administration; (2) genetic
damage (genotoxicity, mutagenicity);
(3) production of tumors (onco- or carcinogenicity);
and (4) causation of birth
defects (teratogenicity). In animals,
compounds under investigation also
have to be studied with respect to their
absorption, distribution, metabolism,
and elimination (pharmacokinetics).
Even at the level of preclinical testing,
only a very small fraction of new compounds
will prove potentially fit for use
in humans.
Pharmaceutical technology provides
the methods for drug formulation.
Clinical testing starts with Phase I
studies on healthy subjects and seeks to
determine whether effects observed in
animal experiments also occur in humans.
Dose-response relationships are
determined. In Phase II, potential drugs
are first tested on selected patients for

therapeutic efficacy in those disease
states for which they are intended.
Should a beneficial action be evident
and the incidence of adverse effects be
acceptably small, Phase III is entered,
involving a larger group of patients in
whom the new drug will be compared
with standard treatments in terms of
therapeutic outcome. As a form of human
experimentation, these clinical
trials are subject to review and approval
by institutional ethics committees according
to international codes of conduct
(Declarations of Helsinki, Tokyo,
and Venice). During clinical testing,
many drugs are revealed to be unusable.
Ultimately, only one new drug remains
from approximately 10,000 newly synthesized
substances.
The decision to approve a new
drug is made by a national regulatory
body (Food & Drug Administration in
the U.S.A., the Health Protection Branch
Drugs Directorate in Canada, UK, Europe,
Australia) to which manufacturers
are required to submit their applications.
Applicants must document by
means of appropriate test data (from
preclinical and clinical trials) that the
criteria of efficacy and safety have been
met and that product forms (tablet, capsule,
etc.) satisfy general standards of
quality control.
Following approval, the new drug
may be marketed under a trade name
(p. 333) and thus become available for
prescription by physicians and dispensing
by pharmacists. As the drug gains
more widespread use, regulatory surveillance
continues in the form of postlicensing
studies (Phase IV of clinical
trials). Only on the basis of long-term
experience will the risk: benefit ratio be
properly assessed and, thus, the therapeutic
value of the new drug be determined.