Clinical Pharmacology and Therapeutics

CLINICAL TRIALS 87
• Discovery
• Screening
• Preclinical testing
• Phase I (usually healthy volunteers)
• Phase IIa
• Phase IIb
• Phase III (1000–5000 patients)
* Registration
• Phase IV
of practice, namely Good Manufacturing Practice (GMP),
Good Laboratory Practice (GLP) and Good Clinical Practice
(GCP). Good Clinical Practice is an international ethical and
scientific quality standard for designing, conducting, recording
and reporting trials that involve the participation of
human subjects. The stages of drug development are outlined
in Figure 15.1.
DRUG DISCOVERY, DESIGN AND SYNTHESIS
Whilst random screening and serendipity remain important
in the discovery of new drugs, new knowledge of the role of
receptors, enzymes, ion channels and carrier molecules in
both normal physiological processes and disease now permits
a more focused approach to drug design. Using advances in
combinatorial chemistry, biotechnology, genomics, high output
screening and computer-aided drug design, new drugs
can now be identified more rationally.
PRECLINICAL STUDIES
Proof of principle
Proof of concept
Cost is approximately £500 million, 60% of which is spent in
clinical trials. Time from discovery to registration approximately
10–13 years
Figure 15.1: Stages of drug development.
Early (exploratory)
development
Late (confirmatory)
development
New chemical entities are tested in animals to investigate their
pharmacology, toxicology, pharmacokinetics and potential
efficacy in order to select drugs of potential value in humans.
Although there is considerable controversy concerning the
value of some studies performed in animals, human drug development
has an excellent safety record, and there is understandable
reluctance on the part of the regulatory authorities
to reduce requirements. At present, the European guidelines
require that the effects of the drug should be assessed in two
mammalian species (one non-rodent) after two weeks of dosing
before a single dose is administered to a human. In addition,
safety pharmacology and mutagenicity tests will have been
assessed. Additional and longer duration studies are conducted
before product licence approval. The timing, specific tests and
duration of studies may relate to the proposed human usage
in both the clinical trials and eventual indications.
CLINICAL TRIALS
Physicians read clinical papers, review articles and pharmaceutical
advertisements describing clinical trial results. Despite
peer review, the incompetent or unscrupulous author can conceal
deficiencies in design and possibly publish misleading
data. The major medical journals are well refereed, although
supplements to many medical journals are less rigorously
reviewed for scientific value. An understanding of the essential
elements of clinical trial design enables a more informed
interpretation of published data.
Assessment of a new treatment by clinical impression is
not adequate. Diseases may resolve or relapse spontaneously,
coincidental factors may confound interpretation, and the
power of placebo and enthusiastic investigators are a major
influence on subjective response. In order to minimize these
factors and eliminate bias, any new treatment should be rigorously
assessed by carefully designed, controlled clinical trials.
All physicians involved in clinical trials must follow the
guidelines of the Declaration of Helsinki and subsequent
amendments.
OBJECTIVES
The first step in clinical trial design is to determine the questions
to be addressed. Primary and achievable objectives must
be defined. The question may be straightforward. For example,
does treatment A prolong survival in comparison with treatment
B following diagnosis of small-cell carcinoma of the
lung? Survival is a clear and objective end-point. Less easily
measured end-points such as quality of life must also be
assessed as objectively as possible. Prespecified subgroups of
patients may be identified and differences in response determined.
For example, treatment A may be found to be most
effective in those patients with limited disease at diagnosis,
whereas treatment B may be most effective in those with
widespread disease at diagnosis. Any physician conducting a
clinical trial must not forget that the ultimate objective of all
studies is to benefit patients. The patients’ welfare must be of
paramount importance.
RANDOMIZATION
Patients who agree to enter such a study must be randomized
so that there is an equal likelihood of receiving treatment A or B.
If treatment is not truly randomized, then bias will occur. For
example, the investigator might consider treatment B to be
less well tolerated and thus decide to treat particularly frail
patients with treatment A. Multicentre studies are often necessary
in order to recruit adequate numbers of patients, and it is
essential to ensure that the treatments are fairly compared. If
treatment A is confined to one centre/hospital and treatment
B to another, many factors may affect the outcome of the
study due to differences between the centres, such as interval