A Textbook of Clinical Pharmacology and Therapeutics

CLINICALTRIALS 87

CLINICAL TRIALS

Physicians read clinical papers, review articles and pharma-

ceutical advertisements describing clinical trial results. Despite

peer review, the incompetent or unscrupulous author can con-

ceal 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 essen-

tial 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 rigor-

ously 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 ques-

tions 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 treat-

ment 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 deter-

mined. 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 neces-

sary 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

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, record-
ing 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 out-
put screening and computer-aided drug design, new drugs
can now be identified more rationally.

PRECLINICAL STUDIES

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 devel-
opment has an excellent safety record, and there is under-
standable 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 dos-
ing 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.

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

• Discovery


• Screening


• Preclinical testing


• Phase I (usually healthy volunteers)


• Phase IIa


• Phase IIb


• Phase III (1000–5000 patients)

• Registration

• Phase IV

Early (exploratory)

development

Late (confirmatory)

development

Figure 15.1:Stages of drug development.