provide the necessary clarification and may repre-
sent corrective action.
37.3 Phase IV studies
Clinical trials conducted by Medical Affairs divi-
sions that are categorized as phase IV studies are
those that are conducted while the drug is already
in themarket. This can include safety and efficacy
questions that arise on further experiencewith the
drug, or the pursuit of clinical trials to examine
the efficacy of the drug relative to newer agents
entering the market. The two main types of stu-
dies that are performed are those that are pursued
to respond to specific requests of health authori-
ties which were stipulated in the initial approval
of the drug (phase IV commitments) and those
studies conducted to answer medical questions
that are raised while the drug is being used in the
clinic. The former can be considered studies ana-
logous to phase IIIb studies which are conducted
at a different time point in the product cycle,
while the latter are usually the results of extensive
discussion with health authorities aimed to
answer specific questions raised by the agency
itself or by members of advisory committees
responsible for providing guidance to the health
authority at the time of initial evaluation of drugs
for approval.
Phase IV commitments can bevariedin aimsand
scope. In order to expedite the market availability
of novel drugs that can improve human health,
health authorities make qualitative assessments of
the value of delaying approval versus requesting
more efficacy or safety information. A process that
allows novel drugs to enter the market while assur-
ing further safety and efficacy monitoring is to
approve drugs with stipulations as to the types of
additional studies a company will commit to per-
forming in a reasonable time period after drug
approval. These phase IV commitments generally
take the form of longer trials assessing safety, or
trials which address efficacy in specific patient
populations which may be at greater risk of side
effects or have the potential to experience a greater
degree of efficacy, but were not studied in the
program designed for original registration, as the
latter usually focuses on patient population in
which the drug would most likely be used.
The design of phase IV commitments can
include the traditional approach of a randomized,
double-blind, placebo-controlled study, an open-
label trial or can be approachedviathe establish-
ment of patient registries. In the case of compara-
tive trials in a phase IV environment, drugs are
much more commonly compared to other approved
therapies. The use of placebo arms is much less
common due to the desire to allow the most ‘real-
world’ use of the drug (where placebo is not given).
The vast majority of such trials are conducted
blinded to study allocation to reduce the chance
that identification of study drug biases the per-
ceived benefits in favor of the novel medicine.
There are, however, examples of phase IV studies
that are conducted as ‘open-label’ trials, whereby
both drugs can be identified by both patients and
treating physicians. The ability to make definitive
conclusions concerning relative safety and efficacy
can be compromised by the potential for bias,
particularly if the outcome measures chosen are
patient- or physician-reported. Nevertheless, this
type of trial can be reasonably conducted in eval-
uating the effect of therapy using more robust out-
comes that would not be affected necessarily by
knowledge of drug allocation, such as blood glu-
cose levels, blood pressure measurements or time
to myocardial infarction and so on.
Often the size of clinical trials in a phase IV
environment, which provides sufficient power to
assess outcomes between two drugs shown pre-
viously to be effective, is large. Thus, in this set-
ting, perhaps more than any other, patient
recruitment and retention are key to the successful
enrollment and ultimate interpretability of trial
results. Pharmaceutical, governmental (i.e. NIH)
and academic groups sponsoring such phase IV
studies often require additional staff to resource
these trials adequately. An industry has developed
to assist sponsors in the conduct of clinical trials,
and can be of particular benefit to smaller compa-
nies which do not have the internal resources to
conduct clinical trials on their own, or by larger
companies whose resources are occupied in other
trials. These include Contract Research Organiza-
tions (CROs) which can design, implement,522 CH37 MEDICAL AFFAIRS