Principles and Practice of Pharmaceutical Medicine

analyze and report the results of clinical trials, and
Site Management Organizations (SMOs), which in
large part participate in the recruitment and mon-
itoring of randomized patients at individual or
small groups of clinical research centers without
the necessary staff to adequately follow clinical
trial subjects.
Phase IV studies can also take the form of patient
registries to determine the effect of a new drug on
very rare outcomes. Such studies can be regarded as
a form of industry-sponsored prospective cohort
study. Generally these registries are established to
exclude the possibility of rare adverse events which
requireverylargesamplesizestodetect.Registering
users of the new medications while in the market
and following outcomes as they occur with simple
questionnaires is one way such research can be
conducted. Within the cohort being followed,
‘nested’ case control studies can also be conducted
to understand the association of very rare outcomes
with drug exposure, adjusting for factors that could
theoretically influence outcomes.
Because of the size of phase IV studies and
particularly for those focused on adverse events,
some special form of safety monitoring is generally
indicated. Although this is more common in the
phase III environment, where the safety and effi-
cacy of the drug are less well known, with broad
exposure of patients and large clinical trials even
for phase IV trials, the potential exists for a large
number of adverse events to occur prior to full
analysis of the data, which would otherwise pro-
vide a signal as to a side effect meriting further
evaluation. If trials are especially large or are
enrolled very rapidly, this is especially useful.
Thus the creation of data and safety monitoring
boards (DSMB) has become routine in pharmaceu-
tical and government-sponsored trials. The respon-
sibilities of DSMB are generally documented in a
charter which stipulates the leadership and mem-
ber, as well as their roles and responsibilities. The
main reason to establish a DSMB is to determine
whether any safety signal is recognized sufficient
to change the course of a clinical trial. Other rea-
sons can include the establishment of a group of
‘disinterested’ individuals who are not directly
connected to the trial to assess trial progress in
regard to outcomes such as efficacy or safety end

points that could lead to a sample size recalculation

or protocol amendments. Usually these boards are

comprised of prominent clinicians and clinical

trialists in the field, epidemiologists and statisti-

cians. There is usually also at least one ‘unblinded’

statistician with knowledge of treatment alloca-

tion, allowing analysis of data based on the treat-

ment in order to assure that any adverse reactions

can be reported to the DSMB according to treat-

ment allocation, if appropriate. The DSMB is led

by a Chairperson who organizes the board and

establishes a schedule of meetings based on clin-

ical trial metrics or time intervals. Decisions of the

DSMB are communicated to the clinicians primar-

ily responsible for trial conduct, which can include

simply continuing the trial, modifying it via

amendment or even potentially halting it.

37.4 Data mining in the phase IV

environment

Phase IV studies can also take the form of retro-

spective pooled analyses which are designed to

reflect the totality of clinical research experience

with a new drug which is usually obtainedvia

analysis of pooled clinical trial databases. Such

‘data-mining’ efforts should not be considered

inferior to data obtained from the conduct of an

individual clinical trial. In fact, there are substan-

tial benefits of such an approach, as the results of a

given trial, especially if the end point is not pre-

specified to be primary because of power limita-

tions, can be afunction of chance. To assure that the

results obtained from pooled analyses are not

biased, a prespecified data analysis plan is often

formulatedas the first step, outliningthe cleargoals

of the proposed analysis as well as its methodology.

Key to this type of analysis is the definition of the

outcome measure. Both efficacy and safety mea-

sures can be the focus of these types of analyses.

Pooled analyses are commonly used to assess

the safety of drugs that have been already evaluated

on an individual subject level by adjudication com-

mittees. Such committees are usually comprised of

a combination of clinicians, epidemiologists and

statisticians, who meet to discuss the specifics of

prespecified, suspected adverse events, in order to

37.4 DATA MINING IN THE PHASE IV ENVIRONMENT 523