INTRODUCTION TO BIOMARKERS - Flow Cytometry in Drug Discovery and Development - page 62

24 h interval, the first at 1:00 pm and the second at 9:00 pm [36]. In this case, the best
design would be to perform measurements of 7- -hydroxy-4-cholesten-3-one in

samples collected before dosing at the same time points as after dosing. Alternatively,
the area under the curve can be calculated and the results compared between placebo-
and drug-treated subjects.
An interesting concept of clinical studies is the use of adaptive trial design,
“adapting by design,” where several doses are being explored in a single trial, but data
are reviewed in real time to allow for an adoption based on the emerging data [37].
This concept assumes that during the course of a clinical study, with multiple doses
and a control arm, the emerging data will guide the clinical team to modify (adapt) the
study dose groups in response to the data being collected [38].
In most early clinical development studies, the biomarker is a secondary objective
together with the PK measurements. However, in a few studies, the biomarker has
been listed as a primary objective of the study. These are usually translational
medicine studies where a biomarker hypothesis is tested and study designed based
on this hypothesis. For example, based on preclinical evidence if it is likely that
subjects with a particular mutation might respond better to a drug that otherwise is
expected to have low response rate in that disease setting, primary objective of this
phase I or phase 0 study would be to stratify patients into two arms (mutant and wild
type) for hypothesis testing and building on this hypothesis based on results of interim
analysis. The clinical team should have a clear strategy as to how this biomarker data
would be used to support further clinical development. Further, in studies where
biomarkers are deemed to be important as primary objectives of the study, collection
of biomarker samples (serum, plasma, tissues, etc.) must be made mandatory and
should be part of inclusion criteria for enrollment. Clinical sites that demonstrate high
success in patient consent for mandatory samples as well as collecting good quality
samples should be selected. Relevant biomarker assays must be developed, analy-
tically validated, and carefully scrutinized prior to implementation into the study. The
number of samples as well as number of subjects needed for obtaining statistically
significant biomarker data must be determined and included in the protocol. Overall,
biomarker development in early trials helps to gather proof of concept for drug MOA,
provides rationale for drug dose and frequency, may explain clinical outcomes, and
may help identify responding patient population.

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3.7.4 Biomarker in Late Clinical Development

When drugs enter into late clinical development (phases III and IVand in some cases
phase II) and measurements of a biomarker are planned, it is of utmost importance
for the clinical team and the biomarker laboratory to discuss the intended use of the
biomarker. This discussion should address the importance of the biomarker in
the planned study and what kind of laboratory qualification will be necessary to
ensure that high-quality biomarker results are delivered. The safety consequences of
incorrectly including a patient into the study have to be discussed when the intended
use is for inclusion/exclusion. This discussion may also lead to further discussion
about the analytical accuracy of the biomarker method. An example of this is