INTRODUCTION TO BIOMARKERS - Flow Cytometry in Drug Discovery and Development - page 53

Althoughmost biomarkers are used to assess the pharmacodynamic effects of drugs to
better understand the dose relationship, we are now entering an era where biomarkers
will play a role in creating a more personalized approach to drug treatment of patients
leading to the development of better and safer drugs for patients. Thus, biomarkers are
emerging to be an integral part of drug development and playing an important role
in screening, diagnosis, prognosis, therapy selection, and disease monitoring. We will
in this chapter discuss the use of biomarkers in different stages of clinical drug
development.
3.2 TYPES OF BIOMARKERS
A biomarker is defined as a characteristic that is objectively measured and evaluated
as an indicator of normal biological processes, pathogenic processes, or pharmaco-
logical responses to a therapeutic intervention [2]. Biomarkers that are typically
evaluated during clinical development of a drug fall into four main categories:
pharmacodynamic (PD) and mechanism of action (MOA), predictive, prognostic,
and surrogate biomarkers [3]. PD biomarkers determine whether a drug interacts with
the target and modulates the biological pathway. The PDmarkers are used to evaluate
theMOA of the drug, to perform pharmacokinetic (PK) and PD (PK/PD) correlations,
and to determine the dose of the drug and frequency of dosing. PD biomarkers
are usually evaluated early in drug development using research-use-only (RUO) tests
that need to be validated for clinical implementation. PD markers that are commonly
monitored in various therapeutic areas include markers of inflammation, prolifera-
tion, and apoptosis.
Predictive biomarkers are those that are used to identify patients most likely to
respond or least likely to suffer an adverse event when treated with a drug. Some of the
widely used predictive biomarker tests include diagnostic tests: testing for protein
expression and gene amplification of human epidermal growth factor receptor 2
(HER2) for Herceptin treatment [4]; test for Philadelphia chromosome (Ph)-positive
chronic myeloid leukemia for predicting response to Gleevec [5]; and KRAS
mutation test for predicting response to anti-EGFR therapies (panitumumab and
cetuximab) in colorectal cancer patients [6]. Greatest impact of predictive biomarkers
occurs when they are developed and validated prior to the launch of the drug.
However, this will require evaluation of the predictive marker(s) in prospective
adaptive trials and in randomized phase II/III studies to determine if the marker(s) is
(are) predictive to the specific treatment.
Biomarkers that predict the course of the disease independent of drug treatment fall
under prognostic markers. CellSearch (for evaluating circulating tumor cells in
prostate [7], breast [8], and colorectal cancers [9]), MammaPrint (for breast cancer
metastasis [10]), and Oncotype DX (for breast cancer recurrence [11]) are some of the
approved prognostic biomarker tests in use to assess disease prognosis. Biomarkers
such as CA 125 or CA 19-9 are widely being used to monitor response to therapy and
predict reoccurrence of ovarian, pancreatic, and colon cancer [12]. Surrogate markers
are those markers that substitute for clinical approved end points and predict clinical