Foreword

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Innovations driving biomarker evaluation and use

John A Wagner
“Advances in multiplexed technology have driven innovative use of genetic Department of Clinical Pharmacology,
and proteomic testing, such as gene signatures in drug development … and are Merck Research Laboratories, 126 East
rapidly expanding into widespread use for individualized testing as diagnostics in Lincoln Avenue, PO Box 2000,
medical practice.” RY34-A548, Rahway, NJ 07065, USA
Tel.: +1 732 594 0274
Fax: +1 732 594 5405
wagner@merck.com

By now, the broad definitions that a biomarker
is a characteristic, measured and evaluated
as an indicator of normal biologic processes,
pathogenic processes, or pharmacological
responses to a therapeutic intervention, and a
surrogate end point that is intended to substi-
tute for a clinical end point and is expected
to predict clinical benefit (or harm, or lack
of benefit or harm) based on epidemiologic,
therapeutic, pathophysiologic or other scientific
evidence, are well known [1] . Biomarkers are
measurements that have become very power-
ful tools for drug development, medical prac-
tice, diagnosis and regulation throughout the
healthcare sector.
Typically, biomarkers start with discovery.
Some of the most compelling recent develop-
ments in biomarker discovery center around
multiplexed platforms, which include genomic-
and proteomic-based biomarkers. Advances in
multiplexed technology have driven innovative
use of genetic and proteomic testing, such as
gene signatures in drug development [2] , and
are rapidly expanding into widespread use for
individualized testing as diagnostics in medical
practice. As highlighted by Boja et al. in this
issue, the development and implementation of
verification methodologies for proteomics is
expected to drive biomarker discoveries into
qualified US FDA biomarkers [3] . The complex
issues surrounding evidentiary links for multi-
plexed biomarkers have also been highlighted
by the controversial use and interpretation of
direct-to-consumer genetic testing [4] .
Discovery and implementation of safety bio-
markers has also enjoyed rapid growth over the
last several years, as evidenced by a dramatic
increase in the use of the safety biomarker QT
interval in US labels, driven, at least in part,
by recent regulatory requirements [5] . Other
innovative safety biomarkers are now emerging,
as described by Khan et  al. in this issue  [6] .
Creatinine has long been recognized as an
inadequate biomarker of renal injury, resulting
in delayed diagnosis, which drives the discov-
ery of novel biomarkers to detect early kidney
damage, including cystatin C and Kim‑1.
“Biomarkers are measurements that have
become very powerful tools for drug
development, medical practice, diagnosis
and regulation throughout the
healthcare sector.”
The use of biomarkers is a major tool
for drug development. American [101] and
European  [102] regulatory scientists strongly
advocate for biomarkers as a centerpiece for
the strategy to increase the efficiency of drug
development. A surrogate end point is a bio-
marker that is intended to substitute for a clini-
cal end point and is expected to predict clinical
benefit based on epidemiologic, therapeutic,
pathophysiologic or other scientific evidence [1] .
In confirmatory drug development, a quali-
fied surrogate end point drives the improve-
ment of public health through the regulatory
review and approval of new therapeutics. In
fact, indications associated with surrogate end
points and efficient clinical end points enjoy
many more approved therapeutics than those
without  [7] . A key biomarker nomenclature
distinction for drug development is between
target engagement and disease-related bio-
markers, which is useful in decision-making
in the context of drug development [8] . Target
engagement biomarkers measure ‘how hard’ a
drug hits a particular target. Disease-related
biomarkers are more closely associated with
clinical end points and can be capable of pre-
dicting clinical benefit, and, thus, can be quali-
fied as surrogate end points. The combination

10.2217/BMM.10.114 © 2010 Future Medicine Ltd Biomarkers Med. (2010) 4(6), 779–781 ISSN 1752-0363 779
Foreword Wagner
of target engagement and disease-related bio-
markers are extremely useful in drug develop­
ment, since target engagement biomarkers
demonstrate that the clinical hypothesis is ade-
quately tested and disease-related bio­markers
are used to test the crucial proof-of-concept
hypothesis. Krishna and Wagner highlight the
role of decisionable biomarkers in early drug
development using the cardiovascular area as
an example [9] . Prospectively used bio­markers
have been demon­strated to improve the quality
of decision-making, accelerate drug develop­
ment, facilitate effective trial designs, drive
dose selection and improve the probability of
success. Also in this issue, Kearns extends the
more routine concepts of biomarkers in drug
development to children, pointing out that
appropriate biomarker use is essential in the
process of pediatric drug develop­ment  [10] .
Terzic and Waldman augment the inf lu-
ence of biomarkers on drug development to
transforming traditional healthcare practices
by using individualized medicine based on
patient‑specific biomarkers of disease [11] .
“Analytical validation of the individual
biomarkers is recognized as having central
importance. Qualification is the critical
evidentiary link between the biomarker and
the disease state. Utilization refers to the
crucial impact of the context on both the
validation and, more importantly,
the qualification.”
The regulatory view of biomarkers is wider
than drugs and diagnostics for medical thera-
peutics. Increasingly, biomarkers are being pro-
posed as the basis of health claims for foods.
Owing to this important trend, the Center
for Food Safety and Applied Nutrition of the
FDA commissioned a study, by the Institute
of Medicine, on a framework of the evaluation
process for biomarkers, with a focus on biomar-
kers and surrogate end points in chronic dis-
ease. The resulting report, entitled ‘Evaluation
of Biomarkers and Surrogate Endpoints in
Chronic Disease’, was published on May 12th
2010 and has far-reaching and high-impact
implications for the use and regulation of
biomarkers [12] .
This landmark biomarker report recom-
mends a harmonized scientific process and a
general framework for biomarker evaluation.
The recommended biomarker evaluation
framework includes analytical validation, qual-
ification and utilization. Analytical validation
780 Biomarkers Med. (2010) 4(6)
of the individual biomarkers is recognized
as having central importance. Qualification
is the critical evidentiary link between the
biomarker and the disease state. Utilization
refers to the crucial impact of the context on
both the validation and, more importantly,
the qualification.
“Biomarkers continue to promise and deliver
important effects throughout medical
practice and the biomedical industry.”
A central tenet of the report is that a uni-
form scientific process and set of criteria for
the success and failure of biomarkers should
apply across the spectrum of healthcare, includ-
ing drugs, medical devices, biologics, nutrients
and foods. In other words, ‘science is science,’
and the same level of scientific evidence for
benefit and risk is needed for foods, drugs or
any regulated medical use. It could certainly be
argued that some interventions, such as drugs,
are inherently riskier than others, including
food, and, therefore, the evidence associated
with biomarker claims made for foods does
not need to be as rigorous or could be dictated
by other standards. However, foods are used
by far greater numbers of individuals with less
professional guidance than drugs. Therefore,
there is no basis for stipulating a lesser evi-
dentiary standard for biomarker claims made
regarding food. A criticism of the report is that
the biomarker evaluation framework lacks the
granularity to maximize its usefulness.
This issue highlights the evaluation and
use of biomarkers in medical practice and
drug development. Numerous benefits are evi-
dent from the appropriate use of biomarkers,
including more accurate and earlier diagnoses,
individualized therapy, improved usage, and
increased efficiency and quality of decision-
making in drug development. Biomarkers
continue to promise and deliver important
effects throughout medical practice and the
biomedical industry.
Financial & competing interests disclosure
The author is an employee of Merck & Co., Inc. and may
potentially own stock and/or hold stock options in the
Company. The author has no other relevant affiliations or
financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from
those disclosed.
No writing assistance was utilized in the production of
this manuscript.
future science group
 Innovations driving biomarker evaluation & use Foreword
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