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
[email protected]

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

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

780 Biomarkers Med. (2010) 4(6) future science group

 Innovations driving biomarker evaluation & use Foreword
6 Kahn E, Batuman V, Lertora JJL: Emergence 12 Micheel CM, Ball JR: Evaluation of
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