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Clinical Pharmacology as a
Foundation for Translational Science
SA Waldman1, RJ Hohl2, GL Kearns3, SJ Swan4 and A Terzic5

he evolution of enabling
technologies and their associated
perspectives into molecular
mechanisms underlying disease has
extended beyond the abilities of scientific
and clinical structures to advance
their translation into new algorithms
that improve the health of patients
and populations.1 Research programs
have yielded a vast array of novel
molecules related to pathophysiological
mechanisms that represent diagnostic
and therapeutic targets that have the
potential for personalized health-care
management. Yet, despite extraordinary
scientific advances, routine successful
translation of discovery into new
therapeutic tools remains a distant vision.
Beyond constraints in bridging discovery
science with clinical translation due to
insufficient facilities, resources, and skilled
specialized investigators, 95% of therapies
brought into product development by
the pharmaceutical and biotechnology
sector eventually fail, primarily reflecting
insufficient efficacy.2,3
Appreciating the importance of
establishing equilibrium between
translation and discovery science, the
US Congress recently enacted the Cures
Acceleration Network (CAN), legislation
aimed at creating formal bridges

between molecular discoveries and

new health-care paradigms. Embracing
this mandate to facilitate translation
encompassed by CAN, the leadership of
the National Institutes of Health (NIH)
has created a vigorous path forward
by constituting a new National Center
for Advancing Translational Sciences
(NCATS). The portfolio for this center
includes advancing novel laboratorybased discoveries into potential
health-care technologies with reduced
commercial risk, in order to enhance their
attractiveness for future development by
the private sector.4 This mandate will be
accomplished by amalgamating programs
existing across the NIH that can advance
the development of scientific discoveries
to cross the translational divide. These
resources include the Molecular
Libraries Program (MLP), which offers
high-throughput screening capabilities
and libraries of compounds useful
for research and as therapeutics. For
example, the Chemical Genomics Center,
part of the MLP, provides a robotic,
high-throughput screening system and
a library of more than 350,000 small
molecules to interrogate fundamental
cellular mechanisms. The Therapeutics
for Rare and Neglected Diseases program
provides resources for preclinical drug

1Department of Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Department of Medicine,
Thomas Jefferson University, Philadelphia, Pennsylvania, USA; 2Departments of Internal Medicine and Pharmacology,
University of Iowa, Iowa City, Iowa, USA; 3Divisions of Pediatric Pharmacology and Medical Toxicology, Childrens
Mercy Hospitals and Clinics, Kansas City, Missouri, USA; 4American Society for Clinical Pharmacology and Therapeutics,
Alexandria, Virginia, USA; 5Divisions of Cardiovascular Diseases and Clinical Pharmacology, Departments of Medicine,
Molecular Pharmacology and Experimental Therapeutics and Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
Correspondence: SA Waldman ([email protected]) or A Terzic ([email protected])

doi:10.1038/clpt.2011.80
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development centered on rare disorders

of limited commercial interest. Finally,
the Clinical and Translational Science
Awards offer a nationwide platform
of institutions with infrastructures of
similar nature and a workforce that
ostensibly could advance the development
of therapeutics through patient- and
community-based studies. Coalescing
these resources has tremendous potential
to foster interactions between public and
private sectors that optimize the utility
of technology cores, minimize risk to
lower barriers to commercialization, and
coordinate transitions across communities
of practice (e.g., academiagovernment,
governmentpharmaceutical company)
that maximize translational efficiencies.
The genesis of NCATS reflects a modern
view of the scientific continuum from
molecules to global populations.5 It
envisions the advance of translation from
a discipline focused on new therapies
that palliate disease to the quantification
of pathobiological risk and disease
prevention.6 This center intends to exploit
existing and developing capabilities
to optimize the evolution of better
patient-centered health-care algorithms.
Furthermore, NCATS expects to catalyze
collaborations between stakeholders
emanating from siloed communities
within and between discovery,
development, and practice, investing
them in a publicprivate partnership
that is science-based, driving clinical
development that enhances efficiencies
and reduces risks associated with the
development of the next generation of
innovative health-care solutions.
Importantly, it is anticipated that
NCATS will contribute to producing
the next generation of clinical and
translational investigators. Equilibrating
the balance between discovery and
translation requires a cohort of
multidisciplinary investigators with
Clinical pharmacology & Therapeutics | VOLUME 90 NUMBER 1 | JULY 2011

fluency in the lexicon and paradigms

characterizing the laboratory and clinic to
enable integration of these widely different
domains.7 Also, rebalancing entails a
transition in professional culture that
rewards team science.8 This envisioned
future will require the creation of a brand
for clinical and translational science
that attracts novice investigators into
training programs in order to produce
the interdisciplinary teams that not only
maintain the balance between basic and
applied science but, most appropriately,
are capable of translating a discovery
into therapeutic interventions with great
promise for good.7,9,10
The creators of NCATS identified
clinical pharmacology as a foundational
element essential to success along the
discoveryapplication continuum.5
This recognition highlights clinical
pharmacology as one discipline at
the center of the field of clinical and
translational science. The key role for
clinical pharmacology in this emerging
science reflects its historic position as the
index discipline bridging the laboratory
and bedside (i.e., the translators of
translational science). Emanating from
the most fundamental inquiries into drug
actions, clinical pharmacology focuses
on two elementary questions: what do
drugs do to the body and what does the
body do to drugs? This concentration
on drug action and disposition yielded
the earliest paradigms of individualized
medicine in which the right drug is used
in the right patient at the right dose.1,11 In
addition, advances in the technologies and
approaches emanating from the field of
pharmacometrics have further positioned
clinical pharmacologists as domain
experts at each node of the continuum of
drug discovery, development, regulation,
and utilization. The continued centrality
of clinical pharmacology in translational
science is evidenced by its leadership
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in key international programs linking

the laboratory and clinic, including the
Pharmacogenomics Research Network,12
the US Food and Drug Administrations
Critical Path Initiative,13 and the Institute
of Medicines Committee on Qualification
of Biomarkers and Surrogate Endpoints in
Chronic Disease.14
Although NCATS offers a unique
opportunity to energize and further
develop the firmly established discipline
of clinical pharmacology in the United
States and many other parts of the world,
it is important that these efforts not be
used as either a tangential or overt attempt
to rebrand clinical pharmacology as the
emerging field of clinical and translational
science.7,9,10 Although translation will be
closely served by clinical pharmacology
especially across the continuum of drug
discovery, development, regulation, and
utilizationthese disciplines intersect as
opposed to merely coexisting. The core
competencies of clinical pharmacology,
including pharmacogenomics,
pharmacokinetics, pharmacodynamics,
pharmacoepidemiology,
pharmacovigilance, and
pharmacometricsto name a few
are tools critical to the therapeutic
translational paradigm. However, they
are also essential beyond the context of
clinical and translational science, and
they will be applied by investigators who
self-identify as clinical pharmacologists
but not as translational investigators.
Conversely, core elements of clinical
and translational science go beyond the
facets of clinical pharmacology; thus,
the portfolio of abilities of translational
scientists who are not trained in clinical
pharmacology, although valuable to the
overall efforts and goals of translational
science, may not be complete as
applied to addressing the intricacies
and idiosyncrasies of the drug therapy
paradigm. The inherent risk in rebranding
12

and folding clinical pharmacology into

clinical and translational science is the
possibility of dilution, attrition, or loss
of those central concepts, approaches,
and techniques that uniquely identify
clinical pharmacologists as practitioners.
The striking contraction of experienced
investigators in the fields of wholeanimal physiology and pharmacology,
which were overshadowed by molecular
experimentation, serves as a warning to
resist enveloping clinical pharmacology as
a discipline into clinical and translational
science, lest we lose the key elements of
the former, as a neglected stepchild, to
the higher-profile elements in clinical and
translational science.
The establishment of NCATS represents
one essential step in advancing the science
of translation. It integrates national
resources and programs to maximize the
discoverytranslation continuum. It should
crystallize partnerships among academic,
industry, and government organizations
that will accelerate the evolution of new
insights in molecular pathobiology into
novel diagnostics and therapeutic tools in
the armamentarium available for patient
care. Furthermore, it should create a
professional development path in clinical
and translational science and medicine
that will prepare the cadre of specialized
investigators invested in the culture of team
science. This vast promise and potential
can be realized only in the context of
meeting the great challenges that work
to minimize the impact of translation on
the health care of populations: inclusion
of broad communities of practice, failure
rates in drug development, establishing
performance metrics, and covering the
translational medicine continuum. The
goal for the new center is to gain early
adoption of the integration of discovery
science into validated transformational
patient-centered algorithms to address
unmet needs in health care. The critical
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path to realizing this goal leverages the

core competencies encompassing clinical
pharmacology as an essential and critical
discipline forming the foundation for the
emerging field of clinical and translational
science. The clinical pharmacology
community should embrace this goal and
work closely with NCATS, its leaders,
and the diverse communities of practice
contributing to the discoveryapplication
paradigm to translate this vision into
a reality that improves the lives of our
patients.
ACKNOWLEDGMENTS
As editor-in-chief of Clinical Pharmacology & Therapeutics,
S.A.W. was not involved in the review or decision process
for this article. As deputy editor-in-chief of Clinical
Pharmacology & Therapeutics, A.T. was not involved in
the review or decision process for this article. As chief
executive officer of ASCPT, S.J.S. was not involved in
the review or decision process for this article. R.J.H. was
president of ASCPT at the time of writing and, as such,
was not involved in the review or decision process for this
article. As secretary-treasurer of ASCPT, G.L.K. was not
involved in the review or decision process for this article.
CONFLICT OF INTEREST
The authors declared no conflict of interest.
2011 ASCPT

1. Waldman, S.A. & Terzic, A. Molecular therapeutics

from knowledge to delivery. Clin. Pharmacol. Ther. 87,
619623 (2010).

Clinical pharmacology & Therapeutics | VOLUME 90 NUMBER 1 | JULY 2011

2. Kola, I. & Landis, J. Can the pharmaceutical industry

reduce attrition rates? Nat. Rev. Drug Discov. 3, 711
715 (2004).
3. Paul, S.M. et al. How to improve R&D productivity: the
pharmaceutical industrys grand challenge. Nat. Rev.
Drug Discov. 9, 203214 (2010).
4. Butler, D. Translational research: crossing the valley of
death. Nature 453, 840842 (2008).
5. Rubenstein, A. Translational Medicine and
Therapeutics Working Group <http://smrb.od.nih.
gov/meetings/nov_meeting/ATTACHMENT7_
TMATPresentationNov102010.pdf> (10 November
2010).
6. Clancy, C. & Collins, F.S. Patient-Centered Outcomes
Research Institute: the intersection of science and
health care. Sci. Transl. Med. 2, 37cm18 (2010).
7. Skarke, C. & FitzGerald, G.A. Training translators for
smart drug discovery. Sci. Transl. Med. 2, 26cm12
(2010).
8. Waldman, S.A. & Terzic, A. Translational medicine in
the era of health care reform. Clin. Transl. Sci. 2, 9697
(2009).
9. Fitzgerald, G. Drug development needs a new brand of
science. Nature 468, 869 (2010).
10. Fitzgerald, G.A. Clinical pharmacology or translational
medicine and therapeutics: reinvent or rebrand and
expand? Clin. Pharmacol. Ther. 81, 1920 (2007).
11. Waldman, S.A. & Terzic, A. Molecular therapy drives
patient-centric health care paradigms. Clin. Transl. Sci.
3, 170171 (2010).
12. Giacomini, K.M. et al. The pharmacogenetics research
network: from SNP discovery to clinical drug response.
Clin. Pharmacol. Ther. 81, 328345 (2007).
13. Lesko, L.J. Paving the critical path: how can clinical
pharmacology help achieve the vision? Clin.
Pharmacol. Ther. 81, 170177 (2007).
14. Mack, A., Balogh, E. & Micheel, C.M. Perspectives on
Biomarker and Surrogate Endpoint Evaluation
Workshop Summary <http://www.iom.edu/
Reports/2011/Perspectives-on-Biomarker-andSurrogate-Endpoint-Evaluation.aspx> (2010).
Accessed 30 January 2011.

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