1. Healthcare

Clinical Utility: Informing Treatment
Decisions by Changing the Paradigm
Robert T. McCormack and Paul R. Billings*
January 29, 2015
*The authors are participants in the activities of the IOM Roundtable on Translating GenomicBased Research for Health.
The views expressed in this discussion paper are those of the authors and not
necessarily of the authors’ organizations or of the Institute of Medicine. The paper is
intended to help inform and stimulate discussion. It has not been subjected to the
review procedures of the Institute of Medicine and is not a report of the Institute of
Medicine or of the National Research Council.
Copyright 2015 by the National Academy of Sciences. All rights reserved.
The types of evidence needed to support the use of genome sequencing in the clinic varies by
stakeholder and circumstance. In this IOM series, seven individually authored commentaries
explore this important issue, discussing the challenges involved in and opportunities for moving
clinical sequencing forward appropriately and effectively.
Clinical Utility: Informing Treatment Decisions by
Changing the Paradigm
Robert T. McCormack, Janssen Oncology; and Paul R. Billings, Thermo Fisher Scientific1, 2
Recent improvements in cancer treatment and patient survival can be attributed, in part, to
several initiatives. Most notable was the challenge by the Food and Drug Administration (FDA)
to pharmaceutical and device developers to identify biomarkers that determine those patients
most likely to respond to a drug. This has long been considered an essential step toward
personalized medicine. Achieving this challenge was greatly enabled by the substantial technical
innovations that made it possible to identify these new markers. The development of nextgeneration sequencing, for instance, provided a groundswell of information on genetic changes
that drive the growth of tumors, and the technology continues to form the basis for development
of these highly specific and effective drugs. Today, more than 100 molecularly defined
biomarkers are associated with commercially available drugs or drugs under development (Aston
and Lovly, 2014).
Our success in developing targeted therapies has been impressive, but the path forward is
challenging and filled with uncertainty. For example, next-generation sequencing and other
newly developed technologies that work sequentially or in parallel to sequencing technologies
have enabled nearly complete analysis of a patient’s DNA (genome), RNA (transcriptome),
protein (proteome), and posttranslational (epigenomic) modifications, yielding significant
insights into the basic biology of cancer. However, these technologies have also brought to light
the true heterogeneity or complexity of common cancers and revealed that tumor resistance to
therapy occurs frequently, underscoring the need to continually assess tumors with these
technologies to anticipate tumor behavior and retarget therapy. All this information is directional
toward developing new anti-cancer treatments, but the data need to be considered with the
understanding that next-generation technologies are new, complex, different in their
performance, and known to introduce errors in reading (Hudson et al., 2014). This complexity
has contributed, in part, to a long-standing uncertain regulatory and reimbursement environment
for in vitro devices that has stymied both investment and momentum in diagnostic technology for
some time (Hayes et al., 2013).
Furthermore, although the clinical trial requirements for pharmaceuticals is understood and
followed for all new drugs, an interesting situation has occurred with next-generation sequencing
1
The authors are participants in the activities of the IOM Roundtable on Translating Genomic-Based Research for
Health.
2
Suggested citation: McCormack, R., and P. Billings. 2015. Clinical utility: Informing treatment decisions by
changing the paradigm. Discussion Paper, Institute of Medicine, Washington, DC.
http://www.iom.edu/ClinicalUtility.
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in cancer. Clinicians quickly realized that driver mutations identified by next-generation
sequencing are not unique to a specific cancer type, thus opening up the potential for off-label
use of the targeted therapeutic. For example, drugs approved safe and effective for use with a
specific mutation in one cancer, such as breast, could be equally safe and effective in other
cancers, such as prostate, harboring the very same mutation. Unfortunately, these situations are
not necessarily “quick wins." Even though the leap for an approved targeted drug that has
demonstrated safety and effectiveness in one cancer to another cancer might be considered less
risky than using a drug without any evidence of effectiveness and unknown safety, much of the
same lengthy and expensive trials to demonstrate effectiveness in the off-label indication are
required by regulators, payers, guideline developers, and providers before it is readily accepted
as standard of care.
Collectively, it is becoming clear that our ability to develop new technology and acquire
potentially breakthrough information to benefit patients has exceeded our ability to readily
reduce that information to practice within the confines of the existing clinical, regulatory, and
reimbursement practices or requirements. The common denominator for much of this difficulty
is insufficient evidence at all levels, from the laboratory test, to the laboratories conducting the
testing, and to the repurposing of drugs for off-label use against a biomarker previously shown to
be susceptible to that drug.
For laboratory tests not developed as a companion diagnostic, the unequivocal demonstration
of clinical utility has become the main requirement for a test to be covered by payers. Simply
stated, clinical utility is defined as the use of a clinical test’s result to make a treatment decision
that positively changes the outcome of a patient (Teutsch et al., 2009). This level of evidence
represents a substantial challenge to all test developers and laboratories. Such studies are long
and represent a human and financial commitment beyond the means of many companies. In
addition, even if reimbursement is achieved, it usually represents a fraction of the company’s
commitment to develop the technology, making such an investment unattractive (Hayes et al.,
2013).
However, recent efforts from all stakeholders to remedy the situation have resulted in
progress across most of these barriers, especially as they pertain to next-generation technologies.
Specifically, FDA guidance to standardize the level of performance across device manufacturers,
technologies, and laboratories culminated in renewed regulatory direction (FDA, 2014).
Although debatable, this guidance is aimed at obtaining a common ground and level of evidence
for all device entities to achieve and move forward more confidently.
Moreover, creative approaches to clinical studies have been implemented, such as stratifying
clinical trials that use participant selection and biomarkers to enable rapid assessment of drug
performance requiring fewer enrollees and, in many instances, less time (Tajik et al., 2013). This
was complemented by efforts to create large databases as repositories for all biology and
treatment decision results that could translate what was learned to a much wider audience of
physicians struggling with the same problem, closing information gaps and guiding treatment
decisions with confidence (Schilsky et al., 2014). These efforts will greatly accelerate clinical
studies into testing these potentially new markers and acquire much-needed evidence and
confidence supporting their use.
The most recent opportunity to overcome these barriers comes in off-label use of currently
approved targeted therapies. The proposed concept recognizes that relevant evidence on the
drug’s safety and effectiveness exists and could translate to other cancers and patients but that
exceptions do exist and patients’ safety must take priority (Di Nicolantonio et al., 2008). This
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recent proposal conceptualizes a clinical registry trial that tightly defines patient eligibility and
reasonable response end points, captures all patients’ demographic and clinical information in a
database for continual learning, and is administered by a national oversight board for objective
decision making. The patient is monitored closely for safety and therapeutic benefit or failure,
and costs and risks are shared by all stakeholders (Schilsky, 2014). A similar model has also
been suggested that proposes data sharing and early reviews of outcomes for appropriateness, but
with the addition of payer coverage of all labeled drugs (Billings and Shather, 2014).
This proposed framework allows for the accumulation of requisite data to fulfill regulatory
and payer requirements for both the drug and device, while offering potentially beneficial
therapy to patients in a controlled-risk environment. Such a departure from standard regulatory,
clinical, and reimbursement practices was many years in the making and is less radical when
viewed as a part of the methodical approach to collecting sufficient evidence from the bench to
the patient, thus assuring patient safety, potential benefit, and possible new device-drug
indications, all developed in a new paradigm. It is most appropriate that new technologies such
as next-generation sequencing that initiated this evolution of personalized medicine are also
largely responsible for this new paradigm.
Below are three key issues we believe should be addressed to facilitate making treatment
decisions using genomic-based technologies:
1. Clinical utility is a necessary addition to the evidentiary requirements for new
technologies, but processes to define and measure clinical utility must be identified.
2. New paradigms in which all stakeholders share the burden and benefits of demonstrating
such a level of evidence are required to rapidly translate findings from discovery to
patient benefit.
3. To accommodate potentially beneficial new technology, there is a need for regulatory and
reimbursement practices to be forward thinking to define a clear path to approval and
coverage, avoiding delays in implementation once appropriate levels of clinical utility
evidence have been established.
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