FEATURE
Features
which has been analytically validated, it has validity in a
specific clinical context.”
One Piece of the Personalized Care Puzzle
IN GOOD COMPANY
Have Companion Diagnostics
Proven Their Mettle?
Advances in the evolving field of precision medicine have
led to the development of therapies that target specific
biologic, including molecular, abnormalities. Companion
diagnostics – tests that identify patients whose cancers
harbor these abnormalities – have, out of necessity, emerged
hand-in-hand with these new therapeutic approaches.
Because these tests are designed to be paired with a
specific drug, the development of both the drug and device requires close collaboration between the manufacturers and the U.S. Food and Drug Administration’s (FDA)
drug and device centers. In August 2014, the FDA issued
final guidance on the development, review, and approval
or clearance of companion diagnostics. Questions about
the practical application of these tests and their correct
interpretation, however, remain.1
ASH Clinical News spoke with regulators and device developers about the challenges of using genomic abnormalities to guide the treatment of patients with blood cancers.
What Are Companion Diagnostics?
Companion diagnostics are best described as medical
devices or tests that provide information that define the
condition of use for another medical product – a drug,
biologic product, or other device. These tests include in
vitro diagnostics that measure a particular biomarker, or
nucleic acid-based tests, which analyze variations in the
sequence, structure, or expression of DNA and RNA.
“A companion diagnostic is required as a condition of
use to make a medical product safe and effective,” Robert
Becker, Jr., MD, PhD, chief medical officer of the FDA’s
Office of In Vitro Diagnostics and Radiological Health
(OIDR), and Elizabeth Mansfield, PhD, director of the
personalized medicine staff at OIDR, explained in a review
article.2 “A companion diagnostic is therefore a subset of
biomarker-oriented tests, which cover all diagnostic tests.”
Generally, companion diagnostics do one or more of
the following:
• Select patients in whom a particular agent or drug
would be effective
• Identify patients who should not be treated with an
agent or drug because of a high risk of adverse events
• Identify patients who match the drug’s or agent’s
indications
• Determine genetic carrier status
Developing a companion diagnostic requires two important components, according to Alessandra Cesano, MD,
PhD, chief medical officer of Nanostring Technologies, a
company that uses a digital molecular barcoding diagnostic technology.
“The first is the analytic component,” Dr. Cesano
told ASH Clinical News. “When you say, ‘With this test,
we measure for A,’ you want to be sure that you actually do measure for A. We are looking for sensitivity
and specificity, but that doesn’t necessarily mean that
measuring A has a clinical impact.”
That comes in the form of clinical validity, she said.
“For any test to be considered a companion diagnostic,
we first need to show that we can reproducibly measure
A. Then, we have to show that when we use this test,
Most hematologic malignancies are caused by a genetic alteration, such as a point mutation, chromosomal aberration,
or copy number variation (TABLE 1, page 43) – all representing new potential therapeutic targets. The FDA has approved
two companion tests and targeted therapies for hematologic
indications (SIDEBAR, page 43 and TABLE 2, page 44).3
One example is the tyrosine kinase inhibitor imatinib. When studies showed that patients with PDGFRB
rearrangements achieved long-term, durable remissions with imatinib treatment, the FDA approved the
PDGFRB fluorescence in situ hybridization (FISH)
companion diagnostic test to inform the use of imatinib
in patients with myelodysplastic syndromes/myeloproliferative disease.3-4
However, relying solely on the results of companion
diagnostics to greenlight a patient for a particular targeted agent would be inadequate, James Zehnder, MD,
professor of pathology and medicine (hematology) at
Stanford University Medical Center in Stanford, California, told ASH Clinical News.
“One aspect of this discussion that doesn’t get enough
attention is that clinical decisions are not made on a
single test result, but by integrating all of the information
available on a patient – clinical, pathologic, radiologic,
and family history factors,” he explained. “That’s an essential part of personalized medical care. It’s not just the
test result that people are acting on; all of the available
information needs to be put into the hopper.”
Advances in genomics have moved the field forward,
but the ability to decode all cancer-associated mutations
– or novel mutations that may be discovered – is still far
in the future. For instance, blocking a hematologic tumor
protein pathway can drive cells to develop compensato