UP FRONT
Companion Diagnostics
Nucleic Acid–Based Companion Diagnostic Tests
Approved by the FDA
TABLE 2.
Disease
Acute Myeloid Leukemia
B-Cell Chronic
Lymphocytic Leukemia
Trade Name
Manufacturer
Submission
Vysis D7S486/CEP 7
Abbot Molecular
FISH Probe Kit
K131508
Vysis EGR1 FISH
Probe Kit
Abbot Molecular
K123951, K091960
Vysis CLL FISH
Probe Kit
Vysis
CEP 12 SpectrumOrange Direct Labeled
Chromosome
Vysis
Enumeration DNA
Probe
K100015
K962873
Source: U.S. Food and Drug Administration. “Nucleic Acid Based Tests.” Accessed June 27, 2016 from http://www.fda.gov/MedicalDevices/
ProductsandMedicalProcedures/InVitroDiagnostics/ucm330711.htm
The Laws of LDTs
Time is one of the points of contention between the FDA and developers of so-called
laboratory developed tests (LDT). LDTs are
assays developed by and used in a single
lab, often one that is affiliated with a major
treatment or academic center. They are not
sold to other labs or hospitals and do not
go through the formal FDA PMA process;
instead, they fall under the purview of
the Centers for Medicare and Medicaid
Services through the Clinical Laboratory
Improvement Amendments (CLIA).7
The FDA has the option to regulate
LDTs, but the agency has chosen not to do
so, explained Pam Bradley, PhD, a staff fellow at the FDA. “We’ve been exercising what
we call enforcement discretion,” she said.
That is changing, though. In 2014,
the FDA issued draft guidance outlining
a framework for regulatory oversight of
LDTs, taking the position that regulatory
oversight of LDTs under CLIA does not
adequately address patient safety concerns
because CLIA officials do not assess or confirm the tests’ analytic or clinical validity.8
“We aren’t looking to disrupt the LDT
industry that physicians and patients rely
on,” Dr. Mansfield emphasized. “Right now,
most LDTs are never seen by the FDA, so if
there is an FDA-approved companion diagnostic, and there are four different labs that
developed their own version of it, we don’t
necessarily know how each LDT performs.”
The proposed phase-in for greater
scrutiny of LDTs is nine years, starting with
tests that would be considered class III
under the FDA review process. “The FDA
review may add a bit of additional time, but
the pay-off is that we will actually understand how the tests work,” she said.
Dr. Zehnder expressed concern that the
additional time will make it more difficult
for assays to keep up with the rapid changes
in medicine. For instance, companion diagnostics for the KRAS mutation have been approved for codon 12 mutations; while those
tests were working through the approval
process, more up-to-date data have emerged
that suggest that codon 2,3,4 mutations in
KRAS and NRAS are also important for
guiding treatment strategies, he pointed out.
44
ASH Clinical News
“It’s relatively quick and easy to update an LDT and use it in the clinic,” he
said, “but taking something like an LDT
through the FDA process, which is not
responsive to new knowledge, is a primary
concern that many of us have.”
Labs that develop and use LDTs are
generally “rigorously inspected” every
two years, Dr. Zehnder added, and must
participate in proficiency-testing to ensure
test quality and accuracy. “The preponderance of data suggests that this mechanism
works fairly well,” he said.
Whatever direction regulation takes,
there is still one elephant in the room
when it comes to measuring the ultimate
value of companion diagnostics and therapeutic benefit – does marrying a genomic
report to a therapeutic strategy truly lead
to better outcomes?
“That hasn’t been proven conclusively
so I’d still call companion diagnostics
experimental,” Dr. Ginsburg said. “This is
going to require clinical trials to generate
outcomes data more rapidly. In some aggressive cancers, it may not take very long
to determine if the pairing of companion
diagnostics and therapies really made
a difference in outcom es, but, in more
indolent cancers, this will prove more
challenging.”—By Shalmali Pal ●
REFERENCES
1. U.S. Food and Drug Administration. “In Vitro Companion Diagnostic
Devices: Guidance for Industry and Food and Drug Administration
Staff,” August 6, 2014.
2. Becker Jr. RJ, Mansfield E. Advances in drug development: companion
diagnostics. Clin Adv Hematol Oncol. 2010;8:478-479.
3. U.S. Food and Drug Administration. “List of Cleared or Approved
Companion Diagnostic Devices (In Vitro and Imaging Tools).”
Accessed June 27, 2016 from http://www.fda.gov/MedicalDevices/
ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm
4. Cheah CY, Burbury K, Apperley JF, et al. Patients with myeloid
malignancies bearing PDGFRB fusion genes achieve durable longterm remissions with imatinib. Blood. 2014;123:3574-7.
5. Vogelstein B, Papdopoulos N, Velculescu VE, et al. Cancer Genomic
Landscapes. Science. 2016;339:1546-1559.
6. Shendure J, Hanlee J. Next-generation DNA sequencing. Nature
Biotech. 2008;26:1135-45.
7. Centers for Medicare & Medicaid Services. “Clinical Laboratory
Improvement Amendments (CLIA).” Accessed June 27, 2016 from
https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/
index.html?redirect=/clia/
8. U.S. Food and Drug Administration. “Draft Guidance for Industry,
Food and Drug Administration Staff, and Clinical Laboratories:
Framework for Regulatory Oversight of Laboratory Developed Tests
(LDTs),” October 3, 2014.
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