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By C. Anne Pontius
10/09/07
Is the FDA Coming to Your Laboratory?
Anne Pontius, MBA, CMPE, MT(ASCP)
You keep hearing and reading about IVDMIAs, but what exactly are they? The
acronym stands for “In Vitro Diagnostic Multivariate Index Assays” and
was given to us from the Food and Drug Administration
(FDA) in a Draft Guidance.
Dissecting this can give you its definition.
Let’s start with “In Vitro,” meaning an environment outside
the living being. In other words, the testing occurs outside the body. Next
we have “Diagnostic,” defined as an instrument or a technique used
in medical diagnosis. Simply restated, a clinical laboratory test. “Multivariate” means
that at least two factors will be utilized to obtain one single test result.
Possible multivariate factors include test results, patient demographics, and
population demographics. “Index” refers to the unique analysis
method or algorithm that is utilized to combine the multivariate factors and
generate a single test result. Finally there is “Assays,” most
likely to represent some tangible language the clinical laboratory would recognize
as its own.
Right off the bat you can probably think of several clinical tests that may
fall into this category, such as glomerular filtration rate, creatinine clearance,
or cholesterol ratios. However, the FDA distinguishes IVDMIAs from those tests
by adding further definition that is lacking in the IVDMIA name. The FDA’s
definition includes that IVDMIAs provide a patient-specific result whose derivation
is nontransparent and cannot be independently derived or verified by the end
user. In other words, the single test result obtained from an IVDMIA could
not have been surmised by a clinician on his/her own even if given the multivariate
factors. If a clinician can conclude the single test result based on the multivariate
factors, either from experience or training, than the test is not considered
an IVDMIA. An example of an IVDMIA would be a gene expression profiling assay
for breast cancer prognosis.
The IVDMIAs are a small and specialized class of IVDs that fall under the
jurisdiction of the FDA when marketed as a service or used by a laboratory
for providing clinicians with information to diagnose, treat, cure, mitigate,
or prevent disease. Historically, the FDA has not routinely entered clinical
laboratories to do inspections, but with FDA authority some clinicians expect
that by utilizing IVDMIAs, they will be receiving FDA inspections in addition
to routine inspections to meet CLIA compliance. Listening to FDA representatives
talk about this, I am left with the impression they will do what they can to
stay out of the clinical laboratories, mainly by relying on CLIA to satisfy
its own requirements. However, if the FDA feels that patient safety is being
compromised with the use of an IVDMIA that has not been FDA-cleared or FDA-approved,
then it can “exercise enforcement discretion”—a commonly
used phrase in conjunction with IVDMIAs. It sounds threatening, and that upsets
clinical laboratories. The bottom line is that if the FDA wants to inspect
your laboratory for compliance with its rules, it has the authority to do so.
The FDA regulations most relevant to clinical laboratories are the Quality
Systems (QS) Regulation and labeling requirements. These rules are designed
to be very flexible to accommodate both high-volume and low-volume laboratories.
Flexibility provides opportunity for the development of an IVDMIA that benefits
patients by treating or diagnosing a disease or a condition that affects or
is manifested in fewer than 4,000 individuals a year in the United States (FDA’s
definition for Humanitarian Use Device). In addition, the flexible nature of
the rules is supposed to reassure clinical laboratories that the least burdensome
approach will be taken when the FDA decides to “exercise enforcement
discretion.” More can be read about IVDMIA in the FDA’s Draft
Guidance for Industry, Clinical Laboratories, and FDA Staff for IVDMIAs at
http://www.fda.gov/cdrh/oivd/guidance/1610.pdf.
The FDA is working on a guidance document intended to bridge the gap between
its QS Regulation and the requirements of CLIA. According to Dr. Courtney C.
Harper, Ph.D., Office of In Vitro Diagnostic Device Evaluation and Safety,
CLIA high-complexity requirements and the QS Regulation are not far apart.
What are notably missing in CLIA, that exist in the QS Regulation, are design
controls. That’s understandable considering the QS Regulation is the
Current Manufacturing Practice Final Rule, available at http://www.fda.gov/cdrh/fr1007ap.pdf.
These rules were written for device manufacturers. In addition, the labeling
requirements can be found at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=809.10.
Several national consortiums, associations, and organizations are providing
input on the content of the final FDA guidance.
The article contains the sole opinions of the author and does not represent
opinions of her employer. Special thanks to Laura Reid, Sr. Director, Marketing
and External Scientific Affairs, Expression Analysis Inc.
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