AMERICAN SOCIETY FOR CLINICAL LABORATORY

SCIENCE

July 15, 2010

Division of Dockets Management (HFA-305)

Docket No. FDA-2010-N-0274
Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockville MD 20852.

Dear Sir/Madam,

The American Society for Clinical Laboratory Science (ASCLS) is writing in response to
the FDA’s request for input and comment concerning oversight of Laboratory Developed
Tests (LDTs). We applaud the FDA for seeking such broad input and commit to continue
to work with the agency on this and other related topics.

ASCLS is the nation's oldest and largest non-registry professional association for non-
physician clinical laboratory professionals. The Society's mission includes promoting
high standards of practice in the nation’s clinical laboratories and ensuring professional
competence, while its ultimate goal is to ensure excellent, cost-effective laboratory
services for consumers of health care. Our membership of nearly 11,000 includes clinical
laboratory directors, managers, administrators, supervisors, and staff at all levels of
practice.

ASCLS commends the FDA for its attempt to frame the issues surrounding LDTs. We
agree with the agency that many of these assays are medical devices. Currently there is
not a comprehensive process with which to oversee these tests. CLIA does not address
the need for clinical validity. In fact proving/verifying clinical validity is a skill set of
very few laboratorians. We view LDTs as similar to IVDMIAs in many ways; today’s
LDTs are more complicated and make claims about their validity that cannot be validated
by other than the developer of the test. The menu of tests has grown to include the very
esoteric; so many laboratorians do not have the resources or specimens needed to validate
the developer’s claims. Therefore, a laboratory that refers specimens to be performed by
a LDT method has no way of knowing whether the test method is scientifically sound.
Information about sensitivity, specificity, predictive values, likelihood ratios, etc. is
typically not available.

This sets the stage for potential misinformation for health care providers, our patients and
the health conscious public. The concept that the scientific community will somehow
sort out the real science from the inaccurate supposes that every scientist in every

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laboratory in this country has the resources to study the test development and method
intensely enough to guarantee patient safety and that simply is not the case.

The FDA has posed a series of questions and we would like to address some of them:

What are the potential benefits of increased FDA oversight of LDTs?

For medical laboratory professionals, the benefits are enormous. Laboratorians
will be able to offer the latest, scientifically and clinically valid tests to their
patients without having to develop the tests themselves. There is an urgent need
for a process that brings translational research to the clinical laboratory for our
patients’ benefit.

What would you like to see done with respect to FDA oversight of LDTs? What
is ideal? What is practical?
We would urge the FDA to look at the guidance written for IVDMIAs and use all
of the elements that apply. We ask that FDA consider oversight for those LDTs
that affect the diagnosis and/or determine the treatment of pathological and
genetic conditions.

To be practical, the FDA needs to find a process, like that of pre-IDE, that will be
user-friendly and facilitates the introduction of technology after advice and
guidance from the FDA; without stifling innovation. The clearer and more
defined the process, the easier it will be to follow.

Suggested approaches of risk stratification of LDTs.

Risk stratification in the abstract is a very logical. However, we question the
FDA’s ability to incorporate a risk stratification since, in clearing methods for
waived status, the FDA has repeatedly stated that they have no way of
establishing risk of harm to the patient. Any risk stratification model, including
the one proposed by the College of American Pathologists (CAP) in 2009, must
include a determination of harm to the patient based on the intended use of the
test and the consequences of an erroneous result.

Any test that claims to diagnose, either specifically or by differentiation, must be

considered to present a high degree of risk to patients. Likewise any test whose
results purport to determine/direct therapy must also be considered high risk. All
high risk tests should go through a formal FDA PMA or 501(k) process.

What might be some of the specific challenges faced by clinical laboratories in

meeting FDA regulations?

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Clinical laboratories are going to struggle with FDA’s terminology and approval
processes because most have never even heard of them much less submitted
anything for FDA approval. Clinical laboratories will need help understanding
what the FDA wants to see in the way of data, designing clinical and performance
studies, etc to FDA’s satisfaction and anticipating the QC requirements that will
meet FDA’s Quality System regulation.

How might increased oversight of LDTs affect diagnostic test innovation? How
could increased oversight of LDTs affect diagnostics used for rare conditions?
There is no question that increased oversight will slow innovation. However, as
clinical laboratories learn the systems, LDTs based on real science should have no
problem gaining FDA approval. Diagnostics for rare diseases always face
challenges – how to validate the method and the clinical significance with so few
specimens. FDA should consider some exceptions for these diagnostics.

What are the challenges associated with validation of LDTs for clinical
laboratories? Should the clinical and analytical validation requirements be
different between FDA regulated and non-FDA regulated diagnostic tests?
The challenges associated with validation of either regulated or non-regulated
tests are the same – using a scientifically and statistically sound process with a
large enough sample size to establish claims for the test. The response time of the
FDA will be a challenge if that turn around time is not efficient and informative.

ASCLS thanks the FDA for the opportunity to comment at this time. ASCLS and its
members stand ready to work with the FDA using the knowledge of our members to help
enhance this process or participate in rulemaking. We thank you for the opportunity to
submit our comments.

Respectively submitted,

Mary Ann McLane, President, ASCLS

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