Georgirene D. Vladutiu, PH.D

Presentation #29 Clinical Laboratory Challenges 1
Introduction
I am a stakeholder in the oversight of laboratory-developed genetic tests
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both as a laboratory professional and as the President of the Society for
Inherited Metabolic Disorders (SIMD).
The SIMD is composed of physicians, laboratory professionals, research

scientists, genetic counselors, nutritionists and nurse practitioners all
invested in the diagnosis, treatment and management of patients with inborn
errors of metabolism, many of which are rare disorders.
These varied SIMD members provide essential clinical services to patients

and families in the United States to prevent death and disability for those
affected by inborn errors of metabolism, including those detected by
newborn screening and those with conditions for which newborn screening
does not exist. In either case, prompt diagnosis and treatment can be
lifesaving; for a number of conditions diagnosis must be achieved within
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and
hours to assure best outcomes – requiring access to local expert laboratories
whenever possible. Biochemical genetic testing also includes newborn
screening, programs based in individual States. The unique case of newborn
screening combines biochemical testing principles with screening principles
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to identify those individuals at increased risk of having an inborn error of
metabolism and therefore in need of diagnostic testing. Without clinical
services for the diagnosis and management of inborn errors of metabolism,
newborn screening cannot achieve its purpose. The provision of care to
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those with inborn errors of metabolism, whether detected by newborn

screening or not, depends upon the availability of biochemical genetics
testing for diagnosis (including confirmation of diagnosis after abnormal
newborn screen or in patients with symptoms) and depends on the
availability of biochemical testing for monitoring of therapy, to assure
adequate treatment and to avoid over treatment (both for pharmacologic and
for nutritional management). The SIMD supports all efforts to improve the
quality of biochemical testing as well as genetic testing in general, but is
also cognizant of the risk of decreased access to biochemical genetic testing
that is currently available and that is required to maintain programs that
prevent death and disability across the United States.
While DNA testing has a role in the diagnosis of inborn errors of

metabolism, biochemical genetic testing is not DNA based testing.
Biochemical testing is defined in a recent CLIAC report and involves the
measurement of metabolites, proteins or enzymes, often on samples
collected invasively. Due to the unique characteristics of biochemical
genetic testing, strategies to regulate laboratory-developed testing primarily
involving DNA testing, by the FDA or any other agency, are generally not
universally appropriate for biochemical genetic testing. We are concerned
that the FDA’s definition of genetic testing for the purpose of this
meeting includes not only lab-developed complex DNA testing but also
biochemical genetic testing.
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Clinical Biochemical Genetic laboratories are highly regulated and required

to have CLIA certification; participate in frequent proficiency testing
programs and have quality control programs in place.
-Personnel must be accredited by state agencies and some by national level

agencies such as NAACLS (National Accrediting Agency for Clinical
Laboratory Science) for technologists.
-Clinical Biochemical Geneticists are (by definition) Board-certified by the
American College of Medical Genetics; the recent CLIAC document
recommends such Board Certification for the technical supervisor of a
laboratory carrying out complex biochemical genetic testing
-In NYS each laboratory director must have a Certificate of Qualification in
Genetic Testing.
-In NYS, the biochemical genetics laboratories must document assurance
from referring physicians that they will provide for genetic counseling of
their patients in the event of positive test results, no matter where they are in
the country. The recent CLIAC document for biochemical genetic testing
makes general recommendations that laboratories engaging in biochemical
genetic testing should provide information regarding any genetic
implications of the testing as part of information available to health
professionals ordering testing and as part of test reports.
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-Most biochemical genetics laboratories are highly specialized, working with
complex tests, requiring interpretation to be provided as part of the report.
While some tests are similar across many laboratories (e.g. amino acid
analysis), many tests are laboratory-developed. Testing is not done on

cheek-swab samples, but on blood, urine and often on samples collected by
invasive means such as muscle and spinal fluid. The recent CLIAC
recommendations recognize the difficulty of collection of large numbers of
abnormal control samples for rare diseases, and the difficulty also of
collection of normal control samples for invasively collected samples,
especially in children.
-While some large commercial laboratories perform excellent Biochemical

Genetic Testing, many Biochemical Genetic Laboratories (especially those
performing diagnostic testing for rare conditions) are hospital-based and
university-affiliated serving a national need due to their individual levels of
specialization. This network of laboratories also provides the relatively local
testing with rapid turn-around for diagnosis of conditions detected by
newborn screening and for conditions with emergency presentations.
-The market share of these academic laboratories is relatively small

compared to large commercial labs but extremely important for the patients
served; in the Biochemical Genetics world there is a supportive relationship
between the relatively limited menu/high volume services of the large
commercial laboratories that provide Biochemical Genetic testing and their
sister academic laboratories (and SIMD membership includes for example
the directors of the Biochemical Genetic sections of the largest commercial
laboratories in the United States).
-While DNA testing is included in many biochemical genetic testing

laboratories, it will not replace biochemical testing due to the need for
quantification of analytes and measurement of enzyme activity in various
tissues to make diagnoses and to monitor therapies.
Concerns of the FDA Regarding LDT Testing
We understand the concerns of the FDA regarding the application of a risk-

based oversight to LDTs.
LDT T
As diagnostic tests play an increasing role in clinical decision making it is
possible that the development of these tests may not be properly validated
for their intended use.
There are also concerns that diagnostic test development may not provide
reasonable assurance of safety and effectiveness.
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The FDA’s concerns are taken into account in guidelines developed by the
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Clinical Laboratory Improvement Advisory Committee (CLIAC) for good
laboratory practices in biochemical genetic laboratories.
This document also provides guidelines for a Quality Management System

(QMS) that overlaps with that of CLIA.
A similar document for clinical molecular genetics service laboratories has

been published in the Morbidity and Mortality Weekly Report, June 12,
2009 also available at the CDC website as indicated.
We understand that the FDA is concerned that large corporations are using
complex tests and algorithms that physicians may not understand
LDT
-Not all laboratories using LDTs are large commercial entities, therefore,
it will be important to define which types of laboratories and which types
of tests should be included in proposed new regulations not covered by
other agencies.
-Biochemical genetic testing requires that physician specialists receive

detailed interpretations of test results; regulation of the use of algorithms
will not change the need for test-specific, patient-specific interpretation
of results for biochemical genetic testing.
-In the end, it will be physicians who will control the success of genetic
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testing going forward depending on their ability to understand test results
and be able to apply them to the diagnosis, treatment and management of
their patients. There needs to be a concerted effort by genetic specialists
combined with regulatory agencies, such as the FDA, to provide CME
credit-based programs for internists, family medicine physicians, and
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others who are not routinely aligned with genetics specialities for proper
training in advances in genetic testing, the benefits and the potential

pitfalls.
As the FDA proceeds to consider a risk-based application of oversight

there are several things to take into consideration.
Risk-
First, the measure of risk will vary depending on the setting of testing, that is
whether testing is prenatal, neonatal, in children or in adults, and whether the
testing is performed in response to a symptom (or an abnormal newborn
screen), or whether testing is presymptomatic or is to derive a perceived
measure of risk. This latter, depending on definition, may include newborn
screening and we are not confident that it is really the intent of the FDA to
include newborn screening – an already closely monitored system – in this
new regulatory oversight development. Another consideration will be
whether “presymptomatic testing” would include testing the newborn sibling
of a child affected with an inborn error of metabolism, for early diagnosis in
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order to receive lifesaving therapy. Attention will need to be paid to the

definitions developed for any new system of regulation to avoid unintended
harm by restriction of currently available and necessary life-saving testing.
The predicted consequences of testing are more important than of the

specific tests performed. That is, the implications of testing including the
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type of therapy implied must be taken into consideration. The implications
of new regulation will also need to be considered.

 P
Impa
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The impact of any new regulation to biochemical genetic testing would
definitely increase the cost of this specialized testing. This will be a
disincentive to innovative test development. Access to specialized testing is
already limited for many reasons, many of which relate to cost, and access
would only further decline. While we are concerned about the risks
associated with limiting the development of new testing – including testing
that is needed to match the new developments in newborn screening – we
are also extremely concerned that we do not abruptly cut off access to
existing services that are essential to maintain health for our patients and
their families.
FINAL COMMENTS:
We ask that
-biochemical genetic testing not be lumped together with DNA testing

for regulatory considerations

-laboratories and their LDTs should be categorized according to a
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risk-based scale in order to assure safety, effectiveness, and
applicability to a clinical diagnostic or predictive purpose.
-an advisory committee to the FDA should be made up of experts in

the development and implementation of LDTs at all levels of
complexity.
 Dis
The Society for Inherited Metabolic Disorders respectfully requests

inclusion in further deliberations and development of next steps toward
increased oversight of laboratory-developed testing.

Georgirene D. Vladutiu, PH.D

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Presentation #29 Clinical Laboratory Challenges 1

I am a stakeholder in the oversight of laboratory-developed genetic tests

The SIMD is composed of physicians, laboratory professionals, research

These varied SIMD members provide essential clinical services to patients

those with inborn errors of metabolism, whether detected by newborn

While DNA testing has a role in the diagnosis of inborn errors of

Clinical Biochemical Genetic laboratories are highly regulated and required

-Personnel must be accredited by state agencies and some by national level

analysis), many tests are laboratory-developed. Testing is not done on

-While some large commercial laboratories perform excellent Biochemical

-The market share of these academic laboratories is relatively small

-While DNA testing is included in many biochemical genetic testing

Concerns of the FDA Regarding LDT Testing

We understand the concerns of the FDA regarding the application of a risk-

This document also provides guidelines for a Quality Management System

A similar document for clinical molecular genetics service laboratories has

-Biochemical genetic testing requires that physician specialists receive

training in advances in genetic testing, the benefits and the potential

As the FDA proceeds to consider a risk-based application of oversight

The predicted consequences of testing are more important than of the

-biochemical genetic testing not be lumped together with DNA testing

-an advisory committee to the FDA should be made up of experts in

The Society for Inherited Metabolic Disorders respectfully requests

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