Public and Scientific Affairs Board

Statement of the
American Society for Microbiology
to the

Food and Drug Administration

Center for Devices and Radiological Health
on

Oversight of Laboratory Developed Tests

Clinical Laboratory Challenges

Presented by:
Paula A. Revell, Ph.D., D(ABMM)

July 20, 2010

The American Society for Microbiology (ASM) appreciates the opportunity to provide
comments to the Food and Drug Administration (FDA) regarding oversight of laboratory
developed tests (LDTs). The ASM is the largest educational, professional and scientific society
dedicated to the advancement of the microbiological sciences and their application for the
common good. The Society represents approximately 40,000 microbiologists, professionally
employed as scientists and science administrators working in a variety of areas, including
biomedical, environmental, and molecular fields as well as in clinical microbiology, clinical
immunology, and molecular diagnostics.

The ASM strongly supports oversight of LDTs and believes that existing regulation provided by
the Clinical Laboratory Improvement Amendments of 1988 (CLIA), when applied appropriately,
accomplishes the goal of oversight through proficiency testing, personnel standards and quality
systems, which includes the verification and validation processes. For the purpose of this
document, verification is defined according to the terminology used by CLIA, i.e., it is the one-
time process to determine or confirm LDT performance characteristics prior to the beginning of
patient testing. Validation (as defined by CLIA) is an on-going process once a test is verified to
assure that it continues to meet the performance characteristics that were originally verified.
There is no doubt that certain patient populations would be better served by strengthening the
existing inspection process, particularly in cases where laboratories do not rigorously verify
these types of assays prior to implementation and validate the assays on an ongoing basis.
However, an appropriate balance of oversight is necessary so as not to impede access to
important LDTs that continue to aid in the diagnosis and treatment of rare, new and/or
reemerging infectious diseases.

Laboratories continue to depend on LDTs to readily and rapidly respond to emerging infectious
disease outbreaks (i.e. H1N1, SARS); to measure viral loads of organ transplant patients; to
detect changes in antimicrobial susceptibility patterns; or to test for diseases that do not have
commercial diagnostic tests available (i.e., herpes simplex virus in cerebrospinal fluid for viral
meningitis, mycoplasma respiratory infections, norovirus outbreaks, and many others), all of
which greatly assist physicians in the appropriate care management of their patients. ASM
concurs with the FDA’s assessment that an increasing number of LDT manufacturers are
corporations rather than hospital laboratories or public health laboratories, and that patient care is
threatened when LDTs have not been appropriately verified.

However, the ASM feels strongly that additional FDA oversight will result in time delays that
will negatively impact patient care. Additional steps via strengthened regulation will require
many hospital laboratories to increase the volume of send-out testing to reference laboratories,
resulting in a time to result that exceeds clinical relevance for patients and physicians as well as
an increase in cost to the health care system. This comes at a time when these laboratories are
reducing their menu of in-house testing because of increased Analyte Specific Reagent (ASR)
oversight by the FDA. Publically funded or smaller laboratories will be at a disadvantage due to
limited resources, combined with increased costs associated with the labor required to complete
and submit paperwork. In addition, potential fees associated with the submission process may
compete with the resources needed to perform the verification. This financial and time burden is
not feasible for a large number of laboratories and may result in only the largest and perhaps
commercial laboratories having the ability to offer LDTs. Furthermore, duplication of
requirements for verification (CLIA plus any additional FDA requirements) will likely drive up
costs to consumers. In summary, additional FDA regulation is likely to be prohibitive for many
laboratories including academic and hospital based laboratories.
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ASM recommends that the FDA and CLIA-approved laboratory accrediting organizations work
together to enhance the CLIA inspection process with respect to verification, to ensure that LDTs
are safe and effective and that patient care is not threatened. Some suggestions are as follows:

• Create a new LDT inspection checklist or add items to current checklists

(i.e., inspection of verification data) with clearly defined expectations, rather than
leaving it up to the interpretation of individual inspectors many of whom have
little, if any, experience with LDTs. For example, the College of American
Pathologists (CAP) has just released a new molecular microbiology checklist that
deals specifically with the essential issues and requirements surrounding the
verification of LDTs and ongoing oversight of such tests.

• Create better standardization of the CLIA verification and validation

requirements to improve the quality of LDTs.

To ensure that LDTs are safe and effective, the ASM suggests that the FDA consider issuing
LDT guidance in the following areas:

• Establish clearly defined requirements for the verification of LDTs, and

clarify the appropriate use of alternate sample types for uncommon analytes (i.e.,
"mock" samples). However, careful consideration should be given to those LDTs
that assist in the diagnosis of rare diseases because the absence of a significant
number of positive samples could make verification of assays that detect rare
diseases impossible if the same requirements for verification are applied to such
tests.

• Establish essential requirements for acceptable sample and reagent

stability, for determination of acceptable limits of detection, and acceptable assay
performance parameters such as: analytical and clinical sensitivity and specificity,
and intra- and inter-assay reproducibility. These same standards need to be
established for quantitative assays as do acceptable requirements for limits of
quantification, linearity and reportable range.

• Establish essential requirements regarding: specimen collection and

rejection criteria, reagent preparation, acceptable control types and limits, and
proficiency testing.

Additionally, ASM believes that it is important for the FDA to develop a risk stratification
framework for LDTs. Risk stratification would likely be based upon the impact of an incorrect
patient diagnosis attributed to the LDT result, and/or the potential for disease transmission due to
the failure to identify a communicable pathogen. Due to the complexity of risk stratification,
ASM recommends that the FDA seek input from clinical experts and laboratorians if the FDA
elects to develop this kind of framework.

Finally, the ASM is concerned about the FDA’s current resource base, including adequate
number of staff, level of expertise and available funding to oversee and enforce stricter LDT
regulation in an expeditious manner. If additional oversight is mandated, the FDA should

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consider creating an expert panel to assist with an enhanced oversight process. Careful
examination of existing models, i.e., New York State’s LDT oversight process, might provide
insight into whether additional regulatory steps and standards have improved quality and safety,
or, if the additional steps have slowed the process, thereby hindering access to such tests.

Thank you for the opportunity to comment.