August 4, 2010

Division of Dockets Management (HFA-305)

Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852

RE: Docket No. FDA-2010-N-0274 – FDA/CDRH Oversight of Laboratory

Developed Tests – Additional Comments

The Association of Public Health Laboratories (APHL) represents governmental

laboratories that detect and monitor public health threats. APHL’s members includes
state, territorial, and local public health laboratories; state environmental testing
laboratories, state agricultural and food safety laboratories; and individual scientists, public
health officials, and academicians. We thank the U.S. Food and Drug Administration
(FDA) for the opportunity to comment on the oversight of laboratory developed tests
(LDTs), and request that the following issues be considered when deciding how to best
regulate LDTs.

Public health laboratories are non-profit, publicly funded, mission based institutions that
perform specialized testing for the detection, characterization, and surveillance of diseases
or conditions of public health significance. This includes testing for infectious and non-
infectious diseases, and newborn screening to detect rare, treatable, conditions. Although
some testing conducted in public health laboratories is diagnostic, much of it is for
surveillance, with the results used to prevent and control the spread of disease in the
community. In many cases, the LDTs in public health laboratories are used during
outbreaks of emerging or newly recognized diseases where there is no equivalent FDA
cleared test. In these situations, technology transfer of LDTs from the Centers for Disease
Control and Prevention (CDC) is critical in order to enable an effective response to public
health emergencies.

Many diseases or conditions of public health concern in the United States are low
incidence and/or may be limited to specific regions of the country. Therefore, commercial
manufacturers may be reluctant to develop tests for these diseases or conditions due to a
limited market size. Measles, for example, is a disease that has been essentially eliminated
from the Western Hemisphere; however, cases still occur in the United States, and
laboratory confirmation remains a critical component to outbreak control and investigation.
There are currently very few commercial suppliers of measles test kits, and due to the lack
of profitability, those manufacturers may cease production of those kits. A similar
challenge exists with mumps testing. Several years ago, Iowa and its neighboring states
observed an outbreak of mumps cases with an unusual epidemiology. The commercially
available serologic tests used in the detection of mumps performed poorly, and traditional
culture-based diagnosis was too slow to meet the surge in testing demand. The State
Hygienic Laboratory at the University of Iowa, in collaboration with the CDC,
implemented a Real-Time PCR assay that reduced turnaround time and was instrumental
in case confirmation. In some cases, public health laboratories are required to provide
confirmatory testing for rare diseases with significant community impacts, such as Dengue
Virus and West Nile Virus. FDA-cleared tests are available for both of these diseases;
however, due to the low prevalence of disease in the community, these assays have poor
predictive value and supplemental tests, many of which are LDTs, are required.

For several reasons, APHL has significant concerns that an overly burdensome regulatory
process for LDT’s will limit the availability of tests that meet the needs of the public health
community. We are very concerned that an in-vitro diagnostic-like regulatory process will
have an adverse impact on disease surveillance and public health interventions by
increasing the time needed for test development and implementation. Currently, LDTs for
low incidence diseases (such as measles, mumps, and polio) are validated to the extent
possible given the rarity of the disease. Stringent regulations could make LDTs for rare
diseases difficult, if not impossible, to validate due to the limited availability of positive
specimens. The unintended consequence of more stringent FDA oversight may be to limit
the development of assays for rare diseases to commercial laboratories and manufacturers,
as public health laboratories will not be able to tolerate costs associated with an extensive
approval process. This will likely limit the diversity of available assays to those tests for
which there are large enough markets to justify the cost of development, and may limit
innovation in the development of new tests. For example, the commercially available
assays used for the detection of measles are predicated on a LDT that was developed
approximately twenty years ago, and at this time there are still no commercially available
molecular tests for measles.

Public health laboratories are unique institutions that conduct a variety of specialized
testing, working with clinical specimens, select agents, and chemical agents not readily
handled in other clinical or environmental laboratories. In the absence of a regulatory
paradigm for surveillance testing, public health laboratories adhere to the standards and
regulations from a number of agencies and organizations including the CDC, U.S.
Department of Agriculture (USDA), Occupational Safety and Health Administration
(OSHA), National Institute for Occupational Safety and Health (NIOSH), Environmental
Protection Agency (EPA), Federal Drug Administration (FDA), College of American
Pathologists (CAP), Centers for Medicaid and Medicare Services (CMS) through the
Clinical Laboratory Improvement Act (CLIA), and Clinical Laboratory Standards Institute
(CLSI). Because public health laboratories handle clinical specimens, they are all certified
under CLIA or CAP, and in some cases licensed by a state based regulator (e.g. New York
State Clinical Laboratory Evaluation Program), and they participate in associated
proficiency testing and quality assurance monitors. In many cases public health
laboratories are dependent on assays developed and shared by the CDC (e.g. emerging or
rare diseases), many of which provide or recommend an external quality assurance
component.

APHL strongly supports a rational quality systems approach to the oversight of LDTs that
meets the needs of both public health and the regulatory community. Any new oversight
should balance regulatory needs with public health concerns, allowing the use of LDTs in
response to public health emergencies. Any risk stratification scheme should not limit the
availability of quality tests. When considering a risk based approach, careful consideration
should be given to the timeliness and critical need for the test, its purpose (e.g. diagnostic,
surveillance, confirmatory), the prevalence of the disease, the availability of appropriate
FDA cleared tests, the availability of GMP manufactured reagents, and the availability of
FDA-cleared instrumentation.

APHL urges the FDA to continue considering the utilization of LDTs in the public health
setting and encourages public health representation on any advisory panels related to the
oversight of LDTs. APHL welcomes the opportunity to work with the U.S. Food and Drug
Administration, other federal agencies, and interested stakeholders and partners on this
important issue.

If there is more information that you believe we can provide, please feel free to contact
Scott J. Becker at 240-485-2747 or via email at scott.becker@aphl.org.

Sincerely,

Patrick Luedtke, MD, MPH Scott J. Becker, MS

President, 2010-2011 Executive Director