Re: Comments to Docket: FDA-2011-D-0360, Framework for Regulatory Oversight of
Laboratory Developed Tests
Comments from Arthur Hagar, PhD, HCLD
Director of Chemistry & Hematology
Georgia Public Health Laboratory
I have serious concerns regarding the effect that the proposed Framework for Regulatory
Oversight of Laboratory Developed Tests may have on newborn screening. Newborn screening
celebrated its 50-year anniversary in 2013. It is a core component of all state public health
departments, and is widely considered to be one of the most successful public health programs.
Because newborn screening is a public health program, all infants born in a state are tested
without regard to social or economic status. While most of the conditions included in screening
panels are considered rare, approximately 1:700 infants have a condition that is detectable by
newborn screening. Nationwide, over four million babies are screened every year.
As stated in the public comment from the Association of Public Health Laboratories:
“The rationale for increased FDA oversight of laboratory developed tests (LDTs) stands on attributes
identified by FDA as having changed the landscape of LDTs over the years, rendering FDA’s current
overall enforcement discretion inappropriate for the modern world. Many of these attributes, such as
offering LDTs beyond local populations, manufacturing LDTs in high volumes, the evolving business
models of laboratories, and using LDTs to screen for common diseases instead of rare diseases, are not
characteristics of public health laboratories. Public health laboratories do not mass manufacture LDTs,
and instead continue to use and develop LDTs to inform public health issues in their local or state
jurisdictions. Public health laboratories do not profit from developing LDTs nor is this their intent—at a
minimum, they break even by offering a test in a fee for service model.”
With regard to newborn screening, I would like to comment on five issues:
Assurance that devices are clinically relevant
Newborn screening is a state activity, and there have historically been differences among states
as to which conditions are screened. In an effort to make screening more uniform the Health
Resources Services Administration (HRSA) formed the Discretionary Advisory Committee on
Heritable Diseases in Newborns and Children (DACHDNC) to create a Recommended Uniform
Screening Panel (RUSP). The DACHDNC reviews the evidence for adding a nominated condition
to the RUSP, and either gives reasons for rejecting the nomination or recommends that the
Secretary of Health & Human Services (HHS) approve the addition of the condition to the RUSP.
One of the primary criteria used to determine whether a condition should be added to the
RUSP is the risk of death or significant intellectual impairment prior to the presentation of
clinical symptoms. Another is disease incidence, because rare diseases are less likely to be
detected clinically in time to prevent significant morbidity. The diagnosis of rare diseases
frequently involves an expensive diagnostic odyssey, and often does not occur in time to
prevent significant morbidity or death. The DACHDNC also reviews published evidence on the
availability of a valid screening test and efficacious treatment. If there is no valid screening test
or effective treatment that can be offered to the patient, the condition is unlikely to be
approved for addition to the RUSP. Thus the DACHDNC reviews provide the clinical relevance
that the FDA seeks, and screening for conditions on the RUSP meet this requirement.
Cost of Submission
Because newborn screening is a public health program and testing is primarily performed in
state public health laboratories, the fees charged for testing frequently don’t cover the cost of
the entire screening program and must be supplemented from other state funds. In addition,
the market for newborn screening testing is small compared to many other clinical testing
markets, and the specimen type (i.e., dried blood spots) is atypical. For these (and probably
other) reasons, there are relatively few IVD manufacturers of FDA-approved kits for newborn
screening tests. As treatment options become available for conditions that once were
untreatable, there is more pressure on state newborn screening programs to expand their
screening panels. This has led to a situation in which states must consider developing a
screening test in-house (i.e., a laboratory developed test or LDT). When Severe Combined
Immunodeficiency (SCID) was added to the RUSP in 2010, state newborn screening programs
came under pressure from various stakeholders to add SCID to their screening panels.
However, there was no FDA-approved test for its detection in dried blood spots. The FDA
approved the first commercial test for quantification of T-Cell Receptor Excision Circles (TREC,
which is the biomarker for SCID) in dried blood spots last month –four years after SCID was
added to the RUSP. During this period, an estimated 300 infants with SCID were born
nationally. If states had to wait for a FDA-approved test to reach market, some of these infants
would have died. And even now, with just a single manufacturer offering a FDA-approved test,
it may be cost prohibitive for many states to add SCID to their panels given the difficulty and
frequent opposition to raising the screening fee, unless they can use a LDT. This scenario will
likely become more common in the future. For example, many states have added or are under
pressure to add one or more Lysosomal Storage Disorders (LSD) to their panels, although none
of these disorders has been added to the RUSP and there are no commercial assays available
for detection of LSD in dried blood spot specimens. Public health laboratories have very limited
resources, and most cannot afford to submit assays to the FDA for 510(k) clearance or
premarket approval. Thus requiring such action will essentially stymie the addition of new
conditions to most state’s newborn screening panels. This will have a negative impact on the
health of many infants, and disproportionally so for those from low income backgrounds whose
parents cannot afford private-sector testing.
Designation of Rare Diseases
The FDA states that it believes it is appropriate to continue to exercise enforcement discretion
for LDTs for rare diseases. The definition of a rare disease included in the guidance document is
based upon the request for designation of a Humanitarian Use Device in 21 CFR 814.102 (i.e.,
that fewer than 4000 patients per year be subject to diagnosis with the device). However, the
NIH Office of Rare Diseases Research (ORDR) includes essentially all of the conditions included
on most state’s newborn screening panels in its list of rare diseases. In addition, the Orphan
Drug Act of 1983 (ODA) defines a rare disease for medical devices as, “any disease or condition
that occurs so infrequently in the United States that there is no reasonable expectation that a
medical device for such a disease or condition will be developed without assistance”. As the
example of SCID demonstrates, the market for newborn screening tests is so small that few IVD
manufacturers are developing assays for it in a timely manner. A more appropriate definition
of a rare disease for newborn screening is the definition used in the ODA for drugs (i.e., any
disease or condition which affects less than 200,000 persons in the United States). This
definition would also appear to be more harmonious with the NIH list of rare diseases.
For these reasons I request that FDA utilize the ORDR’s list of rare diseases for establishing
whether a LDT automatically qualifies for enforcement discretion with regard to premarket
approval requirements. Laboratories would still need to notify the FDA of these tests as
described in the guidance document, and have to meet all requirements of the Clinical
Laboratory Improvement Amendments of 1988 (CLIA’88) for high-complexity testing. In
addition to strict personnel, quality control, and proficiency testing standards, CLIA’88 requires
documentation of analytical validity. If laboratories seek enforcement discretion for a rare
disease LDT that is not on the ORDR’s list, they should be expected to provide full
documentation to FDA establishing that the LDT was developed to diagnose or to help diagnose
a disease or condition that affects less than 200,000 persons in the United States. Failing that,
they should have to file for 510(k) clearance or premarket approval.
Designation of a Health Care Facility
FDA needs to consider that newborn screening laboratories function as part of newborn
screening programs, which are exactly what they state: screening programs. The programs are
designed to identify infants that are at higher risk of having one of the conditions being
screened. All positive screens are referred for active follow-up, which involves a medical
professional (i.e., doctor, nurse, genetic counselor) with training and expertise in the disorder
contacting the infant’s healthcare provider and deciding whether a repeat screen, referral to
diagnostic testing, or visit to a specialty (e.g., metabolic) clinic is appropriate. No program of
which I am aware encourages treatment based solely on the newborn screening test results. In
fact, most states’ newborn screening reports include comments that the results are not
intended to be diagnostic, all positive results need to be confirmed, and a normal result does
not rule out the presence of a disease. Importantly, most states’ list of reportable diseases
includes all of the conditions on the state’s newborn screening panel. There is constant
communication among the screening laboratory, follow-up staff, medical specialists, hospitals,
and various healthcare providers (e.g., pediatricians). We have representation from the clinical
specialties, private-practice pediatricians, and the hospital association on our Newborn
Screening Advisory Committee. We get feedback on which positive screens are confirmed as
true positives, and regularly meet to review any “missed” cases or delayed diagnoses. Cutoff
values and screening algorithms are adjusted as necessary to reduce the number of false
positive and false negative screens. Thus while the various newborn screening stakeholders are
physically separated, the newborn screening program functions very much as a true healthcare
system.
Risk Stratification
I support the risk-based approach that FDA proposes in the guidance document. For the
reasons stated in the paragraph on Health Care Systems, however, it seems appropriate to
classify LDTs for newborn screening as low risk. The risk is certainly no greater than if screening
is not performed. And the manner in which most newborn screening programs function
mitigates against adverse outcomes for infants that have positive screens.