FDA public meeting on Oversight of Laboratory Developed Tests

July 19-20, 2010

Comments submitted by
Marie L. Landry, M.D.
Director, Clinical Virology Laboratory, Yale New Haven Hospital
Professor, Department of Laboratory Medicine, Yale University School of Medicine

The Clinical Virology Laboratory at Yale New Haven Hospital serves a 944-bed tertiary care teaching
hospital that includes a cancer hospital, a large transplant program, and a children’s hospital. These
patient groups are heavy users and beneficiaries of laboratory developed viral molecular testing.

In the more than 30 years that I have supervised diagnostic virology testing, we have always relied on
laboratory developed tests (LDT), initially viral culture, electron microscopy, and antigen detection, and in
the past 10-15 years, nucleic acid detection most often by PCR.

We currently do 24 lab-developed viral PCR assays (including both qualitative and quantitative tests) and
almost none have FDA cleared options. These assays were originally developed by experts in the field,
have been published in peer-reviewed journals, and include a number of CDC assays.

Many LDT viral PCR tests are now standard of care: CSF tests [HSV, EV, VZV, JCV], viral load in blood
[CMV, BKV, EBV, adenovirus, HHV-6], respiratory viruses [hMPV, influenza A, B and H1, H3, swH1
subtypes, adenovirus, rhinovirus], norovirus, and parvovirus B19.

Particularly in large tertiary care centers with critically ill, often immunocompromised patients, we are
highly dependent on LDT. Since our testing is almost all on-site, we get substantial physician feedback
about the quality and impact of our testing. We have an ongoing dialog on clinical correlation and impact.
It is very rare that we have had problems with false positives (we have usually detected them prior to
reporting), and no more often than with viral culture or antigen testing. False negatives are less of a
problem with molecular tests than with conventional assays.

The ability to set up laboratory developed molecular assays for viruses quickly and use a single platform
and common protocols when appropriate, is cost effective, increases throughput, greatly reduces
turnaround and thus increases clinical impact, and provides a critical service to our patients and to our
infection control team. For example, in our laboratory we were able to set up the CDC swine flu PCR
assay virtually as soon as the protocol was posted on the WHO site and the primers and probes were
obtained. Validation was done by sending the first 200-300 samples in parallel for testing at the state lab.
This was of great benefit to our patients and to the public health as the state laboratory was quickly
overwhelmed.

In our laboratory, we generally confine PCR tests to inpatients or immunocompromised hosts, so most
testing is not fee-for-service. Cost effectiveness, quality and time to result are key. Our LDT perform as
well or better than most commercial assays, and the cost is less. Indeed several international studies of
CMV and EBV quantitative PCR did not show an advantage for commercial tests over LDT (Am J
Transplant. 2009 Feb;9(2):258-79).

The “value-added” of FDA oversight for viral LDT is not apparent and would likely be burdensome. Test
volumes keep increasing and our patients are sicker. The laboratory is overworked. Additional regulatory
burden for viral assays would be very detrimental and have a negative impact on patient care and cost.

Clear and detailed guidelines from CLSI and CAP for validating and monitoring assays, followed by CAP
inspections and CAP proficiency testing should be sufficient. Laboratories would benefit from more
detailed guidelines on test validation from CAP and CLSI and the ability to obtain answers to questions as
they arise. Ready availability of universal standards would be very helpful as well.
Although LDT will continue to be essential, many laboratories would undoubtedly welcome high quality
FDA-cleared tests if reasonably priced, user friendly and if multiple analytes could be done efficiently on
one platform. Doing proper validations, QC and continuous monitoring of laboratory developed tests is
indeed a lot of work.