June 30, 2011 - ASM Presented Comments on the Reclassification of Molecular Diagnostics for the Rapid Detection of Mycobacterium tuberculosis Complex

Department of Health and Human Services
Food and Drug Administration
Microbiology Devices Panel

Reclassification of Molecular Diagnostics for the Rapid Detection of Mycobacterium tuberculosis complex [Docket No. FDA-2011-N-0002]

To Whom It May Concern:

The American Society for Microbiology (ASM) appreciates the opportunity to provide written comments to the FDA Microbiology Devices Panel of the Medical Devices Advisory Committee regarding the reclassification of molecular diagnostics for the rapid detection of Mycobacterium tuberculosis. 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 more than 38,000 microbiologists professionally employed in a variety of areas, including biomedical, agriculture and environmental microbiology, as well as public health and clinical microbiology and immunology.

The ASM strongly supports the reclassification of molecular diagnostic devices for the detection of M. tuberculosis (MTB) from PMA approval to 510(K) clearance. Support for the reclassification is based on:

  • The existence of a predicate device that is FDA approved for the molecular detection MTB (Gen-Probe MTD).
  • There is only one in vitro diagnostic product commercially available for the molecular detection of MTB (Gen-Probe MTD). Although this product was approved through the PMA process, it requires a significant amount of molecular expertise to perform to ensure accurate results.
  • Although the risk to both the patient and to public of inaccurate test results may be perceived as higher for MTB and certainly for MDR or XDR MTB, a rapid diagnostic test for MTB would be used as a screening test. As a screening test, it would augment and not replace routine direct smear or mycobacterial culture. It is the position of the ASM that the benefits of early detection of MTB outweigh the risks associated with a false negative result with a test that has high specificity and positive predictive value. Therefore, it should not be categorized as a Class III device requiring PMA.
  • Consistent with the WHO endorsement of the Cepheid GeneXpert MTB/RIF assay (RUO), the ASM recognizes there is a critical need for molecular diagnostic devices for MTB with the following attributes: easy to use, provides random access testing, and has high accuracy for detecting MTB in smear-positive and smear-negative respiratory specimens with high positive predictive values.

ASM recommends that the FDA consider 510(K) submission for all new molecular MTB assays intended for the purpose of detecting MTB from smear-positive and smear-negative respiratory specimens. We propose that the following minimal requirements for assay performance be considered for this mode of submission:

  • Functional equivalence to the Gen-Probe MTD assay
  • Sensitivity (vs. culture) for smear-positive respiratory specimens ≥90% (including all levels of smear positivity)
  • Sensitivity (vs. culture) for smear-negative respiratory specimens ≥60%
  • Inhibition rate <5% and not inhibited by a moderate quantity of blood
  • Specificity ≥99%

It should be emphasized that performance characteristics (as outlined above) should not be the only consideration for a molecular diagnostic device for MTB detection. The ASM supports the 510(K) submission pathway for devices that are:

  • Closed system
  • Random access

These attributes allow laboratories without significant molecular expertise the opportunity to perform rapid molecular diagnostic tests for MTB. In addition, many larger laboratories in the United States continue to send MTB molecular testing to a reference lab due to the costs associated with batch testing small numbers of samples. Allowing laboratories of all sizes and expertise access to MTB molecular testing is critical to decrease the time to result of MTB detection from direct respiratory specimens.

Although the need to quickly determine rifampin resistance is of critical clinical and public health importance, at this time the ASM does not support the reclassification of a molecular rifampin resistance detection device. A significant amount of clinical data will need to be obtained to determine the positive and negative predictive values in areas of low prevalence in the U.S. We realize there is a pre-existing FDA cleared closed platform multiplex assay that detects both the organism and a resistance marker (Cepheid SA Nasal Complete, Cepheid MRSA/SA SSTI), but we assert that the risk to the patient and public health is much greater with the misdiagnosis of MDR-TB.

In summary, the ASM is fully supportive of reclassifying molecular diagnostic devices aimed at the detection of MTB from primary respiratory samples to 510(K) clearance. Increased access to FDA cleared rapid, molecular diagnostic devices for MTB has the potential to greatly impact patient care and reduce transmission potential throughout the United States.

Thank you for the opportunity to comment.