Quantiferon Gets Nod; CDC Will Craft Guide

Quantiferon, a one-step blood test for latent tuberculosis infection, got approval from a Food and Drug Administration (FDA) panel on Oct. 12. TB researchers hailed the Microbiology Devices Panel's approval, saying that the favorable judgment clears the way for the refinement needed to show how the new test can best be used.

"For the first time in a hundred years, we have a new test to aid in the diagnosis of latent TB infection," said Gerald Mazurek, M.D., an epidemiologist at the Division of Tuberculosis Elimination (DTBE) at the CDC, and the principal investigator of the CDC's Phase III trials of Quantiferon. "It's not a perfect test yet, but this gives us the framework in which to evolve," Mazurek added.

The FDA panel put no restrictions on how the test could be used, other than to note that data are still lacking on test performance in certain groups, including HIV-positive people, transplant patients, pregnant women and children. One condition attached to the approval was that the test should not be used within 30 days of applying a tuberculin skin test (TST) because the tuberculin antigen in the TST sometimes provides a transient immune reaction that might render a false positive result from Quantiferon.

Questions about discordant results with Quantiferon and the TST did not dissuade the panelists. "We felt that given the limits of the tuberculin skin test, [Quantiferon] offers advantages," said Roxanne Shively, M.S., senior scientific reviewer in the FDA's bacteriology branch and a member of the FDA review team. "We felt that the concordance issue wasn't as important as being able to get results."

The challenge now, according to Shively, is for the CDC to determine how best to interpret results in clinical settings and for TB control purposes. Most panel members felt it would be better for the CDC to provide physician training than for the manufacturer, Cellestis Ltd., to set up educational components.

The panel's decision makes way for further trials and plans to substitute more specific antigens for the tuberculin presently used in the assay. This step has the potential of eliminating false positives due to cross-reactions with BCG or atypical mycobacteria, said Mazurek. Quantiferon already outperforms the TST when discriminating between subjects infected with latent TB and those infected with an atypical mycobacterium or who have been vaccinated with BCG.

According to Mazurek, the most likely first large-scale users will be the US military, jails, or other entities that currently use the TST to get baseline screenings on large groups of people. Some experts believe that Quantiferon might also work as a back-up test for situations in which TST screening has resulted in suspected false positives.

As a condition of its approval, the FDA panel listed five tasks that Cellestis must perform, including provision of more reproducible studies across sites; provision of an analysis of data, stratified by different cut-points and by different sites, and statistical revalidation of data; and inclusion of an educational component on how to use the test. Complying with the conditions should not prove difficult, said Shively and Mazurek.

Like the skin test, the results of Quantiferon are read quantitatively, with cut-off points established to designate whether the test is read as positive or not. Unlike the TST, Quantiferon subjects do not have to return a second time for a reading.

The test was first developed by an Australian veterinarian to detect latent TB infection in cattle. The assay was purchased by Cellestis, which has been collaborating with the CDC to shepherd the assay through Phase III trials in the US.

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