FDA to clear Gen-Probe for smear-negative use
Label wording may limit test to higher-risk patients
The U.S. Food and Drug Administration (FDA) is expected to give final approval soon to the Gen-Probe Amplified Mycobacterium Tuberculo sis Direct (MTD) Test for use on smear-negative patients.
Until now, the test has been approved officially for use only on specimens from smear-positive patients, although some laboratories have been using the test all along on smear-negative specimens and for other "off-label" purposes as well.
"This just takes it out of that iffy, never-never land where you don’t know whether or not you’ll be challenged, or even sued," says Antonino Catanzaro, MD, professor of medicine at the University of California School of Medicine in San Diego.
The FDA is still debating exactly what the product’s new label will say and how closely the wording will circumscribe when and how the test should be used on smear-negative specimens. That’s because a recent clinical trial showed the test performs well on such specimens, but only when they come from patients judged by physicians to be at least fairly likely to have TB.
At the same time, the trial showed that as a screening device used on a strictly pro-forma basis among low-prevalence populations, the test has little value. If someone hauled 100 people in off the street and tested them, the only positives would probably be false.
"What all this means is that the best [new] use for this test is when you have a patient whom you think has TB, but who is still smear-negative," says Catanzaro. Before the FDA’s latest move, he adds, the only choices available in such circumstances were as follows: "You can either say you must have been wrong, or you can keep ’em in the slammer, which means if it’s really not TB, then they’re not getting treated for what’s really the matter. Or, for $1,000 you can order a bronchoscopy."
With the Gen-Probe test, physicians "have a fast, relatively inexpensive way to rule out TB that lets them get on with finding out what’s the real problem," he says.
Expressing all this in a package insert has proven more contentious work than might be imagined, with Gen-Probe offering strong resistance to the FDA’s desire to include qualifiers such as "highly suspicious."
"We’re trying not to have them include phrases like that, because we think that kind of qualifier is just too subjective," says Vivian Jonas-Taggart, MS, the molecular biologist who guided the development of the test. "If you pull 10 pulmonologists into a room and ask them what they mean by highly’ suspect, they’ll have an argument about it. It’s very subjective."
Also, of course, more restrictions could mean fewer sales. With only about 100 steady U.S. customers for the technology so far, there’s room for sales to grow, and they ought to, Catanzaro contends. "I think that in their zeal to prevent overuse of this test, the FDA has actually created a tremendous under-use of it," he says. "The whole concept of early diagnosis is very important to TB control, and that’s exactly where this test can help."
Wasting precious dollars on isolation
Hospitals, for one, should jump at the new chance to cut down on needless isolation, he adds. "Our calculation is that 67% of the dollars spent to treat TB’ is actually spent treating people who don’t have TB. A lot of that is money wasted on isolation or on giving anti-TB drugs to TB suspects for six, seven, or eight weeks, only to find out eventually that patients don’t really have the disease."
Even used judiciously, some experts add, the test isn’t a "magic bullet" both in an original trial and in the most recent one, it did yield some false results.
But that doesn’t dampen Catanzaro’s enthus iasm. "Think about it. You give a patient a cup for the specimen, and he puts in his girlfriend’s spit instead. Or maybe he doesn’t cough deeply enough. Or maybe he coughs deeply, but the area that’s got TB is temporarily plugged up," he explains.
Even the test’s manufacturers may have contributed to initial disenchantment with the test by claiming too much for it, he adds. "It was like, Well, you can all hang up your stethoscopes, ’cause this test will do all the work for you,’" he says. "But it wasn’t that extraordinary — it was a human test."
Modifications incorporated in the second-generation version of the test try to take into account such limitations by designing the test to work with a larger amount of specimen than before. The newest version of the test also takes less time, so "same-day results" can truly make it back on the same day, not early the next morning.
Even the most cautionary skeptics — for example, Leonid Heifitz, MD, director of TB laboratory services at National Jewish Hospital — agree the test offers genuine value in two specific situations: namely, to rule out TB meningitis and to rule out TB among HIV-negative patients.
That’s because in the first case, the cerebro-spinal fluid of patients is nearly always smear-negative, Heifitz points out. Yet if other indica tors are present, such as decreased levels of protein and glucose, then a quick positive result from a Gen-Probe test can speed the patient more quickly to life-saving therapy.
The same applies to HIV-positive patients with pulmonary symptoms because their sputum is often scantily supplied with TB organisms.
"No matter how good, we cannot rely on any one test alone," adds Heifitz. "It’s good that people are using this test, but there always needs to be a backup, and the lab report should have the disclaimer that we don’t guarantee 100% if the test comes back negative."
That doesn’t mean people shouldn’t use the test under some circumstances, says Catanzaro. "Just because something is complex doesn’t mean we shouldn’t use it," he says. "Lots of things about modern life are more complex. We use them anyway because they help us do a better job."
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