Patient advocates, clinicians, entrepreneurs, and FDA’s top brass deliberated at a congressional briefing here Thursday over how much regulation is needed for lab developed diagnostic tests.

Nobody questions the high standards and thorough review drugs undergo before reaching the market, said Jeff Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.

“You care if that drug works, but why wouldn’t you care if the test that determines whether or not you’re going to get that drug also works?” he asked.

Shuren argued that the reliability of laboratory developed tests (LDTs), which have been largely unregulated, is inconsistent and could put patients at risk. Last year, his office released a report listing 20 LDTs that had produced clinically erroneous and even invalid results.

In the last several years, the number of therapies targeted to specific genetic factors has soared, and this has created a market for molecular tests to determine whether patients have those factors.

Right now, he continued, “If you take the same patient sample and you send it to different labs you can get different results.”

Shuren has been pressing for more stringent FDA oversight for tests that have previously not fallen under the agency’s purview.

Today, there are two categories of molecular tests: laboratory developed tests and FDA-reviewed diagnostic kits.

LDTs are tests made and used in a single laboratory. Currently, LDTs are not subject to FDA review. However, the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvements Amendment (CLIA) oversees the laboratories, conducting reviews and inspections to ensure that they have adequate equipment and personnel trained to perform tests of different levels of complexity.

Test kits sold commercially to be performed in other facilities, on the other hand, undergo individual FDA reviews — either through the premarket approval process or, if they are similar to existing approved products, the 510(k) clearance pathway.

In 2014, the FDA published a draft rule outlining a framework through which the FDA could expand its jurisdiction over molecular tests to also include LDTs.

Many clinicians working in the laboratories that perform LDTs disputed the recommendation.

One pathologist, Anthony John Iafrate, MD of Massachusetts General Hospital and a professor at Harvard medical School in Boston, said he’s “very comfortable” having both FDA approved tests and non-FDA approved tests. He questioned the prevailing message that all LDTs are dangerous and all FDA approved tests are good.

He noted that many FDA approved tests are not performed in a way that conforms to the package insert, making them essentially no different from LDTs.

Iafrate, whose lab conducts over 1,000 LDTs, argued that having laboratories prove clinical utility for every analyte each time they want to launch a new test is impractical. Clinical utility is a test of the meaningfulness of whatever’s being measured in clinical practice.

For example, “[w]e know that EGFR mutations predict an EGFR inhibitor response,” he said. “Why would I need to perform a very expensive large clinical trial to show that my test predicts that?”
Iafrate said that a few “common-sense” changes to the CLIA could provide the oversight that’s needed.

He believes tests of analytical validity should be prioritized over. In other words, his lab would need to show his test is as good a test as another tests for the same genetic variation.
He also underscored the fact that LDTs do indeed have oversight. Labs undergo proficiency testing that, while not a “deep dive,” looks at a sampling of tests.

“All the labs that do this type of testing have to subscribe to and pass, and if they don’t pass there are real repercussions.”

Lastly, blanket oversight of LDTs would result in a “definite, sizable increase in costs” for labs like Iafrate’s. He estimated that his lab would have to hire two or three regulatory compliance professionals to manage the work load.

It’s unclear from the guidance documents how sweeping the regulations would be and whether equivalency data could be used in place of full premarket approval submission. However, if a clinical trial is required for even one test, “we couldn’t do it,” Iafrate said. “I would close the lab.”

For his part, Shuren said that many people are confused about what is required in a premarket approval application. He noted that, often, applicants leverage information already available in the clinical literature for support. He also noted that the FDA is currently working alongside the National Institute of Standards and Technology to develop reference material standards — “things you can take your test and measure it against to assure its level of accuracy.”

Also, the agency’s draft framework indicated that not all LDTs would have to go through the PMA process. Those classified as low-risk could simply be registered without a need for clinical validation studies, as would those intended for rare diseases or for which no FDA approved test is available.

According to some estimates, about 60,000 LDTs are in use today.

The briefing was hosted by the nonprofit group Friends of Cancer Research and by the Deerfield Institute, a market research firm in New York City focused on medical technologies.

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