WASHINGTON -- When a drug fails or has serious side effects, the public hears about it -- think thalidomide, Darvocet -- but when a test for diagnosing disease or determining treatment fails, no one is the wiser, according to the FDA.
Earlier this week, the agency released a report citing 20 laboratory developed tests (LDTs) that may have resulted in patient harm.
LDTs are a subcategory of in vitro diagnostic devices (IVDs) "intended for clinical use that are designed, manufactured and used within a single laboratory," noted the agency.
The report highlighted 20 instances where tests produced false positive or false negative results, or both. It also cited tests that were intrinsically flawed at the outset -- rooted in poor science or unreliable biomarkers.
Jeff Shuren, MD, director of the Center for Devices and Radiological Health (CDRH) at the FDA, has been lobbying to expand oversight of LDTs since 2007. In 2014, the agency published draft guidance explaining to Congress and the public its plans for increased regulation of moderate and high-risk tests.
On Tuesday morning, Shuren continued pushing Congress to support this new framework for expanding LDT regulation.
Shuren told the House Energy & Commerce Committee in his opening statement, "The public must be assured that the tests used in the provision of health care, whether developed by a laboratory or other manufacturer, are accurate and reliable."
The FDA has had the authority to regulate IVDs since 1976 under the Medical Device Amendment to the Federal Food, Drug, and Cosmetics Act (FD&C Act), the agency argues. For a time, the agency decided not to closely monitor LDTs because few tests were available and most used very simple technologies. Moreover, the FDA did not want to burden small labs with the need to prove safety and effectiveness, which could be prohibitively expensive.
In more recent years, LDTs have grown in complexity and prevalence and are now used in detecting and treating more common diseases, Shuren explained. They are also being marketed more aggressively.
At a previous hearing in May, Shuren leveraged Congress' enthusiasm for Obama's Precision Medicine initiative, when he cautioned that "bad tests" could impede the success of the program.
"Imprecise medicine results from bad tests, misdiagnosis. You get the wrong treatment, or you get no treatment at all when you should, and as a result, patients get harmed and health care costs go up," he said.
He cited a genetic test for coronary heart disease that used a gene assay to predict people's response to statin treatments. A meta-analysis of 19 clinical studies showed the tests did not work, as did a randomized placebo-controlled trial that included 18,000 patients, he said. Moreover, a total of $2.4 billion had been spent on the flawed test. "And that test is still available today," he told Congress.
Monday's report included the KIF6 "StatinCheck" Genotyping Assay. It also included OvaSure, a diagnostic used to detect early stage ovarian cancer in women at high-risk. The report noted, "only one in 15 patients who tested positive actually had the disease." The remaining 14 risked undergoing removal of healthy ovaries -- if another test method did not reverse a misdiagnosis.
Half of the case studies related to cancer -- detecting the disease or the risk of disease or guiding treatment. Other tests included ones used to diagnose Lyme disease, human papillomavirus (HPV), fibromyalgia, chronic fatigue syndrome, autism, and pertussis.
And in one case, a defective non-invasive prenatal test (NIPT) or "cell-free DNA test" used to detect fetal chromosomal abnormalities, was found to have contributed to decisions to abort healthy fetuses.
The agency's report outlined the strategies FDA intends to use to regulate high- and moderate-risk LDTs including:
- Requiring adverse event reporting requirements
- Implementing premarket review of performance data
- Eliminating "unsupported manufacturer claims"
- Mandating "adequate product labeling" (e.g., information on how to interpret test results)
The majority of the subcommittee expressed support for the the agency's oversight paradigm. Rep. John Sarbanes (D-Md.) called it "a very reasonable undertaking."
However, several subcommittee members did not see a need for more oversight.
Rep. Michael Burgess (R-Texas) said, "We're talking about a proposal that may not just stifle but eliminate medical innovation, something [at] which this country has excelled for decades."
Burgess scoffed at the idea that vast numbers of ineffective LDTs were being used unbeknownst to the public.
"It took you three years to provide us with 20," he told Shuren.
Burgess calculated that with over 11,000 LDTs in use and 20 failures, "the rate at which you've detected a problem is [0.18%]."
Shuren disagreed, reminding Burgess that it was impossible to calculate the rate of inaccurate tests without a reliable reporting system to capture problems.
Shuren also defended his recommendation against alternative proposals to divide responsibilities for LDT oversight between the FDA and the Centers for Medicare & Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA), based on the type of test or who developed it. Most labs offering LDTs have relied on CLIA certification as evidence of quality, although that process does not evaluate specific tests, but rather the availability of equipment and qualified staff.
Both Shuren and Patrick Conway, MD, deputy administrator for innovation and quality and a chief medical officer at CMS, agreed that such a proposal was impractical and a waste of resources. Moreover, CMS employees lack the expertise to determine the clinical validity of a test, Conway said.
The American Cancer Society Cancer Action Network (ACSCAN) said in a press release, "It is paramount that patients and their physicians know that regardless of how or where a test is manufactured or performed, they can trust the information produced by that test."
ACSCAN further noted, "The FDA is the most appropriate agency to evaluate the analytical and clinical validity of diagnostic tests, along with their safety, to help ensure that patients and their doctors are able to make appropriate treatment decisions based on accurate information."
Some, but not all, laboratories have endorsed the agency's plan, Shuren said.
"Our message and our invitation to the rest of the lab communities is to put down the swords for the sake of our patients. It's time to end the saber rattling and instead partner with us moving forward."