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Pathologists' Group Accuses FDA of Making 'Dubious Claims' in LDT Harms Report

NEW YORK (GenomeWeb) – The Association for Molecular Pathology, a group that doesn't want the US Food and Drug Administration to regulate most lab-developed testing procedures, found a lot wrong with the agency's recent report characterizing such tests as potentially harmful.

In November, the night before a congressional hearing on regulation of lab-developed tests (LDTs), the FDA released a report highlighting 20 examples where tests not regulated by the agency could have or did cause patients harm. The report was the FDA's long-awaited counterpoint to lab industry players and pathologists who have maintained that LDTs regulated under CLIA, the traditional oversight framework, are safe and for the most part aren't harming patients.

"The [FDA] report fails to acknowledge that even if all of the case studies presented had concerns that might have been addressed by FDA oversight (although, this is clearly not the case), these tests are a miniscule fraction of the thousands of [lab test procedures] that are designed, developed, validated, and interpreted by appropriately trained and qualified health care professionals," AMP said in its response.

After reviewing the agency's allegations, AMP believes that "only a few" of the 20 tests could cause harms that FDA oversight would have actually prevented. But the group adds that had the Centers for Medicare & Medicaid Services' authority under CLIA been "fully exercised," that would have been even more successful at addressing these potential problems.

One such example in the FDA's report is a test for the KIF6 variant, which some studies had shown to be associated with heart disease risk and statin benefit. A large study ultimately didn't bear out the statin benefit association, but by that time 150,000 tests had been performed, costing the healthcare system $2 billion, according to the agency. AMP's response to this example is that if CLIA were modernized, third party expert reviewers could assess tests like this for clinical validity.

Currently, only analytical validity of tests is assessed under CLIA. The FDA has proposed to evaluate LDTs for analytical and clinical validity in a risk based fashion.

Based on the 20 examples, AMP accused the agency of making "dubious claims" in its report, of leaving out critical context in presenting the cases, and of relying on news media reports instead of information from peer reviewed literature to make allegations of harm. As a result, the FDA's report could cause the public to "unduly question the quality of care provided to them by their physicians," AMP said.

At the same time, AMP also concluded many of the 20 examples in the FDA's report are the result of physicians using treatments outside of established medical practice or failing to follow up a screening test with more confirmatory assessments.

For example, the FDA report cites a PCR test at Dartmouth-Hitchcock Medical Center that reported false-positive results for whooping cough and caused doctors to erroneously declare an outbreak in 2006. Subsequently, 27 cases deemed to be positive by the PCR test was tested by culture and came up negative. The FDA claims that its oversight would have ensured that the PCR test met minimum performance standards and that the manufacturer's claims were accurate.

AMP, however, faults a clinician for the mishap. The group noted that the lab performing the PCR test was investigated by the CDC and the College of American Pathologists at the time, and was found to be working properly. "The actual problem was that the clinician incorrectly interpreted the results of the test and made an incorrect clinical decision," AMP said. FDA oversight of LDTs "will not control how clinicians choose to act on test results. FDA has no authority … to regulate the practice of medicine."  

AMP's argument is largely the same when it comes to non-invasive cell-free DNA prenatal testing, which the FDA report cited for having high false-positive results. In one case, this led to an unnecessary abortion. According to AMP, physicians should confirm a screening test with more definitive diagnostics before deciding to perform an abortion. "This is best addressed through practice guidelines," which several groups have issued, AMP added.

Groups representing pathologists and the lab industry have recently acknowledged that there are gaps in the oversight of LDTs but want to see these addressed by expanding the CLIA program rather than through the FDA. AMP stuck to this position in its statement and asked Congress to "insist" as much. Additionally, AMP wants the Department of Health and Human Services and the Office of Management and Budget to conduct a scientifically rigorous analysis of the impact of FDA regulation on LDTs before allowing the agency to step into this role.

Advancing a CLIA-focused approach also has its challenges, however. At the congressional hearing in November, Patrick Conway — chief medical officer of CMS' Office of the Administrator — repeatedly said that his agency lacks the bandwidth to take on additional responsibilities and felt the FDA should take the lead. Of course, Congress could give CMS additional resources, but many industry observers believe the climate on Capitol Hill makes this unlikely.

Moreover, since the FDA believes it has the statutory authority to regulate LDTs, agency officials have argued that creating another oversight framework under CLIA would be duplicative and a waste of resources. The FDA doesn't claim that its oversight will be perfect or ensure that there are no faulty LDTs on the market. However, the agency wants to put in place a system for identifying and tracking LDTs so errors and patient harms are identified and more quickly addressed.

In its report, the agency pointed out that in 2014, it issued 31 warning letters to in vitro diagnostic manufacturers for various regulatory violations, classified and reviewed 313 product recalls, and inspected design validation issues and inadequate follow-up of device failures. "The same sorts of problems would be expected with LDTs, but could go undetected because there is generally no premarket review and limited adverse event reporting for LDTs," the FDA noted.