CEO SUMMARY: Forty years ago, pathologists in hospital and academic labs worked closely with treating physicians to produce laboratory-developed tests for discrete clinical cases. Seeing that, the FDA decided not to regulate those tests, an FDA official said. Over time, however, use of LDTs became a serious concern when labs developing LDTs were no longer involved with their use for individual clinical cases. These labs marketed their LDTs nationwide and made claims about their validity that were unsupported by evidence, the official said.
IN RECENT COMMENTS, AN FDA OFFICIAL confirmed two points. First, the federal agency will continue to promote the guidance it proposed last year for labs offering laboratory-developed tests. Second, the FDA recognizes that it is possible that a lawsuit may result from clinical labs wanting to challenge the FDA guidance for LDTs.
These comments were made by Alberto Gutierrez, PhD, Director of the FDA’s Office of In Vitro Diagnostics and Radiological Health. He was one of four speakers who participated in a webinar sponsored by the Harvard T.H. Chan School of Public Health and STAT News.
FDA oversight of LDTs
Separately from this webinar appearance, the FDA gave lab executives and pathologists an idea of the evidence that it will put forward to demonstrate that LDTs can harm patients. On November 16, prior to a Congressional hearing on LDTs, the FDA issued a 39-page FDA report, “The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies.” The report said that some “LDTs provided information with no proven relevance to the disease or condition for which they are intended for use, while still others are linked to treatments based on disproven scientific concepts. In addition to patient harm, inaccurate or unreliable tests can be costly to society.”
In response to the release of this document, the Association for Molecular Pathology said only a few of the 20 LDTs in the FDA’s report could cause harm that FDA oversight might have prevented.
The examples were outlier assays; a problem with treating physicians using treatments outside accepted medical practice; analytical errors, which both FDA and CMS acknowledge are best addressed by CLIA; or failure of treating physicians to follow up a screening test with a diagnostic confirmation test, declared AMP. Along with AMP, other clinical lab associations have challenged the FDA’s authority to regulate LDTs as proposed.
But in remarks during the webinar on December 11, Gutierrez explained much about the agency’s thinking on LDTs. He predicted that the FDA will proceed with its guidance despite the pushback from clinical labs. He invited clinical labs to work with the FDA to improve its review processes.
In his remarks, Gutierrez explained that soon after the passage of the Medical Device Amendments of 1976 (MDA), the FDA reviewed the need to regulate LDTs. “Early on we made a determination that there were certain tests that were created typically in hospital and academic laboratories where the pathologist worked on the clinical case and that likely would not need our overview. And so we decided not to regulate those tests,” he explained. But over time, the development, use, and spread of LDTs became a serious concern, he said.
A Shift to Widespread Use
“In the mid 1990s, the FDA saw a shift from labs becoming more of a service to providing these tests to physicians,” continued Gutierrez. “With the ability to ship samples all over the country, we saw a shift of labs not being near the patient or being part of the patient treatment.
“[Along with that trend]… we also began to see where labs created one [LDT] test and marketed it all over the country with claims that were done by the company,” he noted. “So the FDA began to regulate these tests in the late 1990s and it proposed several ways to move forward.
“In 2010 we said we would regulate these tests the way we regulate everything else and we put a draft proposal together in 2014,” added Gutierrez. “The idea [behind the draft proposal] is to bring laboratory-developed tests on the same par, if you like, [with the way] that we regulate all other things, which is to look at pre-market claims they make and determine whether they [the claims] are clinically valid or not.”
During the webcast, a video was shown of a couple who had a prenatal screening test done to test for the presence of trisomies 13 and 18, which are chromosomal disorders that lead to mental retardation and birth defects. The couple became distraught after getting a false-positive result and no information about the need for follow-up testing.
“The example in the clip is a good one,” Gutierrez commented. “The com-pany set up and marketed it [the LDT] really erroneously because the test is actually a very good test as a screening test and it should be a screening test. It’s much better than the previous way that prenatal screening was done. But the fact is that, because of the prevalence of the disease—and no test is perfect—you are going to get false results.
“If the prevalence drops, the number of false positives is going to increase,” he added. “So the fact that the company was selling this [LDT test] as extremely accurate and not telling people beforehand that when they get a positive result it was unlikely to be a positive result, particularly for trisomy 13 and trisomy 18, [is problematic].
“Those are the kind of things that we want to be able to regulate and have companies be wholly responsible for making claims that are appropriate for what they have,” he said.
A Question of authority
Asked if the FDA has the statutory or regulatory authority to regulate claims about LDTs, Gutierrez stated, “We do. If you look at the 1976 statute, it talks about the type of tests, and the type of in vitro reagents, and the type of things that we regulate. It does not limit us to regulating based on where they are made. So we believe we actually do [have the authority]. That’s the reason we are going through a guidance process.
“The labs are fairly upset and claim that, one, we don’t have the purview of the labs and, two, they say we probably should have done this through rule-making because we are imposing new regulations on them,” he continued. “As it turns out, it really was a policy decision back then [after 1976 by the FDA] and that policy decision was exploited—to a certain extent.
Guidance Is ‘Best Thing’
“The FDA thinks that doing this with guidance is the best thing to do,” added Gutierrez. “The reason is that things that go into law and that go into regulations are typically very difficult to change.
“LDTs are an area that will be difficult to regulate,” he emphasized. “There is a broad set of tests. Some of the LDTs are very good. Some of them require a lot of expertise from the pathologists and some of them don’t.
“Regulating LDTs in a way that makes sense and that does not disrupt what’s going on [in labs] is going to be difficult,” he acknowledged. “So doing it through guidance allows us to step into this area in a way… where a third party [the FDA] will be looking at their clinical ability.” Gutierrez also added that the FDA will push for labs offering LDTs to be better with the quality systems that support the LDT results they report… “without hopefully stopping a lot of really good work.”
Asked if the FDA were concerned about labs pushing back against the FDA’s efforts, possibly with a legal challenge, Gutierrez responded, “The plan is to move forward with the guidance that we’re doing. Are we going to get sued? A lot of people think we might and that would obviously be problematic.
A Lack of Transparency
“We have been trying to work with the laboratory community,” he continued. “In reality there have been some advances. One of things we tried to do in the mid 2000s is we identified a set of tests that we were particularly concerned with. Those were tests done with proprietary data that were not published. And we felt that an independent review would be needed for those tests.”
“[Since then,] the laboratories have come around in their proposals and have made several legislative proposals to Congress,” he stated. “Even the laboratories that have been most opposed to the FDA have at least understood that perhaps there are some set of tests that probably should be reviewed by the FDA.
In that respect, “we have come a long way,” commented Gutierrez. “There is a consensus now that LDTs should show that they are clinically valid before they are offered and that somebody should be able to verify that.”
Going Too Far?
Some labs are afraid the FDA might go too far, he added. “I understand that if the FDA overregulates [LDTs] there will be a problem,” Gutierrez explained. “So we clearly have to, and we would like to, get the cooperation of laboratories because we are not going to be able to do it well unless the laboratories cooperate.
“We think we will continue down the path of our guidance though we are sure that the laboratories and Congress will continue looking at legislative proposals—in part because, if there is a lawsuit it will be somewhat uncertain what we will be able to do or not,” he stated. “I do think we will move toward something that is at least more regulated.”
One area of concern is whether the FDA will apply the LDT guidance retrospectively or for new tests only. “The draft guidance is a way to put a proposal on the table and get feedback,” he commented. “The draft LDT guidance did apply to old tests that are out there, but we proposed a nine-year implementation [plan] so that people will have plenty of time. And that implementation will be risk-based so that the tests that are currently the highest risk would be first” and “…most LTDs would be considered moderate risk and would be [evaluated] five to nine years down the road.”
Gutierrez concluded by saying the agency has been considering some of the comments labs have made on the proposed LDT guidance. “We could grandfather what’s there but then shorten the implementation,” he commented, citing one example.
FDA to Congress: Draft LDT Guidance Has a Goal to Improve Patient Safety
IN CONGRESSIONAL TESTIMONY last month, Jeffrey Shuren, MD, JD, said the FDA’s effort to regulate laboratory-developed tests is driven by an effort to minimize patient harm. Shuren is the FDA’s Director of the Center for Devices and Radiological Health. He addressed the House Energy and Commerce Committee’s Subcommittee on Health.
Regarding LDTs, Shuren said, “The real loser here is patients. Doctors and patients don’t care about who makes their test. They do care that their tests are accurate, reliable, and clinically valid.”
He also acknowledged that some labs are cooperating with the FDA on its efforts to develop an oversight system for LDTs.
“Now some labs have already been working with us and we congratulate them for crossing that picket line,” observed Shuren. “Our message and our invitation to the rest of the lab community is to put down the swords. For the sake of our patients, it is time to end the saber-rattling and partner with us moving forward.”
Shuren testified on November 16, the same day the FDA released its latest report on the need to regulate LDTs, “The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies.” In that report, the agency said FDA oversight of LDTs is needed to address the following concerns:
- Lack of evidence supporting the clinical validity of tests
- Deficient adverse event reporting
- No premarket review of performance data
- Unsupported claims from manufacturers
- Inadequate labeling of tests
- Lack of transparency in how LDTs are developed
- No comprehensive list of all LDTs in use.
The FDA also is concerned about the uneven playing field in which these tests are developed. If a laboratory is developing an LDT and conducts the research needed to validate their tests and seek premarket review from the FDA, it is at an unfair disadvantage when other labs do not follow the same standards to support their claims and the safety and efficacy of their device, the report explained.
LDTs also threaten the scientific integrity of clinical trials, because clinical investigators often rely on LDTs when selecting patients for participation in trials. If the tests used to select patients are inaccurate, then the scientific conclusions derived from these trials also could be inaccurate, the FDA said.
FDA Lists 20 LDTs That It Considered Problematic
EVERY PATHOLOGIST AND LAB EXECUTIVE following the FDA’s effort to regulate LDTs will find the federal agency’s report, “The Public Health Evidence for FDA Oversight of Laboratory-Developed Tests: 20 Case Studies” to be informative.
The authors analyze the quality issues associated with each of the LDTs. Included is an assessment of potential patient harm, whether from issues associated with sensitivity and specificity, or from how physicians utilize the test to diagnose a patient and then determine appropriate treatment. The full report can be accessed at the FDA website or with this URL: Here