August 20, 2015 | It’s been just over a year since the FDA released its plan to regulate laboratory developed tests, or LDTs. A staple of the American healthcare system, LDTs are developed and performed entirely within one laboratory ― usually part of a hospital or academic medical center, but more and more including for-profit companies. Cutting-edge tests, especially in genetics and oncology, often emerge first from the LDT system, where they are exempt from FDA review; instead, the laboratories that perform them are monitored by the Centers for Medicare and Medicaid Services under a different system established by the Clinical Laboratory Improvement Amendments (CLIA) of 1988. The CLIA program is widely respected for its oversight of laboratories, but does not involve any individual review of new LDTs before they are put into use, something the FDA is eager to change.
At the time the FDA’s plan for LDTs was released, we wrote that “fierce political wrangling is now expected” over the issue, and that has certainly been the case. Companies who sell FDA-regulated test kits ― who increasingly find themselves in competition with LDT providers ― have largely lined up behind the proposed regulations, as have certain healthcare groups like the American Society of Clinical Oncology. The College for American Pathologists, the main accreditor of laboratories, has worked with the FDA to shape the regulations even while voicing concern about the burden to labs they may represent. And many other groups, most notably the Association for Molecular Pathology (AMP) and the American Clinical Laboratory Association, have been fighting to keep LDT oversight entirely under the CLIA protocol. All have been lobbying regulators and the legislature for their preferred plans.
Earlier this month, the AMP released its own, alternative plan to modernize the way LDTs are regulated. The AMP proposal, which was presented to the Senate Committee on Health, Education, Labor and Pensions, would provide some individual review for LDTs, but would keep their oversight firmly under the CLIA program.
Diagnostics World senior science writer Aaron Krol spoke to Roger Klein, Medical Director for Molecular Oncology at the Cleveland Clinic and Chair of the AMP’s Professional Relations Committee, about his organization’s new plan for LDT regulation, and the reasons it’s seeking to keep these tests outside the FDA review process. This interview has been edited for length and clarity.
Diagnostics World: The AMP has been one of the strongest opponents of FDA regulation of LDTs. Do you feel that coming forward with an alternate plan to regulate these tests gives you more credibility?
Roger Klein: As the leading organization of experts in molecular pathology and molecular diagnostics, I believe that we’re generally perceived to have a great deal of credibility. But as experts in the field, we took a look at the CLIA regulations themselves, and we understood that they were written at a different time with different technologies and practice patterns. What our proposal does is attempt to take those regulations and make them fit better with contemporary practice.
I would say that FDA has put forth no evidence, and nor has anybody else, that there is a systematic problem with laboratory testing in the United States. It’s important to understand that the CLIA regulations themselves are actually a minimum bar, which isn’t reflective of what most labs are doing today to ensure quality. Most laboratories that are performing complex molecular testing either get accredited by the College of American Pathologists, or have to satisfy the requirements of the State of New York, both of which go well beyond CLIA in a number of respects. We’re all deeply committed to ensuring that laboratory testing is performed correctly and accurately, and that we do the very best we can for our patients.
There are a number of differences between the AMP and FDA proposals to regulate LDTs, but the biggest is surely that you would give the Centers for Medicare and Medicaid Services, rather than the FDA, jurisdiction over these tests. What’s your reasoning for that?
It’s pretty straightforward. CMS already regulates these tests, and CMS’s regulatory framework is geared toward laboratories. The CLIA program is intended to ensure that laboratories are performing well and providing excellent testing to patients, whether those tests are developed in-house or whether they’re purchased kits.
The FDA’s statutory and regulatory framework, on the other hand, is based on regulation of medical devices. That includes in vitro diagnostic testing kits that are manufactured, packaged and distributed in interstate commerce, and while those don’t necessarily fit ideally into the current framework, I don’t think there’s any dispute that those are medical devices. When you have a test kit, and you’re marketing and manufacturing that test kit and distributing it to a wide range of users over whom you have no control, the regulatory framework that’s required for oversight is distinctly different from that for a test that is provided by a single laboratory.
However, laboratory developed tests are really services, and we’re really talking about regulation and oversight of laboratories. Our proposal takes the current CLIA oversight framework, and builds upon it in acknowledgement of changes in technology, changes in practice patterns, and also in consideration of stakeholder concerns.
The AMP has favored the phrase “laboratory developed procedure” over laboratory developed test. But a lot of the tests that the FDA has cleared as in vitro diagnostics ― for instance, the cystic fibrosis tests from Illumina ― use the same kinds of complex lab processes and computational workflows that seem to define a procedure. Why should procedures developed in a single lab be viewed differently?
I think central to this concept is the notion of a professional activity. The pathologists who perform this work, and our colleagues who are physicians and board-certified doctoral scientists, are professionals. When we’re designing a test, we’re implementing it, overseeing it, validating it, and continually monitoring and improving it. We see that as our professional practice. It’s very different from the commercial activity of producing a test kit and selling it.
At my institute, we perform the cystic fibrosis test that Illumina provided. These are high-complexity tests and they require skill to operate and interpret, but they’re very different conceptually from a test that we’re designing, developing, monitoring, and improving ourselves. Now, there can be significant interpretive components to these kits, in terms of understanding what the answer means for a specific patient. But in deriving that answer, the instruments and software are playing the chief role. When you’re doing a laboratory developed test, the professionals involved are much more central to the test activity.
The AMP proposal would define “high-risk” LDTs, which need more examination before they can be cleared for use, largely based on whether they use proprietary algorithms. Why focus on these algorithms, as opposed to the FDA proposal that bases its risk categories on a test’s indication for use?
As professionals, we go through board certifications, and residencies and fellowships that involve years of training. And much of what we’re doing uses methodologies that we can readily understand and monitor, so we can safely provide testing based on our training and abilities. So the indication for use alone would be far too limiting in terms of a risk categorization, because it wouldn’t take into account the people and the methods of running the test.
But when a test uses proprietary algorithms, it’s not readily understandable by an educated user like a pathologist or a clinician. That contributes to higher risk. We need the ability to understand the performance characteristics of the test. CLIA inspectors need access to sufficient information to fully evaluate the test.
Is focusing on the algorithms also a way to separate commercial labs from academic and hospital labs, in terms of the level of oversight their tests go through?
Most of these algorithmic tests do tend to be offered by commercial entities, partly because they require a different level of capital than is available in a hospital or university setting. And of course those companies have very different missions from other laboratories. Most of us are not-for-profit. We’re really focused on patient care, and our testing is supportive of the medical activities that go on within the health system. But our purpose in designing those risk categories wasn’t to separate commercial laboratories from hospitals or academic health systems, but rather to focus on a characteristic of the test that we felt created a somewhat greater level of risk.
Do you think we need a stronger mechanism to pull LDTs out of use if there’s evidence that they’re not analytically or clinically valid?
There needs to be some regulation in that regard. But CLIA has a very strong analytical framework, and if a test isn’t performing properly, CLIA is designed to remove it from use. That’s particularly important with respect to analytical performance, because the end user may not have the ability to evaluate that independently. Truthfully, clinical validity tends to be less of a problem.
If something’s demonstrated to have no value, and it’s used in a manner that potentially could create harm, clearly there has to be a vehicle for removing it. But you also have educated users on the other end. I’m at Cleveland Clinic, one of the largest healthcare institutions in the country. The way we set up tests is we talk to our colleagues, the treating physicians, and we discuss what tests they need to help manage their patients. So we’re not pushing tests onto them. We’re working together to evaluate tests for their clinical value.
You have an interesting proposal whereby, when labs or manufacturers change FDA-approved tests in ways that substantially alter their performance characteristics, jurisdiction would automatically move to CMS and this new LDT review process. Is that meant to ease the regulatory process for tests that get revised?
This is a really important section. Companies often put tests through FDA ― either through the clearance or approval process ― which professionals in the laboratory adapt to different uses. A perfect example is the gene BRAF. There’s a mutation in the codon V600 that we’ve used for years in colon cancer, to help us evaluate whether a person has an inherited disease called Lynch syndrome. But then, years later, along came the discovery that BRAF mutations are also prevalent in melanoma, and a drug was designed to target melanomas with BRAF mutations. So you have a situation where there’s an alternative use for a test that you’ve been doing for years. With proper internal validation, there’s no reason one can’t adapt an FDA-cleared test to a new purpose ― particularly in academic centers where people have a lot of experience and are trying to advance the field.
You hope to require that reviews for new LDTs are performed in a specific timeframe ― up to 90 days for the high-risk procedures. How would CMS get the funding to process reviews that quickly?
The administration of the program would build on the current fee-based system. The CLIA program is funded by the laboratories, and there are fees attached based on the size of the laboratory. And just as in the current program third-party accreditors play a very significant role in administering CLIA oversight, we also would envision that something similar would happen for pre-introduction review of tests. Those same accreditors, or other accreditors, could apply to become reviewers.
The use of third-party reviewers is also a part of the FDA’s proposal for regulating LDTs. Some other areas of overlap include exemptions for high-need tests, and allowing labs to submit scientific publications or well-curated databases as evidence for a test’s clinical validity. Why do you feel that those measures are inadequate to protect labs from undue burden if LDTs are reviewed by the FDA instead of CMS?
Again, FDA would review these tests under the preexisting constraints of medical device regulations. And we have industry members in our organization who can tell you that the costs of doing FDA submissions are quite substantial. A pre-market approval application can run into the hundreds of thousands, and sometimes even millions of dollars. For the vast majority of laboratories, this is simply not achievable. We’re undergoing tremendous scrutiny from payers, and when we do molecular testing, we often either don’t get reimbursed, or get reimbursed at levels below our costs. The idea that we could invest hundreds of thousands of dollars, or even thousands of dollars, to prepare submissions to FDA for tests on which we basically lose money, is obviously a non-starter.
The FDA has been very concerned about adverse events from errors in LDTs. How would AMP address monitoring and reporting adverse events?
I think FDA’s own regulations don’t really meet the need here. FDA’s standards for reporting adverse events were written for true medical devices, where you’re talking about events that cause death or serious injury ― the way you’d look at a pacemaker or some type of implantable device. I’ve been doing this for quite a while, and I’ve never seen a lab test kill somebody. The FDA standard would create an administrative burden on laboratories, who would be required to set up a bureaucratic procedure to evaluate lots of potential events, with likely very little gain.
What we’re really talking about with lab tests is errors that are harmful to patients, or a hazard to public health. And here, the CLIA regulations already require error reporting. We monitor our tests, and when we become aware of an error we’re required to notify the ordering physician of that error, and we have to do so in a timely fashion and document it. So what we’ve done is build upon that idea, and require laboratories to have a mechanism for ordering physicians to report laboratory errors.
The FDA believes it already has jurisdiction over LDTs. Do you think that keeping these tests under CMS oversight requires new legislation?
Absolutely not. The CLIA statute is quite broad. It instructs CMS to ensure the validity of tests. So it doesn’t require legislation to keep laboratory test regulation within CLIA. FDA does take the position that they have authority, but we’re among those who have not acknowledged FDA jurisdiction, and there are legal scholars and others out there who have a firm conviction that FDA lacks jurisdiction.
The AMP recently presented this proposal to a Senate committee that covers healthcare affairs. Would you hope for legislation that makes CMS regulation of LDTs explicit?
Our proposal was intended to assist the Senate Health, Education, Labor and Pensions Committee as they were looking at the issue of regulation of laboratory developed tests. We wanted to put together a concrete proposal that was sufficiently specific to inform their deliberations.
But as an organization, what we’re hoping to do is to help patients and help the field. We’re letting FDA know about our proposal, we’re letting CMS know about our proposal, and we’re letting the legislature know about our proposal. If you look at how molecular diagnostics and molecular pathology has grown in the past ten to fifteen years, it’s really remarkable the strides that have been made in terms of what we can do to help patients in genetics, in oncology. We don’t want to squelch that. We want to ensure that the field can continue with the vibrancy that has characterized it since its inception. But we also want to make sure that patients have a level of assurance in the quality and reliability of the testing, and in their safety. And we’re optimistic that our ideas will be embraced.