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Pathologists Take Alternative Lab Test Regulation Proposal to Senate

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NEW YORK (GenomeWeb) – The Association for Molecular Pathology has come up with its own plan (see PDF below) for regulating laboratory test procedures as an alternative to the US Food and Drug Administration's draft guidance.

The proposal seeks to maintain oversight of lab-developed test procedures (LDPs) largely under the traditional pathway via the Centers for Medicare & Medicaid Services' Clinical Laboratory Improvement Amendments (CLIA), but with changes that expand the agency's regulatory muscle.

AMP suggests updating CLIA regulations so CMS can establish a public database that houses validation information on test procedures; rely on third party reviewers (such as the College of American Pathologists) to ensure clinical and analytical validity of high and moderate risk LDPs; and create a more standardized process to track adverse events. These additional capabilities would be funded through an increase in user fees.

AMP has been working on this proposal for some time as a counterpoint to FDA's draft guidance to regulate what the agency calls lab-developed tests (LDTs). The lab and pathology community's beef with FDA oversight is that the agency's regulations are more suited for devices. So, they've chosen the acronym LDPs, instead of LDTs, to emphasize that lab testing procedures are akin to the practice of medicine, which is out of the FDA's regulatory purview.

"FDA proposed taking laboratory-developed procedures and plopping them into the current medical device regulations with a series of exemptions and exclusions," Roger Klein, chair of AMP's professional relations committee and a molecular pathologist at the Cleveland Clinic, told GenomeWeb. "Our proposal is very different. It really builds on the current CLIA program and expands it in key ways in order to bring it in line with contemporary technologies and service delivery. It also answers some potential stakeholder concerns."

The FDA and groups in the life sciences community that support the agency's desire to regulate LDTs have pointed out that CLIA is an outmoded regulatory framework for the increasingly complex technologies and business models underlying today's diagnostics. They have noted, for example, that under CLIA the clinical validity of an LDT isn't ensured, and that there is no adverse events reporting system to make the public aware when a test malfunctions and causes harm.

Under AMP's plan, CMS would review tests within a three-tier, risk based construct like the FDA does, except under CLIA, the classifications will differ dramatically. For example, FDA has said in its draft LDT guidance that it plans to first regulate the highest-risk tests, which include LDTs with the same indication as FDA-approved companion diagnostics, screening tools meant to be used in asymptomatic patients, and high-risk diagnostics for infectious diseases.

Within AMPs plan though, only so-called multi-analyte assays with algorithmic analysis (MAAAs) (e.g. Genomic Health's Oncotype DX or Agendia's Mammaprint) would fall in the high-risk category. AMP's plan mandates that labs with high-risk MAAAs also reveal their proprietary algorithms to reviewers and make summary validation information public if they wish to be overseen under CLIA.

"We really viewed high risk tests as those that … an inspector would have trouble evaluating without additional information," Klein noted. "Many of these tests have complex algorithms that aren't disclosed, and they tend to be sole source. There is no reason the CLIA framework couldn't evaluate these tests as long as sufficient information is provided to the reviewer."

If labs choose to keep their algorithms proprietary, then according to AMP's proposal, their other option is the FDA premarket review route. This idea may not sit well with some developers of MAAAs, but then, this wouldn't be the first time that labs developing "generic" tests and those advancing MAAAs or "boutique" diagnostics have disagreed on policies.

As a counterpoint, Sheila Walcoff, a regulatory policy consultant that advises labs, including those that market MAAAs, pointed out that accrediting bodies, including CAP and the New York State Department of Health, have been inspecting and certifying such algorithm-based diagnostics for a decade, previously known as in vitro diagnostic multivariate index assays. Even the FDA, she pointed out, abandoned its initial plan to regulate IVDMIAs in favor of bringing all LDTs under its oversight.

Enhancing CLIA

"The vast majority of tests [in AMP's risk framework] will fall into the moderate- or low-risk categories," Klein said, noting that the methodology underlying LDPs would be a factor in establishing the level of risk.

Tests that are not MAAAs and used to inform treatment decisions and disease prognosis, as well as tumor profiling panels and sequencing procedures for inherited conditions, would be moderate-risk LDPs, according to AMP. Low-risk LDPs would be those the lab isn't claiming as the only tool for diagnosis or prognosis and for procedures where incorrect results won't cause serious harm. Some examples are Factor V Leiden testing, cystic fibrosis carrier screening, and LDPs for public health emergencies.

AMP has included certain exemptions for low-risk tests, as well as those for public health surveillance or compassionate use. However, developers of high- and moderate-risk LDPs will have to provide evidence of analytical and clinical validity, and submit summary information for the public database. Labs can use a variety of sources in this regard, including published literature, guidelines, and data registries.

"Literature sources of clinical validity are really going to be key for most tests," Klein said, noting that the majority of LDPs developed at hospitals or places like Cleveland Clinic are advanced when there is a clinical need, based on peer-reviewed, published data, in collaboration with other physician experts. "The process at reference labs is fundamentally similar," he said. "People are looking at the literature and finding tests that are clinically meaningful."

Moreover, there is a "three-of-a-kind" rule where after three labs submit clinical validity information for a test, other labs performing tests for the same biomarker for the same purpose could refer to information in the CMS electronic database to back their claims. An AMP spokesperson explained that this provision aims to save labs from having to "repeatedly and unnecessarily" assemble data about biomarkers with accepted validity. Labs would only need to collect data under AMP's plan when there is no other way to provide the necessary validation information.

In developing this proposal — which AMP estimates would take four years instead of FDA's nine-year phase-in plan — the association has also addressed concerns the lab community voiced about the agency's draft guidance. At a public meeting to discuss the guidance earlier this year, many speakers complained that FDA's submission requirement wouldn't allow labs to "tweak" tests and make improvements that they do on a daily basis. In the present proposal, labs wouldn't be required to submit LDPs for another review unless the change "significantly" alters performance characteristics or the change pushes the test up to a higher risk classification.

"Modifications in our proposal would be treated far differently than the FDA treats them," Klein said. For example, labs with FDA greenlit in vitro diagnostics need to garner additional clearance if the test is altered to assess frozen tissue instead of fresh samples. Klein added that labs would also need to submit to the FDA if they expand the indication for a particular analyte, such as BRAF mutations, into other disease settings.

Under AMP's plan, "if the performance characteristics of the test don't change, there wouldn't be a need for a new submission," he said. "We've tried to preserve the elements of flexibility inherent to the CLIA process while … providing a somewhat higher level of review that would enhance the oversight of the test development and introduction process."

AMP's proposal would also update the list of analytes for which proficiency testing is required. CAP currently runs a proficiency testing program for a number of analytes, where CMS compares the ability of different labs to gauge specific markers. Lab industry representatives often highlight this program as an example of how labs are already subject to rigorous evaluation. AMP is seeking to expand this program and require that all LDPs undergo some form of proficiency testing, either through a CMS-approved program or an alternative scheme.

However, Walcoff suggested that expanding proficiency testing may not be the kind of lab oversight that satisfies policymakers looking to protect public health while promoting innovation.

"Many policymakers have long expressed concerns regarding any proposal that uses a specific technology platform or relies exclusively on the application of legacy approaches, such as traditional inter-laboratory proficiency testing, as the primary basis for defining risk and regulatory burden," said Walcoff, formerly a senior science and public health official at HHS. "Given how fast software technologies are evolving to enable more precision medicine, the result is inevitably a chilling effect on innovation that does not lend itself to those legacy oversight approaches."

Moreover, because this proposal would increase CMS' oversight responsibilities and require more funds, labs would also likely have to pay higher user fees. Klein noted that the burden would be heavier on labs performing more tests compared to smaller labs. While those that want regulation to remain under CLIA don't foresee this as problematic, labs are under increasing financial duress. They were not too happy, for example, with the resources required to voluntarily submit test information to NIH's Genetic Testing Registry. 

"Is anyone going to run with joy at the prospect of having to pay more fees? No, they're not," Klein said, recognizing that the lab industry has experienced substantial reimbursement cuts in recent years. Still, Klein estimated that the increase in lab user fees under CLIA would be more modest compared to what labs would pay to garner FDA approval for tests. "It can be done in a way that doesn't force labs to stop testing and doesn't stop innovation," he said.

Congressional backing?

AMP this week shared its plan with the Senate Health, Education, Labor, and Pensions (HELP) Committee, and the association is planning to take the proposal to the House Energy & Commerce Committee as well. Meanwhile, the House E&C Committee is already giving serious consideration to a regulatory proposal crafted by a small group of influential labs and test manufacturers. The Diagnostic Test Working Group (DTWG) has conceived a regulatory framework for a new category of tests, dubbed in vitro clinical tests (IVCTs), which would spread oversight responsibilities across the FDA, CMS, and the states.

Although the House E&C Committee has incorporated these ideas into draft legislation and has been gathering input on it, key life sciences stakeholders have yet to fully back it. AMP told the House E&C Committee it likes that the draft bill "keeps LDPs outside of the medical device regulatory framework," but had reservations that the plan "was not developed from the perspective of maintaining patient access to innovative and accurate tests." The American Medical Association has issued statements on FDA's LDT guidance that appear more in line with AMP's CLIA-focused solutions. The American Clinical Laboratory Association has also spoken favorably of keeping regulation of LDPs under CMS since the lab industry group believes the FDA lacks statutory authority to regulate such test procedures.

While it's not clear how legislators will receive AMP's plan, in the Senate, the HELP Committee is still considering different proposals on lab test regulation. And this is certainly not the first time that a CLIA-centric approach has been floated. Several years ago, Congressman Michael Burgess (R-Tex.) proposed a bill that would keep LDT regulation out of FDA's hands.

"Our goal here is to assist the HELP committee as they look at the area of laboratory test regulation," Klein said. "We're optimistic our ideas will be given serious consideration and a system where the vast majority of lab tests are overseen under CLIA will be preserved."


This article has been updated with additional details on AMP's position on the House E&C Committee's draft legislation. An earlier version inaccurately suggested that AMP hadn't provided comment.

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