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Amid Competing LDT Regulatory Proposals, Common Ground but Key Disagreements for Congress to Consider

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NEW YORK (GenomeWeb) – Congress currently has before it legislative proposals for regulating laboratory developed tests (LDTs) from three influential groups — the Diagnostic Test Working Group, the Association for Molecular Pathology, and the College of American Pathologists.

CAP, which issued a plan most recently, wants to improve regulation for the majority of LDTs through the Clinical Laboratory Improvement Amendments, except for high-risk tests, which the organization said should be overseen by the US Food and Drug Administration.

AMP's approach is also CLIA-focused, but instead of LDTs, the group uses the term lab-developed procedures (LDPs). AMP would also have high-risk LDTs overseen by FDA, except multi-analyte algorithm-based assays (MAAAs) are the only tests in its high-risk category. These tests could also be overseen under CLIA, according to AMP, but the labs would have to reveal their proprietary algorithms to reviewers. (CAP's high risk definition includes tests that "produce a result that is not independently verifiable," which sound a lot like MAAAs, but the organization clarified that their high-risk category is broader than AMP's and recognizes that new types of tests could fall into this bin in the future.)

Roger Klein, chair of AMP's professional relations committee and a molecular pathologist at the Cleveland Clinic, told GenomeWeb that AMP developed its proposal with input from many professional societies and lab groups, including CAP.

"Therefore, it should not be surprising that there are similarities in the proposals," he said. "We view concordance between our proposal and CAP's plan as evidence that we have successfully done our job. These consistencies imply CAP's endorsement of the fundamental principles underlying our plan, the most important of which is the centrality of CLIA to the LDP oversight process."

The DTWG's plan, meanwhile, would create a whole new category of tests, dubbed in vitro clinical tests (IVCTs) — a term that could describe LDTs or kits. Under this plan, FDA would have authority over test development and validation, CMS would remain in charge of traditional lab activities necessary to perform tests, and states would oversee accuracy of test interpretation. As previously reported by GenomeWeb, the DTWG involves Becton Dickinson, Roche, Mayo Clinic, LabCorp, Abbott, and ARUP Labs.

All these groups have taken their proposals to Congress, but at this point, it's anybody's guess whether legislators will pick a favorite or incorporate the best ideas from the different plans. The House Energy & Commerce Committee has incorporated the DTWG's ideas into draft legislation and has been seeking stakeholder comment on it. However, Andy Fish, executive director of the diagnostic manufacturers' group AdvaMedDx, told GenomeWeb that no groups have outright backed the draft legislation.

"In fact, a number of [stakeholders] from the patient advocacy side submitted comments that were highly skeptical, and they were concerned about the proposed revisions to [test] risk classifications and evidence thresholds," he said. Fish guessed that after considering the feedback, the House E&C will likely produce another draft legislation on the topic and may hold a hearing on the issue.

The Senate also has expressed interest in addressing diagnostics regulation as it works on its version of the 21st Century Cures legislation, according to experts following the process closely. R. Bruce Williams, a member of CAP's Board of Governors and chair of its Council on Scientific Affairs, told GenomeWeb that "the Senate seems very interested in a hybrid approach" involving CMS and FDA. And this blend is best achieved under CAP's plan, he believes.

Williams also highlighted that the American Medical Association backs CAP's approach. Legislators certainly pay attention to AMA's stance on healthcare policy matters and the association has been vocal about its objections to FDA's draft LDT guidances. The association has called for improving LDT regulations through CLIA, as well as for limiting the agency's regulatory reach to direct-to-consumer tests and tests with methodologies that aren't transparent (i.e. MAAAs).

Meanwhile, AdvaMedDx is standing behind a FDA-led risk-based framework for regulating all LDTs. Fish noted that AdvaMedDx has continued to work with the FDA to refine its draft plan. Although the organization hasn't taken a position on these other legislative proposals, CAP and AMP's approach to carve out FDA regulation only for a subset LDTs is inconsistent with AdvaMedDx's policy stance, Fish said.

"Frankly, both the Senate and the House are interested in finding paths forward that have the most stakeholder consensus," Fish said. However, with all these different proposals in play, he recognized, "there's not necessarily a whole new level of consensus developing."

The fundamental issues haven't changed a lot.

Same issues, old divisions

Stakeholders in the lab, pathology, diagnostic, and health technology sectors have been arguing about LDT regulation for several decades (see GenomeWeb's timeline on LDT regulation). Since 1992, time and again, the FDA has tried to regulate these types of tests and then pulled back due to objections from different stakeholders. The sticking point remains whether FDA has the authority to regulate LDTs. If so, should FDA regulate all LDTs or just the high-risk ones? And ultimately, how is risk defined?

"The fundamental issues haven't changed a lot," Fish said. "The proposals we've seen come forward are reflective of continued concern within the lab community about FDA oversight."

MAAAs are another sticking point that has stalled FDA oversight of LDTs and will likely continue to be controversial. When the FDA first tried to regulate IVDMIAs in 2006, it made diagnostic manufacturers unhappy. They called the plan "piecemeal" and complained that regulating just IVDMIAs would create an uneven playing field.

Many in the lab community, including pathologists, had a different perspective. In a 2009 report, CAP's Technology Assessment Committee, outlined all the ways that MAAAs (back then they were called in vitro diagnostic multivariate index assays, or IVDMIAs) disrupt the work of pathologists. The committee noted that IVDMIAs are "problematic" because proprietary algorithms hinder pathologists' from understanding or interpreting how the test result is obtained. Moreover, since an IVDMIA is usually performed only at the one lab that developed it, this may have a financial impact and "take services away from pathology laboratories," the committee noted.

In releasing its draft LDT oversight framework last year, FDA claimed it was trying to level things out between kit developers that submit their tests to the agency and LDT providers that can more quickly, and some would say more easily, introduce tests under CLIA for the same indications. Although groups representing diagnostic and health technology firms, such as AdvaMedDx and the Coalition for 21st Century Medicine support a plan (with certain revisions) under FDA's aegis, most of the lab industry remain opposed.

These policy divisions are old, and the lines are drawn between the disparate business models and financial interests of labs that perform "generic" LDTs (i.e. KRAS testing) and labs with "branded" tests (i.e. Genomic Health's Oncotype DX). In a throwback to 2006 — when the FDA sought to regulate algorithm-based tests as a subset of high-risk LDTs — both CAP and AMP's proposals again deem such tests high risk and would have them regualted by the agency.

Indeed, labs performing MAAAs — which Williams acknowledged fall into the high-risk category as described by CAP — usually have CLIA certification or CAP accreditation, or both. But in CAP's experience accrediting such labs, "there is some proprietary material that we aren't able to view as deeply as we think may be beneficial for patient safety," Williams said. CAP accreditors look at aspects of MAAAs "as best as possible," he noted, "but the FDA would have more authority to look at these [tests] … a bit more in depth than we can at the current time."

Conversely, there also are detractors of CAP's and AMP's ideas. Williams expects some stakeholders will not like CAP's proposal that FDA regulate high-risk tests. "I think people who want [to keep regulation] entirely under one or the other," CLIA or FDA, "will be less happy with this," he said. "But we think this is a very reasonable approach."

Paul Radensky, who represents the Coalition for 21st Century Medicine, told GenomeWeb that the group "does not support risk-based classifications that identify algorithms or technological features as the basis for assigning risk."

The coalition, which has among its members CareDx (maker of the MAAA AlloMap) and Foundation Medicine (developer of the next-generation sequencing test FoundationOne), has submitted comments on FDA's LDT regulation proposal and pointed out areas that still need "substantial work," said Radensky, a partner at the law firm McDermott Will & Emery. The coalition, he added, has also worked over the years with congressional stakeholders to advance a risk-based regulatory framework under FDA that recognizes the differences between clinical diagnostics and medical devices.

Amid these competing proposals that promise to be a better alternative to FDA's plan, the agency has continued to exercise its authority over diagnostics, whether marketed as an LDT or in a "direct-to-consumer type model." Last week the agency sent an "untitled letter" to Pathway Genomics raising questions about the clinical validity of CancerIntercept Detect, a liquid biopsy test Pathway recently launched for early cancer screening in high-risk but otherwise healthy patients.

The agency said the test "appears to meet the definition of a device" and expressed concern about the lack of published evidence backing the company's marketing claims. Pathway plans to meet with the FDA and issued a statement explaining that physicians are involved in its service. "CancerIntercept Detect is a laboratory-developed test and, as a CLIA- and CAP-certified clinical laboratory, we are offering it as such," the firm added.

In Fish's view, all the reasons FDA is now moving forward with LDT regulation — increasingly complex technologies, changing business models, marketing claims unsupported by clinical evidence, and growing concern for patient safety — remain valid. There are groups that support FDA's position, he said, highlighting that the Republican-led House E&C believes the agency should have a role in overseeing LDTs.

I think it would actually help this debate to see FDA's final guidance.

A win for accrediting bodies

Fish thinks it's possible to get stakeholders to agree on LDT regulation, if the field can get beyond its divisions over FDA's role. There are core principles, such as the need for regulatory transparency and stakeholder input, that all the different groups agree on and can start discussions from.

"Different stakeholders have different views about whether a regulatory framework for laboratory developed tests or procedures should fall under CLIA or FDA’s jurisdiction. We understand and respect the views of each organization," Radensky told GenomeWeb. "That said, [the Coalition for 21st Century Medicine] believes it is important to work toward consensus recognizing that there are a number of areas where stakeholders agree, even though there may be disagreements in some areas."

One commonality across the different proposals is the reliance on third-party accrediting bodies. A proposal that relies heavily on third party accreditors, such as CAP, the American Association for Laboratory Accreditation, and others, could be financially beneficial for these groups.

For example, CAP launched its accreditation program in the 1960s, and it currently includes 7,600 labs. According to CAP's tax form submitted to the Internal Revenue Service and posted by Citizen Audit for 2013, the most recently available year, the organization reported $172.5 million in total revenues, $122.5 million of which was attributed to laboratory improvement programs, such as proficiency testing, and $30.5 million from accreditation.

"We don't have any commitment under anyone's proposal … to be a third-party accreditor for complex labs," Williams said. "If we do, … then we'd take a look at what would be required to do that."

Although FDA's draft plan also lays out a significant role for third-party accreditors, Williams said CAP doesn't back it because that plan would be more burdensome and expensive for labs. "Even for moderate complexity [LDTs], FDA has them going through a 510(k) or a premarket approval process," he noted. "To have that sort of development would … hinder innovation."

In the end, these seemingly insurmountable divisions may only be settled by congressional action. "A lot of the same lines that were drawn five years ago are drawn today," Fish said, while acknowledging that there is also a great deal of uncertainty around how Congress will move forward on this issue.

Of course, there is the chance that FDA might finalize its LDT guidance before Congress figures out legislation that has bipartisan support. "I certainly think it makes sense for FDA to finalize its guidance. Congress can act any time it desires to do so," he said.

"I think it would actually help this debate to see FDA's final guidance," Fish added. "It will then be clear how the agency has proposed to address stakeholders' concerns that have been raised on the draft."

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