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Small Group of Labs, Dx Manufacturers Float Alternative to FDA LDT Guidance

NEW YORK (GenomeWeb) – Is it possible to craft a framework for regulating diagnostics that pleases everyone? A small group of labs and test manufacturers has taken a shot at it by coming up with its own proposal for regulating so-called in vitro clinical tests that it hopes will be an acceptable compromise for industry players that often disagree on the regulation of laboratory-developed tests (LDTs).

According to multiple anonymous sources with first-hand knowledge of the effort, the participating companies include Becton Dickinson, Roche, Mayo Clinic, LabCorp, and ARUP Labs.

After the US Food and Drug Administration last year issued a controversial draft proposal for regulating LDTs, labs represented by the American Clinical Laboratory Association and pathologists who are part of the Association for Molecular Pathology said the agency's plan wasn't in line with how these groups contribute to healthcare. Labs said they were providing testing services, not manufacturing devices; while pathologists similarly said that their work was the practice of medicine and out of the scope of device regulations.

The new proposal by the so-called Diagnostic Test Working Group (DTWG), available here, tries to address these concerns and align regulations closer to real-world practice. Their plan creates a new category for the in vitro clinical test (IVCT), which would comprise both test kits and platforms, as well as laboratory test protocols. IVCTs would be a new category under the US Federal Food, Drug, and Cosmetic Act and wouldn't be overseen as devices, drugs, or biologics, according to a draft of the plan.

Moreover, depending on a lab's or manufacturer's activities, regulation would be spread over the Centers for Medicare & Medicaid Services, FDA, and the states. IVCT design, development, validation, platform manufacturing and preparation of materials (such as reagents) for use at more than on lab or entity would be under FDA's aegis. CMS would have jurisdiction over typical lab activities, such as preparing reagents intended for use at a single lab, developing lab operating procedures, the pre-analytical process, performing an IVCT, and reporting the IVCT results. Finally, the states, which traditionally have had authority over the practice of medicine, would continue to look after interpretation of test results and consultation with medical professionals.

According to sources familiar with the DTWG proposal, it was drafted by Ralph Hall, a partner at the law firm Leavitt Partners and an expert on FDA regulation. Representatives from the labs and manufacturing firms that participated in putting the plan together did so with the caveat that their participation doesn't mean the companies would ultimately support it. Small or single-source labs, proprietary labs, and drug companies were not part of this drafting process. However, the DTWG plans to involve them in later iterations of its proposal, according to sources. On deadline, Hall did not respond to a request for comment.  

Industry observers have noted the DTWG's proposal may sit better with lab and manufacturing groups than FDA's LDT draft guidance. "In our view, this proposal is an intriguing start towards a potential LDT compromise," Jeff Gibbs, an expert on FDA-related legal matters at the law firm of Hyman, Phelps & McNamara, and Allyson Mullen, a lawyer specializing in device and diagnostic regulations at the same firm, wrote in the FDA Law Blog yesterday.

"There are certainly many areas of clarification and development that are still required and many key details will still need to be worked out," they said. "We expect that many laboratories will prefer the DTWG's proposal as it would mean less onerous regulation compared to FDA's proposed LDT framework."

Historically, the FDA has exercised "enforcement discretion" over LDTs, leaving oversight to CMS under the Clinical Laboratory Improvement Amendments. But the agency has long felt that CLIA regulations weren't sufficient to address increasingly complex tests that were being developed and widely marketed by labs. As such, despite much pushback from the lab community, the agency has now decided to lift its longstanding enforcement discretion and phase in all LDTs under its oversight in a risk-based manner.

Under its plan, the FDA plans to continue to exercise this discretion for Class I devices, as well as for LDTs for rare diseases and for unmet medical needs. Labs performing these tests will not have to submit them for premarket review, but will have to register and list them. For Class II and Class III LDTs, or moderate- to high-risk tests, FDA will phase in registration, listing, adverse events reporting, as well as 510(k) and premarket review requirements. It hopes to prioritize oversight of tests with the same indication as FDA-approved companion diagnostics, as well as screening tools meant to be used in asymptomatic patients and high-risk diagnostics for infectious diseases.

In contrast, "the premise of the DTWG's proposal is that the FDA's device regulation, which can't be changed except for by law, doesn't suit diagnostics," Amy Miller, executive VP of the Personalized Medicine Coalition, told GenomeWeb. "When the FDA drafted its framework, it was constrained by law. This working group was not constrained by law, so they started with the premise that device regulation just doesn't fit diagnostics, no matter where they come from. And it doesn't fit the rapid rate of change in diagnostics in terms of the modifications that must be done to diagnostic tests."

In some ways, the FDA's draft guidance has pitted labs and manufacturers against one another. Diagnostic manufactures who have submitted tests (i.e. companion diagnostics for personalized drugs) for premarket review with the FDA have said the current regulatory framework allowed labs to take a less rigorous path under CLIA and launch competing tests. Labs have countered that any improvements to regulation should be made under CMS, and that FDA oversight would lead to duplicative requirements.

The DTWG's proposal tries to ameliorate the differences among industry players and unite them under one workable plan that addresses the sticking points for different players.

"The existing regulatory structure, under which regulatory requirements are tied to the type of entity (i.e. a manufacturer or a laboratory), will be replaced by a construct under which the type and level of regulation is based on the activity being performed, regardless of the type of entity performing that activity. All entities performing the same activities will be regulated equally," the group said in a document summarizing its proposal.

For example, the same requirements will apply to a laboratory when developing an IVCT (i.e.a finished test or protocol) for distribution to another facility as apply to a manufacturer that develops an IVCT for distribution," the group added.

The framework also proposes specific resrources to CMS and FDA to help them carry out their regulatory responsibilities. It includes the creation of a new FDA center with "exclusive jurisdiction" over all test development activities, and proposes that CLIA regulations be modernized under CMS.

The DTWG plan also keeps more or less intact certain aspects of the current regulatory system that seem to be working. An advisory panel would determine the risk an IVCT poses to patients' health under similar high-, moderate-, and low-risk categories. Labs with high-risk tests would have to establish analytical and clinical validity and submit information to obtain approval from the FDA before commercialization. Labs with moderate-risk tests would have to submit evidence on analytical validity and information to support "reasonable belief of clinical validity," but FDA may request additional information in the post-market setting. Providers of low-risk tests would not have to submit premarket data but notify the agency about the test 10 days after commercialization.

Industry representatives have also criticisized FDA for setting its evidence bar for diagnostics too high. In the proposal, DTWG states, "It is presumed that clinical trials are not needed to demonstrate analytical validity or clinical validity." The plan would allow labs and manufacturers to submit data from published literature, as well as a range of other evidence. The FDA can reject a submission and ask for more data but will have to defend this request based on scientific criteria and make the request in writing from a high-ranking agency official.

PMC's Miller thinks this part of the proposal may be an attempt to make premarket submission requirements more manageable for labs that want to quickly bring to market follow-on tests, not so much novel tests. "For example, for new EGFR tests, that's a pretty well understood marker," she noted. "Furthermore, if you think about it from the perspective of labs launching next-generation sequencing tests, when does a marker move from a research marker to an actionable marker? I think part of this proposal is trying to keep up with the rate of scientific advancement."

Labs have also expressed concern that the FDA's proposal would mean they would have to make a submission informing the agency of every tweak they made to the lab process. This worry is lifted in the DTWG proposal since lab processes would remain under CLIA. However, test developers would need to submit information to the FDA if they modify a high-risk or moderate-risk test and that modification changes the test's intended use or a patient's diagnosis or therapeutic strategy.

The FDA has maintained that it is concerned that unregulated, faulty LDTs on the market may cause patients harm. Under FDA oversight, labs would be required to report death or serious injury that occurs due to a faulty IVCT. The DTWG plan would also have a system for tracking adverse events when death or serious injury is caused by an IVCT error, but the drafters of the proposal specify that an error in lab operations (i.e. human factor issues) isn't due to a faulty IVCT and will be managed under CLIA. 

Finally, in keeping with the spirit of aligning the interests of the lab and manufacturing communities, the DTWG proposal would offer incentives, such as priority review vouchers and protections for lab-manufacturer collaborations.

The DTWG plan reads a lot like legislation and that's no accident. The group has presented its proposal to the US Senate Committee on Health, Education, Labor, & Pensions, as well as the House Energy & Commerce Committee staff spearheading the 21st Century Cures initiative. Sources said legislators are interested in the DTWG proposal because it dovetails with their interest in putting out bills related to FDA and NIH issues.

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