FDA’s LDT proposal means ‘whole new ballgame’ for labs

Kevin B. O’Reilly

October 2014—The Food and Drug Administration’s plan to subject many laboratory-developed tests to a new layer of regulatory requirements over the course of the next decade is drawing sharply contrasting reactions from stakeholders who view it as either an essential step to improve patient safety or a hindrance that will stifle diagnostic innovation and test improvement.

Despite that fundamental disagreement on the policy’s substance, there does seem to be consensus among informed observers that the FDA is determined to take action, that legislative intervention to block the agency faces long odds, and that the agency’s final guidance will create a regulatory challenge for labs unrivaled by anything out of Washington since CLIA ’88.

The FDA framework was unveiled in detail July 31 as part of a statutorily required notification to Congress 60 days prior to publication as a draft guidance. The agency on Oct. 3 gave notice in the Federal Register that the draft guidance was publicly available. The 41-page document—“Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)”—can be found at http://j.mp/ldtdraft.

The FDA’s plan has sparked concern among some organizations within lab medicine and raised worries about how the agency will answer key questions that could have significant consequences. These include what counts as a laboratory-developed test, which tests will fall under the premarket review requirement, and how requirements for good manufacturing practices—heretofore applied solely to medical device manufacturers and known as quality system regulations—will be applied to clinical labs and harmonized with existing CLIA requirements.

“It’s now clear that the FDA will no longer take a hands-off approach,” said Richard S. Cooper, manager of the National Healthcare Practice Group at the law firm of McDonald Hopkins. Cooper said the FDA’s proposed changes—while not as far-reaching as CLIA because they would only apply to labs with LDTs—could represent the biggest change to laboratory regulation since that landmark federal legislation.

“This is the first step in a change in approach. And it’s a fairly comprehensive, and fairly material, change,” Cooper said in a Sept. 17 webinar hosted by The Dark Report. “Obviously, if the FDA goes forward, it intends to take a very meaningful, very robust role in regulating laboratory-developed tests.”

In the same webinar, Jane Pine Wood predicted that final guidance won’t arrive sooner than the summer of 2015. Wood is a colleague of Cooper’s at McDonald Hopkins and represents clinical, anatomic, molecular, and toxicology laboratories. She advised lab leaders not to delay preparation given the likelihood of some kind of change in LDT oversight.

“This is going to be a whole new ballgame for a lot of labs,” she said. “This is going to push them into an area where they may not have any experience, or may not have the appropriate personnel to assist. The earlier you get started on the process, and the earlier you get educated about what’s proposed and what ultimately comes down the road, the earlier you can take the appropriate steps.”

Laboratory leaders should review which LDTs they are offering and evaluate where they are likely to fit within the FDA’s proposed oversight scheme, Cooper added.

“You might also think about which LDTs you want to consider bringing online before the effective date of the final guidance,” he said. “You’re also going to need personnel or consultants who are versed in FDA requirements so they can step into the role of FDA compliance advisor and help make sure you’re compliant from that standpoint. We may see some of our lab clients investing in new hires that have FDA experience, likely drawn from the medical device field since that’s the category under which these tests are viewed as falling.”

Labs also should assess the likely cost and compliance impact of the FDA’s plan on their operations, Wood said.

“It’s no longer a free-market situation where these facts are strictly determined based on internal capabilities,” she said. “You now have to answer to an oversight agency, and that will have a material impact on your timetables.”

Under the FDA plan, labs would have to tell the agency about most of their LDTs through a formal notification process that is spelled out in a separate, 28-page Oct. 3 draft guidance available at http://j.mp/ldtnotification. Lab-developed tests used in forensics, histocompatibility, stem cell, or tissue transplantation laboratories would be exempt from the notification and other requirements. Other tests deemed to pose low risk would not be required to get premarket review, and neither would tests used for rare diseases.

“Traditional LDTs”—the FDA’s term for tests that use only legally marketed components, require nonautomated interpretation, and are used in the care of patients within a single health care organization—also would fall into the low-risk category. Tests in this category would receive regulatory treatment similar to what is given to class I medical devices.

High-risk LDTs would be treated like class III medical devices, meaning requisite premarket review within one to five years after the FDA guidance is finalized. The agency said it will use expert advisory panels to help classify tests based on risk and various factors (“What makes a high-risk LDT?” page 6).

The FDA will give its highest priority to reviewing LDTs with the same intended use as companion diagnostics or class III medical devices that have already received the agency’s approval or clearance. Also, certain LDTs used to determine the safety and effectiveness of blood or blood products would be subject to the agency’s highest priority review. Tests in the highest-priority category would have to be submitted for premarket review within a year after the FDA finalizes its LDT guidance.

Another category of lab-developed tests, those deemed to be of moderate risk, would have to be submitted for 510(k) clearance within five to nine years of final guidance from the FDA. The agency said it plans to use “accrediting third parties to carry out review of most moderate-risk LDTs requiring a premarket notification.”

The FDA’s tiered, risk-based framework is similar to the oversight approach the CAP outlined in April 2010. The College’s regulatory model (http://j.mp/cap-ldtapproach) seeks “targeted FDA review and approval of clinical claims for only high-risk LDTs, with oversight of compliance by laboratories performing high-risk LDTs by CMS and CMS-deemed accreditors.”

The CAP met with the FDA to clarify sections of the agency’s proposed guidance.

“The CAP will further evaluate the proposed oversight guidance and continue discussions with the FDA and key stakeholders,” CAP president Gene N. Herbek, MD, said in a statement. “The College will also be vigorously engaged during the public comment period and other forums to ensure the final guidance documents improve patient care, meet public health needs, and ensure access to accurate and safe LDTs.”

“The CAP will work to ensure LDT oversight assures quality laboratory testing for patients in a manner that is consistent with principles outlined by the CAP,” Dr. Herbek added. “The proposed FDA guidance embodies a number of those key principles. Where there are differences, the CAP will work with stakeholders so requirements do not impede innovation or increase administrative burden on laboratories. The CAP will provide its recommendations and propose changes to improve the guidance during the public hearing and comment period.”

Alberto Gutierrez, PhD, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health, said in a Sept. 3 CAP webinar that the agency would hold a public meeting “sometime in early January” of 2015. According to the agency’s Federal Register notice, comments on the draft guidance should be submitted by Jan. 31, 2015. That notice also includes instructions on how to comment and is available at http://federalregister.gov/a/2014-23586.

“We don’t really know, or have a lot of control over, how much time the process will take,” Dr. Gutierrez said. “Sometimes it’s highly unpredictable. This draft guidance took four years. I don’t think it will be that long, but I don’t have a good hold on how long that will take.”

The timing of the FDA’s final LDT guidance could be critical for labs whose tests would be subject to the agency’s new enforcement plan, according to Wood.

“This is an important takeaway,” she said in The Dark Report webinar. “If you have an existing LDT and are likely in the higher-risk category where premarket review is required, you definitely want to file the notification in the six months after the final guidance. What that means is your LDT is already on the market. So, until the FDA comes back to you and says, ‘Time’s up; you’ve got to file for premarket review,’ you can go ahead and manufacture your LDT and provide it to the public. But after the guidance is finalized, you can’t put it on the market until you have the premarket review.”

Outside of the FDA’s fairly explicit warning on which LDTs will get the highest priority review, the agency’s risk-classification scheme paints with a broad brush. In its notice to Congress, the FDA said it would be another 18 months after final guidance on LDTs before the agency would issue subsequent draft guidance with further details “to describe what the agency considers generally to be class I, II, or III.”

That opacity is part of what bothers Edward R. Ashwood, MD, about the FDA’s plan to regulate LDTs. He is president and CEO of ARUP Laboratories, which by his count offers “well more than 1,000” LDTs to its customers.

“They say they’re going to take a year or more to figure this out, and establish an advisory committee to give us advice on what category your device falls into. Well, who does the risk analysis?” Dr. Ashwood tells CAP TODAY. “When I see how they’ve classified tests so far, that’s where I become skeptical.”

Dr. Ashwood and 22 other lab medicine leaders from the Mayo Clinic, Brigham and Women’s Hospital, Stanford University Medical Center, and other prestigious academic medical centers wrote a letter this summer asking the White House Office of Management and Budget to put a stop to the FDA’s moving forward with its LDT framework. That did not happen, much to Dr. Ashwood’s dismay.

The FDA’s plan is “as bad as it could be for the future of laboratory medicine and pathology,” he says. “They are converting almost all clinical laboratories into manufacturers.”

He notes that the agency said that significant modifications to already approved devices will be considered LDTs and would receive greater scrutiny as such under its plan.

“What’s a major modification? If you’re using a robot to do the manual steps indicated in a test kit, does that count? What if you’re changing the reagent volumes specified in the kit, or replacing a buffer with a better buffer? Where does it stop?”

“Quite frankly,” Dr. Ashwood says, “we use a lot of FDA-approved kits but without following the standard operating instructions that come with those kits. We modify them and make them better.”

Another burdensome element of the FDA plan, according to Dr. Ashwood, is that when 510(k) submission is required, that would entail stating an LDT’s intended use.

“We don’t do that now,” he says. “Oftentimes, a laboratory-developed test’s intended use changes with time. The more you know, the more intended uses there are. It’s hard to specify that intended labeling up front and never deviate from it. It’s going to cost a lot, and it’s going to be very resource intensive, and not make anything safer or anything more effective.”

Roger D. Klein, MD, JD, chair of the Association for Molecular Pathology’s Professional Relations Committee, also objected strongly to elements of the FDA’s LDT plan. In a position statement, the AMP has said lab-developed tests should be called “laboratory-developed procedures,” arguing that the term better captures their nature as medical services as opposed to medical devices (Ferreira-Gonzalez A, et al. J Mol Diagn. 2014;16[1]:3–6).