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FDA Draft LDT Guidance Slated for Release in 60 Days; Industry Readying Recommendations, Objections

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Originally published Aug. 5.

NEW YORK (GenomeWeb) – In notifying the US Congress last week of its plan to release a draft guidance on regulation of laboratory-developed tests, the US Food and Drug Administration has essentially given industry players and legislators opposed to such government oversight more time to formulate their battle plan.

According to a provision in the Food and Drug Administration Safety and Innovation Act, the FDA was required to inform legislators of its intent to release the draft guidance, along with a copy of the "anticipated" document. After 60 days, the FDA will officially publish in the Federal Register its draft guidelines, which lays out a risk-based framework for bringing LDTs under the agency's oversight over the next 10 years or more (see related story for further analysis of the guidance).

Traditionally, the agency has exercised "enforcement discretion" over LDTs – tests manufactured by and used at a single lab – leaving regulatory responsibilities to the Centers for Medicare & Medicaid Services under CLIA. However, since enactment of the 1976 Medical Device Amendments, the technology underlying LDTs has become more complex and, accordingly, business models have changed so that many tests marketed as LDTs are not developed at a single lab and don't fit FDA's definition of an LDT. In this evolving environment, the FDA has been discussing since the 1990s the need to bring LDTs under its oversight.

In 1997, the agency published a rule laying out regulations for marketing analyte specific reagents, which are used as part of LDTs to measure a substance, such as a nucleic acid sequence. However, noting that some industry players weren't following this rule, the FDA sent a number of warning letters to companies and ultimately issued guidance on the topic.

Then, in 2007, the FDA tried to regulate a subset of high complexity LDTs, dubbed in vitro diagnostic multivariate index assays – tests developed and performed at a single lab that employ a proprietary algorithm to gauge multiple analytes. However, the agency eventually scuttled those plans, deciding instead to tackle overarching, risk-based guidelines that address regulations for all LDTs. That intent has been hard fought by the lab industry and it has taken the agency until now to present for public scrutiny the details of its regulatory framework.

Some industry observers that PGx Reporter spoke to said they saw it coming, since stakeholders had kicked up public debate in recent weeks around why the FDA should or shouldn't release the document. Last month, five senators – Richard Blumenthal (D-Conn.), Sherrod Brown (D-Ohio), Richard Durbin (D-Ill.), Edward Markey (D-Mass.), and Elizabeth Warren (D-Mass.) – penned a letter to Brian Deese, the acting director of the Office of Management and Budget, calling for "prompt action in releasing draft guidelines" on LDTs. To this, lab directors from more than 20 healthcare organizations quickly responded, also writing to Deese asking the Obama administration to block the FDA's intent to regulate LDTs.

Lakshman Ramamurthy, an FDA regulation and policy expert at the healthcare advisory firm Avalere Health, initially thought that the LDT guidance would surely be released after the 2012 presidential elections. "We're coming upon the last two years of an administration on its second term,” Ramamurthy, a former reviewer at FDA's device division, told PGx Reporter this week. “If there was a time to release the guidance, it wasn't going to be better than now."

On the other hand, Amy Miller, executive VP at the Personalized Medicine Coalition, hadn't expected FDA to give notice of the guidance as soon as last week. She thought the Obama administration would wait till the bitter end of its term, and push the guidance out the door on its way out of Washington. The PMC, a non-profit organization that engages the life sciences community on issues impacting the advancement of molecularly guided precision medicine, put out a white paper last year highlighting different stakeholders' positions on how best to regulate LDTs.

In the life sciences field, the topic of FDA regulation of LDTs has historically pitted industry stakeholders at opposing ends of the policy spectrum – with certain lab groups maintaining that improving oversight of LDTs is possible without FDA intervention, and drugmakers and diagnostic kit manufacturers asserting that lack of FDA involvement creates an uncertain regulatory environment.

In response to the news last week that the FDA had given Congress notice regarding the imminent release of the LDT draft guidance, the American Clinical Laboratory Association issued a statement of caution against over-regulation. ACLA, which has long battled against FDA regulation of its industry players, noted in its statement that during the decades of the FDA's "enforcement discretion," the lab industry has developed many innovative diagnostics and contributed to the advancement of the personalized medicine field. "We’re reviewing the guidance in depth and will be speaking with our member labs and other stakeholders to determine the impact and next steps," Alan Mertz, ACLA president, told PGx Reporter.

Providing the opposite response was AdvaMed, a group that represents the interests of firms making medical devices or test kits – the component parts of which, unlike LDTs, can be developed at multiple firms and the entire testing system can be placed and performed at different labs. "AdvaMedDx has long advocated for a risk-based framework for the regulation of all diagnostics, regardless of where a test is made. The framework issued [by the FDA] outlines a clear and transparent path forward that is risk-based, phased in, and promotes both innovation and the public health," Khatereh Calleja, the group's VP of technology and regulatory affairs, told PGx Reporter. "This is a win for patients and fosters a flexible approach to oversight that promotes safe and effective diagnostics with [a] focus on higher-risk tests."

The American Association for Clinical Chemistry, an organization representing medical professionals working in laboratory medicine and clinical lab sciences, is also taking the next 60 days to gather its members' views on the guidance and is planning to issue formal comments once the document is officially published. AACC spokesperson Molly Polen said the association will specifically seek input from members on how the FDA's new policy affects patient access to testing; if the guidelines improve patient safety and care; if the guidance will hinder the development and introduction of new technologies; and whether the regulatory and cost requirements of meeting the guidelines will hinder labs' from providing tests.

Although by giving Congress notice of its plan to release the draft LDT guidance, the FDA has given all stakeholders for and against regulation more time to weigh in on the matter, it is no accident that the agency issued its notice to Congress on July 31, a day before legislators are slated to go on a five-week summer recess. Once back in session in the fall, Capitol Hill will be in a frenzy of election activity.

Industry observers had opined in the past that the lack of FDA action on the LDT guidance may have been due to the fractious political climate on Capitol Hill around the implementation of the Affordable Care Act. In recent years, FDA officials had at times hinted that its framework for LDT regulation was nearly complete or close to being released only to subsequently fall silent on the topic without taking any action. For example, many agency watchers thought that the LDT guidance was surely coming last summer, after FDA Commissioner Margaret Hamburg made a strongly worded, if somewhat oddly placed, speech at a major oncology conference about how complex diagnostics, regardless of whether they are LDTs or kits, must be developed at the "same demonstrated standards."

Shortly after that, ACLA filed a citizen petition asserting that the FDA lacked the legal authority to regulate LDTs. A letter from nine democratic members from the House of Representatives followed, urging the Obama administration to release the LDT guidance. At the time, it seemed like a political maelstrom was forming with the LDT guidance on the horizon, but the controversy dissipated once again amid continued reports that the guidance was held up within the Obama administration for political reasons.

Now, amid elections and a laundry list of talking points on competing policy issues, the FDA's draft LDT guidance may not receive the kind of attention from anti-big government factions in Congress that it otherwise might have. "From their point of view, if the Obama Administration and the FDA were looking for a convenient window in which to release draft guidance, then they've found it," according to Ramamurthy. In his view, OMB had to release the guidance ahead of the November congressional elections, because "if both houses of Congress turned over [to the Republicans], then the guidance may never have been released."

On Nov. 4, 471 seats in Congress – all 435 seats in the House and 36 Senate seats – will be up for election. The Republicans control the House of Representatives by 17 seats, while Democrats lead in the Senate by eight seats.

FDA regulation of LDTs may still come up in Congress, however, under the broader topic of the US government's role in healthcare matters. The day before the FDA gave notice of the draft LDT guidance, House representatives authorized Speaker of the House John Boehner (R-Ohio) to sue President Barack Obama for allegedly abusing his powers in issuing executive orders related to the implementation of the ACA.

"I would expect notices from some of the members of Congress who think about this a lot, … some congratulating [the] FDA and some saying, 'Ugh, too much regulation is not good for innovation,'" PMC's Miller said. Over the years, PMC has taken a leadership role in educating lawmakers on policy issues impacting the personalized medicine field.

Miller noted that a congressional hearing focusing on FDA regulation of LDTs was possible in light of recent efforts on Capitol Hill on the 21st Century Cures Initiative. Through this initiative, spearheaded by Rep. Fred Upton (R-Mich.), chair of the House Energy & Commerce Committee, representatives are gathering input on the scientific and policy gaps hindering medical advances. The impact of genomic research on personalized medicine is a point of particular interest for legislators involved in this effort. "That would be a natural place for [the LDT guidance] to get some attention," Miller noted.

Other legislators likely to closely vet the provisions in the draft LDT guidance include Senator Orrin Hatch (R-Utah) and Rep. Michael Burgess (R-Tex.). Both congressmen have sponsored legislation on the regulation of diagnostics. Three years ago, with the "Better Evaluation and Treatment through Essential Regulatory Reform for Patient Care Act," or BETTER, Hatch sought to create a single regulatory path under the FDA for IVDs and LDTs. Meanwhile, around the same time, Burgess sponsored the "Modernizing Laboratory Test Standards for Patients Act," which would keep LDT oversight under CMS, but expand the center's regulatory authority by granting it the ability to assess whether marketed LDTs are "clinically valid."

Referencing Burgess' bill, ACLA's Mertz reiterated his organization's belief that improvements in oversight of LDTs can be achieved without burdensome FDA regulations. For example, one of the areas that the FDA has tried to address in its LDT framework is establishing requirements for adverse events reporting for all tests. "We certainly believe adverse event reporting can have a valuable and critical role in improving quality," Mertz said. "We definitely believe this can be achieved through updates to CLIA. In fact, we supported the [Burgess bill] back in 2011 which proposed that same improvement, among others, to CLIA."

Once the FDA does officially release the guidance, the agency plans to hold a public meeting for industry players to present further ideas and air objections. Miller believes that stakeholders will likely bring up well-worn concerns, such as whether the agency has the resources to regulate LDTs manufactured and sold by some 2,000 US labs, and how labs can meet regulations in a way that doesn't overburden them.

"I think it's good that the FDA has given the community and itself a good long time to adjust [to the new LDT oversight guidelines]," Miller reflected. "By starting with LDTs that act as [already approved] co-developed tests, that gives them a rather small slice of the LDTs to start with, which will allow the agency and the community to work out some kinks"

Even though the FDA's proposed LDT framework will be phased in over many years, one point that the agency hasn't addressed is how it plans to garner the resources to carry out this immense effort. "While [the] FDA has expanded its authority, they've given no indication that they are also planning to hire the added expertise and personnel to actually handle this undertaking without creating backlogs in applications for new tests," Mertz pointed out.

"The FDA is doing important work," Ramamurthy added. "But for all its authority, the FDA does depend on [congressional] appropriations."

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