MOUNTAIN VIEW, California (GenomeWeb) – Free from political pressures, Robert Califf, who on Jan. 20 stepped down as US Food and Drug Administration commissioner, candidly spoke at a conference yesterday about the need for greater oversight of laboratory-developed tests.
While a swathe of the lab industry would disagree, investors and drugmakers at the Personalized Medicine World Conference (PMWC) conceded that regulation isn't always a negative, and has, for example, spurred greater use of biomarkers in drug development to improve understanding of disease biology.
"[I've got to] mention LDTs," Califf, a cardiologist who led the agency for a year, said at the PMWC yesterday. He characterized the fallout from FDA's controversial decision to lift enforcement discretion and regulate LDTs as a "fascinating saga."
The agency has long felt that the current oversight provided by the Centers for Medicare & Medicaid Services under CLIA has critical gaps and is putting patients at risk. However, for more than two decades, the lab industry has aggressively fought against FDA regulation by threatening legal action and lobbying Congress. Despite industry objections, the FDA two years ago pushed ahead a draft guidance outlining a risk-based oversight plan for LDTs. However, following the November elections, the agency said it would hold off on finalizing those plans in order to consider input from other groups and await further input from the new administration.
Then, a week before Donald Trump was sworn into office, the agency released a discussion paper outlining a revised regulatory framework for LDTs based on more than 300 comments to its draft guidance, a public workshop, and meetings with stakeholders. The paper allowed the agency, without issuing enforceable regulations, to publicly respond to the lab industry's concerns about burdensome requirements, demonstrate that it had listened to critics of the draft plan, and lay out the rationale, once again, for why FDA needed to step in to look at aspects of test development that CMS doesn't.
"I think the community better take this really seriously," Califf said discussing LDT regulation at the PMWC. While on the one hand regulation shouldn't stifle innovation, he noted that doctors can't be left to figure out which test they should order.
"We've got to come up with some middle ground, so regardless of where you are in the US you can get a reproducible laboratory result," he said, especially when patients' treatment decisions depend on those results. "I think that's upcoming work for this year," Califf added.
However, the FDA's device division released a list of guidances that it will prioritize this year, and LDT regulation isn't among them. Some industry observers have opined that the agency missed its chance to advance broad oversight of LDTs in the current political climate, and will regulate ad hoc in situations where a test could harm patients.
"Regulation is not necessarily a bad thing," reflected Alexis Borisy of Third Rock Ventures, which has backed cancer genomic profiling firm Foundation Medicine and many other personalized-medicine focused companies. Borisy observed at the meeting that although diagnostics are much less regulated than drugs are, tests operate in a more challenging commercialization and reimbursement environment.
As a way to improve reimbursement prospects for their tests, some companies are taking them thorough FDA review to demonstrate analytical and clinical validity. Foundation Medicine, for example, recently announced that it would seek Parallel Review of its FoundationOne next-generation sequencing test, an LDT, in an effort to simultaneously garner FDA's nod and a national coverage determination through CMS.
On the drug side, the Personalized Medicine Coalition estimated that six out of 22 new drugs the FDA approved last year referenced biological markers or diagnostics that can be used to guide therapeutic decisions. From 2014 to 2016, nearly one out of four drugs the FDA approved was a personalized drug.
Immunotherapy has been a particularly ripe area for the agency's personalized medicine activities. At the PMWC, executives from drug companies advancing anti-PD-1 and anti-PD-L1 immunotherapies discussed how biomarkers and diagnostics were integral to understanding disease biology and identifying which patients benefitted from their drugs.
"We would not have gotten breakthrough status for pembrolizumab [or Keytruda] in lung [cancer], without PD-L1 as a selection strategy," said Kenneth Emancipator, head of companion diagnostics at Merck. Further, although Bristol-Myers Squibb was first to market with Opdivo (nivolumab) in the squamous cell lung cancer population, Emancipator said that a biomarker strategy ultimately helped Merck be the first to capture the first-line lung cancer indication for Keytruda last October.
But as in the case of PD-L1 expression, biomarkers that provide some insights into tumor biology don't always neatly bucket responders and non-responders, which creates challenges for sponsors and regulators, noted representatives from BMS and Genentech. In such scenarios, the FDA has also shown flexibility, particularly by introducing the category of complementary diagnostics, which can be used to guide treatment strategy but aren't required for the safe and effective use of a drug, like companion diagnostics are.
Steven Averbuch, VP of development, oncology, and pharmacodiagnostics at BMS, said that after studies showed that patients with low PD-L1 expression still responded to Opdivo, the sponsor and the FDA together decided this biomarker information should still be in the drug label so doctors could use it to determine the best treatment strategy for their patients.
The FDA approved Opdivo in 2015 for advanced non-small cell lung cancer patients who have progressed on platinum-based chemotherapy. The agency simultaneously approved a PD-L1 immunohistochemistry test to identify patients who might derive the most benefit but didn't require testing as a condition for prescribing the drug. However, last year, in the first-line NSCLC setting, Opdivo failed to meet its primary endpoint in an molecularly unstratified population. "We're trying to take the learnings from PD-L1, not as a binary marker, but as a continuous marker," and figure out how to apply such markers to segment patient populations receiving therapy, Averbuch said.
Regulators' "judicious use of this complementary diagnostic label really reflects their philosophy," observed Daniel Chen, global head of cancer immunotherapy development at Genentech, which last year received FDA approval for Tecentriq (atezolizumab) in two cancer indications with complementary diagnostics.
"They do think this information is important," said Chem. "But they also see that the future is going to be complicated. By using this complementary label, it not only gives them flexibility, it gives treating physicians flexibility, and it gives the field, as it moves forward and tries to build on top of this foundation, much greater flexibility."
Some industry observers have noted that in a crowded immunotherapy market, the availability of multiple PD-L1 tests, the availabilty of FDA approved kits and unapproved LDTs that seemingly gauge the same analyte, and the companion versus complementary diagnostic categories, are actually confusing physicians. This has led to some to suggest that drugmakers work with regulators to advance one test.
"That's not how science works," said Chen. "We don't all just know the answer ahead of time and have something that we're all going to use so we avoid complexity. Science is complex." Although right now different assays are measuring different tumor biologies, "over time … we'll grow to understand this biology better," he said.