FDA Aims To Finalize Framework For Lab-Developed Tests In Near Term

Article preview from "The Gray Sheet" - June 21, 2010

FDA could have a final framework in place for overseeing a greatly expanded range of laboratory test services within months of a public meeting scheduled for July, according to agency officials.

FDA Aims To Finalize Framework For Lab-Developed Tests In Near Term

Article preview from "The Gray Sheet" - June 21, 2010

FDA could have a final framework in place for overseeing a greatly expanded range of laboratory test services within months of a public meeting scheduled for July, according to agency officials.

The framework, plans for which were announced June 16, would represent the first comprehensive blueprint for FDA oversight of so-called laboratory-developed tests, or "home brews," since the implementation of FDA device and diagnostics regulations in 1976.

The agency says it has been practicing "enforcement discretion" for the past 34 years for home brews, defined as tests offered as a service out of the same lab in which they were created.

From the perspective of manufacturers of test kits, which are packaged and sold to labs as physical products, the framework represents an opportunity for a more level regulatory playing field between their products and home brews.

Such kits typically require pre-market review and post-market compliance under FDA regulations; home brews, meanwhile, are made by labs certified as "high complexity" by CMS under the Clinical Laboratory Improvement Amendments, but are not individually reviewed by a national third-party entity.

What the oversight structure will look like for lab-developed tests and how similar it will be to oversight of test kits, however, remains to be seen.

FDA has scheduled a public meeting July 19-20 in Maryland to discuss with stakeholders how the agency will regulate lab-developed test services. CDRH Director Jeff Shuren says his staff is not coming to the meeting with predetermined plans.

"Before we move forward we wanted to first engage in a public dialogue about what would be the appropriate application of our regulatory authorities, appropriately tailored for the lab community," Shuren said in an interview.

FDA specifies that it will employ a risk-based approach to overseeing lab-developed tests. In addition, Shuren said that the agency plans to implement the framework through guidance document development, though some stakeholders question whether that will be sufficient.

FDA says it will use the discussion from the meeting to develop a draft oversight framework for public comment "very quickly."

"Getting a final framework in place is going to take at least several months," Shuren said. After that, the agency will phase in the new requirements based on the clinical risk of each test.

"It is likely there would be an expectation that the higher-risk tests would come into compliance with whatever the framework is ... sooner than the lower-risk tests," he explained.

Lab-Developed Test Makers Signal Some Support

FDA does not have an accurate count of the number of additional tests that would fall under its active oversight umbrella once it adjusts its long-held enforcement discretion policy. For this reason, the likely first step for the new framework will be establishing a government registry of lab-developed tests so the agency can "get our hands around the universe of LDTs," an agency spokeswoman said.

The National Institutes of Health has already announced efforts to host a voluntary registry of genetic tests in collaboration with FDA.

Companies and labs that offer home brews have historically been reticent about FDA involvement in their activities, citing important differences between their offerings and kits, the effectiveness of CLIA and state regulations, and concerns about impeding innovation.

But home brew makers have more recently signaled support for engaging in discussions on FDA-centered, risk-based oversight as a preferred alternative to current regulatory ambiguities and prior attempts by FDA to target subgroups of lab-developed tests.

"We are pleased that they are having this public meeting, and giving all stakeholders - the public, patients, consumers, everyone - an opportunity to talk about what the proper oversight role is for FDA," Alan Mertz, president of the American Clinical Laboratory Association, said in an interview.

The home-brew test service market consists of a diverse set of players, including traditional hospital and public health laboratories, large clinical laboratory companies (Quest Diagnostics and LabCorp, for example) and a growing list of firms that are setting up high-complexity CLIA labs as a means to launch their tests without having to make the significant investments necessary for an FDA submission.

That last category of firms, including Genomic Health (Oncotype Dx), Genzyme Genetics (oncology and reproductive testing offerings), Biodesix (VeriStrat), CardioDx (Corus CAD) and many more, tends to be focused on complex genomic, proteomic and other molecular diagnostic assays intended to either inform individual treatment choices or predict disease risk.

FDA cites the growing application of the CLIA pathway by corporations, rather than traditional labs; the expanded use of non-FDA-approved lab-developed tests for "high-risk but relatively common diseases and conditions;" and the increasing complexity of the tests as primary reasons for deciding now to depart from its longtime hands-off policy.

The move also comes as the agency is increasing its focus on the nascent field of personalized medicine.

In an article posted on the New England Journal of Medicine website June 15, FDA Commissioner Margaret Hamburg and National Institutes of Health Director Francis Collins say the use of non-FDA-validated home brews to distinguish patients that will respond safely to drugs for cancer or other diseases is not appropriate.

"This undermines the approval process that has been established to protect patients, fails to ensure that physicians have accurate information on which to make treatment decisions, and decreases the chances that physicians will adopt a new therapeutic-diagnostic approach," Hamburg and Collins assert.

They cite reports of problems with non-FDA-approved lab-developed tests, including erroneous findings that certain women were negative for a mutation conferring high risk of breast cancer; false readings from ovarian cancer assays; and "flawed, mishandled data" underlying a Down syndrome test.

- David Filmore

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