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After Long Silence on LDT Regulation, FDA Commish Revives Thorny Topic at ASCO

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This article has been updated with information about a Citizen Petition filed against FDA regulation of LDTs by the American Clinical Laboratory Association, and with quotes from Sherri Bale. Originally published June 4.

CHICAGO – Regulation of laboratory-developed tests may once again be at the forefront of the US Food and Drug Administration's agenda, according to statements made by Commissioner Margaret Hamburg during a plenary session at the American Society of Clinical Oncology's annual meeting.

In front of thousands of researchers, oncologists, and representatives from major drug and diagnostics firms, the agency chief bemoaned the fact that although advanced diagnostics "are the cornerstone" of personalized medicine, "unfortunately … not all complex diagnostics used in cancer diagnosis and treatment have been developed to perform at the same demonstrated standards."

Hamburg's comments come as the agency last week approved two new melanoma drugs with a companion test – GlaxoSmithKline's BRAF inhibitor Tafinlar (dabrafenib) and MEK inhibitor Mekinist (trametinib) with BioMerieux's ThxID BRAF Kit. Pointing out that 40 percent of the drugs approved in 2012 were oncology drugs, Hamburg highlighted that several of those treatments were also targeted to a molecularly defined patient subset and required the help of a companion test to pick out best responders.

In a draft guidance on companion diagnostics released two years ago, the agency recommended that companies garner FDA approval for tests that are used to determine whether or not a patient should receive a drug. Still, because LDTs have traditionally been under the purview of the Centers for Medicare & Medicaid Services' Clinical Laboratory Improvement Amendments, many LDTs compete on the market alongside FDA-cleared tests that gauge the same analyte. Many diagnostics and drug developers that have invested in getting the agency's nod have complained that this dual regulatory pathway creates an unequal playing field, since garnering FDA's stamp of approval for a test often requires more time and resources.

In her speech, Hamburg recalled the example of OvaSure, a screening test for ovarian cancer that was launched commercially as a laboratory-developed test and without FDA clearance. In 2008, the FDA issued a warning letter to Laboratory Corporation of America about marketing OvaSure without its go ahead, and subsequently the test was pulled from the market. Shortly after OvaSure was launched, however, many health care providers raised alarms about the need for more validation for OvaSure and the Society of Gynecologic Oncologists issued a statement in this regard.

The test seemed initially promising, but "it had not yet undergone adequate validation, and though concerns were raised, the test was used across the country," Hamburg said. "Although the FDA did not consider OvaSure to be a laboratory-developed test, it was offered as an LDT, and like many LDTs developed today it was developed without FDA oversight."

Acknowledging that the FDA did not know how many women may have received erroneous results from OvaSure, Hamburg warned that "advanced diagnostics to make critical, potentially life-altering treatment decisions exposes patients to obvious risks if these tests do not perform as expected," and "false results put patients at risk for a mis-diagnosis or a wrong diagnosis that could result in inappropriate treatment or no treatment at all."

Historically, the FDA had exercised enforcement discretion over LDTs, tests developed by laboratories for use at that particular facility. However, as these tests became more complex technologically and companies began marketing them more broadly, the FDA expressed its desire to regulate LDTs as medical devices.

Since then, LDT regulation has been a bitterly divisive issue within the life sciences industry, with many labs asserting that FDA regulation of LDTs would be burdensome and hinder development of tests for rare conditions. Moreover, as advanced diagnostics move toward next-generation sequencing platforms, FDA's current regulatory framework is particularly ill-fitted to track the numerous changes and adjustments lab professionals must make on a daily basis to such tests.

A few days after Hamburg's speech at ASCO, the American Clinical Laboratory Association filed a Citizen Petition asking the FDA to refrain from issuing guidance to regulate LDTs as medical devices under the Federal Food, Drug, and Cosmetic Act, and to confirm that LDTs are not devices as defined by the Act. ACLA is a non-profit that represents the interests of US labs that develop and perform LDTs.

"CLIA allows laboratories the flexibility to develop and validate LDTs quickly to respond to public health needs," ACLA wrote in the petition. "Laboratories are able to update LDTs regularly as medicine advances, so that patients have access to the most advanced testing."

The Personalized Medicine Coalition issued a white paper recently in which it laid out the various requirements under CMS's CLIA pathway and FDA's regulatory route. Many life sciences firms are members of this non-profit organization, and the PMC issued the white paper "to facilitate conversations about solutions to the tensions" between FDA regulation and CLIA, "because it is the tensions that might hurt personalized medicine," Amy Miller, VP of public policy at PMC, told PGx Reporter.

"Personalized medicine is improving patient quality at an unprecedented speed," Miller added. "Because of the CLIA path to market, innovative personalized medicine diagnostic tests are impacting patients in record time."

Since under the current regulatory framework, FDA-reviewed tests can be copied by labs creating competitive challenges, Miller noted that such LDTs are not necessarily bad tests just because they don't have the FDA nod. "Their clinical validity has been demonstrated in the labs, yet that demonstration of clinical validity is not in the public sphere," she said. "Perhaps making this data readily available could ease tensions."

Meanwhile, many in the drug industry have taken the position that with the growing importance of diagnostics in personalizing care, all tests should be regulated by the FDA under one pathway to ensure the right patients are getting the right drug.

At ASCO, AdvaMedDx, a group representing the interests of diagnostics developers, released a statement urging the FDA to issue risk-based regulation of advanced molecular tests. The group advised the agency to focus its "limited resources" on tests that pose the highest risk to patients; to expedite access to lower-risk tests and exempting well-established tests; and to extend oversight to higher-risk tests developed by labs.

Hamburg reiterated at the meeting that the FDA is in the process of developing a risk-based regulatory framework for LDTs. "The agency is working to make sure that the accuracy and clinical validity of high-risk tests are established before they come to the market," she said. "The risk-based framework that we have under development will ensure that diagnostics used in cancer treatment will provide medical professionals with a critical baseline for confidence in the tests they order for their patients. Our intent in considering what to do about LDTs is to provide for safe and effective diagnostics while promoting innovation and patient access."

Although the FDA has repeatedly expressed its intent to issue guidance on LDT regulation, significant industry pushback and a politically divided government in Washington, DC, has likely thwarted the agency's action in this regard. After a long period of silence, however, the FDA is once again talking about LDT regulation.

Hamburg's comments come as FDA's Center for Devices and Radiological Health has missed an internal deadline to finalize the companion diagnostics guidance by March 31. Industry observers PGx Reporter has spoken to believe FDA might be ready to finalize this guidance and in the document the agency may address LDT regulation in some way.

ACLA asserted in the Citizen Petition that because the FDA hasn't yet issued formal guidance regulating LDTs, but has only stated its intent to do so, "the clinical laboratory industry has not challenged FDA's assertion of jurisdiction in court."

Furthermore, the US Congress enacted the FDA Safety and Innovation Act last year, which includes a provision restricting the FDA from issuing guidance on LDTs without 60 days notice to two congressional committees and without releasing the details of its regulatory plan.

The FDA has maintained it has the legal authority to regulate LDTs, and that the changing complexity and use of such tests places them in the category of devices that the agency oversees under the Federal Food, Drug, and Cosmetic Act. "The nature of laboratory-developed tests, including testing for cancer, has changed dramatically over the past three decades," Hamburg said at the meeting. "The number of LDTs have grown exponentially, and the technologies have become more sophisticated and complex. Results from these tests are rapidly becoming a staple of medical decision making, particularly for cancer."

Without naming a specific test, Hamburg pointed to how advanced molecular tests are being used by those with a family history of cancer to decide whether to take preventive action. "And yet, LDTs are currently marketed without FDA pre-market review to determine whether they are safe and effective, whether they are accurate and clinically valid," she noted.

There are a number of companies offering LDTs through CLIA certified labs that fit this description, including Myriad Genetics, GeneDx, and Ambry Genetics. Direct-to-consumer genomics firm 23andMe also markets LDTs that gauge hereditary cancer mutations among a slew of other disease-linked markers, but the company has filed for 510(k) clearance for a number of its tests (PGx Reporter 8/1/2012).

Myriad also recently announced that it had filed an investigational device exemption application with the agency to use BRACAnalysis as a companion diagnostic to gauge best responders in a pivotal ovarian cancer drug trial (see related story, in this issue).

"Myriad supports an efficient and effective CLIA regulatory process for laboratory developed tests and is working closely with the FDA on the development of its companion diagnostics for investigational cancer medicines," a Myriad spokesperson told PGx Reporter. "Myriad is committed to being an industry leader in understanding and communicating the benefits of genetic testing, and we welcome the opportunity to discuss any proposed changes to the future of the US diagnostic regulatory process with policymakers and stakeholders."

Outside of the companion diagnostic setting, Myriad performs BRACAnalysis in a CLIA certified lab as a test that gauges women's risk of familial breast and ovarian cancer, and results of the test can influence a woman's decision to get a mastectomy or oophorectomy. Since first becoming commercially available in the US in 1996, Myriad boasts performing approximately one million BRACAnalysis tests. Myriad has maintained that its test is backed by published data and is well validated.

"Myriad believes all diagnostic tests should have rigorous analytical and clinical validity, as well as clinical utility data, regardless of whether tests are regulated through CLIA or the FDA," the company spokesperson said.

GeneDx performs hereditary cancer tests in its lab using a next-generation sequencing platform. Sherri Bale, managing director of GeneDx, observed that to date the agency hasn't been very specific about how it intends to deal with the wide array of LDTs that fall in varying risk categories.

The FDA "it seems ... [is] leaving the door open to regulate [LDTs]. But they leave the door open to regulate any LDT, so this isn’t a very definitive statement," Bale told PGx Reporter. "I think the sequencing of genes for mutations that are causative of inherited cancer in individuals who are at high risk because of family history is a completely different issue, and I can only hope that those tests will still be recognized by the FDA as a different kettle of fish."

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