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Amid 'Chaos,' FDA's Gutierrez Offers Insights on Agency's Regulatory Stance on Molecular Tests

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Originally published Feb. 12.

If Alberto Gutierrez had to describe the current state of personalized medicine regulation in one word it would be "chaotic."

At a conference in Mountain View, Calif., in January, the director of the US Food and Drug Administration's Office of In Vitro Diagnostics described the regulatory environment for the field as such, but then went on to provide some insights on what FDA's device division is doing to bring more clarity to the molecular diagnostics industry.

Although the FDA didn't release any guidelines in 2012 focused specifically on molecular diagnostics, agency officials from the Center for Devices and Radiological Health have previously maintained that efforts are ongoing at the agency to develop processes to advance personalized medicine and make this information more accessible to the public (PGx Reporter 1/2/2013).

According to the agency's priorities for 2012, a final guidance on companion diagnostics was slated to be cleared internally within CDRH by June 30. By Dec. 31, CDRH had planned to clear a draft guidance on the co-development of therapeutics and devices.

This year, CDRH has prioritized releasing the final companion diagnostics guidance by March 31 and issuing the Rx/Dx codevelopment draft guidelines by Sept. 30. Also by Sept. 30, CDRH, in collaboration with the National Institute of Standards and Technology, plans to develop genomics standards — specifically to "select and sequence the human DNA and microbial DNA reference materials to support analytical validation of genetic sequencing technologies."

Additionally, the agency has yet to present its regulatory framework for lab-developed tests, which can be approved or cleared by the FDA, but have most readily been overseen by the Centers for Medicare & Medicaid Services.

During his presentation at last month's Personalized Medicine World Conference, Gutierrez reiterated that even though historically the FDA had chosen not to regulate LDTs when they were based on simpler technologies and not marketed as broadly as they are today, the agency has always had the authority to regulate all tests regardless of whether they are developed by a lab or by a test manufacturer.

"The law that essentially gave the FDA jurisdiction over medical devices, it includes a very broad definition of devices and among that is reagents, instruments, software," Gutierrez said. "Those are all considered in vitro diagnostics. It doesn't say anything about where those tests were developed or done."

In the 1980s, LDTs were largely being used in the academic setting or in hospitals, for a limited number of patients. But the situation started to change in the mid-1990s, and as the agency sees it today, LDTs are being marketed "across the US."

"No one really defined what a laboratory-developed test was," Gutierrez reflected. "In a sense, it became a loophole where a lot of people began to bring [to market] devices that clearly did not include what we had considered to be laboratory-developed tests."

In surveying the LDT industry, the agency says it has identified companies making unsubstantiated claims that cost the healthcare system money and may be harmful to patients. Gutierrez highlighted labs offering to test patients for "chronic fatigue" and labs that have diagnosed patients with Lyme disease, even though "our best scientists and the Centers for Disease Control and Prevention … can't actually detect Lyme disease in those patients."

When LDTs Become Medical Devices

When discussing FDA's regulatory plans for molecular diagnostics, Gutierrez cited the diagnostics shop CardioDx. Although the company is marketing its Corus CAD test as an LDT, Gutierrez said he's not sure he'd agree that that's the right pathway for the test.

CardioDx sends physicians a collection kit to gather the necessary biological sample the test will analyze. By doing so, in the agency's view, CardioDx is using the sample collection kit as a medical device. As a result, this has regulatory implications for the tests associated with the sample collection kit.

"By sending out the collection device CardioDx is making claims on that device, and the risk associated with the collection device are the same risks associated with the test that would be performed on the samples collected," Gutierrez told PGx Reporter.

Before Gutierrez's presentation at the meeting, CardioDx CEO David Levison gave a talk about the company's efforts to garner reimbursement for Corus CAD. The test gauges the expression of 23 genes via real-time PCR to help physicians exclude obstructive coronary artery disease as the cause of cardiac symptoms in stable non-diabetic patients. CardioDx launched Corus CAD as an LDT in 2009, and the company has said that the test has been used in more than 31,000 patients and is covered by Medicare.

"Based on the talk given by the CEO of CarioDx, it seemed that [the company was] relabeling and repackaging the collection device," Gutierrez said.

The company would also need to fulfill regulatory requirements if it were using a research-use only collection kit for the test. "It may be a little more difficult if the collection device is RUO," Gutierrez noted. "In that case, though, changing the intended use from research-use-only to one of clinical relevance puts them in the same place since the collection device would then become a medical device."

In a statement, CardioDx told PGx Reporter: "We comply with all currently applicable federal and state regulations and are CLIA certified, as required. CardioDx is closely monitoring FDA’s development of guidance for products such as Corus CAD and is committed to continued compliance with all regulations that may be applicable to our products."

According to Gutierrez, although the FDA hasn't yet done so, the agency still plans to issue guidance outlining regulation of LDTs. In the past, the agency has projected timeframes for issuing this guidance (or a number of guidances on the topic), but has failed to release it (PGx Reporter 7/20/2011). Instead of committing the agency to another hard deadline that it may or may not be able to meet, Gutierrez stated at the meeting that the agency hoped to release a guidance on this topic in the "near future."

Consumer Genetics

The agency's stance on the regulatory status of sample collection kits that are part of molecular diagnostics being marketed as LDTs would also apply to companies marketing genetic tests directly to consumers on the web without garnering the agency's blessing, Gutierrez added.

DTC genetic testing firm 23andMe, for example, sells tests online that gauge people's ancestry, disease risk, and likely response to certain drugs. After customers pay for testing, the company sends them kits by which they can submit a saliva sample for analysis. According to Gutierrez, the FDA views these kits as medical devices, which in turn would have regulatory implications for the associated genetic tests.

23andMe last year submitted the first of several 510(k) applications for its test, called the Personal Genome Service (PGx Reporter 8/1/2012). A 23andMe spokesperson told PGx Reporter recently that the FDA has responded to the firm's initial 510(k) application and that the company is continuing its dialogue with the agency "to address their questions and move our application forward."

The agency has said it intends to issue regulatory guidelines for the consumer genetics industry. Most of the companies previously marketing tests DTC are either no longer in operation or are marketing their services to doctors rather than consumers. 23andMe is the only US-based company still selling genetic testing and data interpretation related to medical conditions and drug response directly to consumers.

Pay Attention to What FDA Does

At the meeting, Gutierrez also elaborated on the agency's thinking regarding the marketing of products labeled research-use-only or investigational-use-only. In 2011, the agency issued draft guidelines on products labeled RUO and IUO in an attempt to stop companies from launching diagnostics labeled as such without getting the FDA greenlight.

In the draft document, the FDA outlined the appropriate and inappropriate use, labeling, manufacturing requirements, and marketing of IVDs for research and investigational purposes. FDA's overarching stance is that products labeled as RUO or IOU, which in most cases haven't been approved or cleared by the FDA as medical devices, should only be used in research and not for clinical diagnosis of patients (PGx Reporter 6/8/2011).

The guidance was controversial among industry players. Most concerning to developers of RUO/IUO products was that the FDA seemed to be holding manufacturers responsible for how their customers were using materials labeled for research. FDA noted in the document that manufacturers who label their IVD products RUO "should not sell such products to laboratories that they know use the product for clinical diagnostic use." In the case of IUO products, manufacturers "should not sell them to laboratories that they know use the product for clinical diagnostic use outside of a clinical investigation."

If a manufacturer learns that a customer is using an RUO/IUO-labeled product improperly, "it should halt such sales or comply with FDA requirements for IVD products, including premarket review requirements, if applicable."

Many manufacturers believe that the FDA is placing an undue burden on industry with this requirement, and claim they have no way of keeping track of exactly how their various customers are applying the RUO/IUO products they've purchased.

In a breakout session at the Mountain View conference, Gutierrez acknowledged that that agency "has created a bit of a storm in a teacup with the RUO draft guidance" by suggesting that marketers of RUO products may be held responsible for customers using these tools in a clinical setting. In this regard, he said people should pay attention "not to what the agency says, but what it does."

Gutierrez then went on to explain that the agency is not going to go after companies that truly aren't aware of how disparate customers are using their products. However, he noted as an example that if one large company acquires another company, and that acquired firm is using the parent firm's RUO products in a clinical setting, then it's obvious that the parent company was aware of how its products were being utilized. Gutierrez went on to suggest that FDA is keeping an eye on such a scenario after a company purchased another in the "prenatal testing space" this year.

While Gutierrez did not mention the company by name, Illumina last month announced plans to acquire prenatal testing firm Verinata Health, which markets a sequencing-based fetal trisomy test on Illumina's HiSeq platform (CSN 1/9/2013). Verinata does use Illumina's RUO products in its tests, but so do a number of other Illumina customers, including rival prenatal testing firms such as Sequenom and Ariosa Diagnostics. Illumina said it had no comment at this time.

"The FDA is planning to finalize the RUO guidance and yes we are planning on making some changes to clarify some of the issues," Gutierrez told PGx Reporter. He reiterated, however, that manufacturers are responsible for marketing and representing the intended use of their products "appropriately."

In the final RUO guidance, the FDA "hopes to make the responsibilities of the manufacturer when a product is labeled RUO clear," he added.

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