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FDA Warns DTC Genomics Firms that Genetic Tests are Not LDTs, May Need Clearance or Approval

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Originally published June 11. Updated June 15.

This article has been updated to include comments from Navigenics and to report that the House Committee on Energy and Commerce sent another letter to 23andMe requesting information on the company's recently reported results mix up.

By Turna Ray

If there was any question about the US Food and Drug Administration's intent to regulate the direct-to-consumer genomics market, the agency gave its definitive answer this week by sending letters to four big players in the field and one instrumentation vendor asking them to submit their genome scans for review and clearance by the agency.

The FDA this week sent letters to Illumina CEO Jay Flatley regarding the Infinium HumanHap550 array; Knome CEO Jorge Conde about KnomeComplete; 23andMe President Anne Wojcicki about the company's Personal Genome Service; Decode Genetics CEO Earl Collier about its DecodeMe Complete Scan; and Navigenics CEO Vance Vanier about its HealthCompass service.

Although FDA has been in discussions with DTC genomics firms for several years, it was moved to action last month when Pathway Genomics decided to market a saliva sample collection kit for its DTC service in Walgreens and CVS Caremark's retail pharmacy stores.

On May 10, FDA sent a letter to Pathway asking the company to explain why its genomic testing service had not been cleared or approved by the agency as it was a test being marketed for the diagnosis of disease. Shortly after the FDA sent its letter, the House Committee on Energy and Commerce announced it was investigating three DTC genomics firms: 23andMe, Navigenics, and Pathway (PGx Reporter 05/26/10).

In similar letters to Illumina, Knome, 23andMe, Navigenics, and Decode dated June 10, the FDA asserts that these firms are marketing gene analysis systems that are considered medical devices under section 201(h) of the Food, Drug, and Cosmetic Act, 21 USC 321(h).

In its letter to Illumina, the FDA acknowledges that the company "has received FDA clearance or approval for several of its devices," but Illumina's Infinium HumanHap550 array "is not one of them." Additionally, the FDA takes issue with the fact that although the HumanHap550 array is labeled 'For Research Use Only,' Illumina "is knowingly providing the HumanHap550 array to 23andMe and deCode Genetics for clinical diagnostic use without FDA clearance or approval."

In its communication to Knome, the FDA points out that the company has never submitted information on the analytical or clinical validity of its tests to FDA for clearance or approval, but Knome's "website states that the KnomeXplorer, the genome browser software used to navigate and explore the complete genome and a component of KnomeComplete describes the genetic basis of specific disease traits or conditions." The FDA believes that based on the information garnered through Knome's service, "consumers may make medical decisions in reliance on this information."

When it comes to Navigenics and 23andMe's testing services, FDA specifically takes issue with the fact that the services predict customers' genetic predisposition to various diseases and their response to prescription drugs such as the anticoagulant warfarin and the anti-platelet agent clopidogrel (Plavix). The FDA has updated labeling for both of these drugs to inform healthcare providers and patients that certain genetic abnormalities can impact their response to treatment. With Decode, FDA seems troubled by the company's tests for gauging cancer risk.

Most importantly, FDA's letters to Decode, Knome, and 23andMe inform the companies that based on previous discussions, the agency does not believe these are laboratory developed tests, which would fall under the purview of the Centers for Medicare & Medicaid Services, because these devices are "not developed by and used in a single laboratory."

In the case of Decode and 23andMe, the agency further notes that their products are not LDTs because these companies "obtained components other than general purpose or analyte specific reagents from other manufacturers" and are distributing saliva sample kits directly to consumers through their websites. In its letter to Pathway, the agency indicated that it considered Pathway's saliva sample collection kit a medical device.

The FDA told Knome that since in a previous meeting the company told the agency that its KnomeComplete service consisted "of a software program that analyzes genetic test results … generated by an external laboratory in order to generate patient-specific report," that test is also not an LDT and is subject to FDA regulation.

In a statement to Pharmacogenomics Reporter, Decode Executive Chairman Kari Stefansson said, “We believe and have always said that the genetic risk factors our tests and scans detect improve the understanding of risk of disease. They thus are of medical value and we believe will eventually become a standard part of healthcare." Stefansson added that the company has not fully reviewed the "technical questions raised" by the agency, but highlighted that Decode's laboratory is both CLIA and CAP certified.

FDA's letter to Navigenics does not reference a prior meeting between the agency and the company. However, according to Navigenics the company has been talking to the agency for some time. Navigenics VP of Policy and Business Affairs told PGx Reporter, "Navigenics has been in consistent, proactive, ongoing dialogue with the FDA for more than three years, and the letter we received from the FDA on June 10 is the next step in this dialogue."

Furthermore, Navigenics was previously using Affymethrix array chips. However, an FDA spokesperson told PGx Reporter, "It is our understanding that Navigenics does not use the Affy chip." As reported by PGx Reporter sister publication BioArray News, there have been conflicting accounts as to whether Navigenics is using Affy's chips.

Raising further questions, in the case of Illumina and Navigenics, the agency does not explain why Illumina's HumanHap550 array and Navigenics' Health Compass service is not considered an LDT by the FDA.

Currently a two-pronged regulatory pathway exists for genetic tests. LDTs are commonly licensed under CMS' Clinical Laboratory Improvement Amendment. The FDA reviews and clears genetic test kits and some high-risk LDTs, but practices enforcement discretion over the majority of low-risk LDTs.

A point of note is the fact that these letters are not labeled on the agency's website as "warning letters," but simply untitled "letters to industry" asking the companies to discuss the regulation of their services with the agency.

"While Warning Letters set out specific violations of law that a company must address immediately or else the agency will take an enforcement action, an Untitled Letter identifies agency concerns and gives a company the opportunity to meet with the agency and to have time to take appropriate steps to address these concerns," Erica Jefferson, FDA press officer, told Pharmacogenomics Reporter. "Based on how the companies respond to the Untitled Letters, FDA may follow up by sending Warning Letters."

It seems that FDA sent these "untitled letters" to the five firms following discussions it had with several DTC firms after Pathway Genomics received its letter from the agency.

"Some of the companies requested meetings with the FDA that were granted," Jefferson said. "The companies came to discuss their business models and what was different or similar to Pathway Genomics' model. These meetings helped inform the agency's decision to send the Untitled Letters."

However, Jefferson added that the FDA sent out letters to the five companies it had been investigating for over a year and had already sent letters informing them that the agency was aware that they were selling genomic tests directly to consumers. "The letters that were sent out yesterday were to companies that the agency had previously contacted and based on the information we had collected determined that they were marketing medical devices that needed to come in to the FDA with a submission for clearance and or approval," Jefferson explained.

Perhaps due to the regulatory uproar around DTC genomics firms of late, representatives from the burgeoning industry were conspicuously absent at the Consumer Genetics Conference in Boston last week. Although Navigenics representatives were present at the event to accept an award for being the DTC genomics firms with the "Greatest Impact on the Consumer Market," at the last minute the company backed out of presenting at the conference without explanation.

However, several presenters at the conference noted that federal regulation of the DTC genomics industry was imminent.

The FDA has backed the idea of listing these firms in a proposed National Institutes of Health genetic test registry as a way to bring more transparency to the DTC genomics industry. The NIH's recent request for information on the registry suggests that DTC genomics firms will be asked to participate (PGx Reporter 06/02/10).

In a statement to Pharmacogenomics Reporter, 23andMe said that although it had initiated discussions with the FDA in October 2007, before officially launching its service, the company believes "any government regulation should have an appropriate framework that does not stifle scientific innovation."

According to a 23andMe spokesperson, the company "carefully explains to customers that the data provided is informational and educational in nature," and that if customers want to make medical decisions based on their Personal Genome Service reports, then they should do so "in consultation with a physician or other appropriate health care professional."

23andMe added that it was "sensitive to the FDA's concerns, but we believe that people have a right to know as much about their genes and their bodies as they choose."

The Google-backed firm informed customers this week that its contracted lab, the Laboratory Corporation of America, incorrectly processed samples, resulting in as many as 96 customers receiving reports that were not their own. The batch of mismatched records loaded on June 1 was due to "human error" and the "incorrect placement of a single 96-well plate used in processing samples," 23andMe explained (PGx Reporter 06/09/10).

After the FDA sent its warning letters to the five firms, the House Committee on Energy and Commerce this week sent another letter to 23andMe requesting documents that will help the committee "learn more about this incident."

A Knome spokesperson said that the company is still reviewing FDA's letter and has no comment at this time.

Illumina did not respond to questions for this article ahead of press time.

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