While You Were Meeting: FDA Mails Letters to 14 More Genetic Test Providers

(Cross-posted to Genomics Law Report.)

Earlier this week the FDA held a widely publicized two-day public meeting to discuss its planned regulation of laboratory developed tests (LDTs) (for more see: Day One Recap and Day Two Recap). Other than Monday morning, when the FDA presented background information on LDTs and some of the considerations that have pushed the agency to pursue a “risk-based application of oversight to LDTs,” the top agency officials at the meeting were conspicuously quiet. Elsewhere, however, the FDA was doing plenty of talking.

In letters dated July 19th, the first day of the FDA’s public LDT meeting, the agency continued its crackdown on direct-to-consumer (DTC) genetic test providers, mailing letters to 14 providers of genetic tests. A list of all 14 companies and tests appears below.

The Letters. The letters are similar to the five untitled “letters to industry” the FDA sent out in early June to 23andMe, Navigenics, deCODE Genetics, Knome and Illumina. While briefer than the earlier letters, the new batch of letters reach the same conclusion: each of the companies is marketing a genetic test that, according to the FDA, meets the definition of a “device” under Section 201(h) of the Federal Food Drug and Cosmetic Act (FFDCA). Therefore, each test must receive FDA clearance (510(k)) or approval (PMA). Not surprisingly, the FDA “conducted a review of [its] files” but was “unable to identify any [such FDA] clearance or approval” for any of the tests. The companies are asked to respond to the FDA within 15 days.

By comparison, the June 10th DTC letters were lengthier and also contained (1) information regarding the specific devices/products identified as problematic by the FDA, (2) a recitation of the FDA’s authority for premarket regulation of medical devices under the FFDCA and (3) a description, in most cases, of a prior meeting between the company and the FDA. The June 10th letters also urged the companies to “take prompt action to respond” to the letter, instead of setting out a definite timeframe.

The other notable difference between the two sets of FDA letters is who signed them. The June 10th letters were signed by Dr. Alberto Gutierrez, Director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD). The July 19th letters, on the other hand, were signed by OIVD Deputy Director James Woods. It appears that over the last month OIVD and Dr. Gutierrez have gained sufficient comfort with their letter-writing campaign to push the task down the chain of command.

The Tests. Here is the list of all 14 companies who received FDA letters dated July 19th:

• Graceful Earth Inc. Concerning the Graceful Earth Alzheimer’s Test
• SeqWright DNA Technology Services, Inc. Concerning the SeqWright Genomic Profiling Service (GPS)
• Interleukin Genetics, Inc. Concerning the Inerent Health
• DNATraits Concerning the Ashkenazi Jews Genetic Disease Panel
• CyGene Direct™ Concerning the Metabolic Health Assessment DNA Analysis Test
• Consumer Genetics, LLC Concerning the AsthmaGEN DNA Test
• Matrix Genomics, Inc. Concerning the Matrix Genomics Breast Cancer Panel
• The Genetic Testing Laboratories, Inc. Concerning The Genetic Testing Laboratories DNA Predisposition Test
• Sequenom, Inc. Concerning the SEQureDx™
• EnteroLab Reference Laboratory Concerning the Gene Test for Gluten Sensitivity/Celiac Sprue
• BioMarker Pharmaceuticals, Inc. Concerning the Gene Essence™
• DNA Dimensions Concerning the Predisposition DNA Test
• HealthCheckUSA Concerning the HealthCheckUSA Celiac Disease DNA Test
• easyDNA Concerning the Genetic Predisposition Health Test

Most but not all of these tests appear to be offered for sale directly to consumers. All appear to be marketed DTC. For some tests it can be difficult to tell. For instance, while Matrix Genomics’ breast cancer test can be purchased directly online, I was unable to find a way to order DNA Dimensions’ “Concerning the Predisposition” test through the company’s website, although the company does have a Facebook page. Others products, such as Sequenom’s SEQureDx™ test which, according to the FDA (pdf), measures “circulating cell-free fetal (ccff) nucleic acids (RNA or DNA) in a pregnant woman’s blood sample for fetal gene and chromosome abnormalities, does not appear to be available for purchase with a physician’s involvement.

The range of tests and test providers makes it impossible to determine why or how the FDA selected these particular tests for the current round of letters. Matrix Genomics, for instance, also offers Alzheimer’s, Heart Attack, Warfarin, Plavix and Parkinson’s tests. The FDA’s letter, however, only mentioned its breast cancer panel. And even with these 14 additional letters, as I wrote last time, there are still dozens – and possibly more – of genetic tests marketed and sold directly to consumers that have not been identified by the FDA. The Genetic and Public Policy Center’s (GPPC) recently updated chart of DTC genetic testing companies (pdf) lists 30 companies, and similar lists from AccessDNA and DNA Test Index include dozens more.

What’s more, as with the case of Sequenom, it’s not clear that the test is being offered directly to consumers. If that’s the case, and the FDA has moved on from sending letters to DTC genetic testing providers to sending letters to providers of more traditional LDTs, then the FDA has thousands of potential letter recipients to choose from at GeneTests.org.

More than a month after the first five DTC letters went out, and in the immediate aftermath of the FDA’s public meeting, companies, consumers, healthcare providers, investors and the general public remain largely in the dark about the factors the FDA is using to determine which tests and test providers to target. Is it a test’s intended use? The fact that it is marketed DTC? The fact that it is sold DTC? The complexity of a particular test? The perceived or actual lack of analytical validity, clinical validity and/or clinical utility? Any or all of those factors, as well as numerous others, might be influencing the FDA’s activity in this area. Until the FDA offers up a general policy for public review – and hopefully for comment as well – there is no way for anyone outside of the agency to know where the FDA might be headed next. For the moment, at least, it appears that company-by-company, test-by-test letter mailing continues to be the agency’s preferred approach.

The Timing. During the FDA’s two-day public meeting earlier this week, the agency repeatedly emphasized that its policy with respect to the regulation of LDTs – including DTC genetic tests – had not been finalized. That was, after all, one of the primary purposes of the meeting: to “serve as a forum to discuss issues and stakeholder concerns surrounding LDT oversight.” The meeting even included an entire session devoted to DTC testing, in which participants were invited to discuss the risks and benefits of DTC genetic tests.

On the topic of the FDA’s willingness to listen to the LDT community, here is what I wrote after the first day of the meeting.

Openness. One reason that a fully articulated regulatory policy is unlikely to emerge from the FDA in short order is that the Agency appears strongly committed to gathering stakeholder input and developing regulations that respond to that input. This is a standard talking point for any regulatory agency, and with numerous conflicting opinions over whether and how the FDA should regulate LDTs, it is obvious that the Agency will not satisfy every stakeholder. Still, I was struck by the Agency’s commitment—in both private and public conversations—to understanding the issues and keeping an open mind about how to proceed. There seemed no reason to doubt Dr. Mansfield when she said that when it comes to LDT regulation, “nothing is set in stone; we have not made any decisions.” This only serves to underscore the importance of participation in the regulatory process which, if attendance at this meeting is any indication, is a strategy that the LDT community has embraced. (emphasis added)

The July 19th letters certainly seem to give the lie to the agency’s position, including Dr. Mansfield’s comments, that nothing is set in stone when it comes to LDT regulation.

The FDA’s policy with respect to DTC genetic tests, while far from clear, certainly seems to be moving ahead unchanged, public meeting or no. The timing of the letters, which were mailed the same day as the meeting began, suggest that the FDA had no intention of revisiting its decision to step up oversight of DTC genetic tests, no matter what might have been said on Monday and Tuesday.

So what are we to make of the timing of the timing of the FDA letters?

On the one hand, as was pointed out by the agency after the previous round of letters, these are untitled “letters to industry” and are less severe than a formal FDA “warning letter.” The letters identify agency concerns and give the named companies time to respond. (Depending on the response, or lack thereof, the FDA may follow up with warning letters down the road.) The letters also subject other lesser-known DTC companies to FDA scrutiny similar to that received by the companies named in the June 10th letters, although, as mentioned above, that level of scrutiny is hardly industry-wide at this point. It is possible that the FDA is slowly but surely identifying DTC (and select other) genetic tests that it believes are particularly problematic, and mailing out standardized letters as it does so. It is possible that the timing is largely coincidental.

On the other hand, coincidence or not, it is difficult to believe that the timing of the FDA’s latest letters won’t provide significant fuel for those who believe that the agency has already made up its mind about how it intends to regulate LDTs – including DTC genetic tests – and that the two-day public meeting was simply window dressing to help bolster the agency’s defense against any future challenges to its soon-to-be-enacted regulatory policy.

While I continue to think that the FDA is indeed listening to the LDT community as it develops its regulatory strategy – if for no other reason than that the topic is so complex that the FDA is unlikey to sort out all of the details quickly, or on its own – this latest development gives me pause. One of the many themes that emerged over the two-day public meeting was that the FDA will need assistance and buy-in from regulated parties in order to effectively implement its new system of LDT oversight, whatever it may be. Allowing those stakeholders to have a say in the development of the FDA’s regulatory policy is an excellent way to secure that assistance and buy-in; but that strategy only works if the FDA can convince the LDT community that it is actually listening. Coincidental or not, the timing of this round of FDA letters is unlikely to help the agency in that regard.

What’s Next. Three of the five companies named in the June 10th letters will be on Capitol Hill first thing tomorrow morning for a House of Representatives hearing on “Direct-to-Consumer Genetic Testing and the Consequences to the Public Health.” The House Committee on Energy and Commerce posted a briefing memo (pdf) for the hearing earlier today. The memo provides additional background information (including information about the GAO investigation, which apparently was initiated all the way back in March 2009) and includes a witness list.

In addition to representatives from Pathway Genomics, 23andMe and Navigenics, the GAO and FDA will be represented. Dr. James Evans of UNC-Chapel Hill, and a member of the SACGHS, will also testify. For those interested in following the hearings from afar, Andro Hsu has posted a link to a live webcast that will, hopefully, be active once the hearings begin.

None of the 14 companies recently named by the FDA have been invited to appear before the House, but that’s no guarantee that Congress won’t invite some or all of them to take their own trip to Washington at some future date.