The FDA Drops an Anvil on 23andMe – Now What? (slightly revised Wed. night)

On Friday, November 22, the FDA sent a nastygram to 23andMe, the only remaining substantial pillar of the “direct to consumer” (DTC) genomic testing industry. The letter, available here, is well worth reading in its entirety, but, in brief, it told 23andMe, in no uncertain terms, to stop marketing its “Saliva Collection Kit and Personal Genome Service” (“the PGS”) on the ground that it was an unapproved and uncleared “device” under the Federal Food, Drug, and Cosmetics Act.  It noted that the PGS, because of its lack of approval or clearance, was both adulterated and misbranded under the Act; the distribution of adulterated or misbranded devices is a federal crime.

23andMe’s initial response, click here, through an unnamed press spokesperson on its blog, was, at least on its face, conciliatory.

We have received the warning letter from the Food and Drug Administration. We recognize that we have not met the FDA’s expectations regarding timeline and communication regarding our submission. Our relationship with the FDA is extremely important to us and we are committed to fully engaging with them to address their concerns.

What’s going on – and what does it mean in the long run?

There has long been controversy over whether and how the FDA should, or can, regulate genetic tests, whether delivered, as 23andMe does, direct-to-consumer or through a medical professional.  These issues simmer below the surface of the cease and desist letter, but it is not clear that, at anything other than the deepest level, they are immediately relevant.

It appears that, for whatever reason, 23andMe chose to ignore the FDA – and the FDA chose not to take it anymore. The FDA letter says

Since July of 2009, we have been diligently working to help you comply with regulatory requirements regarding safety and effectiveness and obtain marketing authorization for your PGS device. . . . As part of our interactions with you, including more than 14 face-to-face and teleconference meetings, hundreds of email exchanges, and dozens of written communications, we provided you with specific feedback on study protocols and clinical and analytical validation requirements, discussed potential classifications and regulatory pathways (including reasonable submission timelines), provided statistical advice, and discussed potential risk mitigation strategies. . . .

However, even after these many interactions with 23andMe, we still do not have any assurance that the firm has analytically or clinically validated the PGS for its intended uses, which have expanded from the uses that the firm identified in its submissions. In your letter dated January 9, 2013, you stated that the firm is “completing the additional analytical and clinical validations for the tests that have been submitted” and is “planning extensive labeling studies that will take several months to complete.” Thus, months after you submitted your 510(k)s and more than 5 years after you began marketing, you still had not completed some of the studies and had not even started other studies necessary to support a marketing submission for the PGS. It is now eleven months later, and you have yet to provide FDA with any new information about these tests. You have not worked with us toward de novo classification, did not provide the additional information we requested necessary to complete review of your 510(k)s, and FDA has not received any communication from 23andMe since May. Instead, we have become aware that you have initiated new marketing campaigns, including television commercials that, together with an increasing list of indications, show that you plan to expand the PGS’s uses and consumer base without obtaining marketing authorization from FDA. [emphasis added]

Note particularly the sentence I bolded.

This sounds as though 23andMe started down the FDA path but, six months ago, not only stopped communicating with the agency but started new and bigger marketing efforts. That sounds as though 23andMe did not just ignore the FDA, but, while walking briskly past it, quickly turned and spat in its face.

Now, I have no inside information on this dispute.  I have the (scathing) FDA letter and the (timid) 23andMe initial response.  Undoubtedly, something was going on other than lost messages at the 23andMe side.  I don’t know whether that something was a plan to fight the FDA’s jurisdiction, on statutory or (novel) constitutional grounds, or a hope that the FDA would back down, or something else entirely. But if you ignore the FDA for 6 months, it is not surprising that the FDA is going to be unhappy with you, wholly apart from the future of FDA regulation of genetic tests.

So this may just be a slap down of an insubordinate, or royally disorganized, regulated firm. Does it say anything more about the future of FDA regulation of genetic tests?

Well, it does say that the FDA thinks it can and should regulate, to some extent, those tests. The letter lays out its reasons: “As discussed above, FDA is concerned about the public health consequences of inaccurate results from the PGS device; the main purpose of compliance with FDA’s regulatory requirements is to ensure that the tests work.”  The letter gives examples, from BRCA 1 and 2 to pharmacogenomic tests where the accuracy, and the patient’s actions on, the 23andMe tests have potentially serious health implications.

Some have argued that the FDA does not have jurisdiction over these direct-to-consumer tests.  (And they include some very smart colleagues and friends of mine.)  How can a plastic tube for collecting saliva be a regulated device? Welcome to FDA law.  The federal statute defines “devices” (“medical” doesn’t appear in the law) as, among other things,

an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, . .  which is–

(2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals

As the FDA’s letter points out, 23andMe markets its genetic tests as,

“providing “health reports on 254 diseases and conditions,” including categories such as “carrier status,” “health risks,” and “drug response,” and specifically as a “first step in prevention” that enables users to “take steps toward mitigating serious diseases” such as diabetes, coronary heart disease, and breast cancer. Most of the intended uses for PGS listed on your website, a list that has grown over time, are medical device uses under section 201(h) of the FD&C Act.”

A plastic tube for collecting spit doesn’t look much like an MRI machine or an implantable left ventricular assist device, but it is an “article” that, from its marketing information, 23andMe “intend[s] for [medical] use.”

Of course, the decision about jurisdiction (if 23andMe actually dares make it) will ultimately be one of statutory interpretation for the courts, informed by and giving appropriate deference to reasonable interpretations by the agency charged with implementing the statute – the FDA.  One never knows about courts, but I think the 23andMe jurisdictional argument is a loser. And, a reality of regulated industries, especially those regulated by the FDA, is that fighting your regulator may well, in the long run, be a very bad idea.

Ok, so FDA does intend to assert regulatory authority here, which its thinks 23andMe has been flouting (not “flaunting” – common misuse). Any other take-aways?

That’s hard to tell.  We’ve all been waiting . . . and waiting . .  . and waiting . . . for long-promised draft FDA guidance on regulating LDT’s, “laboratory developed tests.”  These include, but are not limited to, genetic tests and have been expected to include considerations of clinical validity. Rumor has it that the FDA thought they were done in mid-2012.  “After the election,” the word was.  Well, we all thought that meant the 2012 election, but that guidance is still stuck somewhere in the Administration.  FDA had promised a risk-based regulatory scheme, but we don’t know what it is.  We do know from its letter that it is worried that 23andMe’s tests have not been validated yet, neither analytically (do they accurately detect the single nucleotide polymorphisms (SNPs) they say they detect) nor  clinically (do those SNPs mean what 23andMe says they mean?  Presumably any long-term FDA strategy for dealing with LDTs, including LDT genetic tests will focus on analytical and clinical validation. (Hint – the clinical validation will generally be a lot tougher than the analytic validation. See the GAO report on terrible inconsistencies in clinical interpretation of the same SNPs by the DTC genomic testing industry, available for download here.) [Italicized portions of this paragraph revised.]

Does this letter tell us anything about the FDA’s position on the DTC part of testing? That’s not really clear. The letter mentions the fear that direct-to-consumer patients may self-manage in harmful ways, but it isn’t clear how much turns on that.  It is the case that, at least under current FDA practice, this would not be an issue if 23andMe were not a DTC company.  The FDA has not regulated so-called “laboratory developed tests” (LDTs), performed from (sort of) scratch by clinical laboratories.  23andMe has a clinical laboratory, but the saliva is not being collected by a doctor, with her own equipment, in her office, but by a tube 23andMe sends out – a “kit” in FDA parlance. FDA regulates diagnostic tests when sold as kits – to consumers, to doctors, or to clinical labs – but not when done directly by the labs based on samples collected by others and sent to them.

Finally, in the long run (which in this field is about 12 months right now), what does this say about genetic testing and the FDA?  In one sense, almost nothing. The SNP chip method that 23andMe uses was never very good at providing useful genetic information. Its advantage has been its low cost. But as sequencing gets cheaper and cheaper, SNP chips have already largely become obsolete for most genetic testing. Don’t look only for SNPs, do a whole exome (the 2 percent or so of the genome that “codes” for protein) sequence for under $1000 or a whole genome sequence for under $5000 (today – under $1000 soon).

In other, probably much more important news, on November 20, two days before its action against 23andMe, FDA just approved as a medical device a next generation sequencing platform from Illumina, two cystic fibrosis tests for that platform, and a kit that allows doctors to come up with other tests for the platform.  Here.  As Francis Collins, director of NIH (and one of the discoverers of CFTR1, the “cystic fibrosis gene,” and Margaret Hamburg, commissioner of the FDA, said in an article in last week’s New England Journal of Medicine, here, this “opens the door for the transformation of research, clinical care, and patient engagement.”

THAT is the future.  The DTC SNP chip era is ending.  23andMe’s two main competitors, Navigenics and deCODEme, already left the market.  23andMe’s SNP chips are slipping rapidly into the past.  And 23andMe knows it. Earlier this year it offered, for $999, a “pilot” of whole exome sequencing.  If the firm survives, it will surely be by offering whole exome and whole genome sequencing.  And, I hope, doing so after analytic and clinical validation that convinces the FDA that its methods are safe and effective. Because tests of unknown accuracy are no better than no tests at all.  I applaud the FDA for taking seriously its mandate to protect public health.

Hank Greely