So the sciency internets are all abuzz about yesterday’s warning letter issued by the FDA to the genetic testing company 23andMe. To me, it’s pretty clear-cut, and, in fact, I thought something like this would happen, so it doesn’t come as a surprise. I think Matthew Herper summarizes very clearly what’s going on here (boldface mine):

It’s worth remembering the history of how 23andMe launched five years ago. Initially it was one of three companies hoping to bring three different personal genomics services to consumers. For various reasons, the others, DeCodeMe and Navigenics, did not survive. But 23andMe managed to squeak by based on the strength of its backers and also through a stalemate with regulators: the company presented its test not so much as a medical device but as a fun way to learn about genetics. It wasn’t a way to find out medically actionable disease risk, it was a way to find out if you had a gene that made your pee smell when you ate asparagus…

But what a large enough database of people who were sharing not only genetic information but information about their health and their bodies offered was something greater: a tool that could be used to find new genetic connections, for detecting drug side effects, maybe even for finding new diagnostics or cures. That’s why 23andMe needs to get to 1 million kits sold – to build that database. That promise has brought on other investors, including Facebook billionaire Yuri Milner.

If the selling point of the 23andMe kit were that it allowed people to participate in science, maybe the FDA could have let this go. But 23andMe’s web site specifically told the story of people who got tests results related to breast cancer genes. The FDA probably felt it had little choice. This is not the story of a big regulator choosing to squash a small company, but of a company that decided that it didn’t have to follow the rules.

After reading the FDA’s warning letter, this leapt out at me (boldface mine):

For example, your company’s website at http://www.23andme.com/health (most recently viewed on November 6, 2013) markets the PGS for 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. Most of these uses have not been classified and thus require premarket approval or de novo classification, as FDA has explained to you on numerous occasions.

Some of the uses for which PGS is intended are particularly concerning, such as assessments for BRCA-related genetic risk and drug responses (e.g., warfarin sensitivity, clopidogrel response, and 5-fluorouracil toxicity) because of the potential health consequences that could result from false positive or false negative assessments for high-risk indications such as these. For instance, if the BRCA-related risk assessment for breast or ovarian cancer reports a false positive, it could lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing actions, while a false negative could result in a failure to recognize an actual risk that may exist. Assessments for drug responses carry the risks that patients relying on such tests may begin to self-manage their treatments through dose changes or even abandon certain therapies depending on the outcome of the assessment. For example, false genotype results for your warfarin drug response test could have significant unreasonable risk of illness, injury, or death to the patient due to thrombosis or bleeding events that occur from treatment with a drug at a dose that does not provide the appropriately calibrated anticoagulant effect. These risks are typically mitigated by INR management under a physician’s care. The risk of serious injury or death is known to be high when patients are either non-compliant or not properly dosed; combined with the risk that a direct-to-consumer test result may be used by a patient to self-manage, serious concerns are raised if test results are not adequately understood by patients or if incorrect test results are reported….

Your company submitted 510(k)s for PGS on July 2, 2012 and September 4, 2012, for several of these indications for use. However, to date, your company has failed to address the issues described during previous interactions with the Agency or provide the additional information identified in our September 13, 2012 letter for (b)(4) and in our November 20, 2012 letter for (b)(4), as required under 21 CFR 807.87(l). Consequently, the 510(k)s are considered withdrawn, see 21 C.F.R. 807.87(l), as we explained in our letters to you on March 12, 2013 and May 21, 2013. To date, 23andMe has failed to provide adequate information to support a determination that the PGS is substantially equivalent to a legally marketed predicate for any of the uses for which you are marketing it; no other submission for the PGS device that you are marketing has been provided under section 510(k) of the Act, 21 U.S.C. § 360(k).

To be clear, the FDA is not claiming you can’t give people their genetic information. But when 23andMe used phrases like “first step in prevention”, they entered the diagnostics realm. Art Wuster lays this out clearly (boldface mine):

My point is that 23andMe’s test should not be treated any differently than other diagnostic tests.

But is 23andMe a diagnostic test? On its website, the company lists the traits and diseases it returns information on. Whilst some of them, like ancestry or odour sensitivity, are harmless, others are specifically designed to inform on the risk for diseases including Alzheimer’s, breast cancer, Parkinson’s, and many more.

To claim that all 23andMe does is return information about variant-gene associations is disingenuous. By extension, there shouldn’t be regulation of any diagnostic test, because all they do is return information on some marker-disease association. This may be a valid point of view, and if you hold it, you need to argue for the deregulation of the diagnostics market as a whole, and not just against the regulation of 23andMe.

What I also find astonishing is the complete disregard for the FDA (boldface mine):

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 nine 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.

On the Twitterz, I wrote that 23andMe’s attorneys should be disbarred for letting things reach this point. Interestingly, it appears that General Counsel left the company several weeks ago (and no replacement has been found). I’m not always a big fan of the FDA (they still haven’t really figured out how to approve new antibiotics), but the reality is that the FDA is like those humongous tractors used to move space rockets: they’re slow, but crush everything in their path. You can’t bullshit these guys–they just keep coming.

Have no doubt–the tone of this letter indicates ‘the nuclear option’ (to use a recent phrase). It’s about as devastating as it gets. How the hell did 23andMe’s leadership (such as it is) let this happen? The mind boggles.

The other thing is that I’ve read some posts and tweets suggesting that this is some kind of war against direct-to-consumer (DTC) testing, that it’s an assault on patients right to know their own medical information (THEY MAY TAKE OUR LIVES BUT THEY’LL NEVER TAKE…OUR GENOMES!!). Did you actually read the letter? Because this is the key phrasing:

“You have not worked with us toward de novo classification“

Translated into English, 23andMe had an opportunity to tell regulators how they should be regulated–and, if they had been really clever, even twist the regulations to harm their competitors. That’s a lobbyist’s wet dream. Instead, they didn’t even bother to respond. Just how stupid and arrogant does one have to be to do that?

Worse, now that there’s blood in the water, more stories of daignosis-related screwups like these will continue to surface.

People often claim things should be run like businesses. Well, not this business.