If you look at the FDA's website, it's littered with dozens of communications begging 23andme to submit some documentation about their product so that the FDA can evaluate the medical claims they're making.

See, e.g., this one from June 10, 2010:

[0] http://www.fda.gov/downloads/MedicalDevices/ResourcesforYou/...

All the FDA wants in this letter is some kind of understanding that their genetic tests are actually valid and correct, since they are making medical claims regarding their accuracy:

> 23andMe has never submitted information on the analytical or clinical validity of its tests to FDA for clearance or approval. However, your website states that the 23andMe Personal Genome Service™ is intended to tell patients in advance how they will respond to certain medications including warfarin and clopidogrel. It also states that the data generated from the 23andMe Odds Calculator, a feature ofthe 23andMe Personal Genome Service™, includes the contribution of single-nucleotide polymorphisms (SNPs) to disease risk. Consumers may make medical decisions in reliance on this information.

The FDA then establishes its ability to regulate this (remember, it's legally required to do this):

> During a meeting between 23andMe and FDA on July 29, 2009, you described the 23andMe Personal Genome Service™ as consisting of a software program that analyzes genetic test results that are generated by an external laboratory in order to generate a patient specific test report. Thus, the 23andMe Personal Genome Service™ is a diagnostic device and subject to all applicable requirements of the Act.

They then very helpfully point them to all the forms, documents, etc., necessary to satisfy the legal requirements:

> For a device requiring premarket approval, the notification required by section 510(k)of the Act, 21 U.S.C. 360(k), is deemed satisfied when a PMA is pending before the agency. 21 C.F.R. 807.81(b).

There's even a helpful mailing address and fax number:

> Please direct your questions and response to: James L. Woods, Food and Drug Administration, 10903 New Hampshire Avenue, W066-5688, Silver Spring, MD 20993

Honestly, this sounds like 23andme has been getting away with something for a while and the FDA is tired of giving them leeway.

The bio on the guy who sent the letter you linked is interesting; not the "career civil servant maybe with a JD" you'd expect from an enforcement action:

http://oba.od.nih.gov/oba/sacghs/roster/bio/2010/Alberto%20G...

As an aside, I think this is not as uncommon as one might think. It's a big government and obviously not perfect at hiring and promotion, but in my experience the upper-middle tier of employees generally know their shit.

I suspect 23andMe didn't provide documentation because they very much want to avoid being treated as a medical service, and fear submitting this documentation would serve to further put them on this path.

There is a bit of a contradiction here that "natural supplements" get this huge pass from the FDA, but applying some math to very, very natural genetic data doesn't.

Blame Congress. While the executive branch may write regulations, they must operate within the mandate defined by Congress.

The DSHEA of 1994 (authored by Orrin Hatch) explicitly forbids the regulation of dietary supplements by the FDA so long as they do not make health claims. Unless that bill is repealed, the FDA has no authority over supplements.

Oh I get this comes from congress and the tortured history of dietary supplements. I'm just taking issue with what might define as reasonable.

I don't see what reasonableness has to do with government.

Since when do "natural supplements" make medical diagnosis? Not even in the same ballpark.

Natural supplements are effectively marketed as medication (despite a label indicating the FDA has not evaluated the claims). Many people I have spoken to genuinely believe natural supplements to be actual medicine based on the way they are marketed.

The issue with incorrect diagnosis is might lead to incorrect or ineffective treatments. "Natural supplements" are the incorrect or ineffective treatments themselves: the unregulated claims they make is very similar in substance and effect to the quasiregulated claims that 23andme is making.

And which ballpark would you say is closer to the area of a "food" or "drug"?

If you look at the FDA's mandate, it is pretty strongly oriented to products for treatment, not medical diagnosis. The medical diagnosis angle is mostly there due to certain forms of quackery.

I develop medical devices use for diagnosis for a living. Some organization has to watch over this stuff, it just so happens to fall to the FDA. What's your proposal? Do you believe that these devices should not be regulated?

If your device is a pen and paper, I don't agree it has to be regulated.

Moreover, it appears from the letter that the concerns are about marketing; ie, presumably the FDA was simply asking for 23AM to clarify their copy to remove any implication that you could use the product as a substitute for a doctor's assessment of your e.g. cancer risk.

It's actually kind of hard to tell -exactly- what the FDA wants without reading the original 510(k) submission. The claims by the FDA directly tie into the original claims by 23andMe as their intended use.

In any case, the FDA right now doesn't just want a change of copy. By "cease marketing", I presume they don't mean advertise it differently, they mean stop offering the product to customers - period.

While the FDA certainly appears to be taking issue with the specific marketing copy, they seem to be more annoyed that 23andMe has basically failed to complete the regulatory submission process - amongst other things failing to provide evidence to the FDA that their product actually works as intended.

> It's actually kind of hard to tell -exactly- what the FDA wants without reading the original 510(k) submission

Well, you don't get this far into trouble with a regulatory agency without having a contact within the agency that you are working with. So, I'm fairly certain that 23andMe probably knows what the FDA wants, but they might disagree. I'll be disappointed in the company if they have ignored the FDA all these years when it was obvious that they'd need to have some sort of approval (even if it was an FDA acknowledgement that they didn't fall under regulation).

What I really want to know is what 23andMe's response to the FDA will be. They must have known this was coming and should have a press release today.

"[...] we have proposed modifications to the device’s labeling that could mitigate risks and render certain intended uses appropriate for de novo classification [...]".

Incidentally, the FDA is lagging a lot of other criticism and restrictions on the 23AM service; for instance, you can't even buy the service in Maryland, which forbids any home lab testing for health conditions not administered by licensed professionals. Similarly, there have been many critiques in the media and elsewhere about the lack of rigor in the 23AM analysis, relative to the importance of some of the conditions the service is implicated in.

Not all of it is reasonable, at all:

"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"

Uh, you don't think the surgeon is going to demand a second BRCA test be done before performing the surgery?

Without an appropriate study to determine reasonable efficacy, it is possible that the diagnostic technique could result in a large number of false positives.

This could result in a large number of unnecessary follow-up BRCA tests which could potentially increase the waiting time for test results or unduly raise costs for lots of patients. Not to mention the stress of feeling like you may be suffering from a potentially expensive and life-threatening illness.

So: totally reasonable.

Your verdict of reasonableness depends on the idea that physicians are not going to be able to properly advise patients who they think might have gotten a false positive result.

Considering that over half of American adults believe Elvis is alive, I think the small percentage who may slightly overreact to the kind of presentation that 23andme gives of these kinds of results is a complete non-issue.

Many physicians are terrible at interpreting results of screening tests:

http://www.bmj.com/content/333/7562/284

For screening tests where the problem being screened for is rare, most results will be false positives, but the result is not intuitive.

Doctors being lousy Bayesians is (if anything) an argument in favor of services like 23andme!

Right. IF 23 And Me can show that its test are accurate. But they can't (or have refused to do so). That's the whole point.

23 And Me should only have to prove that it is better than the alternative, not that it is accurate (to determine whether the service is of net benefit to the public). Depending on the counter-factual, 23AM could provide a relatively inaccurate test that would still be better than no test.

Unfortunately for us, the FDA is on a quest for "safety"; the agency does not try to help the citizenry live longer or happier.

Safety isn't part of a long and happy life?

> 23 And Me should only have to prove that it is better than the alternative,

23andMe isn't even doing that.

You seem to believe the average doctor is well-versed in the mechanics of genetic testing, or (perhaps equivalently) that the average doctor isn't wholly dependent on the mechanisms of FDA approval for product selection.

Any doctor educated in the past two decades is well versed in genetic testing, and any doctor specializing in areas where genetic testing is a frequently used aspect of planning/diagnosis (such as OB/GYN) will be highly familiar even if trained long ago.

The 23andme product explains explicitly how it should be used by a physician, and there are all kinds of warnings and checkboxes before the user is shown any data that falls into the area of overlap.

Perhaps any one of several trained medical professionals on HN could chime in here to explain (a) how suitable 23AM's current product is for clinical use and (b) how competent a typical physician is at evaluating clinical genomics products without FDA's assistance. 'carbocation? 'niels_olson?

('carbocation has already expressed some tacit support for FDA's action, but I'm not qualified to interpret it in the context of this particular subthread).

> The 23andme product explains explicitly how it should be used by a physician

Generally, for diagnostic tools, drugs, etc., it is not enough that the product labelling explains how it should be used, but it is required to demonstrate to the FDA that there is evidence that it works as marketed when used according to those directions. The FDA Warning Letter specifically calls out 23andMe's failure to either identify existing approved products on the market to which the product is equivalent (which wouldn't reduce the requirements for proving this) or to meet the requirements for demonstrating the effectiveness of their offering as a new product without existing, approved equivalents.

How do you think 23andme should answer that question?

There are at least three different products in the space and to claim similarity would be to likely invite over-regulation:

- "full scan" companies, that do a full genetic scan and do not limit the scan to SNPs

- personal genomics companies that focus on SNPs

- medial diagnostics like the MSAFP test

> How do you think 23andme should answer that question?

I don't know enough about 23andMe's operations and those of what appear from the outside to be generally similar services to answer that. Assuming that they really are an innovative service, they would need to conduct and provide the studies supporting the validity of their innovative service.

  Any doctor educated in the past two decades
  is well versed in genetic testing

I'm not sure what definition of "well versed in genetic testing" you had in mind but this is untrue for most or all reasonable definitions.

  any doctor specializing in areas where genetic testing
  is a frequently used aspect of planning/diagnosis
  (such as OB/GYN) will be highly familiar even if trained long ago.

Also an overstatement. The trouble is that "genetic testing" is a large and complex field. Are you referring to a single-gene test for a well-known and well-characterized disease? Or whole exome sequencing? Because in the coming years doctors will come into contact with both. In general these tests will require specialist interpretation; not general physicians or OB/GYNs.

Regardless of whether physicians are skilled or not at helping their patients interpret the results of a proprietary test, the point I was making is that if the test produces an unacceptably high number of false positives then this would result in an unnecessary increase in the number of times physicians have to actually have those conversations.

If physicians are forced to waste huge amounts of time and effort to console an influx of patients who have been wrongly told they have some terrible disease, this is going to reduce the amount of time they have available to work with patients with actual terrible diseases.

If other medical device/diagnostic makers have to comply with the law, so should 23andme.

What if it results in some accurate positives and saved lives? You think the FDA should limit access to information curious people can obtain for $100 about their own genome that might help them behave proactively toward their own health just in case it results in more patients behaving proactively?

I don't know a single person who thinks Elvis is alive...

Why more than 1 follow up test?

Multiple unneeded follow-up tests across the population, not per person.

There is always a point in any discussion of medicine where broad "public health" concerns creep in.

If we really cared about public health we'd have a drastically different system.

In any case I think it's hard to make a persuasive argument that if the members of the public were only kept more naive about their own health risks, public health would improve.

The point isn't necessarily the second test (which would have to be done). It's also the emotional distress caused by a potential false positive, which could be severe. You could imagine in an extreme case some one finding a result with a poor prognosis and deciding to commit suicide. Now, if that result was a false positive, you can see where you'd want to have some assurances that their test was accurate.

This is an extreme example, and I have no knowledge that it ever happened, but it is possible.

This might not even require a technical fix with the test, but rather a marketing and reporting of results.

From what I understand, the test doesn't attempt to diagnose an existing condition. Instead, it shows whether you have a gene that indicates a predisposition to the condition. In that case, prophylactic measures can be taken, once confirmed and if desired. This is what drove Angelina Jolie's decision to have a double-mastectomy.

That's a hugely significant difference vs. actually being diagnosed with a life-threatening condition. I don't think people would commit suicide or become unduly despondent if they learned they have a gene. They would just know they need to take action, get further testing, be vigilant, etc. It's not much different (in spirit) from knowing that your family history predisposes you to a certain condition.

It's all about education and results reporting. Where you or I might see a result as a predisposition to a phenotype with a statistical probability, someone else might see a death sentence.

That could be one area that the FDA might be trying to address.

I agree that it has to be clearly reported and explained.

But, you know, there are in-home HIV tests that are FDA-approved. They tend to stress professional counseling and/or follow-up testing, etc. They also explain such somewhat-technical details as the window between infection and antibody formation, so it's an education process there as well. But, I think the availability of such a test is testament to the fact that easier access to important knowledge re: one's status may be worth the risks.

HIV tests are pretty simple, from a diagnostic test point of view. It's really a boolean - HIV present, or not present. The meaning of a particular genetic variant is much more ambiguous.

It's odd to me that you're saying HIV tests can give definitive devastating diagnoses to people alone in their homes, yet they are OK; but genetic testing provides a range of possibilities and recommends further investigation, but they are somehow so devastating that they would drive someone to despair or suicide.

I'm not trying to equate things to HIV tests, and it's probably a poor example. I'm not sure what the reporting process for an in-home HIV test would be. I recently had a doctor tell me that she's not allowed to actually give the results of an HIV test over the phone for fear of patient reactions.

What I was trying to say was that that class of test should be easier to use and get a definitive yes/no answer with a smaller false positive rate.

>I don't think people would commit suicide or become unduly despondent if they learned they have a gene.

What if the gene essentially means "you and your husband shouldn't have children?"

I think one can make a million hypothetical arguments against the testing. But, I just don't see people taking the test at face value and making major life decisions without further follow-up. I think most reasonable people would consider it a screen.

If the testing was wildly inaccurate, then that's another issue. It almost becomes more an FTC consumer protection-type matter at that point. But, there is no indication that this is the problem. They go on to state that their testing is done in CLIA-certified laboratories:

https://www.23andme.com/howitworks/ (near bottom of page) http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA...

BTW, I'm not really defending the service, per se. In fact, I have issues with it that are more along the privacy lines. I just don't see where there's any proof that it has an outsized chance of ruining lives any more than, say, in-home HIV testing.

They'd probably feel a hundred times worse if they found out by observing the symptoms in those future children.

People get wacky when facing things like this. Remember the stories of Steve Jobs turning to crazy diets instead of treating his cancer medically?

If you dump a bunch of information in front of people who may or may not be prepared from an intellectual or emotional perspective to deal with it, they may take dramatic and unwarranted action.

Dont take my freedom to decide because of homeopathic weirdos like Jobs. I'm not one to usually complain about the nanny state, but this is deep into nanny statism here.

Have you lived or travelled extensively in countries that don't have public health or regulatory infrastructure?

Organizations like the FDA and EPA were created in response to very real failings. The problem for many of us who grow up benefitting from these safety nets is that we don't have a sense of how hard-won these battles were. Life is good and so we start chipping away at the "nanny state" to get a tiny little bit more freedom. Actually more like a lack of inconvenience, not really freedom.

I've been thinking about this a lot lately. Is this just a natural social cycle?

I don't think it's a natural social cycle, it's the outgrowth of the general mistrust of government that has festered over the last 30-40 years or so. I don't think that our political institutions have dealt with the changes in the media well.

The ideology that inspired the construction of these safety nets is gone for the most part -- we've degraded to bread and circuses. The political machinery on one side focuses on handing out stuff in exchange for votes, and the other side focuses on vilifying "those people". Nobody believes in anything anymore.

Don't take away my freedom to trust test results.

When there is no qualitative requirement to make effective medicines, you'll find (literally) the industry degenerate into snake oil and the types of patent cures that ultimately led to the creation of the FDA.

Public health isn't nanny statism.

That really doesn't matter. The responsibility for correct results falls on the Device Manufacturer (in this case 23&me), not on the physician that ordered the test.

I work for a large Medical Device manufacturer and questions like this come up all the time when we do Hazard Analysis. While the physician (or lab rules) may require a second confirmatory test, and that may give us warm fuzzies, it really can't be considered to be a hazard mitigation. It's still up to the manufacturer to not make the mistake in the first place.

But if another company like 23AM pops up, they could be the "second company". If companies are not required to prove that they are reliable, then you could too easily get multiple false positives.

no, because presumably a licenced doctor would rely on a test provider that was FDA-approved.

The info that the company had lots of notice and apparently didn't do anything is very crucial to understanding this.

Thanks for the info.

What does "predicate" mean in this context?

(expanding a little on nknighthb's comments):

The primary path to approval to market for a new device or drug is the PMA (pre market approval). This is fairly extensive an costly for the company (e.g. clinical trials). A 510(k) filing allows you to take a short cut by identifying a "predicate device" that is "substantially equivalent". In other words you are saying "we do the same as X but we [also do Y/do this differently/etc.]". At least, you are claiming this for the scope of your "indications for use" (which are the only uses you can market your device for).

This doesn't let you off the hook entirely at all. You still need to demonstrate safety and efficacy, perform risk analysis, follow standard manufacturing and product development methodologies (e.g. ISO13485, IEC60601, etc. ), but it is a lot faster and less involved than a PMA.

If you don't use one of these accelerated paths, you'll need a PMA before you can market your product in the US.

The key issue here is that 23andme has filed one or more 510(k)'s, but have failed to support them properly.

As far as I can tell, you could translate that as "existing product". Given A and B, if A is already legally marketed, and B is basically the same thing, B has a lower bar to clear. Googling for "legally marketed predicate" turns up results like a 501(k) for a catheter[1] that the manufacturer says is "substantially equivalent" to another catheter already on the market.

[1] http://www.accessdata.fda.gov/cdrh_docs/pdf/K963092.pdf