Tag Archives: 23andMe

by | March 18, 2018 · 6:27 PM

Medical Strategy or Marketing Strategy?

A well-known direct-to-consumer (DTC) genetic testing company now has FDA approval to include a very limited form of BRCA testing with its DNA genotyping product. I refrain from mentioning the company’s name because they already got enough free press from the announcement. You probably know what company I am referring to, and if you don’t, well, follow the above link. Sorry Unnamed Company, but I am not going to make the free advertising that easy for you, no matter how insignificant the source. Besides, I see it as a bigger issue than just one company’s policy.

For now, the analysis is limited to the three BRCA1&2 mutations that are more common among Ashkenazi Jews. Actually, the company offered the same 3 mutation test until they were slapped with a cease and desist letter from FDA in 2013 to stop all medically related testing. So this new announcement amounts to a resurrection of a nearly decade-old policy, not a groundbreaking innovation. Funny, though, that there was not this much to-do when the test was first offered.

The genetic counseling community is in a bit of a dither about this, including me, though admittedly part of the reason I am writing this blogpost is to help me figure out just what I am dithering about.

Some of the concerns are obvious. People may be under the misconception that a negative result = no increased risk of hereditary breast/ovarian cancer and thus some high risk women may forego potentially lifesaving surgery and appropriate screening strategies. Then there is the worry that patients will not follow through with genetic counseling if the testing is positive, or that high risk patients will not seek genetic counseling and more testing if the result is negative. If you are not Ashkenazi Jewish, the test does not seem to offer much benefit. And even for Ashkenazi Jews, the testing does not include the ~10 other genes linked to hereditary breast cancer and the ~10 other genes linked to hereditary ovarian cancer.

The company recommends verifying positive results with an experienced clinical lab.  For that matter, then, why not verify a negative result, if there is that much uncertainty? Why bother having a test if you can’t fully trust the result? I suspect though that there is probably little reason to doubt the test result and that the company makes this recommendation to keep FDA happy and to minimize their legal exposure rather than concerns about assay validity.

Incidentally, the cost of the company’s product is really not much different than the more comprehensive multigene hereditary cancer panels offered by some of the clinical testing labs, and in some cases more expensive.

Eight years ago I shared my first experience with a patient whose BRCA carrier status was detected through DTC testing. My patient’s experience and a few more cases I encountered since then have not been that different than my patients who went through the usual counseling and testing process. A 2013 study by the company  showed that the 11 women and 14 men who discovered their BRCA status through DTC testing had experiences similar to my patients. That last statement is brimming with caveats – small sample size, at least for my patients they were savvy enough to want to see a genetic counselor, personality traits of the earliest users of new products, no long-term follow-up, etc. But I am not aware of any independent, large-scale studies of patients who learned their BRCA status through DTC testing to more definitively address the pros and cons, other than studies offering BRCA testing that targeted all Ashkenazi Jewish women.

I readily admit that I may be proven wrong, but I am guessing that most of the consumers of this DTC product – note they are not patients because the test is not intended for clinical use – will opt to learn their BRCA status. After all, people have this testing to learn about their genetic makeup. I am also guessing that this may be the company’s proverbial toe-in-the-water; I would not be at all surprised if additional clinically useful testing is part of the company’s future product and marketing plans.

At heart, I don’t like the idea of DTC BRCA testing. I think about all the ways it can go wrong, and inevitably some of those ways will come to pass. But will it go right often enough, and go wrong infrequently enough, that there will be adequate benefit to justify offering DTC testing? Undoubtedly, some of my uneasiness stems from a professional conflict of interest; DTC eliminates my role as an interface between patients and testing. Personally, I think being a middleman is a good thing because it can help patients take a thoughtful deep breath before leaping into the gene pool. But that could be because I have been trained to think that way and because it supports the value of my professional career. What I really should want is for patients to have access to genetic information in a manner that is affordable, accurate, psychologically and emotionally appropriate, and medically useful. If DTC and other forms of offering BRCA testing works for many men and women, then I should swallow my professional pride and acknowledge it.

So having stewed on this for a while, I have come to the realization that my argument isn’t with this company per se. Other companies aggressively market hereditary cancer and other genetic testing to average risk people. For example, one company approached my institution with the idea of offering their product to all women coming in for breast imaging, with saliva kits kept in the mammography center along with a prescription pad with a genetic counselor’s name on it acting as an ordering provider for the test (legal in my state). Although many labs employ genetic counselors who work directly with patients to review test results, this is still not the same experience as meeting with a genetic counselor before undergoing testing to explore the complex medical and psychological issues surrounding genetic testing. And the highly respected Dr. Mary-Claire King has advocated for population based genetic screening for establishing hereditary breast cancer risk. Are DTC clinical testing and other consumer-friendly strategies disruptive ideas that will bring about much-needed change or are they just bad but well-intentioned ideas that will also fill company’s coffers and keep investors happy?

Having sifted through and weighed my thoughts and feelings about DTC testing or other genetic test delivery models, I have concluded that my problem is not with DTC or other models per se. My argument is with how these new testing approaches are introduced into clinical practice, typically under some version of the banner of liberating testing and bringing it to the people. I do not doubt the labs’ sincerity when they say they are trying to improve access to medical care and reduce the suffering from cancer and other illnesses. But these are as much marketing strategies as they are medical strategies. Labs should not be calling the shots on the introduction of new tests and practice models because, in the absence of well designed studies, we really have no idea if these new approaches are effective in reducing cancer risks and increasing high risk screening when indicated, or if they are in the patients’ best emotional and psychological interests. Just throwing a mess of tests out there and encouraging everyone to take one is, in my view, irresponsible.

A better approach is to first conduct controlled and ideally randomized studies that evaluate both new and novel testing strategies to determine the most beneficial one(s) for patients, or if different types of patients benefit differently from different strategies. For example, age, family history, medical history, psychological functioning, and socio-economic status could all conceivably affect outcomes, not too mention the all too real possibility that many Americans may lose health insurance in the near future. While labs should play a critical role in that evaluative process, to keep it as clean as possible the studies need to be conducted and overseen by researchers who have no financial benefit from the outcomes of such studies.

We are in this together, so let’s work together.

2 Comments

Filed under Robert Resta

Tagged as , , , ,

by | April 9, 2017 · 7:32 PM

FDA and 23andMe change their Facebook status to ‘in a relationship’

In 2007, 23andMe launched their personal genome scan, a SNP-based test that offered consumers an estimate (some might say a guess) as to how certain elements of their genotype might contribute to their likelihood of having an array of traits and diseases. It was a great success, if success was to be measured in ink and column inches rather than actual dollars. Anne Wojcicki’s company quickly came to represent the embodiment of direct-to-consumer genetic testing, an icon of what was more a movement than an industry.

 

For that reason, six years later, when the FDA surprised 23andMe with a cease and desist order for their genome scan, it could reasonably be taken as a rejection of not only one company but the entire DTC ethos. At the time, many canny observers pointed out that the FDA’s drastic move seemed to have more to do with 23andMe’s attitude than it did with any specific risk posed by testing. As Duke University genetic professor and trenchant observer Misha Angrist was quoted as saying at the time, the FDA missive read “like the letter of a jilted lover…‘We went on fourteen dates! We exchanged all these e-mails! We held hands in the park! Now you’re telling me, “Fuck you,” and kicking me to the curb.’ ”

 

In response, a chastened 23andMe kept a toe in the DTC puddle by offering testing for ancestry and non-medical traits like sleep patterns and eye color while negotiating a slow courtship of the regulatory body. Eventually they got flowers back from the FDA – or rather a single flower, permission to offer just one carrier test, for the aptly named Bloom syndrome. But this blossom, like many others, was freighted with greater significance, and now that they were friends again the FDA decided that other DTC carrier tests would no longer require individual premarket approval, allowing 23andMe to add back a layer of medical testing to their business model.

 

The FDA drew a line between giving out information on carrier status (okay) and giving out information that was diagnostic (not okay). This created the odd situation where 23andMe could tell a customer if he or she had, for example, one CF-causing variant but was forbidden to inform them if they had two, since that was a presumptive diagnosis. Let’s leave aside how confusing this all gets, since sometimes people can have two disease-causing variants and remain healthy, and sometimes carriers can have medical complications. I’m not even going to mention that. See how I didn’t mention that? The bottom line was that 23andMe could inform you of a risk for something that might happen, but only if it was a mere possibility and not if it was certain or highly likely.

 

Two years later, the FDA has come out with another announcement – this time I assume that 23andMe is less surprised than the rest of us – that will expand the universe of what is available through DTC testing. The company will now be allowed to provide testing for susceptibility to 10 diseases and conditions with significant health implications, including late-onset Alzheimers disease, Parkinson’s. celiac, Gaucher’s disease type 1, hemochromatosis, and others. Again, this isn’t just a bouquet of flowers being handed out to a patient suitor. It signifies a change in thinking at the FDA about the value of DTC genetic testing, which they noted in their press release “may help to make decisions about lifestyle choices or to inform discussions with a health care professional.”

 

No but really this is getting embarrassing get a room you two.

 

The FDA announcement indicated that these 10 diseases were merely a beginning. In the future, 23andMe and other trusted practitioners will be able to introduce tests with less regulatory scrutiny. The FDA’s commitment to a streamlined and less burdensome process demonstrates a new interest in making DTC genetic testing widely available.

 

The important thing, emphasized Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, was that consumers did not come away believing that genetics was destiny. “…it is important that people understand that genetic risk is just one piece of the bigger puzzle, it does not mean they will or won’t ultimately develop a disease.” For this reason, the FDA has doubled down on it’s practice of differentiating between susceptibility and diagnosis.

 

Conceptually, this makes sense. Practically, in some cases, it creates a situation where DTC customers can access the sort of probabilistic information that we are generally loathe to give out in a clinical setting – like their chance of getting late-onset Alzheimer’s disease – but are blocked from getting exactly the sort of definitive, actionable information we value the most.

 

Possibly, this might serve to differentiate the realm of DTC testing from the kingdom of clinical medicine. Genetic counselors, often DTC skeptics, might feel more comfortable adopting a live and let live approach if areas central to GC practice like susceptibility for cancer and heart disease were reserved for the clinic. Still, when it comes to ApoE, it is a bit of a paradox that the solution to information deemed too hot to handle by counselors is to give it out with no counseling at all. The impact, I am inclined to believe, will be to speed the integration of probabilistic testing into genetic practice. In the meantime, it will almost certainly herald a period of rapid expansion of health and wellness testing in the DTC space.

 

Leave a comment

Filed under Laura Hercher

Tagged as , , ,

by | December 20, 2013 · 10:20 AM

The Bumpy Road From Bench to Bedside: Top 10 Genetics Stories of 2013

10. 23andMe and the Thanksgiving Week Massacre

Image

You can get anything you want…except personal genome screening.

The Monday before Thanksgiving 2013 the FDA issued a letter to 23andMe directing them to cease and desist sales of their personal genome service (PGS) within 15 working days.  In shutting down 23andMe, the government agency was in effect shutting down an industry, since 23andMe was the last player standing of any significance in the fledging direct-to-consumer genetic health information services field.  This added some drama to the situation and some volume to the howls of outrage from libertarian-minded science geeks who not only liked but believed in 23andMe.  To be entirely fair, its hard to blame the FDA for taking down the last lonely cowboy, since 23andMe has helped a number of competitors out the door, dipping into their deep pockets and selling their test at a loss.

Of course this is 2013, and information never really goes away.  The FDA ban covers the PGS – the advice, not the SNP data.  There are no rules that prohibit giving back sequence data sans annotation.  Those willing to do their own digging can use promethease, a free online tool for SNP analysis.  And the FDA cannot regulate promethease because it is not for sale – impersonating a doctor for money is against the rules, but giving out crap advice for free is the god-given right of cranks and yoga enthusiasts and pretty much every neighbor I have ever had.

Destroyed or not (and we shall see; I’m expecting a resurrection, minus a few of the more controversial tests like BRCA 1 and 2), the entire personal genomics industry isn’t much more than a blip (the company claimed to have scanned 500,000 people since 2006, but did not say how many were paying customers).  For a more thorough discussion of the issues involved in this case see here, but for the purposes of this column, I would make two general points about why this story was significant.  First, it indicates that the FDA is willing to play a more active role than the heretofore have in the regulation of genetic testing as a medical device.  Second, and with all deference to point one and the need for some regulatory power, the story demonstrates the essential futility of trying to control the flow of information in the internet age.

9. The Supreme Court delivers a verdict in the MYRIAD Lawsuit, bringing clarity and … myriad lawsuits.

Three years after District Court Judge Robert Sweet shocked the genetics world by declaring gene patents a “lawyers trick,” the Supreme Court weighed in, ruling unanimously that naturally occurring DNA sequences are laws of nature, and thereby striking down a number of the patents held by Myriad Genetics on BRCA 1 and 2.  In their opinion, the Court distinguishes between genes as they appear on the chromosome and cDNA, the edited form obtained by working backwards from a gene product – a transcript of the performance rather than a copy of the script, so all the notes and stage directions are missing.  The Court’s reasoning – that cDNA is not found in nature – is not entirely true, and future cases may challenge that notion, but for the moment the message is clear: DNA patents are out, and cDNA patents are in.  This splitting-the-baby approach may have been a judge’s version of a lawyer’s trick, because it invalidated gene patents, which the justices clearly felt were problematic, but did not in a single swipe eliminate all claims relating to DNA, thus wreaking havoc in biotech.

Did I say things were clear?  Well….  This was a result that satisfied the genetics community, which was never comfortable with the restrictions and costs imposed by Myriad’s decision not to license its BRCA patents.  There was celebration in the air as rival labs announced the availability of BRCA testing, or maybe that was gunfire, since Myriad immediately declared its intention to defend its remaining patents.  Here is what clarity looks like in December 2013:

Screen Shot 2013-12-20 at 11.53.24 AM

Okay.  So perhaps not entirely clear.  But the decision does resolve some theoretical issues going forward, as we put to rest whatever anxieties there might have been about negotiating a genome littered with patents in the age of next-generation sequencing.  And if not the final word, it is still an important moment in the BRCA saga, a story that has kept us entertained for years, a story that has had everything: Mary Claire King, dueling labs, Mormons, the ACLU, Clarence Thomas, even a cameo by Angelina Jolie.  It is the story of a test that single-handedly brought into being the field of clinical cancer genetics.  It is a story that defines its time, and somehow to me, this decision, this imperfect and welcome decision, feels like the end of an era.

8. North Dakota passes an anti-abortion law that is the first of it’s kind (but may not be the last).

Remember the law restricting abortion that North Dakota passed last March — no abortions after the fetal heartbeat can be detected, about the 6th week of gestation?

No, not that one.

It’s the other North Dakota law, the one that makes it illegal for a physician to provide abortion:

“with the knowledge that the pregnant woman is seeking the abortion solely: a) On account of the sex of the unborn child; or b) Because the unborn child has been diagnosed with either a genetic abnormality or a potential for a genetic abnormality.”

Sure, there are loopholes here you could drive a Mack truck through.  It requires doctors to know the woman’s state of mind.  Isn’t ambivalence the natural state of all mankind?  In practice, the law is of so little significance that North Dakota’s only abortion clinic dropped their legal challenge to ND 14-02.1-02.  The clinic, like the media, has chosen to focus on the fetal heartbeat law, which a judge has blocked pending a ruling.  But google the story, and you will see that groups like LifeNews and American United for Life are paying close attention.  “Dismissal of the portion of the lawsuit challenging the ban on sex-selection or genetic abnormality abortions should be seen as a victory, for now,” said the New American.

Take home: prenatal diagnosis is on the radar of the anti-abortion movement.  This law is not a burst of craziness or the brainchild of some random legislator in North Dakota.  It is a response to the increasing capabilities of genetic and prenatal testing, an informed, calculated, ideological response, not just to abortion but to the idea of selecting against certain fetuses.  The eugenic capabilities of prenatal screening concern large swaths of the population: push those buttons, and they will push back.

7. Sequencing, The Next Generation: Oxford Nanopore offers researchers a chance to beta test the adorable MinION.

After many years of development and a couple of false starts, Oxford Nanopore seems poised to usher in 3rd generation sequencing.  It’s nanopore technology offers longer read lengths (and thus fewer alignment and assembly issues), relatively low costs and real-time capabilities, with the potential to bringing sequencing of DNA, RNA and protein expression to the bedside.  The company did a much buzzed show-and-tell at ASHG in October, and has issued an invitation to researchers to apply for up to 50 free MinION sequencers, in a tone that veers from infomercial (“additional shipping charges” will apply) to vague (“at least two days notice will be given of closure of the registration period. This will be noted on our website and on Twitter”) to zen (“We are requesting little information about your intentions for MAP and no supplementary information is necessary”) to hard-nosed (“Competitors of Oxford Nanopore and their affiliates need not apply”).

Image

The MinION is the smaller of two Oxford Nanopore products in development, and it’s so cute if they put a brushed aluminum bezel around it they could sell it at Apple (I hear the iphone 7 is going to have gene sequencing anyway).  For data reads, it plugs in to a computer via a USB port.  A larger-capacity product, GridION, is essentially lots of little minions in a bigger box (maybe they should have called it PlantatION).  To get a sense of how the technology works, check out the video on the Oxford Nanopore website.  “Oxford Nanopore designs and manufactures bespoke nanopore structures,” says the narrator in a lovely Downton Abbey accent strikingly at odds with a technology that has been called, in that most 2013 of phrases, “disruptive.”

6. “Anonymous” gets outed.

In January, Whitehead Institute fellow Yaniv Erlich and fellow MIT hacktivists announced that they had successfully identified participants in the 1000 Genomes Project whose DNA was published “anonymously” online, using only publicly accessible databases like genealogy websites, where DNA markers are linked to surnames.  Designed to test the limits of de-identification, the project was a wake-up call for any researcher, institution or biobank who offers donors hard and fast promises of anonymity.

With proof-in-principle established by the Cambridge crew, MTV tested clinical applications with its November premiere of Generation Cryo, a reality show following a young woman conceived by donor sperm who enlists a crew of half-sibs to find their collective donor dad.  “Perhaps he doesn’t want to be found,” suggests one adult to 18-year-old Breeanna Speicher, who pauses to think about that momentarily before ignoring it entirely and rededicating herself to her quest.

Will she find him?  Chances are she’ll be knocking on his door any day now.  Why?  Because DNA is THE BEST IDENTIFIER IN THE WORLD.  Anonymous DNA is an oxymoron.  And anonymous DNA donors are an endangered species.

5. Two-year-old girl gets a trachea manufactured from her own stem cells.

Image

Fabricated organs were everywhere in 2013.  In April, a team of Japanese scientists led by Takanori Takebe announced in Nature that they had succeeded in creating tiny but functioning livers from human stem cells, able to perform basic liver functions when transplanted into mice.  In April, researchers in San Diego produced what Gizmodo called “itty-bitty livers” using a 3-D printer; later versions lasted as long as 40 days.  In August, Nature profiled researchers in Kyoto who had managed to turn murine induced pluripotent stem cells into sperm and eggs – and to prove that they were real by using them, creating viable and fertile mouse pups.

But the organogenesis story of the year concerns a real treatment for a real girl: 2-year-old Hannah Warren, born without a windpipe.  A trachea is not as complicated as a liver or as sexy as sperm and eggs, but you can’t survive without one.  So the little Korean-Canadian girl who had never lived a day outside the ICU flew to the United States to be operated on by Dr. Paolo Macchiarini, the Italian director of a Swedish Institute.  They used a windpipe grown with her own stem cells on a matrix of plastic shaped to resemble a trachea.  The parents could not afford the operation, so Children’s Hospital of Illinois donated its services. There’s a lot of messages in this story: the incredible potential of the technology, of course, and the global nature of it all.  The fact that it was possible but unaffordable says something important about the future as well.  And finally, unhappily, it must be reported that little Hannah Warren died of lung complications in July, three months after her surgery.

And that’s the final message: it may sound like magic, but this ain’t no fairy tale.

4. The Archon Prize is cancelled for lack of interest.

In 2003, proponent of gladiatorial science Craig Venter announced a contest: $500,000 for the development of technology that would bring down the cost of genome sequencing to $1000.  Subsequently re-branded as the Archon X Prize for genome sequencing, the challenge helped make ‘the $1000 genome’ a meme that represented the future of the field.  The Archon prize, after serving for a decade as goal and talking point for rival sequencing companies, was scheduled to be held as a month-long competition in September 2013, until it was abruptly cancelled in August for lack of interest.

An event that did not happen is an odd candidate for a top ten story of the year, but think about what this cancellation suggests.  First, it suggests our technological horizons have changed so rapidly that we became bored with the goal even before we reached it.  Peter Diamandis, X-Prize chief executive, acknowledged in the Huffington Post that the $1000 genome remains elusive – costs still linger closer to $5000 — but suggested that the field has moved on.  “Genome sequencing technology is plummeting in cost and increasing in speed independent of our competition.”  Second, it suggests that in 2013 our ability to produce sequence data has so outpaced our ability to process and understand sequence data that a competition to produce more of it, more cheaply, seemed suddenly like not such a good idea after all.

3. First gene silencing drug approved by the FDA.

Gene therapy and gene silencing are mirror images – turning genes on, turning genes off – and for years they have shared the burden of great potential with not much to show.  But this may be starting to change.  And although the trickle remains a trickle, gene therapy continues to show progress in clinical trials, and in January a gene silencing drug was approved for the first time by the FDA.  Called Kynamro, the drug is intended for familial hypercholesterolemia homozygotes.  In preliminary tests, it reduced LDL levels by 25%.

Raising the stakes on gene silencing, Jeanne Lawrence of UMASS published an article in Nature in July, detailing how her team was able to use the XIST gene to silence a single copy of chromosome 21 in trisomic cell lines.  The authors expressed a hope that the technique will eventually lead to treatments for features of Down Syndrome.

2. The best thing since sliced bread?  Maybe better!  CRISPR slices genomes to order.

On December 12th, researchers operating out of an assortment of low-rent facilities in Cambridge, MA published a report in Science identifying genes involved in acquired resistance to chemotherapy, the first discoveries made by systematically testing human cell lines using the miraculous new technology, CRISPR.

This powerful gene editing technique hijacks a component of the bacterial immune system – a sort of programmable warrior armed with enzymatic, DNA-snipping scissors and a list of targets written in a DNA code — snippets from viruses that attack bacteria.  The system, elucidated by Jennifer Doudna of Berkeley and Emmanuelle Charpentier of Umea University in Sweden, was re-jiggered to use as a guide an RNA molecule that could be made to order.  The result: a mechanism for cutting DNA at will throughout the genome, effectively repressing or even altering genes in a very specific and targeted fashion.

The new technique has drawn raves for its versatility and ease of use (“A total novice in my lab got it to work,” marveled Nobel Laureate Craig Mello) and has been used successfully in all five food groups of the genetics lab: yeast, bacteria, fruit flies, zebrafish and mice.  In February, George Church announced that he had used CRISPR to alter human induced pluripotent stem cells, adding: “results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.”

Potential uses for CRISPR beyond interrogation of cell lines include: development of model organisms, modeling the effects of specific genes and gene changes, somatic cell gene therapy, and new treatments for acquired diseases with genetic components such as cancer and AIDS.  And of course, as George Church points out – with an enthusiasm that may not be shared by all – as a platform for germline gene therapy and genetic enhancement of embryos.  But, I mean, besides that, it is hardly interesting at all.

Image

1. ACMG produces guidelines for reporting of incidental findings in whole genome and whole exome sequencing.

The ACMG guidelines are the genetics story of the year because both their existence and the controversy surrounding them illustrate exactly where we are today:

1. Desperately in need of guidelines, because exome and genome sequencing are a clinical reality today,

AND

2. So unready to deal with all the information that comes along with sequencing that we can’t even agree on what to call it: incidental findings; secondary findings; opportunistic findings; unanticipated news.

Here are some crib notes, without recapitulating the argument in its entirety (covered here and here, for starters).  Many people believe that access to genetic information is a right, and argue vehemently that doctors and other genetics professionals should not function as intermediaries, deciding what information is significant, what information is superfluous, and what information patients may be unable to handle or comprehend.  This is a sort of a power-to-the-people argument, wherein ‘power’ is defined as genomic information (which may be a bit of a stretch.  Jus’ saying).  The other side is concerned about the logistical and ethical complexities of giving out information which is not well enough understood – ‘well enough understood’ being one of those ill-defined metrics that, like Justice Potter Stewart’s description of obscenity, seems to come down in the end to “I know it when I see it.”

The ACMG came out somewhere in the middle, and has been soundly criticized by all sides, which I think means they must have done something right.

FOLLOW ME ON TWITTER!    here

1 Comment

Filed under Laura Hercher

Tagged as , , , , , , , , , , , , , ,

by | November 29, 2013 · 7:31 PM

THE FDA CALLS A PENALTY ON 23andMe

IS THIS THE GAME WE WANT TO PLAY?

On Monday, the FDA celebrated the start of the holiday season by sending a letter to 23andMe, informing the direct-to-consumer personal genomics service that they must cease and desist offering their signature test.  The proximal cause of this action, as described by the FDA and not disputed by the company, was that 23andMe had ceased to participate in a process of establishing their PGx test as “validated for its intended uses.”  They had, the FDA suggested, dropped the ball – well, not just dropped the ball, but kicked it out of bounds, an old soccer trick for delay of game, which Mya Thomae and Dylan Reinhardt suggest might have been exactly what the company had in mind, playing for time while they attempted to accumulate better data than what-all they have right now.

The FDA move prompted a vast twitterlanche of commentary, ranging from indignant outrage to smug satisfaction (Dietrich Stephan, founder of the erstwhile DTC competitor Navigenics, said, “Engaging the FDA as a partner to bring the most robust and safe new type of test to market is diagnostics 101”).  Genetic counselors might be suspected of indulging in a bit of schadenfreude, since the relationship between 23andMe and the GC community has inclined in the direction of mutually suspicious, if not downright frosty.   The company, which advocates for access to one’s DNA information with almost a religious fervor, sees GC’s as gatekeepers, as a self-anointed coterie of priestesses guarding the oracle at Delphi.  Genetic counselors, for their part, tend to perceive the very existence of 23andMe as an affront, as though the possibility that a subset of people might benefit from genetic testing without access to counseling was insult and injury — an existential threat.

To be fair, nobody reacts well to the suggestion that their chosen profession is a cabal that threatens the freedom and well-being of fellow citizens – not even investment bankers, and at least they get to soothe their wounded souls with lots of material goods.  But pettiness is unbecoming and unproductive, and we would all do well to remember that a groundbreaking organization like 23andme is a part of the energy and excitement of the field – an expression of an explorer’s mentality that draws people to the potential of genetics in 2013.  That’s not only fun and sort of cool but also incredibly powerful because it attracts the kind of intelligence and curiosity that makes big new ideas possible (David Dobbs does a thoughtful and balanced job making the case for 23andMe in this piece for the New Yorker).

So minus any animus toward 23andMe, was this a reasonable move by the FDA?  There are two main questions that have been raised: 1. can they regulate? and 2. should they regulate? (a third question, HOW DARE THEY?, has also gotten a lot of play but I am going to ignore that one because, c’mon guys get over yourselves this isn’t ONE STEP FROM TOTALITARIANISM).  The first one takes up the issue of whether or not a personal genomics test falls under the FDA jurisdiction.  I am going to say yes, but will not rehash those arguments here, since they have been more ably covered elsewhere – I particularly recommend this piece by Hank Greely at the Stanford Law School Center for Law and the Biosciences blog.

So, should they regulate?  The rationale for regulatory action in the letter to 23andMe is a risk of harm to customers, including the possibility that a customer might alter his medication without medical advice or misunderstand her risk for breast cancer and have an unnecessary prophylactic mastectomy.  While theoretically true, it seems wildly unlikely that very many people would insist on a mastectomy without getting more information than mail-order genetic results – and those cases might be more indicative of out-of-control anxiety issues and irresponsible medical practice than the power of a PGx report.  More commonly, misunderstanding the limits of the test in terms of risk reduction might empower a customer to skip out on appropriate preventative measures. Either way, this is nothing new — a rehash of concerns genetic counselors have had about DTC testing since its inception.  In practice, perhaps the best summary of the clinical impact to date comes from Anders Nordgren, who called it “Neither as harmful as feared by critics nor as empowering as promised by providers.”  Having spent hours poking through the generally well-written and thorough 23andMe reports, and spoken to some of their customers, I would suggest that misunderstanding the results that come from 23andMe could pose some risk — real risk, to be sure, but limited risk.

However, it is possible to envision a scenario where a genetic testing sold DTC did pose a significant danger to consumers, with inaccurate results, irresponsible advice, tests used to market scam treatments or preventatives.  None of this is farfetched, and some of it has already been documented.  For this reason alone, the possibility of FDA action is an important deterrent.  A company like 23andMe, which makes real efforts to be thoughtful and responsible, will ultimately benefit from the restraint on less scrupulous entities.  And of course, it is possible that 23andMe would have been less thoughtful and less responsible if they had not been motivated by the threat of FDA action.  So arguments against regulation in general based on the fact that 23andMe is well-intentioned are misguided.

But despite a bias in favor of showing some muscle, I have questions about how much time and energy the FDA should spend cracking down on the likes of 23andMe.  Is it, I wonder, the best use of resources?  For one thing, attempts to stop the free flow of information in 2013 are fingers in the dike. Razib Khan at Slate expands on this argument, suggesting that companies pushed by the FDA could simply move offshore, away from any regulation.

And more importantly from my point of view, the emphasis on negative action diverts us from the possibility of doing something positive.  Rather than keeping consumers away from tests we think are insufficiently documented, how about providing a resource to the general public that endorses tests that are ready for prime time?  After all, a few bold individuals may be excited at the prospect of downloading Promethease to query their own exome data but most people would rather not, thank you very much.  Most people would be happy to have some guidance.  They can get that guidance from the company, but even the classy companies have a vested interest in hyping the significance of their results – that’s what they’re selling, right?  There is an opportunity here for the government and the genetics community to create a trusted source of information that is neutral, unbiased and supports a best-case scenario use of genetic testing by those eager to take the plunge.  Hell, you could imagine tying in such a resource to something like ClinVar or GenVar, so that early adapters could contribute to publically accessible databases rather than giving it to 23andMe to sell.

After years of running up and down the pitch, the FDA has demonstrated that it knows how to blow the whistle – that’s good.  I’m pretty sure 23andMe will be back – and that’s good too.  But if we really want something great to come out of this discussion, let’s stop doing color commentary on the FDA action, and imagine what it could be like if we changed the game.

Follow me on twitter!

10 Comments

Filed under Laura Hercher

Tagged as , , , , , , , ,

by | November 27, 2013 · 11:09 PM

FDA Letter to 23andMe: A Genetic Counselor’s Breakdown

FDA letter Nov 22

On Friday, November 22 Food and Drug Administration issued a warning letter to direct-to-consumer genetic testing company 23andMe. Many in the genetics community are experiencing a little déjà-vu this week, with the ensuing discussions in mainstream media and within online communities reminiscent of 2010 when FDA issued warning letters to 5 direct-to-consumer companies that were operating at that time. (Check out this post from Genomics Law Report for a good overview of the issue at that point in time.)

Regulation of direct-to-consumer genetic testing companies is complex and often confounded by thoughts and opinions regarding DTC advertising, DTC genetic testing, the validity and clinical utility of SNP-based panels, consumer rights and privacy, to name a few. I have personally fallen into a rabbit hole of articles, blog posts and twitter discussions in the past few days (see “Recommended Reading” section below). All of these outlets are debating the same issue, but this particular issue has an infinite number of very subtle angles.

The term “direct-to-consumer” conjures up strong emotions for genetic counselors. No doubt you will see some of this played out on The DNA Exchange in the next few days. However, in discussing the most recent FDA letter with a number of people (both colleagues and non-GCs) I’ve realized some basic review and clarification might be helpful. Hopefully this will serve as a nice starting point to frame our discussions on this issue in the days to come.

The full letter can be found on the FDA website here.

The 23andMe response has been posted here.

There are two basic aspects to the FDA  letter:

1. Marketing 

In the FDA’s words “…Your company’s website markets [your test] 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….To date, 23andMe has failed to provide adequate information to support a determination that [your test] is substantially equivalent to a legally marketed predicate for any of the uses for which you are marketing it…”

My takeaway:  23andMe’s marketing materials claim their test can prevent serious diseases. The company does not have FDA clearance nor has it provided the appropriate evidence to make this blanket claim. This speaks most strongly to the clinical validity and utility of SNP-based testing—an issue that hits close to home for a lot of us. I think it is important that the FDA is highlighting the lack of evidence around prevention and predisposition testing for common disease.  However, we need to recognize that 23andMe is also testing for additional variants beyond SNPs.

Anecdotally, I’ve noticed that genetic counselors continue to use the terms “direct-to-consumer genetic testing” and “SNP-based testing” interchangeably, which is both incorrect and adds to overall confusion. Genetic testing for common complex disease (primarily based on SNP information) is still controversial in our profession. However, as noted in the letter, 23andMe is a direct-to-consumer company that is also providing carrier testing for Mendelian diseases as well as the 3 common Ashkenazi Jewish BRCA mutations. To dismiss the 23andMe service by saying “this test doesn’t tell you anything!” undermines some of the routine testing that we do within a clinical setting. One cannot argue that 23andMe’s service “doesn’t tell you anything” and “has the potential for serious harm” in the same breath.

2. Direct-to-consumer health information

In the FDA’s words: “Some of the uses for which [personal genome service] is intended are particularly concerning… 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.”

 My takeaway: 23andMe is providing health information and test results directly to consumers without the involvement of a physician. This could lead to medical mismanagement, “serious injury or death.” I believe the DTC aspect of the testing (in comparison with the SNP-based aspect) is still the biggest challenge to the 23andMe model. Genetic testing for disease causing mutations without appropriate clinical context, family history review and individualized interpretation is where real potential for harm lies.

Suggested Reading (Or, some of the more interesting articles I have come across so far)

Also, if you’re interested in learning more about FDA regulation of medical devices, I found this video on their website.

2 Comments

Filed under Allie Janson Hazell

Tagged as , , ,

by | October 16, 2013 · 11:10 AM

A SCIENCE WRITER USES HER CHILD’S 23ANDME TESTING EXPERIENCE AS A HOOK, AND CATCHES MORE THAN SHE BARGAINED FOR

Once, when out fishing for flounder, my mother caught a shark.

That story arose in my mind yesterday, as I was reading an article published in FastCompany by a science writer working under a pseudonym.  The writer (who calls herself Elizabeth, so let’s go with that) has a five-year-old daughter adopted from Ethiopia.  Her editor suggests that she do a piece 23andMe from the point of view of a mother considering testing her own little girl.  As for the decision about whether or not to test – that was up to her.

But it’s a better story if you do the test, right?  An even better story if you find out something interesting.  Which is not so likely, since the experts you contact are telling you that most of what 23andMe has to offer is not clinically significant.  A few things that are meaningful, a few things you might not want to know… but Anne Wojcicki, founder of 23andMe, says it is a parent’s duty to arm herself with her child’s genetic blueprint.  Ultimately, Elizabeth says, she finds the ‘knowledge is power’ argument persuasive.

So, anyway the kid turns out to be a ApoE 4 homozygote.  23andMe quotes a 55% chance of ApoE 4 homozygotes being diagnosed with Alzheimers between the ages of 65 and 79.

I spoke with Elizabeth while she was writing the article, but before the test results came back.  “Do you judge me for having my daughter tested,” she asked?  I said no at the time – and for the record, I stick with that.  We were talking then about privacy and confidentiality issues, and in that context I have concerns about the DTC industry in general and 23andMe in particular, but I can completely understand the desire of a mother raising her child without access to any medical or family history to get whatever information she can.  We talked about the limitations of SNP data on common disease.  This wasn’t a genetic counseling session, but I am a genetic counselor, and I am extremely regretful that I didn’t think to discuss ApoE, and perhaps urge her not to unlock that box.

Elizabeth spends the last third of the article grappling with the downstream issues that follow from that significant result.  She acknowledges difficult decisions they will face around when and if to tell the child.  “Never!” suggests a psychologist friend of mine with whom I share this story.  But in my experience information finds it’s way out, no matter how deeply buried, as if knowledge were a seed searching for the sun.  And in this case it is only shallowly interred – after all, she has shared her story in print.  The pseudonym makes it more private, but won’t the ruse – and the reason — be an open secret among her close friends and family?

Interesting to me that 23andMe publicized this story, tweeting about it yesterday morning:

Image

I would have thought this particular personal journey represented something of a worst-case scenario for them.  Judging by reactions among my friends (not very scientific, I know) it was not a great advertisement for their product.  But then, I do them a disservice to suggest that they are simply marketers.  No question, the folks at 23andMe are true believers.  Emily Drabant, a neuroscientist at 23andMe, tells Elizabeth that their database will help pharma locate people with her daughter’s geneotype who don’t get sick, so they can uncover the reasons why some people stay healthy despite their genetic predisposition.

Wherever you stand on DTC, it is easy to see Elizabeth’s story as a parable.  For enthusiasts like Wojcicki, it is a tale about embracing the power of information as a call to action and an opportunity for intervention.  For haters, it is a harbinger of exactly the type of harm they picture when they think about DTC: inappropriate testing of minors, lack of pre-test counseling (that one makes my stomach hurt), post-test distress.   For me, having planted my standard awkwardly in the muddy soil of ambivalence, I see it as further evidence that DTC is a decent option only for a select few, and should not be mistaken for a new world order.

Here is the model set forth in this article: mother tests child, discovers disturbing information, goes on a mission to find out what it means and – hopefully – how to use what she has learned to her kid’s advantage.  This makes for a lovely read (it’s actually a very good article: balanced, well-written, funny at times).  But it’s important to note that to the extent something good comes out of this, it is because Elizabeth has access to resources and information beyond the factually accurate but necessarily limited and impersonal explanation on the 23andMe website.  “Our daughter is going to get Alzheimers,” she wails to her husband, after ‘blundering past the notes of caution’ to unlock her results.  Next steps for a science writer doing a feature on 23andMe?  First, a personal conversation with Anne Wojcicki, who cancels her next appointment when she hears about the ApoE finding.  Discussions with Drabant, the neuroscientist.  Discussions with geneticist Ricki Lewis, and with Bob Green up at Harvard, who spearheaded the REVEAL study that investigated the impact of receiving ApoE results on individuals and family members.  A conversation with Jennifer Wagner, a lawyer specializing in issues related to genetics and genetic discrimination.  We cannot hypothesize that this is the experience of the average consumer.  Wojcicki and the legion of science bloggers who can’t understand why everyone doesn’t want to test their children should consider the likely experience of a parent receiving this result with no more resources than Google and a distant memory of high school biology.

Ultimately, we are informed, Elizabeth comes to terms with the good and bad of genetic testing for her child.  “I choose to think of this as a potentially beautiful new world opening up for her–but one that requires an extraordinarily thoughtful bravery from all of us.”  Even so, she notes that the “best advice” she got was to “burn that damn report and never think of it again.”  Despite the positive rhetoric, her enthusiasm for that advice suggests she learned something she would in retrospect choose not to know.  Elizabeth went fishing for flounder, and caught a shark.  At least my mother could throw her fish back.

ENJOY THIS? FOLLOW ME ON TWITTER

8 Comments

Filed under Laura Hercher

Tagged as , , , , , , ,

by | June 26, 2012 · 3:15 PM

23andMe Reveals a Snippet of it’s own DNA

You have got to feel sorry for 23andMe.

Ha!  What a funny thing for me to say.  Genetic counselors don’t feel sorry for 23andMe.  After all, they offer a service of which many of us are deeply distrustful, suspecting that for all the data they provide, all the fact-filled blurbs and fancy graphics, their outpouring of information often serves to obscure rather than to illuminate the more significant truth: that most of the time, these reports are not a valid or reliable source on which to base decisions about your health and well-being.  That their message promotes a kind of mantra of genetic determinism that complicates our job, since it creates expectations that cannot be fulfilled.  That their credibility and media presence have less to do with scientific bona fides than an intimate relationship between their founder Anne Wojcicki and Google’s Sergei Brin, which gives 23andMe access to both some very deep pockets and the reflected glory of an association with the epitome of technological wizardry.

And now they are doing research, and they don’t even have to bother with an IRB.  It’s so unfair.

But really, you should feel sorry for 23andMe.  I’m serious.

It’s not easy being them.  Think about it this way: the entire premise of the 23andMe sales pitch is that they can offer you valuable information.  Valuable how?  Well, presumably because it will SAVE YOUR LIFE, or something to that effect.  “Personalize your healthcare,” they say on the website.  “Prepare for serious diseases.”  However, at the same time, 23andMe can not say that any of this valuable information is diagnostic.  They have to be careful not even to imply that it is diagnostic, because offering diagnostic information constitutes a medical test, and medical tests are subject to a much more rigorous degree of government regulation.  If you were a company, would you care to invite a greater degree of scrutiny from the FDA?  No, you would not.

It’s a fine line they walk.  You’d have to be clear-headed and on your game to walk a line like that.  I bet those guys in corporate communications at 23andMe have to stay stone cold sober all the time.  You know that show Mad Men?  The opposite of that.

Now, a tough job gets even tougher.  Last month, 23andMe announced their first-ever patent, awarded for a method of determining an individual’s risk for Parkinson’s disease, a finding drawn from a study of 5,000+ PD patients who were offered the 23andMe genome screen virtually for free – what the company refers to as “the largest Parkinson’s community for genetic research in the world.”  This was a big day for the company, since the patent represents not only a new potential line of revenue but proof in principle for their strategy of crowd-sourced genetic research.  Given their outsider status, 23andMe was probably prepared for a certain level of pushback from the standard-bearers of academic research.  What they may not have expected was that their big day would be marred by an insurrection in the ranks – but to their apparent surprise, the announcement drew outraged responses from many 23andMe research participants. 

It turns out that many in the “Parkinson’s community” felt betrayed by the patent application, perceiving it as an unexpected move to monetize on the part of the company they believed was only interested in a cure – after all, Sergei Brin himself has revealed that he has a genetic risk for PD.  While the press releases from 23andMe emphasize the importance of the patent as not a money-maker but an inducement for other companies to use this information to develop treatments – “the patent will be important for a biotech or pharmaceutical company to pursue drug development” – the majority of the voices making themselves heard seem to find this a dubious distinction.  Admittedly, it defies logic to assume that a commercial entity would file for a patent merely so someone else could (eventually) make a profit, and in fact if we are looking for evidence of capitalistic intent, we can find it conveniently staring out at us from the informed consent that all 23andMe customers are required to sign: “If 23andMe develops intellectual property and/or commercializes products or services, directly or indirectly, based on the results of this study, you will not receive any compensation.”

So why did so many research participants feel deceived by a naked expression of commercial intent?  Well, it turns out that, once again, hard cold facts spelled out in black and white, however clearly stated, were less convincing than a fundamentally different message that was never articulated but merely implied, insinuated, forcefully and emotionally conveyed by the fundamental nature of the language used.  “Join us” they said.  “Everyone can help.”  23andMe research is billed as a community effort, “powering research breakthroughs.”  It’s like a research Wiki.   “I had assumed that 23andMe was against patenting genes and felt in total cahoots all along with you guys,” said one research participant. “If I’d known you might go that route with my data, I’m not sure I would have answered any surveys.”

Okay, so as insurrections go, this one is a bit of a tempest in a test tube.  Should we care?  Is it a problem if a small number of people who didn’t read the fine print feel misused?  C’MON PEOPLE.  You haven’t been abused.  You haven’t been robbed.  You did not sacrifice flesh or blood — just a little spit.  But the objections of the 23andMe crowd should be noted by all companies (or researchers) who want to make use of the DNA and altruism of willing donors.  It’s a very fine line you draw for yourself when you unpack those chromosomes: hard to walk, easy to trip over.  If you tell people that the genomic revolution is all about their health, and it turns out to be more about your profits, once-willing participants may be more inclined to spit at you than spit for you.  If 23andMe plans to make data mining an integral part of their revenue stream – and this patent is one pretty clear indication of their intent – then they will have to find a way to convince their target audience that this is a chimera of a company, a capitalist beast with the loving heart of a non-profit enterprise.

 

4 Comments

Filed under Laura Hercher

Tagged as , , ,