Regulation of personal genomics: what next?

(Dan Vorhaus’ comment on a previous post recaps a number of key issues discussed during Regulation Week here at Genomes Unzipped, so I’ve promoted it to be the final post of the week – and the final post, for the moment, on the regulation of the direct-to-consumer genetic testing industry. These are questions we all – and especially the FDA – need to consider carefully over the next few weeks. Next week we’ll be getting back to the science, at least until the next regulatory scuffle emerges. DM)

1) Wait and Talk. On the topic of “don’t knock it until we see it,” while I think Jeff and Kate’s point is well-taken, I would also suggest that it is incumbent upon the regulated community – which includes companies, investors, customers and even clinicians – to speak up about what does and does not make sense when it comes to a regulatory solution. The FDA’s public conversation was part of that process, but that was (a) not directed specifically at the regulation of DTC testing and (b) should mark the beginning, not the end, of the dialogue. There are still a number of options on the table, and not all of them are equal. Waiting passively for regulators to act may not be the best strategy.

2) Line-Drawing. It’s clear that whatever regulatory system emerges – and this applies to the much broader category of lab-developed tests (LDTs), as well as to DTCs – the issue that Caroline, Misha and so many others have identified is going to be one of, if not the, most difficult to solve: what counts as a medical interpretation worthy of heightened regulatory scrutiny?

Regulating all genomic interpretations is incompatible with providing broad access to genomic information, since only a handful of people can interpret the raw data on their own (and I’m certainly not one of them). But determining where to draw that line, particularly given the interconnectedness of gene-trait associations and the rapid rate of change in the science (both discussed in this comments thread), is going to be fiendishly difficult. The key will be to come up with some standard-setting body that strikes the proper balance between involving stakeholders (this is an issue that should not be determined by the FDA – or any other agency – acting on its own) and minimizing the number of voices so that the body is nimble enough to respond to changes in the science. I’m not sure there are any perfect solutions here.

2a) Useful to Whom? A sub-point here is whether that line-drawing incorporates (i) analytical validity, (ii) clinical validity and/or (iii) clinical utility. I think that there is widespread agreement on (i), a general agreement that (ii) is important, although no clear agreement on how to assess it, and very little agreement about whether (iii) is appropriate. The issue of clinical utility gets at one of the core tensions here: is my genomic information useful when I say it is useful, or only when my doctor (or some standard-setting body) says it is useful?

3) What is special about DTC? When it comes to the regulation of DTC genetic tests – as a subset of all other genetic tests – I think we (and regulators) need to be much clearer than at present in explaining where, exactly, the concern lies. Is it that individuals are being misled by untrustworthy businesses? If so, then the Federal Trade Commission (or possibly the FDA acting in a similar role; the Genomics and Personalized Medicine Act would have the two agencies work together) has a clear role to play. Is it that genetic tests are not appropriately evaluated beyond analytical validity? If so, then it’s not clear that DTC tests should be regulated differently than the broader category of LDTs. Or is that individuals cannot be trusted to appropriately handle certain types of genetic information and interpretations? If so, then it may be that certain types of information simply cannot be presented directly to consumers, although then we return immediately to the line-drawing problem discussed above.

It is insufficient to know that the FDA intends to regulate DTC genetic tests (as they clearly do); what is needed is a clearer explanation as to whether, why and how DTC genetic tests are to be regulated differently from other types of tests.

4) Transparency First. Finally, I can only echo Daniel’s comment that, no matter what, there is a need for greater transparency. By this I think we both mean a more proactive approach to data collection (i.e., what genetic tests are available, how they are marketed, how they are used by individuals and what impact – positive or negative – they have on end users, both with respect to and apart from influencing medical decisions) and greater regulatory openness. Without such transparency it is difficult to see how any government entity can expect to craft a regulatory framework that strikes the proper balance between the protection of the public and the preservation of innovation and long-term growth in the area of genetic testing and personalized medicine.

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15 Responses to “Regulation of personal genomics: what next?”

  • “Or is that individuals cannot be trusted to appropriately handle certain types of genetic information and interpretations?”

    I’ve been holding back to allow someone from the Land of Liberty to enjoy themselves with this one, but given the silence I will point out that people cannot be trusted with the vote – they have voted in fools. They cannot be trusted with liberty. Some become criminals. Obviously we all need to be kept under lock and key for our own good. The only problem is – who can be trusted with the key? Or perhaps more pressingly, who can be trusted to feed us in our confinement? Is it just me, or is there a problem here?

  • Dan is almost certainly right that there is no perfect way to ‘draw the line’ however I’d suggest that those interested in enabling access to genome information should be motivated to propose and debate alternative strategies, and in so doing shape the debate. To my mind, an important metric to compare different ‘lines’ could be how the potential to do harm differs between alternatives. GNZ could be a great forum to kickstart the debate – lots of engaged experts from different backgrounds. To kick things off (and possibly to get a kicking) how about:

    Any interpretation that reports an increased risk of greater than five-fold for any disease with an ICD10 code.

    This would include both single variant and multilocus predictive models.

    It is easy to criticise, but proposing better alternatives might be more constructive.

    One potential problem: could a customer infer that they have a high risk genotype by omission, in other words if you know the standard format of the report and you don’t see a prediction for disease X should you be worried?

  • Vincent Plagnol

    I guess to make this proposal work, you will need to bar from the customer’s report any variant that can generate that sort of increase in risk.

    But while your “line” seems relatively sound to me, it will be very difficult to implement in practice. By not reporting BRCA risk for example you encourage other web sites located in remote and unregulated locations to take on that job. And they might do an horrible job at it. It reminds me a bit of the debate about legalizing drugs: it could be that by making them legal, you have a better chance of controlling them. Perhaps preventing customers to know their BRCA status can lead them toward less regulated and more dangerous locations to get the answers they need.

    Thinking ahead, things will probably only get worse when customers will start sequencing tumor tissues: in these cases there might be very strong markers of survival rate. And customers will go wherever it takes to get the answers they are looking for. So forbidding these “high risk” interpretations will be incredibly difficult to implement.

  • @ Matt Hurles – I take it that you are interpreting “the potential to do harm” as “people may be upset”. That is indeed a very real possibility, that both 23andMe and deCODEme are well aware of. It is approached in various ways.

    1) Self-selection tier one. Customers are self-selected. Some of my family simply would not want to know their health risks and decided against testing by 23andMe. They understand themselves best. They know if they would be inclined to brood over risks. Those whose curiosity outweighs such concerns are likely to be customers.

    2) Self-selection tier two. Some customers are only interested in the use of genetic testing in ancestry search. (Conversely of course there will be people with no interest in the ancestry side.) 23andMe responded by creating separate packages for ancestry and health, so allowing customers to have the choice not to view health risks.

    3) Self-selection tier three. 23andMe issues warnings at the outset about the possibility of customers been upset, and keeps selected reports locked for all customers unless the customer elects to open them. These reports are not selected on individual level of risk, but because the diseases concerned are deemed particularly distressing. DeCODE locks all reports and requires the customer to elect to open each one.

  • Vincent,
    I wasn’t suggesting to remove variants that might be used to estimate a risk greater than the regulatory threshold. I don’t think is workable, the list of proscribed variants would change as predictive models improve. Also, I don’t think it accords with the underlying rationale, which is to regulate interpretation rather than data generation.

    I think that with this this regulatory threshold we are drawing a line above which a company wanting to make money from providing genomic interpretation direct to a consumer would have to adhere to a stricter regulatory regime. We need to separate data generation from interpretation. It is entirely feasible that company A may generate data and company B will interpret it – it just hasn’t been the predominant model up to now.

    I don’t think the illegal drug analogy works. Regulation is not making something illegal, it is simply providing rules for legal practice. It allows companies not adhering to the rules to be shut down.

    I think there will inevitably be websites that provide genome annotation free-of-charge, and that some will be better than others. It is not clear to me that this is something that regulation can tackle. There is probably a free speech issue here. Presumably there is no legal restriction on putting up a website saying that if your blood cholesterol is above X then you’re going to die in a car accident in the next 10 minutes, or if your height is more than Y then you’re risk of T2D is increased 100-fold.

  • Vincent Plagnol


    I do not disagree with you. What I was trying to say is that genome data is just data, it can be uploaded and interpreted anywhere once it has been generated. If the regulations on interpretation are too strict so that costs increase too much (either in terms of money or delay between scientific discovery and clinical tests) other unregulated websites will provide a cheap and low quality service and people will, unfortunately, use these.

    It seems to me that any regulation for genetic testing, and in particular where we draw the line between medically relevant or not, should be defined not only by what we think is the right thing to do, but also by what is practical. And this completely free internet market for data will probably bring the regulation bar lower than we all expect (or make regulation irrelevant). But I may be wrong about it.

  • @Vincent,
    ah yes. The whole back alley genome interpretations.

    1. The scientific and medical community should point them out, much the way Daniel and I have on our blogs.
    2. The Press can follow suit and shine light down those dark alleys
    3. Countries that house the companies can call investigations if indeed there interp. Is B.S.
    4. The first 3 sound exactly like what has went down in DTCG land already.

    Now who is buying the tests?

    This while thing is about trust. We are not talking about street junkies looking to get a fix. Nor pregnant women looking to abort a baby. This is not that, however what we are talking about today is likely to be different than ten years from now. Predictions and choices based on interpretation will likely be much more important then. Which is why we have the gravitas today.

    There may be a sliding scale here today, but that scale may change tomorrow. Ok to get 9p21.3 today, but not 3 years from now? Maybe.

    The bet some DTCG are making is that they can try to create a craze again. “get it before you have to go to one of those horrible doctors who want to hide all your medical secrets from you!”

    “F’ Da Man!”

    stupid and sophomoric.

    The real engagement here should be this.

    Is this a call related to medical or not?
    If medical, regulate as such.
    If not, regulate as not.

  • Or to put it another way, this is a simple demarcation dispute, with the medical profession attempting to defend its vested interests against the encroachment of the pure scientists/medical researchers and consumer rights to access their own genomic data.

  • This issue is part of a much larger picture. The US economy is crippled by staggeringly high healthcare costs, and yet the US ranked only 37 on The World Health Organization’s ranking of the world’s health systems in 2000.

    Many observers agree that prevention is better than cure. To have individuals look after themselves, stay healthy and in work would be a huge boost to the nation’s economy in every way. So why does this not happen? Obviously people are reluctant to give up instant pleasure for long-term advantage.

    But another problem is that the medical profession makes no money out of healthy people. Shifting the focus from care to prevention is liable to involve fighting all the way against a conservative profession, as outlined in the excellent lecture I mentioned in comment on an earlier thread: Leroy Hood, MD, Institute for Systems Biology: P4 Medicine (Predictive, Personalized, Preventive, & Participatory): Catalyzing a Revolution from Reactive to Proactive Medicine:

  • Steve,

    so how would you define what is medical and what is not:

    Any OR with any ICD10 code? Or do you permit a little recreational (and educational) genetics on ICD10 codes as long as the ORs are akin to that one might commonly know from one’s (say) BMI, age, and sex?

  • Dr. Murphy

    Does your hospital give patients their health record? My hospital does not, for fear that they will poke around, find a mistake, and sue us. In today’s litigious climate this is not an invalid fear.

    There also seems to be a consensus here that it is legal to provide patients with raw data but not with interpretation. Before going down this path too far, has the Food and Drug Administration actually been quoted on this? The results of a lab test are close to raw data, after all, yet lab tests are also now being regulated by the FDA, to the chagrin of our laboratory director.

  • @Matt,
    It Depends…….

    @Dr. Kent,
    Patients have a right to their records and can formally request them at Yale, Norwalk and Greenwich where I am. They should be able to have these records. At least all the lab tests and scans are commented on by physicians/clinicians prior to them having the results. I agree that this is a risky business and am a big proponent of reforming malpractice law.

  • @Steve

    “it depends” means that you accept that some ORs on some ICD10 codes under some circumstances are effectively ‘non-medical’.

    What are those circumstances?

    It would help me (and possibly others) to understand your perspective better.

  • For definitions of medicine, just put “define: Medicine” into Google.

    Medicine is an applied science, devoted to preventing or alleviating or curing diseases and injuries. Genetic testing could be considered an addition to the doctor’s toolbox. But that does not turn genetics (a pure science) into medicine. The dividing lines between pure and applied are often blurred, since one and the same person can have both a medical degree and a research degree in medical science.

    For the purposes of this thread, the point at issue is whether a test which (for example) indicates that a couple has a 1-in-4 chance of a child with sickle-cell anaemia is actually diagnostic. It does not diagnose that either of the couple is actually ill and needs treatment. It is a prediction that most people would place in the realm of genetic counselling, rather than medicine per se. According to Wikipedia, a genetic counselor is a medical genetics expert with a Master of Science degree. In the Unites States they are certified by the American Board of Genetic Counseling.

  • @Matt
    My tongue in cheek response was to make fun at the definition of disease/medicine. The ICD10 is done to help classify diseases for public health and insurers, not for physicians. There are many disease states missing from these “systems”

    Odds Ratios have nothing to do with disease or pre-disease IMHO. They are just a statistical artifact….

    I assume the IOM and NIH plus FDA will come out and decide on this stuff. FDA is already looking at a panel to eval calls, I am sure the same thing will be done with what is disease…..

    My litmus is this. Does it affect well-being? In any way, be it molecularly or anatomically or physiologically or psychologically. That is a disease state.

    BRCA mutations affect DNA repair, carriers of CF can have associated disease. Sickle carriers have been reported to have problems, 2C19 mutants have problems metabolizing medications, 9p21.3….maybe, ARMD SNPs absolutely, this is the problem, the more we know, the less we are sure. But in these cases, clearly there is justification to regulate as medicine.

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