DTC Genetic Testing and the FDA: is there an end in sight to the regulatory uncertainty?

Disclaimer: Genomes Unzipped received 12 free kits from Lumigenix for review purposes, and Dan Vorhaus has provided legal advice to the company. We plan to release a full review of the Lumigenix service in early July.

Last month three direct-to-consumer (DTC) genetic testing companies opened their mailboxes to find a slightly ominous but entirely expected letter from the FDA. The three recipients (LumigenixAmerican International Biotechnology Services and Precision Quality DNA) received substantively equivalent letters, with the FDA warning each company that its genetic testing service “appears to meet the definition of a device as that term is defined in section 201(h) of the Federal Food Drug and Cosmetic Act,” and that the agency would like to meet with company representatives “to discuss whether the service [they] are promoting requires review by FDA and what information [they] would need to submit in order for [their] product to be legally marketed.”

Translated from bureaucratese, that means that the FDA views these services as ones that may need to be formally reviewed by the agency and either approved or cleared before they can be legally sold. The FDA letter asks each company to describe its service and to explain either (1) why it does not require FDA approval or (2) how the company plans to pursue such approval.

This is a strategy that the FDA has pursued with a growing cadre of DTC service providers. These letters (currently 23 and counting1) represent the only public and company-specific actions the agency has taken to date with respect to DTC genetic testing. While many DTC letter recipients are engaged in dialogue with the FDA, those conversations have occurred beyond the public’s view. Until now.

Ending the regulation guessing game? For more than a year, the FDA has dealt with DTC genetic testing providers by mailing (and publishing) an initial letter followed by the initiation of a private dialogue and a company-specific regulatory determination. The agency has yet to publish, or even to propose, anything resembling industry-wide regulatory guidance for current or prospective personal genomics companies.

For their part, personal genomics companies have been reluctant to publicly disclose the nature of their conversations with the FDA. Recently, however, a new approach appears to be emerging, at least on the company side.

Last month, a recent DTC letter recipient (Precision Quality DNA) published a strongly worded response to the FDA on its website. Another letter recipient, Lumigenix, soon followed suit, launching a new corporate blog with the publication of its own more measured response to the agency. Each company undoubtedly has its own reasons for bucking the prevailing trend and choosing to take its conversation with the FDA into the public square. There should be little doubt, however, that the FDA’s current company-by-company approach to personal genomics regulation, which has left the industry with a considerable measure of uncertainty, was a major contributing factor in each decision. As Dan and his colleague Allain Andry noted last summer, the effects of that regulatory uncertainty can be substantial.

They include:

  • Reduced access to capital. Genetic testing companies may find that investors are more cautious about making new and add-on investments.
  • Fewer new products. Companies may delay plans to introduce new products both because of lack of funds and concern about the regulatory response to innovative products or business models.
  • Fewer entrants. Numerous investors, and companies in related industries, have been preparing to enter into the genetic testing field. Many of those plans may be put on hold.
  • Litigation risks. The well-publicized GAO report and Congressional hearings, which highlighted apparent operational deficiencies of some DTC companies, could lead to tort (e.g., negligence, emotional distress, malpractice), securities or other lawsuits from plaintiffs’ lawyers and litigious customers. Although the GAO report and Congressional investigation focused on DTC genetic tests, the broad and negative public attention focused on genetic testing could spur similar litigation against more traditional genetic testing developers and providers.
  • Reduced access to technology. Companies dependent on third-party providers for some portion of their own test or business might find their options limited if regulatory uncertainty or changes discourage such collaborations.
  • Encouraging overseas development. Increased regulation – or even the possibility of increased regulation – may encourage companies and investors to focus on developing new products and businesses overseas in advance of, or instead of in, the United States, with potentially detrimental consequences for patients and consumers in this country.

Current and prospective DTC genetic testing providers alike are no doubt burdened by some or all of these challenges. Lumigenix, in particular, appears hopeful that a more public DTC discussion might help to lessen the effects of regulatory uncertainty, noting at several points in its response to the FDA the company’s desire to work with the agency to develop “a clear and reasonable system of oversight for the emerging field of personal genomics.”

The challenge of “clinical” DTC claims. Perhaps the greatest area of current DTC regulatory uncertainty concerns the ability of companies to provide interpretations of personal genomic data with potential clinical or medical significance. The FDA has consistently maintained that its regulatory interest lies first and foremost with clinical genetic tests, with a test’s intended use determining whether it qualifies as clinical.

The FDA’s emphasis on clinical genetic testing has presented personal genomics companies with a dilemma: offer medically relevant personal genomic results in response to consumer demand and thereby risk stricter scrutiny from regulators, or attempt to cater to regulators (but risk losing customers) by removing or deemphasizing results that could be construed as clinical.

Personal genomics companies have deployed a variety of solutions in response to this dilemma. 23andMe, for instance, has simply braved regulatory ire by continuing to offer tests for the BRCA breast cancer risk variants, pharmacogenomic response and other serious disease mutations. Pathway Genomics responded to its own FDA letter by promptly eliminating the ability of consumers to purchase its product without physician involvement. Carrier testing company Counsyl avoided a letter entirely by dropping DTC marketing as soon as the FDA began to make serious regulatory overtures.

Lumigenix, for its part, has thus far taken an intermediate approach, steering clear of reporting on variants with unambiguous clinical relevance while maintaining DTC access to its service. In its response to the FDA, Lumigenix emphasizes that the company “strongly believes that individuals should have the right to access their own genetic information,” but explains that Lumigenix has opted to exclude certain information from its current service to avoid any clinical confusion:

In order to ensure there is no doubt about the educational purpose of our service, Lumigenix’s current service intentionally excludes certain categories of genetic tests. For that reason, Lumigenix’s does not currently include in its customers’ genomic reports results from genotype data known to be associated with or to indicate:

  • carrier status for a recessive disease (e.g., Cystic Fibrosis or Tay-Sachs disease);
  • pharmacogenomic status related to an individual’s likely response to certain medications (e.g., Warfarin or Clopidogrel); or
  • a serious or untreatable illnesses with a large genetic component (e.g., breast cancer, Huntington’s disease or Alzheimer’s

We understand that some individuals desire such results for their informational value. But we also acknowledge that the risks associated with personal genomics, including the risk that an individual will make an important medical or other decision without first consulting a healthcare professional, are not equal across all categories of genetic tests.

For that reason, Lumigenix has decided to focus its current service on providing personalized genetic information pertaining to genetic ancestry, non-medical traits and conditions, and certain relatively common medical- or health-related conditions that tend to be influenced by many genes and include a substantial environmental component.

It’s worth noting that Lumigenix is still early in its conversation with the FDA and has not yet had the same length of time to respond (e.g., in the form of modifications to its service or business model) as earlier DTC letter recipients, including 23andMe and Pathway Genomics. Lumigenix’s response does, however, hint that changes may be in store: the company applies the adjective “current” in describing its service eight separate times in its response to the FDA.

The range of approaches taken by personal genomics companies on this issue alone reflects a much broader uncertainty about the industry’s regulatory future in the hands of the FDA. The agency’s reluctance to publicly pursue a comprehensive personal genomics regulatory framework is understandable, particularly in light of the rapid pace of scientific and technological innovation and the paucity of data about DTC genetic tests and their affect on consumer behavior. Still, for so long as the FDA continues with its current private, company-by-company regulatory approach, personal genomics innovation and investment are likely to remain hampered by uncertainty.

A glimpse into the regulatory future. Interestingly, despite Lumigenix’s focus on non-medical data as part of the formal interpretations it provides to its customers, the raw data generated by the company’s genome-wide test contains plenty of medically relevant genetic variants. For example, there are at least 196 sites on the chip that match the position and sequence of known Mendelian disease mutations, including 12 in the BRCA1/2 genes and 6 in the cystic fibrosis gene CFTR2. Lumigenix simply does not report on or interpret these variants, although customers can choose to explore those variants on their own, including through the use of free software such as SNPedia’s Promethease.

This approach to medically relevant personal genomic data, at first blush needlessly confusing and inefficient, is unsurprising in light of the FDA’s insistence that their regulatory target is not genomic data but the claims – particularly clinical or medical claims – made on the basis of those data. Last August, for example, reporter Mary Carmichael and Dr. Elizabeth Mansfield, Director of Personalized Medicine for the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), had the following exchange:

[MC]: I want to move on to whether the issue with direct-to-consumer is actually providing data to people, or is it the interpretation algorithms these companies are using? So, would a company need to be approved just to provide a raw SNP list to people?
EM: They would if they made medical claims about that data. If they don’t make any medical claims about that data, then they’re free to provide information as far as we’re concerned.

Over the past year, nothing has happened that would suggest that the FDA has revised its policy on this point. This bodes well for both DTC companies and their customers because, barring a striking reversal by the FDA, high-quality personal genomic data appears likely to remain readily available, including via direct-to-consumer channels. Whatever else the FDA may have in store for the personal genomics industry, the availability of raw genomic data should enable DTC companies to remain on the market in some form.

Still, the increasing availability of raw personal genomic data will itself soon pose a challenge for the FDA. Already widely accessible and inexpensive, personal genomic data will soon transition from SNP chips to whole-genome sequences. As data proliferates alongside increasingly numerous and sophisticated publicly available software tools (like PrometheaseSNPTips and Interpretome, the topic of a recent post) used to mine those data, the FDA will find that focusing on all-inclusive providers of DTC personal genomics services is insufficient. As the separation of testing (genomic data generation) from interpretation (genomic data analysis) accelerates, the FDA will be faced with a growing array of personal genomics service providers, many of whom are likely to provide software-only tools and will see no pressing need to operate from within the United States (and within easy reach of the FDA).

How the agency responds to the inevitable expansion and diversification of the personal genomics industry – e.g., with an expanded letter-writing campaign or a concerted effort to develop flexible and forward-looking industry guidance – remains to be seen.


1. The count: Pathway Genomics (May 2010); 23andMe, Navigenics, Knome, deCODE Genetics, Illumina (June 2010); Graceful Earth, SeqWright DNA Technology Services, Interleukin Genetics, DNATraits, CyGene Direct, Consumer Genetics, Matrix Genomics, The Genetic Testing Laboratories, Sequenom, EnteroLab Reference Laboratory, BioMarker Pharmaceuticals, DNA Dimensions, HealthCheckUSA, easy DNA (July 2010); Lumigenix, Precision Quality DNA, American International Biotechnology Services (May 2011).
2. Analysis by DM: I looked at the overlap between the SNPs included in my raw data from Lumigenix (available for download here) and the disease mutations in the full version of the Human Gene Mutation Database (available only via an academic collaboration or a license fee, unfortunately). I counted positions where both the position and both alleles matched. Note that this approach won’t detect disease-causing insertions and deletions, only SNPs.

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10 Responses to “DTC Genetic Testing and the FDA: is there an end in sight to the regulatory uncertainty?”

  • Dan,

    Great post. Very interesting to get a glimpse behind the veil, however partial. So what is the law behind interpretive services? Seems like return of raw data, or at least identified variations from a standard reference sequence (if we can agree on one) should become an industry norm, demanded by consumers, patients, research participants and anyone else getting genomic analysis that will provide data needing to be reinterpreted over the course of one’s life. That means regulating the test will be for accuracy of sequence data, but interpretation likely to be a series of subsequent steps spread out over time. Does not seem like a clean fit to FDA statutory authority, but I don’t know this area of law.

  • Margaret Hamburg

    FDA has been silent here because there is major turmoil within CDRH, and if you talk to folks in DC there are strong doubts that Shuren will finish out the year.

    In the meantime it’s a very smart move by Lumigenix and PQDNA to keep this battle public. Mansfield and Gutierrez prefer to try to intimidate companies in conference rooms after softening them up with a surprise attack press release. But last summer they almost fired Erica Jefferson, their press flack, after that devastating Newsweek interview where their backroom attempt to put the screws on Illumina and stop it from supplying to 23andMe was leaked.

    Mansfield and Gutierrez literally approached Illumina and said “you have ambitions of being a player in the diagnostics market. we have no actual authority here, but we are ‘requesting’ that you cut off your supply of chips and reagents to 23andMe.”

    In other words, “nice diagnostics company, shame if something happened to it”. If the FDA has control over even part of your business, you are forced to abide by their “requests” about other parts of your business, even if they have no authority over it.

    The equation is very simple. The FDa wants to portray itself as a force of nature and these innovative companies as the bad guys. In this the FDA will be abetted by collaborators and fellow travellers like Stuart Hogarth and Mya Thomae, who are directly enriched by government action.

    The primary way to fight back is to point out over and over again that this is not an *FDA* policy, but the attempt of a specific group of four rogue bureaucrats within the agency (Elizabeth Mansfield, Courtney Harper, Alberto Gutierrez, and Jeffrey Shuren) to build a legacy for themselves. They want to get a paragraph on the FDA’s about page like Frances Kelsey, congratulating them for making CDRH the sole regulatory authority over the human genome.

    Might seem irrational, this kind of status game. But winning a permanent increase in budget is the currency in their realm, just like first author papers are the currency for academics and A1 clips are the currency for reporters.

    Bottom line: this is not an “FDA” initiative. Few people within the agency were prepared for this degree of backlash or the public burning in effigy that Shuren received in March on Youtube. They are scared that Shuren’s attempt to expand authority has actually painted a target on CDRH’s back for budget cuts.

    The sooner that Lumigenix, Andre, 23andMe, and Pathway understand this the better. They and their customers should contact their representatives with only one demand: Jeffrey Shuren is a rogue bureaucrat, who perjured himself before Congress on a videotape seen by 5000 people…in an attempt to destroy a fledgling industry on behalf of his “traditional manufacturers”. He must be forced to resign.

  • @Robert

    as far as i know there is no specific regulation on the interpretation. I think it is also going to be hard to write one. Now for example, in California and New York State some companies cannot sell genetic tests – I wonder if the same ban would apply if they were selling an interpretation service to a customer who already had his/her results. I suppose that would be impossible to enforce anyway. The Interpetome (free) service mentioned above uses your genetic data, but it processes it on your computer, there is no data upload to the Interpretome service. How could a New Yorker be banned from going to that site?

    When it does become predominantly an interpretive service it will in some ways resemble other healthcare sites like WedMD, Medscape, Mayo Clinic etc, some are public funded, some are for profit – but they all give actual medical advice. Some of it is even personal medical advice based on genetics or results from risk factor algorithms that they host. Genetic results become just another form of biomarker – which is sensible, they don’t act alone

    Any sort of regulation will be difficult – a popular view from this site and others is that getting transparecny right is a more urgent issue

  • GenomeWeb reported on this paper last week:

    Deploying whole genome sequencing in clinical practice and public health: Meeting the challenge one bin at a time
    Berg, Jonathan S.; Khoury, Muin J.; Evans, James P.
    Genetics in Medicine. 13(6):499-504, June 2011.
    doi: 10.1097/GIM.0b013e318220aaba


    Like most people, I guess, I can’t see the paper itself, but the report, and Q&A with the first author, says that it:

    outlined a binning scheme for classifying variants that are found incidentally during the process [whole-genome sequencing] in order to decide which ones to report back the patient.

    Go read the whole thing, but one highlight is that Jonathan Berg goes on to say:

    The binning idea came from Jim Evans, my colleague and co-author on this paper, and the bins are really defined by the clinical utility of the information. If the finding of abnormalities in this gene is clinically actionable, it would be bin 1. If the variants are clinically valid, and clinically useful, but not something that you necessarily have to act upon, they would be in bin 2. If they are things that we absolutely have no idea how to interpret, they would be bin 3.

    and he further divides bin 2 into:

    These are things that we have some clinical validity and scientific evidence behind but that don’t necessarily evoke an actionable response clinically. We separated these into three categories. They are essentially based on the risk of knowledge, the risk of learning something in those bins. For example, the bin 2A category are pharmacogenomic markers and GWAS-type risk SNPs, the types of things you would find in many of the direct-to-consumer profiling studies; they clearly are not causing a lot of anxiety for people to learn about them, and they don’t necessarily have a lot of clinical utility yet because we really don’t know how to combine risks into any sensible risk calculation yet. Even if you did believe that a combination of SNPs increased your risk for diabetes two-fold, there are no clear guidelines that we would want to do anything different than what we already recommend, in terms of living a healthy lifestyle and other recommendations. Those types of things we view as having personal utility, but we don’t feel like they would be clinically actionable yet. There is room to move between these categories, clearly.

    Bin 2B are other Mendelian disorders for which we don’t necessarily have a treatment but that are not terribly horrifying diseases and might be useful to know about. You might consider carrier status for recessive conditions in that category, that people who are of reproductive age might be interested in. We put APOE4 allele status in that category, too, partly because it’s a bit more predictive than many of the GWAS risk alleles, and it’s a little bit more risky knowledge to have in terms of a person’s possibility of life insurance discrimination or long-term care insurance discrimination. So it’s a little bit more risky information that we would think as genetics professionals that people ought to think carefully about before deciding to learn that information, for example.

    And then the third category within bin 2, bin 2C, are what we consider to be the very, very small number of conditions where learning that you are going to be affected with that condition could be utterly devastating. The examples would be things like Huntington’s disease, the prion disorders, and early forms of dementia and neurodegenerative conditions — conditions where we really don’t have anything to offer in terms of therapy, prevention, or delaying onset. There is clear evidence from the clinical genetics literature that people who have a family history of those conditions often choose not to learn if they are at risk. And so if people would make a rational decision not to learn that information, then we think that it ought to be in that sort of protected category, where in order to gain access to that information, you really ought to get specialized counseling about what that information might mean to you.

    My view, is that this same binning process could be applied to GWAS results such as you’d purchase from 23andMe.

  • Dan, Daniel and Luke: We all want to see evidence of the harms and benefits of DTC testing before proclaiming them to be true. So too would I like to see evidence that a Congressional hearing and some FDA action(and inaction) has led to the vast harms you cite (reduced access to capital for DTC companies, fewer new products, fewer entrants, litigation risks, reduced access to technology, and encouragement of overseas development). Show me the data. Employing the old threatening tropes of “decreased access, fewer great new products, discouraged innovation” that big Pharma unfurls every time a piece of pill-related regulation seems unnecessary. Attributing all of these harms to FDA’s DTC work to date seems unwarranted without some direct evidence.

    Don’t get me wrong, my layman’s view is that the FDA process has been confusing, lacks transparency, and may or may not be leading where we want to go.

    However, I see a lot of assumptions being made in your post. For example, you mention that “High-quality personal genomic data appears likely to remain readily available”. What metrics are you using to judge which of these various companies’ data are high in quality? Who creates the metrics? Who is doing the measuring? Nobody? Assuming such measures exist, should companies that are not delivering high quality data be asked any questions? I guess my point is just because the FDA is not doing a great job does not mean there is no job to do. I know that is no revelation to you, but I think this post of yours is heavy-handed.

  • @Dave

    In terms of the raw accuray, we’ve actually done quite a bit of work using multi-way call anaylses (using data from deCODEme, 23andMe v2 and v3, and lumigenix), and information from different family members, to get a pretty good handle on the error rates for these companies. This is why I’m very confident in stating that the raw data is of high quality.

    But I see your point that this sort of data not being readily available to everyone. That is why we support efforts such as the NIH’s Genetic Test Registry (and possibly even a mandatory version of that), that makes sure that there is full transparancy about what DTC tests can and cannot do, in terms of establish metrics of accuracy and predictive power.

  • Dave: do you seriously propose that last July’s spectacle did not result in decreased access to capital? Go try to raise a round while stating that the FDA might call a reporter at anytime to tell them your business is suddenly illegal.

    I guarantee you have never raised VC or run a business in your life; your insouciance on this matter is matched only by your ignorance.

    For his actions last May Gutierrez should be clapped in irons. Not even a guidance, let alone an NPRM was issued. It was completely lawless. He was making it up as he went along. A man who had never stood for election threatened startups and multibillion dollar companies alike with federal sanction unless they followed his invisible guidelines, guidelines which he himself could not articulate when asked.

  • John: Your righteous indignation has been duly noted.

    Nowhere did I write that the FDA’s actions have not affected the industry. The font may be hard to read from high atop your horse- but what I said is that these broad claims about the FDA as the source of all industry’s woes are unwarranted, in my mind, until someone produces some systematically collected data to that effect.

    You are right, I am ignorant about how exactly DTC companies have faltered as a direct result of the FDA actions to date. Hence my call for some unbiased data. I did not say the data do not exist- I have not seen it, and would very much like to.

    I do not think insouciant means what you think it means, as I am neither casual nor apathetic about these issues. I strongly believe in careful unbiased analysis of facts before I accept the types of broad assertions made above. I say the same thing about the assertions that DTC testing will be harmful to customers.

  • Hence my call for some unbiased data

    The sad thing is that collecting this data means allowing regulators to randomly kill companies until there is a sufficient body count of broken startups to claim statistical significance.

    But if you are genuinely a seeker of truth, you should check out this study:


    and this one:


    …of course, Shuren’s FDA selectively ignores any studies that don’t ultimately serve to increase its budget.

  • Dave –

    Thanks for the comment. As you say, any claim – whether the dangers of DTC genetic test or the harm inflicted by an uncertain DTC regulatory policy – would be more persuasive if backed by data. Unfortunately, as you well know, certain types of data are easier to gather and publish than others.

    Thankfully, you (and others) are working on gather data describing how individuals understand and respond to DTC genetic tests. As for data demonstrating or disproving the effects of regulatory uncertainty, I’m not a researcher but I presume somebody could attempt to compile data by speaking with DTC investors, entrepreneurs and executives. However, that population strikes me as significantly smaller, less easily identifiable and (likely) less willing to candidly answer a survey than the population of DTC customers.

    That said, I can tell you, from my own experience, that I have observed multiple situations in which one or more of the effects of regulatory uncertainty we describe above have adversely impacted an existing or contemplated DTC genetic testing company. Unfortunately, those examples generally implicate confidential information, which means I cannot share them with you (or other readers) with the desired degree of specificity.

    We can also extrapolate from other areas, e.g., medical device innovation, where regulatory uncertainty and stringency has been accused of being a key factor in raising the cost to develop new devices and driving companies and products overseas, with at least some data to support those claims.

    Ultimately, I agree with you: more and better data would be helpful across the DTC regulatory conversation, including with respect to the effects (harmful, positive or otherwise) of the FDA’s current approach. If you have suggestions for how to collect this data I know that I, and I’m sure Daniel, Luke and others, would be excited to hear them.

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