What Five FDA Letters Mean for the Future of DTC Genetic Testing

The FDA has published online letters sent to five personal genomics companies – 23andMe, Navigenics, deCODE Genetics, Knome and Illumina – informing the companies that they are manufacturing and selling medical devices without appropriate FDA premarket review and approval. No surprise that the news that the FDA has sent out letters to some of the most well-known providers of DTC genetic testing products is already making waves. (Daniel MacArthur was the first to point me to the AP story, and Mary Carmichael of Newsweek and Andrew Pollack of The New York Times were among the first to dive into the substance of the letters.)

Below, we will discuss the immediate and long-term implications of the FDA’s most recent regulatory actions for the five companies receiving letters, as well as for the DTC genetic testing industry. First, however, a review of the letters themselves is required. Each of the five two-page letters is signed by Alberto Gutierrez, Director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), and follows a similar format throughout. To gauge the impact of these letters we will take them paragraph by paragraph.

1. The Devices in Question. Each letter begins with a description of the product the FDA has determined qualifies as a device under Section 201(h) of the Federal Food, Drug and Cosmetic Act (FDCA). Section 201(h)(2) of the FDCA defines “device” as:

an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is…intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals

The agency’s letter focuses in on the second half of the 201(h)(2) definition, and adds in language from 201(h)(3) which allows the FDA to categorize products as a device if they are “intended to affect the structure or any function of the body of man.” The “devices” identified by the FDA are: 23andMe Personal Genome Service™, Navigenics Health Compass, deCODEme Complete Scan, KnomeComplete™ and the Illumina® Infinium HumanHapp 550 array. It’s difficult to see how any of these products would fall under 201(h)(3) but not 201(h)(2) but, regardless, the FDA is making a clear statement: based on the plain language of the FDCA, it considers these products to be medical devices.

2. Has Your Doctor Seen This? The second paragraph, which appears to be identical in every letter, is a generic overview of the Medical Device Amendments (MDA) to the FDCA. The MDA grants the FDA the authority to require premarket regulation of medical devices. The letter stresses the importance of demonstrating both analytical and clinical validity to ensure that “individuals are not misled by incorrect test results or unsupported clinical interpretations” and that the products are “used to support good healthcare decisions.”

We wrote earlier this week about the difference between analytical and clinical validity, and the role that CLIA (which is administered by CMS, not the FDA) is meant to play in ensuring the former. The letters clearly indicate that the FDA has its eye on both measurements of genetic test quality, as it should. More significantly, the letters appear to indicate that the agency considers the products in question to provide “clinical interpretations” and/or to be used in “healthcare decisions.” In the long-running debate over whether DTC genetic testing qualifies as clinical medicine, it appears that the FDA may have come down on the clinical side of the fence, at least for these particular products.

In fact, Director Gutierrez clarified this point in an interview this afternoon with Newsweek. Director Gutierrez seemed particularly concerned with products that report on genetic variants related to drug metabolization:

If you’re making a claim about [a genetic variant that affects the metabolism of the anticoagulant drug] warfarin, and somebody decides based on the result they get that they want to change their dosing, that is a fairly risky decision. That could affect their health. If they’re not feeling well on their current dose and the drug is expensive, we don’t know what they would do.

These concerns are reiterated, albeit in less detail, in several of the actual letters (see next paragraph).

3. Where’s the Approval? The third paragraph in four of the five letters informs the company that the FDA has not received any information pertaining to the analytical or clinical validity of the products for use in the FDA’s “clearance or approval” of the products. The letters go on to describe the type of genetic information provided by the companies that is of particular concern in this regard, for example the warfarin and clopidogrel response information reported by 23andMe and Navigenics and the breast cancer risk and detection information provided by deCODE. The FDA, echoing Gutierrez’s comments above, warns that “consumers may make medical decisions in reliance on this information.”

The use of the word “consumer” is an interesting choice, particularly in light of the focus that the FDA is clearly placing on the potential clinical use of the products. It is particularly confusing in certain letters, 23andMe’s for instance, where the recipient of the genetic information is referred to in the same paragraph as both a “patient” and as a “consumer.” Clearly, one task for the future regulation and description of genetic testing products will be to clean up the terminology.

It’s also important to point out that Illumina receives special treatment in this paragraph. Of all the companies receiving letters, Illumina is the only one not to offer at least one product directly to consumers (the company does offer a commercial whole-genome sequencing service, although that product requires the participation of a healthcare professional). Illumina’s letter notes that the company has “received FDA clearance or approval for several of its devices,” but not for the HumanHap550 array. “Yet Illumina is knowingly providing the HumanHap550 array to 23andMe and deCODE Genetics for clinical diagnostic use without FDA clearance or approval” despite its being labeled “For Research Use Only.” As Gutierrez notes, “…Illumina has to follow the law, and they are aware that the chips are not being used for research only.”

Again, it appears that the FDA’s determination that the products are being used for clinical diagnostic purposes and delivered directly to consumers appear to be important factors, with the FDA drawing no enforcement distinction between enabling DTC genetic testing and providing the DTC genetic tests themselves.

4. We Know What You Said Last Summer. All but one of the letters then go on to describe a meeting last summer between the company in question and the FDA (July 29th for 23andMe, July 31st for Illumina, August 6th for Knome and August 13th for deCODE.) Surprisingly, there is no mention of a Navigenics / FDA meeting although, in part due to this paragraph’s conspicuous absence from the Navigenics letter, I wonder if this may have been an inadvertent omission.

During these summer meetings the companies presented information about their products to the FDA. On the basis of that information, as well as other available information (e.g., the FDA notes that 23andMe has “recently begun distributing the collection kit for your device through a third party distributor, Amazon.com”), the FDA has concluded that the products in question are diagnostic devices subject to FDCA regulation.

In its letters to 23andMe, Knome and deCODE, the agency goes on to explain that, since the products are “not developed by and used in a single laboratory,” it does not consider them to qualify as laboratory developed tests (LDTs). This is an important point because the FDA has long exercised “enforcement discretion” over LDTs, choosing generally not to regulate this category of test, one which includes a majority of currently available genetic tests. Since so many genetic test providers – not just those of the DTC variety – have relied on the LDT determination as a basis for skirting FDA regulation, this section in particular is likely to raise the blood pressure for companies that purport to offer one or more LDTs but do not conduct all of their development, testing and interpretation in house.

5. Where is Your Letter? Next is a paragraph, nearly identical across all five letters, that reminds the companies they have not received what FDA believes to be the necessary regulatory approvals. Or, as the agency puts it, “we are not aware that you have an approved application for premarket approval (PMA) in effect pursuant to” the FDCA, nor have you “notified the agency of your intent to introduce the device into commercial distribution as required by section 510(k)” of the FDCA.

Briefly, the FDA regulates medical devices in three classes.

Class I devices are simple devices that pose a minimal risk, and are generally exempt from FDA premarket approval or clearance. However, registration of the device is required (as is true of all FDA regulated devices).

Class II devices represent an intermediate level of risk, and require regulatory clearance (as opposed to an “approval”) before they can be sold in commerce. The FDA must determine that the “device to be marketed is as safe and effective, that is, substantially equivalent (SE), to a legally marketed device not subject to premarket approval.” The clearance track for Class II devices is set forth in section 510(k) of the FDCA.

Class III devices are the riskiest device class, and the products that receive the most stringent FDA scrutiny. FDA approval is required before the device can be sold in commerce, and is granted only when the FDA determines that there is “sufficient valid scientific evidence…that the device is safe and effective for its intended use.” The regulatory submission is substantially more detailed than under 510(k), and the FDA is not obligated to respond as quickly.

The FDA letters provide no real insight into whether the agency considers the products it has identified to represent Class I, Class II or Class III devices, a classification that will determine the size of the regulatory burden imposed by the FDA.

6. We Will Be Waiting. Finally, the FDA advises each company to “take prompt action to respond to this letter” and offers to meet with the company to “discuss whether there are tests you are promoting that do not require review by FDA…”

“Prompt” is not defined, and most or all of these companies have had open channels of communication with the FDA for some time now, so it is unclear what type of timetable this imposes. It is clear, however, that this is an invitation to further agency dialogue, and that these companies decline only at their peril.

The second part of the paragraph – the agency’s offer to “discuss whether there are tests you are promoting that do not require review by FDA” – strikes us as a possible opening, at least for some of the identified companies and tests. Last fall, 23andMe, following in the footsteps of its competitor (and recent FDA regulatory target) Pathway Genomics, announced that it was breaking up its genetic testing service so that it could offer separate products for customers seeking to explore their genetic ancestry but who were not interested in the more medical applications of personal genetics, or vice versa. (23andMe also offers a combined product that includes all of those features). As I wrote at the time, that is just the sort of distinction that might be significant to the FDA as the companies and the agency discuss which specific products require premarket clearance and approval (more on this below).

What Does It Mean For the Five Named Companies? The immediate implications of the FDA’s letters may be less significant than some might initially suspect. After years of speculation about whether and how the FDA would regulate DTC genetic testing products, the agency has now publicly delivered at least a partial answer: it considers these specific products to be medical devices requiring either premarket clearance or approval, and it does not consider them to be LDTs subject to regulatory enforcement discretion.

For the companies named in the letters, at least, this provides a concrete agency determination to which they can react. It’s unlikely that the response from any of the companies will be to pull their products completely off of the market and, as The New York Times reports, Director Gutierrez has indicated that “it would be unfair to remove the tests from the market because the agency had not, until now, clearly told the companies that the devices needed approval.”

[Added in Edit, 6/11: Turna Ray of Pharmacogenomics Reporter has published her own recap, which contains additional comments from Erica Jefferson, an FDA press officer. Jefferson’s comments make a point of distinguishing the five untitled “letters to industry” from “warning letters.” Jefferson explained the difference between the two types of letters:

While Warning Letters set out specific violations of law that a company must address immediately or else the agency will take an enforcement action, an Untitled Letter identifies agency concerns and gives a company the opportunity to meet with the agency and to have time to take appropriate steps to address these concerns…Based on how the companies respond to the Untitled Letters, FDA may follow up by sending Warning Letters.

Jefferson also added that the letters were sent based in part on recent discussions between the FDA and several of the companies that took place in the aftermath of the FDA’s decision to send Pathway Genomics a similar letter last month. According to Jefferson, those meetings “helped inform the agency’s decision to send the Untitled Letters.” End Edit, 6/11]

So, at least for the moment, we may see little or no immediate change while these companies weigh their options internally and through discussions with the FDA. What exactly are those options? They obviously vary based on the specific company and product, but here are a few of the most likely possibilities:

Wave Goodbye. For products that have failed to meet expectations, or are no longer an integral part of the company’s future plans, one possibility is to simply pull the product from the market. The most likely candidate for this response would appear to be the deCODEme test, which is considerably more expensive and less popular than a number of its competitors. deCODE Genetics recently emerged from a well-publicized bankruptcy, and there have been hints that deCODEme might not be part of the reorganized company’s long-term plans. (However, in comments today to The New York Times, neither deCODE or its head of research, Kari Stefansson, indicated that they would do anything other than cooperate with the FDA). If deCODE or any other company does decide to pull its test from the market, existing customers will likely be anxious to know what will happen with their genetic data.

Say Hello (to the FDA). For other companies (e.g., Illumina, a company with considerable experience navigating the FDA approval process), the path of least resistance may be to simply agree with the FDA and seek the appropriate clearance or approval. The viability of this option will depend on how the FDA intends to categorize the specific product (e.g., Class I, II or III) and whether the company believes (a) it can bear the burden imposed by such a regulatory submission and (b) that its product will be approved without changes to its substance or commercial availability that would materially undermine the product’s commercial viability.

Change Pathways. Perhaps the most palatable option for many of these companies is to consider altering the product in a manner that would convince the FDA it no longer qualifies as a device requiring premarket approval or clearance, for instance by removing the ability of consumers to purchase the product without the participation of a healthcare provider.

In his interview with Newsweek, Director Gutierrez discloses that Pathway Genomics was not sent a letter yesterday because the company responded to the agency’s previous letter and has indicated that “they are planning to move away from direct-to-consumer testing…” While that disclosure is news to me, and not one I believe the company has made publicly (the website still appears to allow consumers to purchase directly), it is not a surprising one. As Gutierrez notes, another genetic testing company, Counsyl, made a similar decision in the aftermath of the Pathway / Walgreens commotion.

Of the five companies that received FDA letters this week, Navigenics and Knome would appear to be the most likely candidates to pursue this option. Navigenics has increasingly shifted its product focus over the past year in the direction of more traditional medical channels (as evidenced by its receipt earlier this year of a clinical laboratory permit from the State of New York, apparently the first awarded to a personal genomics provider), and this development could be the final nudge it needs to pull the plug on its DTC option. Similarly, Knome, which once offered whole-genome sequencing directly to the super-rich for $350,000, has increasingly positioned itself as a provider of genomic software and interpretation, with a focus on research and clinical applications. As with Navigenics, if Knome can forestall FDA regulation by eliminating all DTC versions of its products, it may have a strong incentive to do so.

A related approach, discussed above, would be for companies to seek different regulatory treatment for products that have clearly different uses. 23andMe, for instance, might seek a different classification for its ancestry testing product as compared to its products that provide genetic testing of a more arguably medical variety, such as disease prediction or drug response.

Prepare for War.  Finally, there’s always the possibility that one or more of the companies will challenge the FDA’s determination that they are either (a) offering a medical device or (b) not offering an LDT. There’s no question that going toe-to-toe with the FDA represents the path of greatest resistance, but if any of these companies feel sufficiently backed into a corner by the FDA’s approach this could surface as a viable option.

While no company has yet indicated its intent to challenge the FDA’s interpretation, 23andMe has thus far been the most outspoken in its criticism of the agency’s recent actions. As reported by The New York Times, one 23andMe director suggested that denying consumers direct access to their genetic information would be “appallingly paternalistic” (a characterization Director Gutierrez found inapplicable to the FDA’s regulatory decision), and the company has indicated that it “disagree[s] with the FDA’s conclusion” but is “open to discussion on ways to regulate the personal genetics industry.” Only time will tell whether 23andMe, or some other party, attempts to challenge the FDA’s regulatory approach to DTC genetic testing.

What Does it Mean for the Rest of the DTC Genetic Testing Industry? For the rest of the industry, the regulatory outlook is little clearer today than it was yesterday. The FDA has offered specific regulatory determinations for a limited set of DTC genetic testing products, but it has not offered broader industry guidance.

From the letters, and from Director Gutierrez’s statements, it is clear enough that the agency considered several important factors in identifying these five specific companies and products as regulatory targets. These include the DTC availability of the product (or, in the case of Illumina, contribution to DTC availability), the perceived medical use of the product and, in all likelihood, the complexity of the testing and interpretation involved in the product.

But how the FDA weighed those factors against others – including the utility of the tests, the reality of its limited regulatory resources, and the presence of numerous other genetic tests offered to consumers and to patients – remains unclear. Keep in mind that the FDA sent letters to five companies that, while they represent some of the best known genetic testing providers, do not comprise the entire DTC genetic testing industry (see, for example, this list at DNA Test Index or this list at AccessDNA). For other DTC companies, as well as companies and investors seeking to break into the DTC marketplace, there continues to be a lack of clarity into the FDA’s DTC genetic testing regulatory strategy.

For that reason and others, my own opinion continues to be that transparency – and not regulation – is what would be most beneficial to the DTC genetic testing industry and its customers at this time. Until companies, consumers and regulators better understand the tests that are available and, importantly, how those tests are being used, it will be difficult to develop a regulatory policy that protects the health and safety of individuals without stifling commercial innovation and individual exploration. In the meantime, expect the FDA’s latest actions – as well as, possibly, the ongoing Congressional investigation – to significantly shake up the personal genomics landscape in the coming weeks and months.