The two-day meeting, which is open to the public, will investigate the following topics:

• The risks and benefits of making clinical genetic tests available for “direct access by a consumer without the involvement of a clinician (i.e., without a prescription).”
• The different types of DTC or direct access tests (e.g., carrier screening, risk prediction in healthy persons, pharmacogenetics, etc.) that might “support differences in the regulatory approach.”
• The “level and type of scientific evidence appropriate for supporting [DTC] claims, including whether it should be different than” what is required for similar clinical genetic tests (presumably, non-DTC in vitro tests, including laboratory developed tests, or LDTs).

A complete agenda and list of speakers has yet to be published, but the fact that the FDA is singling out DTC genetic tests for specific attention is sure to be a welcome sign to many.

In the whirlwind of activity this past summer, DTC genetic test providers were haled before both Congress and the FDA to defend their businesses, even as the FDA simultaneously unveiled plans to regulate all LDT tests. The frenetic pace of activity left industry, the public and, seemingly, the FDA with a number of unanswered questions. Chief among them: does the FDA consider DTC genetic tests to be LDTs, or do the unique issues raised by direct consumer access to these relatively new products merit separate regulatory consideration? This confusion was reflected in the FDA’s two-day public meeting on LDT regulation and in the written public comments submitted over the following months, which saw a disproportionately high number focus primarily or exclusively on DTC genetic tests, despite the fact that those tests comprise only a fraction of the tens of thousands of LDTs the FDA is seeking to regulate.

Which is what makes next month’s DTC-only meeting such a good idea. The meeting is a tacit acknowledgement by the FDA that the agency needs to continue to gather data and viewpoints about DTC genetic tests, along with the unique opportunities and challenges they present, separately from its ongoing efforts at LDT regulation. As a recent Nature Biotechnology editorial suggests, it may also mark the start of a shift in the FDA’s attitude toward the regulation of DTC genetic tests, prompted in part by recent direction from President Obama and the White House, to take a closer look at how agency regulations burden small businesses and to demonstrate an “increased flexibility” in reducing those burdens. That’s significant, especially when coupled with the results of a recent study published in the New England Journal of Medicine by researchers from the Scripps Translational Science Institute (pdf). The Scripps study evaluated the responses of over 2,000 DTC genetic test customers (who used Navigenics’ Health Compass product) and found no significant post-test anxiety or other adverse results. While it will take time to assess the full impact of both the Scripps study (which will require, among other things, longitudinal follow-up and independent confirmation) and the Obama Administration’s new regulatory policies, Nature Biotechnology opines that these signs suggest that the FDA’s “stance to the DTC genetics sector has been perhaps too aggressive” thus far. We agree.

Whatever the FDA’s attitude toward DTC genetic tests in the past, the upcoming public meeting is a positive development. By continuing to facilitate public dialogue—the public may submit comments to the agency in writing until February 23 and apply (until February 15) to make an oral presentation at the meeting—the FDA is sending a clear signal that it recognizes it cannot develop an appropriately tailored system of oversight for DTC genetic tests without consulting, directly and repeatedly, the public it seeks to inform and to protect.

One final note on timing. In early January, despite the ongoing legal and regulatory uncertainty and before the Obama Administration unveiled its new business-friendly approach to regulation, we wrote that direct federal regulation of the DTC genetic testing industry in 2011 appeared highly unlikely. As we head into the spring, with the FDA still clearly in information-gathering mode and Washington’s short-term focus on other priorities, including lessening regulatory burdens overall, there is no reason to adjust that prediction. This should come as welcome news for those who have argued that what the DTC genetic industry needs today is greater transparency and better data, not heightened regulation.

1. Will the $1,000 genome live up to the hype?

2. Will personal genomics stay DTC?

3. How will the ongoing gene patent debate affect the progress of personalized medicine?

4. When and where will the next regulatory shoe fall?

5. Who will control the data?

A year later the question that comes first to mind is, has anything really changed?

The short answer is no, not fundamentally, although that is not meant to imply that nothing of note happened in 2010. Far from it, as significant legal, regulatory, policy and technological developments continued to reshape the personal genomics landscape.

With that in mind, we welcome 2011 with a look back at the year that was, and a look ahead at what to expect from 2011 and beyond.

The $1,000 Genome. With the draft human genome sequence turning 10 this past year, numerous media outlets reflected on the contributions of genomics and personalized medicine over the past decade. A frequent focal point – and measure of success – was the march toward what Keith Robison has termed the “arbimagical goal” of the $1,000 genome. Companies and investors continue to be enamored of low-cost, high-throughput genome sequencing, as evidenced in part by the IPOs of Complete Genomics and Pacific Biosciences this past fall.

At the same time, as we’ve written previously, the goal is not inexpensive genomics, but personal genomics. What matters is not how much it costs to generate a genome sequence (i.e., raw data), but what you can do with that genome once you have it. Thus, genomics is only personal once both the data and the interpretation are individually tailored.

2011 seems likely to be the year in which we finally crack the $1,000 barrier for a data-only genome, driven in large part by continued advances in sequencing technology, including Ion Torrent’s new Personal Genome Machine. But interpreting the data is another story. Already the dominant meme of 2011 is: “$1,000 genome; $100,000 analysis?”

If you’re waiting for a $1,000 genome delivered by your doctor, complete with advice about how to use the data to improve your health, Matthew Herper of Forbes advises you not to hold your breath. Likewise, analyst Amanda Murphy of the investment firm William Blair, believes that “the wide-scale incorporation of whole genome sequencing into the clinical realm is 10 or more years away.” Herper, Murphy and others think interpreted, clinical-grade genomes are going to remain elusive and expensive, particularly in the short-term and certainly for 2011. At Genetic Future, Daniel MacArthur largely agrees, but notes that for consumers willing to take more of a do-it-yourself approach, a $1,000 genome is a distinct and near-term possibility.

By 2012, motivated do-it-yourself (DIY) genomics pioneers like MacArthur will be able to locate cheap data and free or nearly-free tools to help make sense of that data for around $1,000 (not counting their own labor costs). And patients with an acute clinical need, particularly sufferers of cancer and certain rare diseases, will find that genomics plays an increasingly important role in their care, with insurers or even researchers or healthcare providers bearing the brunt of the cost.

However, the majority of us – non-scientists and generally healthy – are likely to find that full-genome sequences continue to remain just out of reach. With the combined cost of obtaining both complete genomic data and a layperson-accessible, reasonably accurate and personalized interpretation of that data remaining well north of $1,000 through 2011 and beyond, the number of consumers who choose to plunge into their full genomes will remain comparatively small. Most individuals will opt to dip their toe in the gene pool, paying several hundred dollars for a more modestly-sized chunk of personalized genomic data (e.g., the 1,000,000+ SNPs genotyped and analyzed by the likes of 23andMe) while they wait for either a clinical (and reimbursable) need to sequence or the cost of an interpreted personal genome to fall further.

As Yogi might say, the $1,000 genome may arrive this year, but it will still cost more than a grand, at least for most of us.

DTC Personal Genomics. For many, “personal genomics” is synonymous with “direct-to-consumer (DTC) genomics.” But despite the continued decline in the cost of genomic data, we begin 2011 with fewer significant providers of DTC genomic services than at the start of 2010.

The major developments have been covered extensively here at the Genomics Law Report. From the Pathway/Walgreens kerfuffle (and the FDA’s response) to the Congressional hearing and critical GAO report (and the FDA’s response), 2010 was certainly a tough year in Washington for DTC companies. (For a complete recap see: The Past, Present and Future of DTC Genetic Testing Regulation.)

While some erstwhile DTC providers (in particular Navigenics and Pathway Genomics) have, at least for the time being, shelved the consumer-facing side of their business, others continue to push forward. 23andMe remains the DTC front-runner, recently raising funds from both venture capitalists and the National Institutes of Health, but a handful of other DTC providers (including deCODE genetics) continue to offer products while a new generation of DIY genomics companies and researchers strive to put genetic data directly into the hands of increasingly large numbers of individuals.

For all of the apparent interest in DTC genomics from Congress and the FDA, the reality is that neither has yet articulated a clear plan to regulate that industry and, at the same time, both lawmakers and the regulators have bigger fish to fry in 2011. DTC personal genomics providers and their tests represent a mere fraction of the laboratory developed tests (LDTs) the FDA has vowed to regulate more aggressively and expansively than ever before (more on this below).

More importantly, the market for DTC personal genomics pales in comparison (at least in terms of market size and clinical importance, although perhaps not necessarily media coverage) to a host of other pressing issues facing Congress, the FDA and other regulatory agencies in 2011. These include, in no special order, the development, regulation and reimbursement of companion and other advanced diagnostics, follow-on biologics, how to deal with a rise in genomic data in regulatory submissions and what to do about whole-genome sequencing in particular and, of course, the fate of the healthcare reform legislation.

Remember, too, that following the recent mid-term election there will be personnel turnover in Washington as well. To cite two examples: the FDA’s No. 2 official, Joshua Sharfstein, has already resigned and one of the most vocal critics of DTC genetic testing during last summer’s House hearing, Congressman Parker Griffith – who compared providing genetic information to consumers with throwing live snakes into a crowded hearing room: useful only to incite panic – failed to win reelection.

Stepping back to view the prospect of DTC genetic testing regulation through this broader lens helps explain why, despite continuing uncertainty and ominous regulatory overtures, the DTC industry is likely to survive 2011 intact. Just as it did in 2010.

That is not to say that industry will not face increased scrutiny in 2011; or that this would be a bad thing.

There continues to be a clear need for more industry transparency, as well as heightened regulation of the advertising and marketing practices of existing genetic testing companies. The arrival of the NIH’s genetic testing registry (GTR), although not without its own critics, remains slated to arrive this spring. The GTR, along with increased enforcement of existing regulations from agencies like the FDA and the FTC, could do much to put a halt to true consumer abuses in the DTC personal genomics market.

There is also a widespread recognition that the DTC industry would benefit from greater standardization. A primary need is for greater definitional clarity. Terms like “DTC genomics” and “DIY genomics” frequently receive user-defined and inconsistent definitions, and no regulation – whether government- or self-imposed – will be practical until this terminological confusion is resolved. More substantively, there is a clear need to develop data standards, including both a standard format for returning genomic data as well as for interpreting and reporting those data. While DTC companies have frequently expressed interest in pursuing the latter, including in cooperation with federal agencies, considerable progress in all of these areas still needs to be made.

Of course, while unlikely, it remains a possibility that regulators or lawmakers will succeed in directly regulating DTC personal genomics in 2011. This could happen as part of the broader LDT regulatory movement or, more likely, take the form of narrower and more targeted regulatory requirements, such as interposing a physician or genetic counselor between the company and consumer at the ordering and/or data delivery stage. Or the FDA could always come up with some other out-of-the-box approach to DTC regulation.

Nevertheless, as we enter 2011 it remains legal throughout most of the United States to provide healthy individuals with direct access to their personal genomic data. While that is not the case worldwide, technological innovation and the proliferation of genomic data and of DIY genomic tools will drive continued growth and diversification of the DTC personal genomics landscape in the United States in 2011 and beyond.

Gene Patents. Without question, last year’s biggest story was – and continues to be – the ongoing Myriad gene patent litigation. Judge Robert Sweet’s jaw-dropping district court decision invalidated Myriad’s challenged patents across the board, for the moment, and thrust the debate further into the public and political spotlight than ever before.

While we entered 2010 anticipating a decision in Myriad, as well as in other important litigation (notably Prometheus and Bilski), we wrote that “there is little reason to believe that 2010 will be the year that the gene patent question will be finally resolved.” And we’re fully prepared to say the exact same thing in 2011 (and possibly in 2012, as well).

Those who first caught wind of the gene patent issue in March of 2010 (when Sweet’s opinion issued) may find it inconceivable that by the end of 2011 – a full 21 months later – there could be no resolution. But courts move slowly, and with the Supreme Court choosing once again to ignore biotechnology patents (the Supremes issued a heavily hyped Bilski opinion that proved to be just hype, and little more), the Federal Circuit rehearing Prometheus and saying exactly what it said in 2009 and the Myriad litigation in all likelihood multiple appeals from reaching its conclusion, a definitive answer does not appear imminent. Those waiting on the courts to resolve the patentability of genes or the increasingly important diagnostic methods at issue in Myriad, as well as Prometheus and Classen, are going to be forced to keep waiting.

Still, just as in 2010, 2011 will see its share of high-profile gene patent opinions issuing from courts. The most eagerly anticipated is the Federal Circuit’s Myriad opinion, which is expected in late spring or early summer. But the likelihood that Myriad or any other legal opinion will bring substantial and lasting clarity to the patentability of genes and related diagnostic methods in 2011 is slim.

However, not all parties are likely to be content to sit idly by and wait for the courts to decide (or not) the issue of gene patents. 2010 saw the publication of the highly publicized and equally controversial SACGHS report on gene patents and licensing. The report sparked plenty of conversation in biotechnology industry and policy circles and, though the SACGHS was disbanded later in 2010, those conversations have not quieted (as evidenced, in part, by the Justice Department’s unexpected amicus brief in Myriad). As genomic sequencing and diagnostic tools play an increasingly prominent role in clinical care, the role of patents – as either facilitators or inhibitors of personalized medicine innovation – will come under increasing scrutiny.

Persistent patent uncertainty continues to be a challenge for biotechnology companies and their investors. In large part for that reason, many are actively seeking out alternative pathways through the increasingly thorny gene patent thicket. Thus, don’t be surprised if 2011’s most noteworthy gene patent developments happen outside of the courtroom.

Legislation and Regulation. There was a lot of talk about regulating genetic testing in 2010, but the most significant regulatory action occurred late in the year with the EEOC’s publication of final regulations for Title II of the Genetic Information Nondiscrimination Act (GINA), which finally took effect this past week. With the increasing proliferation of genetic information, expect to see GINA – now in its third full year as law – in the headlines with more frequency in 2011.

As for genetic testing regulation, yes, 2011 could be the year that the FDA implements sweeping regulatory changes for laboratory developed tests (LDTs), including most genetic tests. But after announcing its intent to do just that back in June, the second half of 2010 came and went without significant follow-up activity from the FDA. After watching the FDA attempt to regulate a subset of LDTs (in vitro diagnostic multivariate index assays, or IVDMIAs) for four years before sending IVDMIA regulation to the regulatory trash heap for good late in 2010, there is good reason to be skeptical.

There’s a reasonable likelihood that the FDA will offer at least one concrete proposal for an LDT regulatory framework in 2011. But don’t expect that proposal – whatever its particulars – to be embraced by regulated entities, and we certainly wouldn’t bet on the FDA being able to finalize such an initiative and produce final guidance (or regulations, depending on which way it chooses, or is forced, to proceed) in the same year.

Other possibilities include two oft-discussed pieces of personalized medicine legislation, the Genomics and Personalized Medicine Act (GPMA) and the yet-to-be-introduced bill from Senator Hatch on advanced personalized diagnostics. But as we sit here today, the most likely scenario is that 2011 will bring no significant new final legislation or regulation affecting genomics and personalized medicine.

Such a rapidly-moving field poses substantial challenges for overburdened lawmakers and regulators even in the best of political environments and 2011, with its newly divided Congress and promise of contentious battles over healthcare reform and other key issues, hardly qualifies as an ideal political environment. Never say never, but those who would bring legislative and regulatory change to personal genomics are likely to spend 2011 primarily laying the groundwork for 2012 and beyond.

Access and Control. Our final question last year continues as perhaps the most important of 2011: who will control the data?

All of the issues above – from how much a genome will cost to who will be able to purchase one and whether a company can patent parts of it – reflect concern with access to and control of genomic data. Laws like GINA protect the use of genetic information in certain contexts, but at present there is no federal genetic privacy law and little consensus on whether an individual owns her own genetic material and data once it leaves her body.

As courts and legislatures continue to wrestle with these issues across an increasingly broad range of factual backgrounds – from state-mandated testing of newborns for genetic disease to the use of forensic DNA to monitor an increasingly broad subset of the country’s criminal (and frequently non-criminal) population – the pressure to clarify the rights individuals have in their genomes will intensify. Will we (along with courts and legislatures) conceptualize genomic data primarily as personal, with the individual the locus of control, or as medical, routing access and interpretation through the healthcare system?

Other challenges of no less importance will continue to demand attention in 2011 and beyond. We have already discussed, above, the issue of access to personal genomic data, and, indeed, no less an authority than NIH Director Francis Collins has written that “free and open access to genome data has had a profoundly positive effect on progress.”

But even as we strive to maintain broad and individualized access to genomic data, we will simultaneously need to ensure that those without the means (financial or otherwise) or desire to pursue their own genomic data are still able to benefit from personalized genomics. Among many, many challenges, this will require continuing the uphill battle to retrofit a healthcare system populated with institutions and individuals largely unprepared to handle the increasing size and complexity of incoming genomic data.

We Will Finish Where We Started. Again. These are big challenges, and they will not be met in full in 2011. We are confident that, when 2012 rolls around, most (and perhaps all) of the same issues will present themselves yet again to the field of personal genomics.

The $1,000 genome will continue to remain more hype than reality for most individuals. DTC personal genomics will continue to spark concern from legislators and regulators, tantalizing unscrupulous businesspeople even as it is embraced by an increasingly broad segment of the population. Gene patents will remain an unsettled area of law, even as public and private efforts to resolve the issue progress. The specter of FDA regulation will continue to loom large—and advance slowly. And, most importantly, while more people than ever before will have affordable and largely unfettered access to their genomic data, that access will be uneven, with many who could benefit most from personal genomics denied that opportunity.

Still, even as personal genomics’ challenges remain largely the same today as they were in 2010, and likely will be again in 2012, progress is apparent. After all that happened in 2010, perhaps all that really changed in the last year is that personal genomics is now a year older, a year wiser and continuing to advance. And perhaps that is enough. At least for 2011.

[Editor’s Note:

On Tuesday, Carmichael and five commentators examined what can be learned from a DTC genetic test. Yesterday, the topic was whether DTC genetic tests are trustworthy, and whether the results can be cause for concern. Today’s topic is the regulation of DTC genetic tests. In addition to several short commentaries, including a much shorter version of the piece below, Carmichael has also posted a lengthy interview with two top FDA officials on the subject of DTC genetic testing regulation.

The column below is an expanded version of what appears over at Newsweek. To see all of the commentaries in Carmichael’s series, click here.]

The recent media attention focused on direct-to-consumer (DTC) genetic tests has left companies, investors, consumers and even regulators scrambling to figure out what comes next.

As the situation stands today, companies and their investors live in a climate of unprecedented regulatory uncertainty, causing delays in the introduction of new products and rendering an already inhospitable economic climate – for both fundraising and sales – even more challenging. Commentators and regulators caution consumers that some DTC genetic tests may be unreliable or, worse, harmful, but have yet to provide clear tools and guidelines for evaluating competing tests. And regulators, including the FDA, must balance their mandate to protect the health and safety of the public with that same public’s desire for autonomy, while also recognizing that innovation is a prerequisite for a healthcare system that must continue to improve outcomes while reducing costs.

Clearly, something must change. But what will that change be? And how will the field of DTC genetic testing evolve? Will DTC be able to continue its current business while regulators and companies engage in protracted negotiations? Will oversight weed out the “snake oil salesmen” and permit legitimate companies to flourish? Will it drive all genetic testing (temporarily) out of the hands of consumers?

Or will the field change in a dramatic and completely unexpected way?

These questions, and others, caused Newsweek science editor Mary Carmichael to realize her oft-debated question – To Test or Not To Test? – might demand an answer sooner rather than later:

. . . I started to worry . . . . How much time did I even have left to decide whether I was going to take a test myself? Even before [last month’s Congressional] hearing, the FDA had announced its plans to regulate all DTC genetic tests, possibly so heavily as to keep them off the market; the hearing was just the sort of thing that could push it to move faster. What if, by the time I finally decided if I wanted one of these tests, I couldn’t buy one anymore?

Setting aside the question of whether Carmichael, or anybody else, should buy a genetic test, this column examines the history of DTC genetic testing regulation in the United States¹ and, in the final section, whether the DTC option is likely to persist in the future.

Because this post is longer than usual, here is a quick, clickable roadmap to its various sections. If you’re already familiar with the history of DTC genetic testing you may wish to jump ahead to the final section or two.

1. 2006: DTC and the First GAO Report.

2. 2007: The Beginning of Modern DTC

3. 2008: SACGHS and a Scare From the States

4. 2009: All Quiet on the DTC Front

5. 2010: DTC Goes to Washington

6. Today: Uncertainty Reigns

7. Tomorrow: Unintended Effects (and More Uncertainty)

8. Beyond: A Delicate Balancing Act

2006: DTC and the First GAO Report. Four years ago last month, the Federal Trade Commission (FTC), Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) published a consumer fact sheet entitled “At-Home Genetic Tests: A Healthy Dose of Skepticism May Be the Best Prescription.” The guidance warned consumers to be wary of claims made by DTC genetic testing companies and to involve “a doctor or trained counselor who understands the value of genetic testing for a particular situation” when ordering or interpreting any genetic test.

The joint agency guidance document was published in concert with a report from the Government Accountability Office (GAO) entitled “Nutrigenetic Testing: Tests Purchased from Four Web Sites Mislead Consumers” (pdf). The GAO report reviewed a “nonrepresentative selection” of genetic tests available to consumers at that time and concluded that those tests “mislead the consumer by making health-related predictions that are medically unproven and so ambiguous that they do not provide meaningful information to consumers.” The report was praised for “drawing attention to potentially important consumer protection issues,” even as it was criticized for “serious methodological flaws that undermine[d]” those very criticisms (pdf).

Whatever its methodological flaws, the GAO’s description of the system of regulation for DTC genetic testing, which it characterized as one of “minimal oversight [that] makes it difficult for consumers to determine whether a genetic test provides meaningful, scientifically based information,” was entirely accurate.

2007: The Beginning of Modern DTC. With the launch of DTC products from a publicly traded biopharmaceutical company (deCODE Genetics) and a Google-backed startup (23andMe) on back-to-back days in November 2007, the modern era of DTC genetic testing was born. With 23andMe, deCODE and, soon, Navigenics, consumers could now pay around $1,000 to review hundreds of thousands of SNPs. Following Knome’s launch, also late in 2007, they could pay much, much more ($350,000) for access to their entire genome.

Despite this dramatic shift in the DTC product landscape, the legal landscape remained essentially unchanged from 2006. Regulatory oversight was still incomplete, confusing and rarely invoked.

At the federal level, while most DTC genetic tests were likely covered from the outset by the Clinical Laboratory Improvement Amendments of 1988 (CLIA), it was typically difficult to determine whether DTC genetic testing companies were operating using CLIA-certified labs. (23andMe, for example, did not begin using a CLIA-certified laboratory until 2008, making the change in response to “evolving” regulatory requirements.) CLIA, which is implemented by the Centers for Medicare & Medicaid Services (CMS), requires laboratories to demonstrate the analytical validity of their tests, and covers most genetic tests regardless of whether they are provided directly to consumers or not.

In addition to CLIA, a limited number of genetic tests were also regulated by the FDA. Although the proposition was not immediately tested, it was widely assumed that DTC genetic tests constituted a new form of laboratory developed test (LDT), a large and well-established category of tests over which the FDA exercised “enforcement discretion.” While the FDA had historically declined to regulate LDTs, in 2006 and 2007 the FDA expressed its desire to regulate certain types of high-complexity LDTs (so-called IVDMIAs). As is still true today, it was unclear where, if anywhere, the newly introduced DTC genetic tests fell within the LDT conversation and FDA’s larger regulatory universe.

In addition to uncertainty at the federal level, some states possessed (and still do possess) statutes that appear to prohibit – or at least restrict – DTC genetic testing (pdf). However, it was unclear whether such statutes, which clearly predate the arrival of DTC genetic testing in its current form, were intended to prevent DTC genetic testing or whether they would be enforced by state regulators in any event. State-level regulatory restrictions contributed to at least one company withholding its service from citizens in at least 10 states at the time of its launch.

Despite all of this legal uncertainty, no federal or state regulatory agency took any formal action immediately following the introduction of DTC genetic testing to the consumer marketplace.

2008: SACGHS and A Scare from the States. During its first full year, the DTC genetic testing marketplace continued to grow as new companies arrived on the scene and existing companies refined and expanded their offerings.

Meanwhile, an influential government policy committee (SACGHS) had undertaken a review of the “U.S. System of Oversight of Genetic Testing.” When it was published in April of 2008, the 276-page report surprised almost no one when it identified major gaps in the regulation of genetic testing, including insufficient oversight of laboratory quality, clinical validity and a lack of knowledge with respect to the nature and uses of genetic tests available for purchase, whether directly by consumers or otherwise. Among the report’s several recommendations were increased FDA regulatory oversight and the creation of a mandatory, public registry for all laboratory tests.

Shortly after the publication of the SACGHS report, public health officials in New York and California sent “cease and desist” letters to a number of genetic testing companies. The states warned the companies – including 23andMe, deCODE and Navigenics, the three most prominent DTC providers at that time – that they were operating without necessary state licenses.

The SACGHS report and state regulatory letters produced widespread debate about the appropriate regulatory framework for DTC genetic testing. Companies were concerned that other states might follow the example set by New York and California and seek to regulate DTC genetic tests directly, potentially exposing DTC companies to a nightmare scenario of inconsistent, state-by-state regulation. Proponents of regulation, meanwhile, argued that the nascent field needed some regulation “lest abuses discredit the whole industry before it has a chance to thrive.”

In the following weeks, months and even years, some DTC companies received state licenses, although this came at the expense of offering tests directly to consumers in some cases. Other companies ceased selling to customers in specific jurisdictions, and still others simply went out of business. At the federal level, the SACGHS recommendations continued to generate far more discussion than action, and the regulatory landscape remained materially unchanged. Meanwhile, major DTC companies continued to press ahead, and 2008 closed with 23andMe’s DTC genetic test being named Time’s invention of the year.

2009: All Quiet on the DTC Front. In comparison to the years on either side, 2009 was a relatively quiet year for DTC genetic testing, at least from a regulatory perspective.

On the commercial side, however, 2009 saw a number of changes ripple through the DTC genetic testing marketplace. As the price of DTC genetic tests continued to fall, a new competitor, Pathway Genomics, arrived on the scene and 23andMe significantly revamped its product offerings and pricing shortly thereafter. Meanwhile, the financial crisis played a major role in causing DTC pioneer deCODE Genetics to file for bankruptcy protection, although the company quickly emerged under private control and its deCODEme test remains on the market today.

To be sure, regulators continued to ponder how to respond to the rapidly evolving genetic testing marketplace, which included but was not limited to DTC products. For example, the FDA continued to express an interest in regulating some LDTs and the California legislature considered a bill – championed by 23andMe – that would create a special regulatory framework for so-called “post-CLIA bioinformatics services,” although nothing would come of either initiative, at least in 2009. Perhaps most significantly, but unbeknownst to either the public or the major DTC genetic testing companies, Congress had instructed the GAO to begin a second investigation into the DTC genetic testing industry, the results of which would not be made public until the following year.

With regulators seemingly on the sidelines, academics and other commentators, including the Genomics Law Report, continued to stress the need for meaningful self-regulation in order to:

(1) discourag[e] consumers from purchasing products not adequately supported by scientific evidence, (2) provid[e] regulators such as the Federal Trade Commission (FTC) with a standard against which to evaluate (and sanction) false or misleading DTC tests or services, and (3) ensur[e] that inevitable governmental regulation is not overly restrictive.

Prominent scientists, including soon-to-be NIH chief Francis Collins and genomics pioneer Craig Venter, also emphasized the need for greater transparency and consistency in the way DTC companies presented genetic risk of disease to consumers. While there was widespread consensus, including on the part of DTC providers, that self-regulation and even some form of government regulation would be beneficial for the industry as a whole, by the end of 2009 no notable changes – government mandated, voluntary or otherwise – had materialized.

2010: DTC Goes to Washington. Although we are not yet two thirds of the way through the year, 2010 has already seen an explosion of activity in the oversight of DTC genetic testing.

The first major development came in March, when the NIH announced the creation of a voluntary genetic testing registry. In its 2008 report (pdf), SACGHS had recommended the creation of a “mandatory, publicly available, Web-based registry for laboratory tests” in order to “enhance the transparency of genetic testing and assist efforts in reviewing the clinical validity of laboratory tests.” The NIH adopted this recommendation with one crucial exception: the registry, at least as proposed, will be voluntary.  However, it remains to be seen, particularly in light of everything that has happened since the announcement in March, what form the NIH’s registry will ultimately take when it debuts later this year or in early 2011.

For DTC genetic testing, the excitement really began on May 11th, when Pathway Genomics announced it was partnering with Walgreens to offer its genetic testing service on the shelves of most of the drugstore giant’s 7,500 stores. The FDA responded almost immediately with an “Untitled Agency” letter to Pathway Genomics in which the agency informed Pathway that it could find no record of the necessary FDA clearance or approval for Pathway’s test. The Pathway letter – which represented the FDA’s first public foray into the oversight of DTC genetic testing – was followed by similar letters to five prominent DTC genetic testing companies in early June and letters to 14 more genetic testing companies in late July. These letters were, of course, something of a surprise to the companies. The FDA could not find evidence that it had approved the companies’ tests because, in at least some and possibly all cases, the agency had not told the companies that such approval was necessary.

In addition to taking aim at DTC genetic testing companies, the FDA also announced that it was shelving its plan to regulate a subset of LDTs (i.e., IVDMIAs) in favor of a new plan to regulate all LDTs. Late last month the FDA held a two-day “Public Meeting on Oversight of Laboratory Developed Tests” to discuss that plan. (It is important to point out that, despite devoting an entire portion of the public meeting to DTC genetic tests, on multiple occasions the FDA has indicated that it considers at least some DTC genetic tests not to constitute LDTs since the products are “not developed by and used in a single laboratory.”)

Not to be outdone, Congress quickly announced its own investigation into DTC genetic testing (one it had quietly initiated the year before) and followed that up with a public hearing on “Direct-To-Consumer Genetic Testing and the Consequences to Public Health.” The centerpiece of July’s Congressional hearing was yet another GAO report (pdf) whose conclusion was announced in the title: “Direct-To-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices.” The GAO also presented a striking and widely circulated YouTube video as partial support for its conclusion. (For a more detailed review of the Congressional hearing and the GAO report please see this recap.)

At the Congressional hearing, Jeffrey Shuren, the Director of the FDA’s Center for Devices and Radiological Health (CDRH), assessed the FDA’s recent activity by agreeing with Congressman Michael Burgess (R-TX) that the FDA “should have acted sooner” to regulate DTC genetic tests. Shuren was likely referring to a perceived failure on the part of the FDA to adequately safeguard the public.  Given the absence of any publicly documented harm resulting from consumer access to genetic tests , however, there are certainly those who would disagree, arguing that the FDA should still refrain from regulating DTC genetic tests.

Listening to Shuren’s remarks at the hearing, one could easily wonder whether his lament was actually directed at the agency having been caught off-guard, at least to a degree, by the debut of the GAO’s striking report, which was unveiled to the public – and the DTC companies themselves – at the hearing.  According to the report (pg. 19) the GAO officially briefed the FDA, NIH and FTC on the contents of the report in late May and early June. However, when I raised this point yesterday during an FDLI webinar on FDA’s (Emerging) Oversight of LDTs, fellow panelist Dr. Elisabeth Mansfield, Director for Personalized Medicine at CDRH, clarified that the GAO’s “briefing” consisted of a teleconference where the FDA learned only the bare fact that the GAO had conducted an inspection and had “found problems.”

Perhaps it is just a perfect storm of coincidences. But in any event, the FDA actions and the GAO report – along with other recent high-profile developments including the Pathway / Walgreens pairing and 23andMe’s “sample swap” – have created unprecedented uncertainty.

Today: Uncertainty Reigns. The GAO report, the FDA’s letters and all of the other events of the past few months have indisputably ratcheted up the level of uncertainty throughout the genetic testing industry.

However, as a purely legal matter, it does not appear that the formal regulatory framework governing DTC genetic testing has changed much if at all in recent months, or even since 2006, particularly at the federal level. Congress has passed no new legislation, and neither the FDA nor any other federal agency has promulgated new regulations or formal agency guidance.   This, of course, is not at all surprising: the rate of development in any new area of science and commerce inevitably surpasses the ability of lawmakers and regulators to keep pace. DTC genetic testing has hardly proved an exception to that rule.

Setting aside the myriad hearings, public and private meetings and statements made to the press by regulators – which, while significant, do not rise to the level of rulemaking – the only formal, public action one can point to is the FDA’s ongoing letter-writing campaign. However, as the FDA has clarified in the past, these “Untitled Letters” remain several steps removed from an FDA enforcement action:

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.

Of course, an absence of documented regulatory change does not imply that the commercial DTC genetic testing landscape has remained anything close to stable.

Responses from DTC companies and investors to today’s uncertainty have varied. Some companies (including Pathway Genomics and Counsyl) have ceased offering their tests directly to consumers, at least for the moment. Others, including two original DTC genetic testing companies (23andMe and deCODE), have expressed a desire to work with regulators while continuing to make their products available to consumers. Many of the major DTC companies, whether or not they are currently offering products directly to consumers, have also criticized both the GAO and the FDA for their approach to DTC genetic testing (see these blog posts at Navigenics, 23andMe and Pathway Genomics) while simultaneously expressing their desire to work with regulators to bring greater oversight to the industry.

Meanwhile, new companies and investors must reevaluate business plans to take into account anticipated regulatory changes.  And customers, including Mary Carmichael, must weigh the possibility that today’s DTC options may disappear from tomorrow’s digital storefronts.

Since 2006, the regulation of DTC genetic testing has been consistently characterized as confusing, incomplete and inconsistently applied. That characterization remains as true today as it was four years ago. So perhaps the only meaningful difference from four years ago is one of degree: more so than at any time over the past four years, there now appears to be a consensus that something must – and will – be done to overhaul the regulation of DTC genetic tests.

Tomorrow: Unintended Effects (and More Uncertainty). But not so fast. Despite the apparent agreement among regulators, industry and most commentators that DTC genetic testing is in need of additional oversight, there is still no guarantee that change is coming soon, or even at all.

Indeed, it is not difficult to look at the events of the past few months and conclude that DTC has been down this road before:

• A GAO report decrying the evils of DTC genetic testing and subsequent Congressional hearing? 2010 and 2006.
• Threatening regulatory letters to DTC companies? 2010 and 2008.
• A controversial FDA regulatory proposal that might – or might not – encompass DTC genetic tests? 2010 and 2006.

Industry watchers who have been around since the beginning would be excused for expressing at least some skepticism that this is the time, finally, when the DTC genetic testing landscape will be fundamentally remade.

Continuing Uncertainty. There is also the possibility that a new regulatory regime for genetic tests will emerge, but that it will push DTC genetic testing to the side and in so doing cause the industry to remain mired in uncertainty.

As the FDA pushes forward with the development of agency guidance for the regulation of LDTs, there are concerns that the agency may carve out many or most DTC genetic tests from this regulatory framework. In June, the FDA expressed its belief that several prominent DTC companies (23andMe, Knome and deCode) are offering tests that do not constitute LDTs because they are “not developed by and used in a single laboratory.”

Recent signals – including the designation of a separate panel for LDTs during the FDA’s two-day public meeting and Jeffrey Shuren’s presentation of DTC genetic tests within the confines of the larger LDT regulatory conversation (pdf) at the recent Congressional hearing – suggest that the FDA may yet find a way to incorporate the regulation of DTC genetic tests into its more ambitious plan to develop a risk-based approach for all LDTs. But for the moment, the FDA appears to be intent on continuing with test-by-test review and regulation.

Unintended Effects. Among its several shortcomings, the current test-by-test approach to DTC genetic testing regulation creates the possibility that a regulatory agency such as the FDA could seek to reshape the industry using indirect methods.

When the FDA sent out its first batch of letters post-Pathway, the one unexpected recipient was array manufacturer Illumina, which, unlike the other companies receiving letters, does not appear to have ever offered its services directly to consumers without the involvement of a physician intermediary. Nor did the FDA allege that it had. Instead, the FDA’s letter to Illumina (pdf) focused on the company’s “Infinium HumanHap550 array used by deCODE Genetics and 23andMe to provide genetic information to their customers.” The FDA charged Illumina with making available an array approved for “Research Use Only” to 23andMe and deCode for use in their own DTC genetic tests.

Why does this matter? As I wrote at the time, not every company has the same set of incentives to resist the FDA’s regulatory proposals. Whereas a company such as 23andMe, which has built its business around DTC genetic testing, has a clear interest in challenging any FDA action that results in its service becoming unavailable to consumers, array manufacturers like Illumina are not similarly situated. As Illumina’s CEO, Jay Flatley, recently noted, the revenue the company “generates from sales of arrays to the DTC market is ‘immaterial.’” By targeting array suppliers such as Illumina, for whom DTC represents only a fraction of their business, the FDA may have identified a way to exert indirect but potentially much more effective regulatory pressure over the industry.

In response, Daniel MacArthur asked yesterday whether the FDA was planning to strangle the supply lines of DTC genetic testing companies by targeting array manufacturers like Illumina. As a regulatory agency charged with implementing legislation passed by Congress, the FDA is extremely unlikely to have an official “agenda” when it comes to DTC genetic testing. That does not mean, however, that the FDA could not determine that genetic testing simply cannot be paired with DTC and still satisfy its interpretation of the law.

If 23andMe or deCode (which is partially owned by Illumina) were to lose access to Illumina’s arrays, would those companies be able to contract with another manufacturer, either based in the U.S. or abroad? Would Illumina take the necessary steps to work with 23andMe and the FDA to clear its array for use in 23andMe’s product? Would this development force such a fundamental shift in the business models of these DTC companies that they would be driven out of business, or perhaps driven overseas?

Even as a hypothetical, the Illumina example illustrates the importance of considering the knock-on effects of regulation. Although the FDA may take the position that its goal is to enforce agency regulations regardless of the effects they produce on a specific business, or even an entire industry, the reality is that there are a number of viable regulatory strategies on the table, and not all of them are equal in their effects.

One of the unfortunate consequences of the test-by-test regulation currently employed by the FDA is that these effects are unlikely to be fully anticipated or explored in advance by regulators. By the same token, one obvious advantage of publicly pursuing a formal system of regulation for DTC genetic testing – e.g., through the development of agency guidance or notice and comment rulemaking – is that such regulatory effects can be explored in advance (in some instances this may even be required of the FDA), rendering them at least intended, even if they remain unwelcome to some.

Other Regulatory Routes. Finally, remember that the FDA may not be left entirely to its own devices in determining how to regulate either LDTs or DTC genetic tests. Several pieces of draft legislation, if enacted, could provide specific Congressional direction as to how the FDA or other regulatory agencies should respond to the challenges raised by these tests.

Current proposals include the Genomics and Personalized Medicine Act – originally introduced by then-Senator Obama and now in its fifth year on Capitol Hill – and the inelegantly named Better Evaluation and Treatment Through Essential Regulatory Reform for Patient Care Act.

The prudent approach – particularly for companies, investors and consumers with an interest in DTC genetic testing regulation – is to assume that some type of regulatory reform is coming to the industry. Unfortunately, important details like “what regulation” and “when will it arrive” continue to remain elusive.

Beyond: A Delicate Balancing Act. Assuming that lawmakers and regulators do decide to develop a formal DTC regulatory regime, the details will be a long time in coming. Stakeholder input will be crucial, and the rapidly changing scientific and commercial landscape will continue to pose a challenge for slower-moving lawmakers and regulators.

Despite all of this uncertainty, it is yet possible to identify (i) several key areas of relative consensus for any prospective DTC regulatory framework and (ii) some of the most pressing areas of dispute that must be resolved in order to proceed.

The First Step: Defining DTC. Before we get to areas of consensus and dispute, however, a brief word about definitions. Any formal regulatory framework will need to set out a clear definition of what, exactly, constitutes a “direct-to-consumer genetic test.” As the personal genomics industry has grown increasingly diverse, the application of the label “DTC” to all consumer-oriented genetic products has become increasingly untenable.

There are, at the moment, at least three different types of DTC genetic tests:

• tests marketed to consumers but ordered and interpreted by a healthcare provider;
• tests marketed to and ordered by consumers but received and interpreted by or only in the presence of a healthcare provider; and
• tests marketed to, ordered by and received by consumers without any requirement that a healthcare provider be involved (although this option is frequently made available to consumers).

While the focus has frequently been on the third and most consumer-oriented type of genetic test, not all so-called DTC genetic testing companies fall into this category. This is significant since the risks – whether hypothetical or actual – of “DTC genetic testing,” as well as the appropriate regulatory response, clearly depend in large part on what exactly is meant by that term.

Finding Common Ground. Although few in number, it appears that consensus is emerging in certain areas pertaining to DTC genetic testing.

Access to Raw Data. Even those who strongly support the robust regulation of DTC genetic testing, agree that individuals should have the right to directly access their raw genetic data (pdf). In public and private comments, the FDA has appeared to embrace this position as well, indicating it is medical claims or interpretations – and not genetic information per se – that concerns the agency.

We need to be careful, however, to define exactly what this outbreak of agreement covers. Although important for what it says about an individual’s right to access their own genome, it likely refers only to the most basic level of access – a large file of As, Cs, Ts and Gs – and to nothing more. This is only a first step. Meaningful “access” for the vast majority of individuals begins only with the ability to access interpreted data.

Registration and Truth in Advertising. As the recent GAO report laid plain, there is a clear need for more robust regulation of the advertising and marketing practices of existing genetic testing companies, including DTC companies, to ensure consumers are not being intentionally or even accidentally misled.

Addressing this issue requires a thorough understanding of the tests currently offered to consumers, including how they are marketed or advertised, how they are intended to be used, and how they are actually used. The FDA has acknowledged several times in public discussions, including yesterday, that the agency lacks this information and that it would be useful in developing appropriate regulations.

While there remains some disagreement over the proper agency or agencies to collect this information and to take appropriate enforcement actions where necessary (the FDA and the FTC have both demonstrated some interest, and the NIH is currently developing a genetic testing registry), there is widespread agreement that these steps should be taken, and soon.

Industry-Wide Standards. Finally, almost since the inception of DTC genetic testing in 2007, there has been a widespread recognition that the industry would benefit from a more standardized approach to interpreting and reporting genetic data.

Early efforts led by the Personalized Medicine Coalition to produce industry-developed standards have stalled, but the inconsistency demonstrated by Collins, Venter et al. and most recently the GAO report have resulted in renewed interest from industry and regulators in addressing this issue.

Here, again, it is important to acknowledge the limited scope of this consensus. There is real agreement that standards are needed. The development and application of those standards, however, raises a host of questions, some of which are discussed below, to which there are hardly consensus answers.

Resolving Disputes. Beyond the few but important areas of consensus described above, it is certain that any emerging regulatory framework will have to tackle numerous difficult questions about which there is a decided lack of agreement. While it is impossible to list all of the areas of disagreement, some of the most pressing issues are:

• whether genetic tests should ever be offered directly to consumers without the involvement of a trained intermediary such as a physician or genetic counselor (i.e., should the third type of DTC genetic testing described above disappear);
• whether to create separate standards for non-clinical genetic tests, including genetic ancestry testing, and how to appropriately define the line between clinical and non-clinical tests;
• how to regulate genetic tests or products that include a large number of interpretations and claims in light of the need to constantly update those claims to best reflect current scientific understanding;
• whether clinical utility, or lack thereof, should be included in determining whether a particular genetic test or association is made available, whether DTC or otherwise;
• how to regulate interpretative tools that do not involve any new testing, but simply offer additional interpretations of raw genetic data already in a consumer’s possession;
• how to address the role of preliminary scientific findings and research in the development of interpretive tools, including genetic tests; and
• whether to focus regulatory efforts on pre-test measures that restrict the availability of potentially harmful genetic tests or post-test initiatives designed to evaluate how consumers perceive, use and react to genetic tests.

The answers to these questions and others, as well as the role industry, consumers and healthcare providers are permitted to play in the conversation, will determine the substance of any forthcoming DTC regulatory framework.

Answering Mary’s Question: To Test or Not To Test? While tomorrow always carries the possibility of a new and clearer day for the regulation of DTC genetic testing, the reality is that, for the moment, all we can say for sure is that the conversation is continuing. What was true in 2006 is still true today: genetic tests are available for purchase directly by consumers, and the regulatory requirements imposed on the companies that offer those tests are unclear and seemingly poised to shift at a moment’s notice.

As I have written several times before, I am optimistic about the long-term prospects for personal genomics in the United States, including DTC genetic testing. As the underlying technology and science continue to improve, the price and value of individual-level genomic data will continue to move in opposite directions, generating increased demand. In time, as increasing demand leads to increasing accessibility and, ultimately, to increasing familiarity – on the part of both consumers and regulators – the development of a tailored system of oversight that permits direct access while adequately protecting consumer safety and ensuring the accuracy and validity of DTC products can be developed.

But none of this will happen overnight. For all of our own interest, DTC genetic testing remains decidedly a niche phenomenon, and the industry poses novel and difficult challenges to regulators. It will take time for these to be ironed out and, in the short-term, it is possible that DTC genetic testing will be presented with a substantially more restrictive regulatory framework than at present.

Ultimately, while I cannot advise Mary Carmichael as to whether she should or should not go through with a DTC genetic test – that’s a personal decision – I can say that if she decides to proceed there is no time like today, for there is no guarantee that the option will still be on the table tomorrow.

_______________

¹The regulation of DTC genetic testing is far from uniform at the international level. Some countries, including Germany, appear to have effectively legislated DTC genetic testing out of existence, at least for the time being. Elsewhere, most notably the U.K., the conversation remains at the level of voluntary guidelines instead of formal – or even informal – regulation. Recent examples include the 2009 House of Lords report on genomic medicine and yesterday’s publication by the Human Genetics Commission of “A Common Framework of Principles for direct-to-consumer genetic testing services” (pdf).

The hearing on “Direct-To-Consumer Genetic Testing and the Consequences to Public Health” was conducted by the House Committee on Energy and Commerce Subcommittee on Oversight and Investigations. The meeting was chaired by Representative Bart Stupak of Michigan. Materials from the hearing, including a briefing memorandum, opening statements from Stupak and Representative Henry Waxman of California and witness testimony are available on the Committee’s website. Also available are materials from the Government Accountability Office (GAO) investigation into DTC genetic tests. These materials include the report the GAO submitted to Congress – “Direct-to-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices” (pdf) – as well as a YouTube video featuring excerpts from undercover phone calls made by the GAO to DTC companies as part of their investigation (both of which are discussed in detail below).

Opening Remarks. The hearings began with opening remarks from members of the House Committee. Chairman Stupak (MI) began (pdf) by reading from a statement in which he identified a familiar set of concerns pertaining to DTC genetic testing:

…how accurate are the companies’ analyses of direct-to-consumer genetic tests? By sending the customer the results of genetic tests without counseling or medical advice may cause more harm than good for some consumers? How accurate is the health information? How do companies explain differences in their analyses? Is there sufficient government oversight of the practices of direct-to-consumer genetic testing manufacturers?

Representative Stupak was followed in succession by Representatives Burgess (TX), Waxman (CA), Griffith (AL), DeGette (CO), Latta (OH), Christensen (VI) and Gingrey (GA).  As expected, there was considerable overlap in the opening statements. Nearly every Representative expressed his or her desire to ensure that the American public was presented with information that was accurate, safe and effective. They differed, however, in how they thought this might best be done.

Burgess and Waxman, for instance, were consistent in their hearing-long concern that the benefits of personalized medicine not be derailed either by unscrupulous DTC testing companies or by overly intrusive government regulation, and generally urged the use of a “deft touch” in regulating the industry. Others, including Representative Parker Griffith, struck a more alarmist tone, comparing the information supplied by DTC genetic testing companies to his throwing a snake into the middle of the Congressional hearing. According to Griffith, when presented with genetic risk information for serious diseases such as Alzheimer’s or cancer, consumers are likely to panic first and ask questions only later, if at all. Representative Phil Gingrey (GA) was on the same page, expressing his concern that DTC genetic testing might lead patients to jump to the wrong conclusions “or, indeed, jump off of a building” without appropriate guidance.

Other Representatives had specific issues they wished to explore. Representative Diana DeGette (CO) focused throughout the day on the privacy of genetic information collected and maintained by DTC companies. She acknowledged, quite correctly, that current laws (including GINA) provide incomplete protection against the misuse of genetic information. Representative Donna Christensen (VI) devoted her opening – and the majority of her subsequent questions – to the treatment of ethnic and racial minorities by DTC companies. Particularly worrying to Christensen were instances (documented by the GAO’s investigation) in which DTC companies failed to adequately notify minority consumers that their test results were incomplete or inaccurate. This typically occurred with respect to traits where the underlying genetic research was conducted in Caucasian populations and not yet verified in applicable minority populations.

Reports from the Regulators. Following the opening statements, the first witnesses called to testify were Gregory Kutz, Managing Director of Forensic Audits and Special Investigations for the GAO and Dr. Jeffrey Shuren, Director of the FDA’s Center for Devices and Radiological Health (CDRH). Kutz began by presenting findings from the GAO’s investigative report into DTC genetic testing products and marketing (pdf).

For those seeing the report for the first time (a group that included all of the DTC companies present at the hearings), Kutz’s testimony and the GAO’s report certainly raised some eyebrows. Although, by the GAO’s own admission, it “did not conduct a scientific study but instead documented observations that could be made by any consumer,” its conclusions to Congress were crystal clear: DTC genetic testing companies provide “results that are misleading and of little or no practical use.” The GAO reached this conclusion following a year-long, two-part investigation into the tests and marketing practices of DTC companies.

Part I: The Tests. During the first phase of the investigation, the GAO purchased 10 tests each from four companies (23andMe, Navigenics, Pathway Genomics and Decode Genetics). For each company the GAO selected five donors and submitted two samples – one containing factual information and one “using fictitious information, such as incorrect age and race or ethnicity.” In findings representative of those published in Nature by Ng et al. last year, the GAO found that the four DTC companies did not provide consistent risk estimates for all customers across the full range of conditions tested. Although the GAO report doesn’t do the math, Kutz testified before Congress that 58% of the time donors received different predictions for the same disease.

The issue of consistent genetic interpretation and risk reporting is an issue that DTC companies have widely acknowledged, both during the course of the GAO investigation and elsewhere. Previous efforts include a collaboration led by the Personalized Medicine Coalition to develop guidelines for scientific validity and 23andMe’s recent letter to the heads of NIH and FDA requesting assistance in developing transparent standards for reporting the positive and negative predictive values of genetic tests. There was widespread agreement among the companies, regulators and Congressmen that this is an area where DTC must improve in order to help avoid consumer confusion and there can be little doubt after today’s hearing that this will be a top priority for DTC companies and regulators alike.

The GAO also investigated how risk predictions matched against factual illnesses and family medical histories, with the GAO and several Representatives emphasizing the example of one donor with an implanted pacemaker for an irregular heartbeat who “was told that he was at decreased risk for developing such a condition.” While this particular example was widely discussed at the hearing, as Steven Pinker eloquently explained last year upon learning that he was at a high risk for baldness despite possessing a flowing mane, prediction is not the same as diagnosis. The fact that the two do not always align is far from damning evidence against DTC genetic testing, or indeed genetic testing in general. Unfortunately, this distinction was largely overlooked in the GAO report and in the Congressional hearing.

The GAO also criticized the four DTC companies for their poor performance in handling samples from (fictitious) African American and Asian customers and the companies’ failures to provide follow-up interpretation and consultation support as advertised. Here is the GAO’s summary of its findings from part one of the investigation:

Comparing results for 15 diseases, we made the following observations: (1) each donor’s factual profile received disease risk predictions that varied across all four companies, indicating that identical DNA can yield contradictory results depending solely on the company it was sent to for analysis; (2) these risk predictions often conflicted with the donors’ factual illnesses and family medical histories; (3) none of the companies could provide the donors who submitted fictitious African American and Asian profiles with complete test results for their ethnicity but did not explicitly disclose this limitation prior to purchase; (4) one company provided donors with reports that showed conflicting predictions for the same DNA and profile, but did not explain how to interpret these different results; and (5) follow-up consultations offered by three of the companies provided only general information and not the expert advice the companies promised to provide.

Part II: The Follow-Up. After receiving and comparing the test results supplied by the companies, the GAO followed up by conducting the second phase of its investigation: “undercover calls to the companies seeking health advice.” The GAO presented excerpts from those calls in the form of a dramatic YouTube video shown at the hearing.

A number of the encounters presented in the video are unquestionably troubling. The first, for instance, is a conversation between a GAO investigator and a company (identified by Kutz at the hearing as Navigenics) representative discussing the woman’s breast cancer results:

Fictitious Customer: So if I’m high risk, does that mean I’ll definitely get breast cancer?

Company Representative: You…you’d be in the high risk of, you know, pretty much getting it.

The GAO reports that “experts” considered “this statement ‘disconcerting’ and ‘horrifying’ because it erroneously implies that the test can diagnose breast cancer and could needlessly alarm consumers.” (Note also that this is a good example of the prediction/diagnosis confusion, discussed above.)

Other DTC encounters that received particular scrutiny included:

• a representative from a DTC company (identified at the hearing as Pathway Genomics) encouraging a fictitious consumer to collect and send in a saliva sample from her fiancé, without his consent, in order to surprise him with the results. Testing without consent - so-called “surreptitious testing” - is illegal in some form in more than 20 states, according to a recent report from the Genetics and Public Policy Center (pdf).
• a representative from a separate DTC company (identified by Representative Stupak as GeneWize Life Sciences) appearing to endorse the use of supplements as an alternative to or replacement for blood pressure and cholesterol medication. Such supplements, whatever their value, have not been approved by the FDA to treat, prevent or cure disease.

The GAO reported that 10 of the 15 companies it investigated engaged in what it termed “deceptive marketing, misinformation, and questionable practices.” There is really little room to disagree with the GAO’s findings. At best the examples highlighted by the GAO report reflect poorly informed company representatives; at worst they represent irresponsible marketing and even outright “fraud,” a term Kutz used in his testimony to Congress.

Where the report is lacking, however, is in its failure to identify which companies were guilty of which practices, and whether such practices are representative of the DTC genetic testing industry as a whole. It was initially confusing – to Congressmen, witnesses and the audience alike – whether the companies selected for follow-up interviews were the same as those selected for initial testing. (They were not; the pool for the second phase of the investigation was expanded by an additional 11 companies.) In testimony to Congress at the hearing, it was frequently unclear whether Kutz’s comments and conclusions (which often referenced various sections of the GAO report, jumping between the two sections) pertained to the DTC companies currently before Congress, to some or all of the 15 companies reviewed as part of the full GAO investigation or to the entire DTC genetic testing industry.

One result of this confusion was a tendency for Congressmen and even other witnesses to default to the lowest common denominator in describing the DTC genetic testing industry. Despite a clear range in testing and business practices (recall that for 1/3 of the companies investigated, the GAO uncovered no questionable marketing behavior) the term “snake oil” was repeatedly invoked to describe all DTC genetic tests.  For example, during one stretch of Q&A, Representative Stupak paused the conversation to remind the audience that “in the last 48 hours this committee went from Gulf Oil to Snake Oil; we are on top of our game.” Representative Griffith took it a step further, accusing DTC companies of being in the business not of selling genetic tests but of marketing, using the tests as a lure to encourage consumers to part with genetic and other information and adding them to marketing lists for vitamins, drugs and supplements (note: the prior link incorrectly identifies Representative Latta).

To reiterate, there is no question that the GAO uncovered disturbing and even “horrifying” instances of misleading and even fraudulent practices employed by certain DTC genetic testing companies. Steps must be quickly taken to halt such practices. But it remains unclear whether the examples cited by the GAO are representative of the entire DTC genetic testing industry and, for that reason and others, what the proper regulatory response to such practices should be.

In its section on Corrective Action Briefings, the GAO report notes that it briefed the FDA, NIH and FTC on its findings in May and June of this year. There can be little doubt that one or more of those agencies will soon take steps aimed at eliminating certain of the practices identified by the GAO. What those steps might be – and whether they will target specific companies or the industry as a whole – remains to be seen.

The FDA’s Plan. While details of what new regulatory oversight might be in store for DTC genetic testing were expectedly sparse, some modest insight came from the testimony of Dr. Shuren of the FDA (written testimony). Shuren’s oral and written comments emphasize that the FDA subjects a genetic test to regulatory oversight only if it qualifies as a medical device; “that is, if it is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease.” Shuren specifically mentioned genetic tests for ancestry or curly hair as tests that would not be subject to FDA regulation (and, it would appear, are likely to be permitted to remain on the market provided they are marketed and sold appropriately). Shuren’s comments lent weight to the argument that the FDA, at least for the moment, considers “intended use” to be a key factor in determining whether and how to regulate a genetic test.

Shuren also made it clear that the FDA did not consider many of the genetic tests provided by DTC companies to be LDTs because they were purchased from another company and not developed in-house. Shuren singled out Pathway Genomics (which operates its own CLIA-certified lab) as an example of a non-LDT DTC genetic test. Shuren did not clarify whether the FDA intended to apply this same rigorous assessment of what is and what is not an LDT to any of the estimated 2,500 – 5,000 (Shuren’s own “conservative estimate”) non-DTC genetic tests currently offered for sale as LDTs without FDA clearance or approval under the Agency’s policy of “enforcement discretion.”

With respect to DTC genetic tests, Shuren’s written comments – briefly echoed in his testimony – reflect the FDA’s previously reported concern with the changing nature and scope of genetic testing. “For example, one company provided test reports for 17 diseases, conditions, or traits in 2008 but provided over 100 types of results in 2010.” Shuren’s testimony cites “escalation in risk and aggressive” marketing as the reasons that ultimately convinced the FDA to send Pathway Genomics a letter on May 10th informing the company that its product was a medical device subject to regulation. Under questioning from Representative Burgess, Shuren admitted that he thought the FDA “should have acted sooner” to address DTC genetic tests.

So what is the FDA’s plan now that the public meeting and Congressional hearing have come and gone? Will the Agency continue to send informational letters to DTC companies and start to take even more aggressive actions? That will likely be part of the strategy – perhaps even a significant part – but Shuren also outlined the barest details of a plan to help allow DTC genetic tests to remain (or at least re-enter) the market. Shuren indicated the FDA was looking into the possibility of working with the NIH, scientific experts and community representatives to review the scientific literature and identify viable genetic association claims and appropriate standards of interpretation. Shuren also mentioned that the FDA is looking at ways to allow the Agency to approve general tests or testing platforms through a scheme that would allow additional data to be added to tests, and claims or interpretations presented to recipients, without having to seek additional FDA approval or clearance. Details of the plan were minimal, and given the context seem likely to apply both to DTC genetic tests and LDTs more broadly, but we will need to wait for the FDA to publicly elaborate on its plans (Shuren’s written comments do not address either of these topics).

None of the above should be taken to suggest that the FDA intends to let DTC genetic testing companies off of the hook when it comes to FDA clearance or approval. In response to questions from Representatives Waxman and Burgess, Shuren indicated that he thought most DTC tests would be classified as Class III or Class II devices (not Class I or Class II, as Burgess had suggested) and that, while companies that come to the FDA with data and low-risk tests in hand might be permitted to remain on the market for an interim period pending FDA review, “if they aren’t ready with the data or there are concerns about patient safety, then we would not allow them to market” their tests.

As usual, precise details and timing remain “to be determined,” or at least “to be publicly announced.”

Over the Horizon. Representatives Burgess and Waxman also pressed Shuren to discuss whether he felt the FDA was prepared to address the challenges of personalized medicine, including technologies (presumably including whole-genome sequencing) that are “just over the horizon.” Waxman, in particular, while expressing his desire to ensure that companies not mislead the public, worried about setbacks that might result from branding the entire industry as a group of charlatans and responding by pulling all of the products from the market. Shuren, for his part, held fast to his line that the FDA’s primary concern was that information presented to patients was truthful, accurate and understandable.

Similarly, Burgess worried whether the FDA possessed the tools (read: resources) to deal with what lies ahead, including the potential regulatory responsibility for entirely new areas of personalized medicine such as DTC genetic testing and LDTs. Shuren responded that the FDA has authority to adapt its current regulations and resources to new technologies, and was considering “down-regulating” less risky devices to make resources available for DTC/LDT regulation.

Finally, Shuren was asked by Waxman whether he thought DTC genetic testing companies were helping to advance the state of scientific knowledge, thereby bringing the ideal of personalized medicine closer to reality. Shuren responded that he believed DTC companies were interpreting and synthesizing scientific research, but not directly contributing. (23andMe general counsel Ashley Gould later offered her own perspective, citing recently published research derived from customer data as evidence to the contrary.)

DTC Takes the Stage. After the regulators stepped down, representatives from 23andMe, Navigenics and Pathway Genomics were invited to testify, along with Dr. James Evans of the University of North Carolina-Chapel Hill. In addition to his many titles and responsibilities, Dr. Evans was the “primary consultant” to the GAO during the course of its investigation.

Evans’ prepared remarks (pdf) largely reflect his opening statement to the Committee, which focused on the need to balance the ample benefits of genetic testing with the critical importance of ensuring that patients and consumers receive high quality and accurate information, that their privacy is protected and that the claims made on behalf of genetic testing “comport with reality.” Throughout his comments Evans was adamant that while more regulation was needed, particularly over DTC genetic tests, individuals should continue to be permitted direct access to their genomic information:

I believe that the public deserves access to the information contained in their own genomes. But they also deserve an honest accounting of what such information means and the assurance that it is derived in a manner that ensures quality, reliability and confidentiality.

The opening statements that followed from Ashley Gould of 23andMe (written testimony), Vance Vanier of Navigenics (written testimony) and David Becker of Pathway Genomics (written statement) were comparatively brief.

Gould talked about 23andMe’s achievements in advancing genomic access and research and, while acknowledging the necessity of a sensible regulatory framework that ensures consumers receive scientifically valid, accurate and understandable information, emphasized the need for more data about the risks and uses of DTC genetic testing prior to regulation. Vance Vanier followed by describing DTC genetic testing as a tool that could help fight preventable disease and emphasized that not all DTC genetic testing companies operate using the same business model or hold themselves to the same standards. Vanier highlighted Navigenics’ focus on clinical genetic testing and its commitment not to sell or share any customer data with third parties (both distinctions from other DTC genetic testing companies). In wrapping up the introductory comments, David Becker of Pathway Genomics largely echoed Vanier and Gould while reminding the Committee that, while he believed a reasonable regulatory framework could be developed to permit DTC genetic testing, Pathway had already voluntarily suspended DTC sales of its products while working with the FDA to address its concerns.

After that the questions – and attacks – resumed. As the only witnesses not provided with access to the GAO report prior to the hearing, the DTC representatives were at a distinct informational disadvantage from the outset. Members of Congress peppered the companies with questions about whether they agreed that the “triumvirate” of companies:

• needed more consistent standards for genetic risk prediction (all three agreed they did);
• needed some form of additional regulatory oversight (all three agreed they did);
• must be willing to implement strong consumer privacy protection measures (all three agreed they did); and
• were providing medical advice and interpretations (23andMe and Pathway largely held to the company line that their tests are for “informational or educational” purposes, while Navigenics embraced the clinical aspects of its service).

As the panel wound down, Representative Stupak pressed the DTC companies to consider withdrawing their products from the marketplace pending development of an adequate system of regulatory oversight. Gould declined to take the bait, focusing on the rights of consumers to access their genetic information. Vanier attempted to argue that such a drastic move would harm not only Navigenics but other small businesses as well, and render the entire industry hostile to investment and invention. Vanier was quickly redirected by Stupak into conceding that the company was pre-profitable and “losing money every year.” Becker again pointed out that Pathway had already ceased offering its tests for sale directly to consumers and saw no need to withdraw completely from the marketplace.

The final line of questioning from Representative Burgess concerned international efforts to review or regulate DTC genetic testing, with all three companies conceding that, to their knowledge, the FDA was taking the lead in pursuing regulatory oversight of the industry. While neither the Congressmen nor the companies seemed overly familiar with international efforts to review and regulate DTC genetic testing, they clearly exist. In the U.K., for instance, the House of Lords reviewed the DTC genetic testing landscape in its 2009 report on genomic medicine and the Human Genetics Commission is currently developing a “Common Framework of Principles” for DTC genetic testing. Other countries have been even more proactive, with Germany enacting legislation that effectively banned all DTC genetic testing just last year. It will be interesting to see whether the heightened scrutiny of DTC genetic testing by U.S. regulators prompts regulatory or legislative bodies in other countries to take a closer look at adjusting or enforcing laws and regulations pertaining to DTC or other forms of genetic testing.

The Future of DTC? Four and a half months ago, in “Why the State of Personal Genomics is Not as Dire as You Think,” I wrote the following:

Over time, the diversification of personal genomics will be a good thing, aiding in the identification of viable business models and separating legitimate businesses from snake-oil salesmen. But it will require time, investment (not all of which will be recouped) and quite probably additional legislative or policy interventions, particularly in the areas of intellectual property and regulatory review that apply to personal genomic services…

Looking ahead, I am confident that [Linda] Avey is correct when she writes that personal genomics will become “such an every day concept that future generations will be amused that we even questioned its viability.” And judging from the abundance of activity and advancement in the field as a whole, as well as the dozens of entrepreneurs and investors that have contacted me in recent months to discuss their plans for starting or growing personal genomics businesses, I think it will hardly take a generation before personal genomics moves mainstream.

In the months since, the field of personal genomics has been shaken by a string of regulatory developments, each seemingly more dire than the last. From the failed Pathway Genomics/Walgreens partnership to the FDA’s letter-writing campaign to today’s events, especially the GAO’s conclusion that DTC genetic tests mislead consumers and are of no practical use, it is clear that “additional legislative or policy interventions” are no longer probable. They are inevitable, and they are likely to be substantial.

In spite of these developments - and no matter how many times the term “snake oil” is thrown around – I continue to believe that it is premature to declare the death of DTC genetic testing, or its close cousin personal genomics. There remains a broad spectrum of possible responses available to Congress and the various regulatory agencies now scrutinizing the field of genetic testing and, while today’s events did not paint DTC genetic testing in the most favorable light, the industry and many of its companies have received considerable (and deserved) praise on other days.

Obviously, much depends on where the regulatory and legal landscape moves from here. Certain possibilities, such as enhanced genetic test transparency and FTC oversight to separate legitimate tests from fraudulent ones, would strengthen the DTC industry over the short- and long-term. Others, including applying the traditional medical device regulation framework to all or most DTC genetic tests, have the potential to deal a considerable setback to DTC companies, consumers and investors. With nearly limitless possibilities, everything hinges on the precise details and timing of the new regulatory framework, whatever it may be.

No matter what comes next, over the long term I continue to believe – based on my day-to-day interactions with investors, companies, consumers and researchers – that there is considerable demand for direct consumer access to personalized genetic information. And this demand is only going to increase with time. The personal genomics landscape is certain to change, possibly drastically, in the coming weeks and months. But I am extremely doubtful that it will be wiped clean. As long as demand persists, I have confidence that companies, consumers and regulators will find a way to work together to continue to provide individuals with direct access to and control over their genomic data.

In letters dated July 19th, the first day of the FDA’s public LDT meeting, the Agency continued its crackdown on direct-to-consumer (DTC) genetic test providers, mailing letters to 14 providers of genetic tests. A list of all 14 companies and tests appears below.

The Letters. The letters are similar to the five untitled “letters to industry” the FDA sent out in early June to 23andMe, Navigenics, deCODE Genetics, Knome and Illumina. While briefer than the earlier letters, the new batch of letters reach the same conclusion: each of the companies is marketing a genetic test that, according to the FDA, meets the definition of a “device” under Section 201(h) of the Federal Food Drug and Cosmetic Act (FFDCA). Therefore, each test must receive FDA clearance (510(k)) or approval (PMA). Not surprisingly, the FDA “conducted a review of [its] files” but was “unable to identify any [such FDA] clearance or approval” for any of the tests. The companies are asked to respond to the FDA within 15 days.

By comparison, the June 10th DTC letters were lengthier and also contained (1) information regarding the specific devices/products identified as problematic by the FDA, (2) a recitation of the FDA’s authority for premarket regulation of medical devices under the FFDCA and (3) a description, in most cases, of a prior meeting between the company and the FDA. The June 10th letters also urged the companies to “take prompt action to respond” to the letter, instead of setting out a definite timeframe.

The other notable difference between the two sets of FDA letters is who signed them. The June 10th letters were signed by Dr. Alberto Gutierrez, Director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD). The July 19th letters, on the other hand, were signed by OIVD Deputy Director James Woods. It appears that over the last month OIVD and Dr. Gutierrez have gained sufficient comfort with their letter-writing campaign to push the task down the chain of command.

The Tests. Here is the list of all 14 companies who received FDA letters dated July 19th:

• Graceful Earth Inc. Concerning the Graceful Earth Alzheimer’s Test
• SeqWright DNA Technology Services, Inc. Concerning the SeqWright Genomic Profiling Service (GPS)
• Interleukin Genetics, Inc. Concerning the Inerent [sic] Health
• DNATraits Concerning the Ashkenazi Jews Genetic Disease Panel
• CyGene Direct™ Concerning the Metabolic Health Assessment DNA Analysis Test
• Consumer Genetics, LLC Concerning the AsthmaGEN DNA Test
• Matrix Genomics, Inc. Concerning the Matrix Genomics Breast Cancer Panel
• The Genetic Testing Laboratories, Inc. Concerning The Genetic Testing Laboratories DNA Predisposition Test
• Sequenom, Inc. Concerning the SEQureDx™
• EnteroLab Reference Laboratory Concerning the Gene Test for Gluten Sensitivity/Celiac Sprue
• BioMarker Pharmaceuticals, Inc. Concerning the Gene Essence™
• DNA Dimensions Concerning the Predisposition DNA Test
• HealthCheckUSA Concerning the HealthCheckUSA Celiac Disease DNA Test
• easyDNA Concerning the Genetic Predisposition Health Test

Most but not all of these tests appear to be offered for sale directly to consumers. All appear to be marketed DTC. For some tests it can be difficult to tell. For instance, while Matrix Genomics’ breast cancer test can be purchased directly online, I was unable to find a way to order DNA Dimensions’ “Concerning the Predisposition” test through the company’s website, although the company does have a Facebook page. Other products, such as Sequenom’s SEQureDx™ test which, according to the FDA (pdf), measures “circulating cell-free fetal (ccff) nucleic acids (RNA or DNA) in a pregnant woman’s blood sample for fetal gene and chromosome abnormalities, do not appear to be available for purchase without a physician’s involvement.

The range of tests and test providers makes it impossible to determine why or how the FDA selected these particular tests for the current round of letters. Matrix Genomics, for instance, also offers Alzheimer’s, Heart Attack, Warfarin, Plavix and Parkinson’s tests. The FDA’s letter, however, only mentioned its breast cancer panel. And even with these 14 additional letters, as I wrote last time, there are still dozens – and possibly more – of genetic tests marketed and sold directly to consumers that have not been identified by the FDA. The Genetic and Public Policy Center’s (GPPC) recently updated chart of DTC genetic testing companies (pdf) lists 30 companies, and similar lists from AccessDNA and DNA Test Index include dozens more.

What’s more, as with the case of Sequenom, it’s not clear that the test is being offered directly to consumers. If that’s the case, and the FDA has moved on from sending letters to DTC genetic testing providers to sending letters to providers of more traditional LDTs, then the FDA has thousands of potential letter recipients to choose from at GeneTests.org. [Update: Kirell Lakhman of GenomeWeb's The Sample writes that Sequenom was the only non-DTC genetic test maker of the 14 and, what's more, "Sequenom hasn't even begun selling the assay. In fact, the company is still collecting clinical samples for studies..."]

More than a month after the first five DTC letters went out, and in the immediate aftermath of the FDA’s public meeting, companies, consumers, healthcare providers, investors and the general public remain largely in the dark about the factors the FDA is using to determine which tests and test providers to target. Is it a test’s intended use? The fact that it is marketed DTC? The fact that it is sold DTC? The complexity of a particular test? The perceived or actual lack of analytical validity, clinical validity and/or clinical utility? Any or all of those factors, as well as numerous others, might be influencing the FDA’s activity in this area. Until the FDA offers up a general policy for public review – and hopefully for comment as well – there is no way for anyone outside of the Agency to know where the FDA might be headed next. For the moment, at least, it appears that company-by-company, test-by-test letter mailing continues to be the Agency’s preferred approach.

The Timing. During the FDA’s two-day public meeting earlier this week, the Agency repeatedly emphasized that its policy with respect to the regulation of LDTs – including DTC genetic tests – had not been finalized. That was, after all, one of the primary purposes of the meeting: to “serve as a forum to discuss issues and stakeholder concerns surrounding LDT oversight.” The meeting even included an entire session devoted to DTC testing, in which participants were invited to discuss the risks and benefits of DTC genetic tests.

On the topic of the FDA’s willingness to listen to the LDT community, here is what I wrote after the first day of the meeting.

Openness. One reason that a fully articulated regulatory policy is unlikely to emerge from the FDA in short order is that the Agency appears strongly committed to gathering stakeholder input and developing regulations that respond to that input. This is a standard talking point for any regulatory agency, and with numerous conflicting opinions over whether and how the FDA should regulate LDTs, it is obvious that the Agency will not satisfy every stakeholder. Still, I was struck by the Agency’s commitment—in both private and public conversations—to understanding the issues and keeping an open mind about how to proceed. There seemed no reason to doubt Dr. Mansfield when she said that when it comes to LDT regulation, “nothing is set in stone; we have not made any decisions.” This only serves to underscore the importance of participation in the regulatory process which, if attendance at this meeting is any indication, is a strategy that the LDT community has embraced. (emphasis added)

The July 19th letters certainly seem to give the lie to the Agency’s position, including Dr. Mansfield’s comments, that nothing is set in stone when it comes to LDT regulation.

The FDA’s policy with respect to DTC genetic tests, while far from clear, certainly seems to be moving ahead unchanged, public meeting or no. The timing of the letters, which were mailed the same day as the meeting began, suggest that the FDA had no intention of revisiting its decision to step up oversight of DTC genetic tests, no matter what might have been said on Monday and Tuesday.

So what are we to make of the timing of the timing of the FDA letters?

On the one hand, as was pointed out by the Agency after the previous round of letters, these are untitled “letters to industry” and are less severe than a formal FDA “warning letter.” The letters identify Agency concerns and give the named companies time to respond. (Depending on the response, or lack thereof, the FDA may follow up with warning letters down the road.) The letters also subject other lesser-known DTC companies to FDA scrutiny similar to that received by the companies named in the June 10th letters, although, as mentioned above, that level of scrutiny is hardly industry-wide at this point. It is possible that the FDA is slowly but surely identifying DTC (and select other) genetic tests that it believes are particularly problematic, and mailing out standardized letters as it does so. It is possible that the timing is largely coincidental.

On the other hand, coincidence or not, it is difficult to believe that the timing of the FDA’s latest letters won’t provide significant fuel for those who believe that the Agency has already made up its mind about how it intends to regulate LDTs – including DTC genetic tests – and that the two-day public meeting was simply window dressing to help bolster the Agency’s defense against any future challenges to its soon-to-be-enacted regulatory policy.

While I continue to think that the FDA is indeed listening to the LDT community as it develops its regulatory strategy – if for no other reason than that the topic is so complex that the FDA is unlikey to sort out all of the details quickly, or on its own – this latest development gives me pause. One of the many themes that emerged over the two-day public meeting was that the FDA will need assistance and buy-in from regulated parties in order to effectively implement its new system of LDT oversight, whatever it may be. Allowing those stakeholders to have a say in the development of the FDA’s regulatory policy is an excellent way to secure that assistance and buy-in; but that strategy only works if the FDA can convince the LDT community that it is actually listening. Coincidental or not, the timing of this round of FDA letters is unlikely to help the Agency in that regard.

What’s Next. Three of the five companies named in the June 10th letters will be on Capitol Hill first thing tomorrow morning for a House of Representatives hearing on “Direct-to-Consumer Genetic Testing and the Consequences to the Public Health.” The House Committee on Energy and Commerce posted a briefing memo (pdf) for the hearing earlier today. The memo provides additional background information (including information about the GAO investigation, which apparently was initiated all the way back in March 2009) and includes a witness list.

In addition to representatives from Pathway Genomics, 23andMe and Navigenics, the GAO and FDA will be represented. Dr. James Evans of UNC-Chapel Hill, and a member of the SACGHS, will also testify. For those interested in following the hearings from afar, Andro Hsu has posted a link to a live webcast that will, hopefully, be active once the hearings begin.

None of the 14 companies recently named by the FDA have been invited to appear before the House, but that’s no guarantee that Congress won’t invite some or all of them to take their own trip to Washington at some future date.

Something Old, Something New. In addition to a reiteration of yesterday’s themes – especially the need for additional data demonstrating how LDTs are used and what harms, if any, they have inflicted on consumers and patients – a few new areas of discussion emerged over the course of the day. Those included:

On Behalf of Our Members. Industry and professional organizations, including the College of American Pathologists (CAP), Association for Molecular Pathology (AMP), American Clinical Laboratory Association (ACLA), AdvaMed and others, were well represented in both the comment and panel sessions throughout the day. While the groups did not see eye-to-eye on every issue, they did share several common concerns. Chief among these was the need for the FDA to involve non-governmental third parties with the design of any LDT regulations and, importantly, with the subsequent communication to and implementation by laboratories and professionals. (No surprise that there were numerous individuals and organizations eager to volunteer for this task.)

Dr. Gail Vance of CAP captured the sentiment when she pointed out that  “FDA-speak is foreign to laboratories. We speak CLIA. We are aligned with CLIA. We don’t have a clue about the FDA.” Speakers throughout the day, especially in the closing session on Education and Outreach, echoed Vance’s concern and stressed the critical role that third parties must play in ensuring that FDA’s regulatory intent, whatever it may be, is translated into laboratory practice.

A Question of Access. The other key difference from Day One was Day Two’s focus on the role of direct-to-consumer (DTC) genetic testing, which occupied a majority of the afternoon.

The DTC discussion began with ten public commentators presenting to the FDA their perspectives on DTC genetic testing and the steps FDA should take (or not take) to regulate the industry. Several commentators, including Gaia Bernstein of Seton Hall University School of Law and Jeremy Gruber of the Council for Responsible Genetics, expressed their strongly held belief that DTC testing without the involvement of a medical professional places individuals at serious risk of adverse outcomes ranging from privacy violations to misguided and dangerous medical decisions. Bernstein took the familiar physician-as-gatekeeper argument one step further, expressing her belief that individuals should be required to engage a medical professional not only to access and interpret genetic information, but even to decide whether and what genetic information was safe to request in the first instance.

DTC genetic testing also had its advocates, including 23andMe co-founder Anne Wojcicki (transcript and slides) and Katherine Borges, Director of the International Society of Genetic Genealogy (ISOGG), who delivered one of the most impassioned arguments for prioritizing individual access over FDA regulation. (The complete text of Borges’ comments is available via The Huffington Post.) Borges sounded a familiar refrain in arguing that the FDA should not restrict consumer access to genetic information “without credible, compelling scientific data to support” such regulation.

The panel discussion following the public comments was a more moderate affair, with Dr. Ann Willey of New York State’s Department of Health taking pains to explain the terminological distinctions between direct-to-consumer marketing in the therapeutic context (where drugs are marketed to consumers but a doctor must still order the drug), direct access testing (pdf) in the medical device/diagnostic context (where an individual may initiate a test, although a healthcare provider is still typically involved in the receipt and interpretation of results) and direct-to-consumer genetic testing as practiced by companies such as 23andMe (where DTC services are marketed directly to consumers, ordered directly by consumers and the results delivered directly to consumers).

As the panel moderator, Dr. Muin Khoury of the Centers for Disease Control and Prevention (CDC), urged the panelists to examine the crucial differences between DTC tests and the broader category of LDTs, the distinctions between DTC advertising, ordering and delivery came up several times. While the full DTC model was not necessarily without its advocates, including Dr. Vance Vanier of Navigenics (a personal genomics start-up that once offered results directly to consumers but has since abandoned that business model), the panel’s lack of a represenative from a company offering full DTC genetic testing certainly seemed an odd choice.

DTC, Risk and the Media. There was one other area of DTC discussion where comments made at the meeting managed only to scratch the surface of an important and ongoing discussion. In addition to arguing for maintaining broad consumer access to genetic data, Katherine Borges also took the media – and particularly journalist Rob Stein of The Washington Post - to task in her public comments for distorting and sensationalizing the risks posed by DTC genetic testing. Borges argued that “sensationalistic media articles that relate anecdotal cases should not be used as a basis to regulate.”

As background, when Pathway Genomics first announced its intent to sell saliva collection kits for its DTC genetic testing service in certain Walgreens stores, Stein and The Washington Post were quick to question the decision, expressing concern that such a move could “open a Pandora’s box of confusion, privacy violations, genetic discrimination and other issues.” It was in that same article that OIVD Director Dr. Alberto Gutierrez first indicated that the FDA had some concerns about Pathway’s test. Concerns that quickly led to Pathway and Walgreens abandoning their commercial partnership, first Congress and then the FDA sending letters to several prominent DTC companies and, ultimately, the FDA’s decision to seek to regulate all LDTs.

This past weekend, as a preview to the FDA’s public meeting, Stein tackled the topic of genetic testing regulation, and examined once again the risks associated with DTC genetic testing. Although Stein’s piece is well-balanced on the topic of regulating genetic tests (both LDTs and DTC genetic tests), several commentators, including Borges and Daniel MacArthur of Genetic Future/Genomes Unzipped, have criticized Stein for misrepresenting or exaggerating negative stories about personal genomics. Stein begins his most recent article by recounting a sample swap that impacted fewer than 100 23andMe customers in early June. At the time I wrote that the sample swap, and in particular 23andMe’s response, was actually evidence in favor of personal genomics. Stein disagrees, but as MacArthur writes (and supports with considerable evidence), the “anecdotes [used by Stein] appear to have been very selectively presented.” [Update: as MacArthur's post makes plain, much of the "evidence" that Stein distorted the 23andMe sample swap comes courtesy of 23andMe customer, genetic genealogist and blogger CeCe Moore, who offers a nearly line-by-line debunking of Stein's portrayal of the event.]

What’s Next. The risks and benefits of DTC genetic testing will receive another airing first thing tomorrow morning, when the House Committee on Energy and Commerce will hold a subcommittee hearing on “Direct-to-Consumer Genetic Testing and the Consequences to the Public Health.” (Details of the hearing have not been published online, but I am told it will be held at 9:30 a.m. in Room 2123 of the Rayburn House Office Building.) In addition to testimony from the three companies who received Congressional letters in mid-May (Pathway Genomics, 23andMe and Navigenics), Turna Ray of Pharmacogenomics Reporter reports that the GAO’s Forensic Audit and Special Investigations Unit will present findings from its investigation of four genetic testing companies (the three receiving Congressional letters, along with Decode Genetics).

After the House hearing concludes, the waiting will continue. The FDA is currently accepting written comments on its proposal to regulate LDTs, and the NIH continues to hold open the window for comments on its forthcoming Genetic Testing Registry. It will likely be September at the earliest before either agency has had an opportunity to review those comments and put forward a more concrete proposal for public comment.

Today the Committee has followed up with another letter, this one directed to 23andMe president and co-founder Anne Wojcicki, inquiring into the circumstances surrounding the company’s recent and widely reported sample swap. The letter (pdf), which is signed by the same four Representatives (Waxman, Barton, Stupak and Burgess) requests the following:

1. All internal and external communications relating to the collection, processing, and analysis of DNA samples affected by incorrect processing, including all communications with third-party laboratories and all instructional documents detailing appropriate handling of DNA samples;

2. All internal company policies, directives, and written guidance materials relating to the company’s handling of errors in the collection, processing, and analysis of DNA samples; and

3. All documents relating to previous instances in which 23andMe customers received DNA results belonging to other persons.

As was true of the last round of Congressional letters, this appears to be a broadly worded request for all relevant information. It’s unclear to me whether the third request – for information relating to prior data mix-ups – is simply a Congressional fishing expedition or a request rooted in evidence that this is a problem 23andMe has had before. 

One thing that this letter makes abundantly clear – coming as it does only a week after the 23andMe sample swap was first reported by Daniel MacArthur of Genetic Future, and just days after the FDA announced its intention to regulate several DTC genetic tests, including 23andMe’s test, as medical devices –  is that DTC genetic testing has the full attention of this particular Congressional Committee.

After spending the majority of the time since its inception three years ago free from significant legislative and regulatory oversight, particularly at the federal level, the DTC genetic testing industry is now indisputably under the microscope.

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.

Today Chairman Henry A. Waxman, Ranking Member Joe Barton, Subcommittee Chairman Bart Stupak, and Subcommittee Ranking Member Michael C. Burgess sent letters to 23andMe, Inc., Navigenics, and Pathway Genomics Corporation in light of recent reports that at least one of the companies is seeking to sell personal genetic testing kits in retail locations, despite concern from the scientific community regarding the accuracy of test results.

The Committee is requesting information from the companies on several aspects of the tests: How the companies analyze test results to determine consumers’ risk for any conditions, diseases, drug responses, and adverse reactions; the ability of the companies’ genetic testing products to accurately identify any genetic risks; and the companies’ policies for the collection, storage, and processing of individual genetic samples collected from consumers.

Signed by the Chairman and Ranking Member of both the full Committee (Henry Waxman and Joe Barton) and its Subcommitee on Oversight and Investigations (Bart Stupak and Michael Burgess), the three letters (23andMe, Pathway Genomics, Navigenics) appear to be substantively identical.

The Committee appears to be interested in gathering information. Lots and lots of information. The letters are impressively broad in their scope, which is unsurprising given that this is the first publicly reported Congressional investigation into the current generation of DTC genetic testing companies. (A previous investigation into several companies offering nutrigenetic testing culminated in this GAO report to Congress.) The Committee is seeking the following information for each DTC company:

(1) description of available tests, including which conditions, diseases, drug responses, etc. are tested;

(2) policies with respect to the involvement or availability of genetic counselors and/or physicians in conjunction with its tests;

(3) scientific support for the accuracy of its tests (including proficiency testing) and validity of its reported associations;

(4) policies for processing and use of DNA samples, including privacy protections and third party use; and

(5) compliance with the Federal Food, Drug, and Cosmetic Act (FFDCA) and FDA regulations.

The DTC genetic testing landscape has certainly shifted dramatically. This time last week, Walgreens and CVS were still planning to offer DTC genetic tests from Pathway Genomics on drugstore shelves nationwide. Since then, first the FDA and now Congress have launched investigations into DTC genetic testing.

As for what happens next, that’s anybody’s guess. The FDA, in its letter last week to Pathway, gave the company until May 25th to demonstrate that it has proper FDA approval or to explain why such approval is not necessary. Congress is proving slightly more generous, giving the three companies until June 4th to respond to its information request. Rest assured that nobody at any DTC genetic testing company, including those not currently targeted by either the FDA or Congress, of which there are plenty, is going to be getting much sleep over the next few weeks.

The Genomics Law Report will have more on this story, and the future of DTC genetic testing and regulation, as developments occur.

According to an MSNBC story, the FDA sent a letter to Pathway “asking the test maker to show it has regulatory approval, or prove why [the test] should be sold without the agency’s blessing.” In response, Walgreens is “elect[ing] not to move forward with offering the Pathway product to our customers until we have further clarity on this matter.”

Back to the Drawing Board. Despite its obvious significance, it is hard to be surprised by this latest development. When the Director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) tells The Washington Post that you would be selling an “illegally marketed device” if you proceed as intended, you should know the letter is already in the mail and retreat to the drawing board as quickly as possible.

The real question is what happens next. For years the FDA has been watching the development of the DTC genetic testing industry from the sidelines. No longer. But what we don’t know is just how extensive a regulatory push the FDA is planning to make.

According to MSNBC, the FDA letter, which was signed by the Deputy Director of OIVD, considers Pathway’s “Genetic Health Report…to meet the definition of a device as that term is defined in section 201(h) of the Federal Food Drug and Cosmetic Act.”

Section 201(h)(2) of the Federal Food, Drug, and Cosmetic Act (FFDCA) 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

That definition covers a lot of ground, but what it almost certainly does not cover is a saliva collection kit on its own (without more, that’s just a means of collecting and storing saliva), which is all that Pathway Genomics was actually planning to place on Walgreens’ shelves. Although I have not seen the full text of the FDA’s letter the excerpted sections strongly suggest that the FDA is focusing its regulatory attention on Pathway’s actual genetic test and its subsequent interpretation of the test results, and not on the fact that Pathway was opening up a new distribution channel for those tests. [See subsequent GLR post for analysis of additional comments from the FDA. The FDA has also made its letter to Pathway Genomics public.]

Industry-Wide Regulation? If that is in fact the case, it’s difficult to see other DTC genetic testing companies escaping increased regulatory scrutiny. As we’ve written several times previously, apart from the matter of visibility, Pathway’s tests appear to be highly similar, both in terms of what they test and how they present the results, to the tests offered by other DTC genetic testing companies. It would come as no surprise to find out that the FDA has sent similar letters to other DTC genetic testing companies, or will in the coming days and weeks. [Update: The New York Times reports that this is exactly what has been happening.] In fact, the only outcome that would surprise me here is if the FDA focused its regulatory attention exclusively on Pathway, while ignoring its competitors.

It should be added that, at least for the moment, all the FDA has done is backed up several public comments that suggest it believes Pathway is on the wrong side of the law with a formal letter requesting more information from the company. That letter also leaves a window, however small, for Pathway to “prove why [the test] should be sold without the agency’s blessing.” Pathway, for its part, continues to claim that it can sell its products without FDA approval because they are “not intended for use in diagnosis, treatment or for the mitigation or cure of a disease,” and therefore fall outside of the FFDCA’s definition of a device.

Will the FDA buy that argument? If it does not, and the agency decides to regulate DTC genetic tests, what will those regulations look like? Will it require Pathway – and other DTC genetic test providers – to pull tests from shelves and websites until they can be reviewed and approved by the FDA, or will there be some manner of regulatory transition period designed to minimize disruption to an industry that is still in its early stages?

A Challenge for the FDA. Despite the flurry of activity over the past few days, the FDA’s regulatory policy with respect to DTC genetic testing leaves us with far more questions than answers.

It has long seemed inevitable that the FDA would regulate DTC genetic tests in some fashion. Indeed, as Turna Ray reported today in Pharmacogenomics Reporter, many of Pathway’s peers have indicated that they would welcome federal regulation:

23andMe, Navigenics, and Decode have all indicated they would welcome more federal guidance for the DTC genomics industry. Particularly after New York and California decided to regulate certain firms two years ago, industry leaders from DTC genomics firms noted that they prefer to have more overarching and definitive guidance from federal health regulators than have to deal with authorities on a state-by-state basis.

The fact that the FDA is finally tackling the regulation of DTC genetic tests is not a problem per se for the industry. But it could quickly become one. To avoid this, what is needed from the FDA is a clear set of guidelines, provided in a timely fashion, that address the agency’s concerns without unduly burdening an industry that is still trying to establish itself. That’s quite a challenge for an agency not always known for its promptness or clarity. DTC companies, customers and commentators will all be anxiously watching to see if the FDA is up to the task.