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.

We also promised to take a closer look in today’s post at several substantive features of the EEOC’s new regulations.

Defining the Terms. The EEOC, the government agency generally responsible for enforcing federal employment nondiscrimination laws, was the logical choice to promulgate regulations under GINA’s Title II, which governs the use of genetic information by employers and similar entities. But not all of GINA’s statutory provisions were within the EEOC’s area of expertise.

For that reason, the EEOC solicited help from outside agencies, including the National Human Genome Research Institute (NHGRI), to aid in developing both the proposed and final regulations. Despite a few stumbles with the science (notably its description of the BRCA1 and BRCA2 genes), the EEOC’s final regulations—as well as its explanatory preamble—are laudably clear and informative. The preamble and the regulations themselves include numerous illustrative examples—something that was largely lacking in the draft regulations—and they should be particularly helpful to the predominantly non-scientific audience tasked with implementing GINA.

For example, public commenters requested additional clarification with respect to what does and does not constitute a “genetic test.” The EEOC responded in spades. According to the EEOC, genetic tests include (i) BRCA testing and other diagnostic cancer testing, as well as prognostic testing for Huntington’s Disease, (ii) carrier screenings of adults to determine the risk of conditions such as cystic fibrosis or sickle cell anemia, (iii) reproductive genetic testing and screening of all kinds, including amniocentesis, newborn screening and preimplantation genetic diagnosis, (iv) pharmacogenetics testing and (v) DNA testing for ancestry or familial/paternity relationships. In short, just about every technology on the personal genomics landscape appears to fall within the definition of genetic test.

Another important definition, clarified in the final regulations, is that of a “manifest” disease. The EEOC clarifies at several points in the preamble its position that genetic information alone is not equivalent to a disease or disorder: “other signs or symptoms must be present.” The EEOC uses the example of Huntington’s Disease which, despite its high degree of penetrance, is not considered to be a present disease even following a positive genetic test until actual symptoms arise.

This distinction is crucial because, under § 1635.12 of the final regulations, employers are not barred from using, acquiring or disclosing medical information about a “manifested disease, disorder, or pathological condition,” even when such disease or disorder has a genetic component. (However, employers may be barred from discriminating on the basis of such information by other federal law, including the ADA.)

The final regulations also provide greater clarity with respect to the definition of “family member,” which includes all dependents (including spouses, adopted children and other people who are not genetically related) and all other persons “related from the first to the fourth degree of an individual.” Other key terms, including “genetic information,” “genetic services,” and “family medical history” also receive helpful background discussion.

Deliberate vs. Inadvertent Acquisition. It is illegal under GINA for employers to “request, require, or purchase” genetic information. In considering what constitutes a “request” for purposes of GINA, the proposed rule was structured to prohibit the “deliberate acquisition” of genetic information. Some commenters, including the American Civil Liberties Union, criticized this proposed rule for suggesting that employers must have the “specific intent” to acquire genetic information to run afoul of the law. (Others suggested that requiring a “purposeful act” was, in fact, what Congress intended.)

In the final regulations, the EEOC sided with the ACLU in determining that “request” extends beyond a specific or deliberate intent to encompass a variety of actions that are “likely to result” in the acquisition of genetic information.

Despite this broad prohibition on the request of genetic information, GINA provides several exceptions, including with respect to “inadvertent requests” and “commercially and publicly available information.” The “inadvertent” request or disclosure scenario was originally inserted by Congress to address the so-called “water cooler problem,” in which employers inadvertently received genetic information, including family medical history, from employees in the course of routine conversations or interactions. Likewise, the “publicly available information” exception was intended to protect employers who acquired genetic information about their employees by, for instance, watching the evening news.

To aid in understanding the specific contours of these exceptions, the EEOC has provided significant clarifying guidance and examples. For instance, while an employer does not violate GINA by participating in “water cooler conversations”—whether those conversations happen around a conventional water cooler or in more modern settings, including on Facebook, LinkedIn or other social media platforms—that information is not an invitation to bypass GINA. The employer and its agents must “not then ask follow-up questions that are probing in nature.”

Similarly, the category of “commercially and publicly available materials” will generally not include materials made available to the public, or to some portion of the public, on a restricted basis (i.e., when more than simple registration is required for access). For example, research databases made available only to the scientific community or Facebook profile information shared only with “friends” (as opposed to information visible in a public database or on a public website) would not satisfy this exception.

Even genetic information that is available to the public on an unrestricted basis—as is true of genetic information provided by individuals, including one of us, who participate in public genomics projects—is not necessarily fair game for employers under GINA. If employers access such sources “with the intent of obtaining genetic information,” particularly if it comes from a source “that focuses on issues such as genetic testing of individuals” they will not be able to take advantage of GINA’s limited exception for publicly available materials.

As the EEOC explains, GINA’s limited exceptions are “intended to protect from liability a covered entity that inadvertently obtains genetic information and not a covered entity that is actively searching for genetic information.”

When it comes to applying GINA’s various exceptions, employers should remember that Title II of GINA serves three related but ultimately separate functions: (i) a general prohibition on the request for or acquisition of genetic information, (ii) an ever-more-complete prohibition on the discriminatory use of genetic information in employment-related decisions and (iii) strict confidentiality requirements pertaining to any sharing or disclosure of genetic information, however obtained, by employers. Thus, even genetic information that is requested or acquired lawfully under one of GINA’s exceptions is still subject to the remaining two prongs of GINA Title II, and it may not be used to discriminate in employment-related decisions or disclosed in violation of GINA’s confidentiality provisions.

No New Exemptions. In addition to clarifying the scope of existing exemptions, the EEOC specifically declined to introduce new exceptions under GINA relating to the use of genetic information in evaluating the ability of an employee (or prospective employee) to safely and effectively perform a particular job. Exemptions proposed by commenters would have permitted a covered entity to request genetic information (i) as part of “a medical examination conducted to assess an individual’s ability to perform a job” or (ii) “to determine whether an individual has a particular manifested disease, disorder, or pathological condition and where information about [that condition], as opposed to its signs and symptoms, is necessary to evaluate an individual’s ability to perform a particular job.”

The EEOC declined to create such an exemption in each case, citing both a lack of authority under GINA and its belief that “there does not appear to be a case in which the diagnosis, as opposed to the signs and symptoms, is necessary to evaluate an individual’s ability to perform a particular job.”

Shortly after the EEOC released its draft regulations we addressed this particular issue, among others, with a pair of GINA-related posts (see here and here). We considered whether there might be situations in which an employer could have a legitimate interest in testing an employee for a genetically-mediated condition, particularly where the employee’s activities might increase the risk or the severity of such condition becoming manifest during the course of employment.

The primary example we considered was that of professional basketball player Eddy Curry, who was traded by the Chicago Bulls after refusing to undergo a genetic test for Hypertrophic Cardiomyopathy (HCM).

As we wrote then:

Curry’s case is a very good example of a more general scenario that I suspect might pose a real problem once GINA takes effect. How will employers and employees handle situations in which an employer suspects that an employee is either suffering from, or at risk of, developing a medical condition with an identifiable genetic component? (In Curry’s case, it was the irregular heartbeat that created suspicion of HCM.) It would seem that, in most such cases, the employer will be forced to take action without a confirmatory genetic test.

The final regulations decline to create an exemption for this scenario and, indeed, it appears that if this case arose today, the Chicago Bulls might be prohibited from even requesting an HCM test. Although Curry did exhibit some physical symptoms, including an irregular heartbeat, the HCM test would arguably have been necessary to evaluate his ability to perform this particular job (that of a professional basketball player), particularly because the irregular heartbeat and other physical symptoms, on their own, may not have been enough for a conclusive diagnosis.

While the EEOC failed to find sufficient reason to create such an exemption, this situation is likely to appear in other contexts in coming years. While genetic information is primarily used to diagnose or guide treatment for manifest diseases or conditions, it is likely to play an increasing role in determining behavioral and lifestyle decisions—potentially including choice of employment—for conditions not yet manifest. Under GINA, however, except where an employer is required to do so by law, it may not “limit, segregate, or classify an individual…because of genetic information with respect to that individual.” There is no exception for imposing a limitation designed solely to protect the well-being of the employee.

As genetic information becomes more prevalent and more useful, we expect to see a growing tension between an employer’s legitimate interest in ensuring the welfare of its employees (for both economic reasons and out of a legitimate desire to protect its employees from harm) and GINA’s broad prohibition on requesting genetic information.

Employee Wellness Programs. One area where employers are already actively attempting to use genetic information—typically in the form of family medical history—to safeguard the health of their employees (and, in turn, decrease employers’ own healthcare costs) is employee wellness programs.

Increasing numbers of employers have implemented wellness programs, which frequently operate by assessing employees’ personal risk factors (including medical, environmental and behavioral) and encouraging the adoption of healthier lifestyles and practices. Many wellness programs include financial incentives (often in the form of premium discounts) for participation and/or completion.

Following GINA’s passage, and particularly the EEOC’s proposed regulations, many employers were concerned that such wellness programs might violate GINA. The proposed regulations permitted wellness programs only if they were offered on a “voluntary” basis (and if certain other conditions were met). Many commenters worried financial incentives or inducements would be deemed incompatible with the requirement of voluntariness.

In its final regulations, the EEOC has addressed this concern by clarifying the circumstances under which an employer may offer wellness programs that include a request for genetic information (including family history). In order for the wellness program to comply with GINA:

• the employee must provide a prior, knowing, voluntary and written authorization to participate in the program (electronic or online authorizations are allowed);
• individually identifiable genetic information may only be provided to the licensed health care professionals or board certified genetic counselors involved with the program;
• any genetic information received from the wellness provider must be in aggregate terms that do not disclose the identity of specific individuals; and
• employee incentives or benefits related to the program must not be conditioned upon the provision of genetic information.

Most notably, the EEOC determined that financial inducements for wellness programs are allowed, but only where the employer makes it crystal clear that neither participation in the wellness program nor the receipt of any benefit resulting from participation is conditioned upon the provision of genetic information.

What’s Next. Although GINA is now two and a half years old, like all new laws it remains subject to a considerable degree of uncertainty. Thus far, we are aware of only one publicly discussed EEOC claim filed under GINA (although EEOC’s legal counsel estimates “around 200 charges have been filed with EEOC under GINA so far“) and no court decisions interpreting the law. The EEOC’s final regulations are well-written and helpful but, ultimately, it will take years before we understand how GINA operates in practice.

On Monday, the twelve founders and co-collaborators at Genomes Unzipped (including me) published our genetic data for the world to see. We released both raw data and a custom genome browser. This morning we began the process of talking about the experience of joining the public genomics movement, something that has already affected each of us in different ways. My first post discusses why my decision to join Genomes Unzipped was not a purely personal decision.

On Tuesday, the Personal Genome Project unveiled its latest phase, announcing the enrollment of its next 1,000 participants (the “PGP-1K”), integration with Google Health for phenotype collection and sharing, the upcoming release of a number of new, public whole-genome sequences and several other exciting developments.

It has been a big week for personal genomics, and I am gratified to be involved in both of these projects. Onward and upward or, as Jason Bobe might say, “to the moon!”

The software-based test can be downloaded from the website of the University of Maryland’s Center for Bioinformatics & Computational Biology, where Salzberg is the director and Pertea is on the faculty. The test purports to test genomic sequence data against a set of known mutations in the BRCA genes. In addition to representing a conceptual alternative for those seeking to evaluate their risk of hereditary breast cancer, the so-called “Salzberg Screen” is also a direct challenge to Myriad Genetics, the FDA and the existing legal, regulatory and policy regimes that continue to struggle to keep pace with the science and technology of genomics and personalized medicine.

Below, we examine how the Salzberg Screen fits—or does not—within the current legal and regulatory landscape, as well as what it signals for the future of do-it-yourself genomics, whole-genome sequencing and the law.

BRCA Background. First, a quick primer on the clinical and legal significance of the Salzberg Screen’s target: the BRCA genes. BRCA-1 and BRCA-2 are perhaps the two most well-known human genes. This stems in part from the role which mutations in those genes play in dramatically increasing the risk of breast and/or ovarian cancer for certain individuals.

The notoriety of the BRCA genes has also been significantly enhanced in the past year thanks to high-profile litigation in both the United States and Australia challenging the validity of the BRCA gene patents held by Myriad Genetics. Myriad’s patents covering the isolated BRCA-1 and BRCA-2 genes, as well as certain methods of diagnosing breast cancer susceptibility, were ruled invalid by Judge Robert Sweet of the Southern District of New York earlier this year. Judge Sweet’s opinion is currently being appealed to the Court of Appeals for the Federal Circuit, where hearings are expected to get underway later this fall. Despite the litigation, Myriad’s BRCA patent portfolio has enabled it to serve as the sole (lawful) provider of BRCA screening in the United States and numerous other countries worldwide.

The Salzberg Screen. Myriad’s role as exclusive provider of BRCA screening is a fact that has clearly irked both Salzberg and Pertea:

We believe that any individual should be allowed to interrogate his or her genome for all mutations of interest, regardless of whether a private company claims to ‘own’ the rights to particular gene mutations. To challenge the restrictive gene patenting system, we have developed a computational assay that, as a proof-of-concept, tests for 68 known variants of the BRCA1 and BRCA2 genes. In other words, we empower any individual using our software (whether this is a private individual, a clinician or a clinical or basic researcher) to test for these mutations and circumvent the gene patents.

The Salzberg Screen compares whole-genome sequence data (or, presumably, data from targeted sequencing of the BRCA genes) against a list of “68 known mutations in the [BRCA] genes” drawn from the Online Mendelian Inheritance in Man (OMIM) database. Salzberg and Pertea readily admit that their DIY screening tool is far from perfect, noting that “…the 68 mutations used in this proof-of-concept assay do not represent a comprehensive list of BRCA mutations,” but pointing out that “additional mutations could easily be added to our test…”

In addition to only testing for a fraction of the publicly identified BRCA mutations, a number that does not include additional proprietary information about BRCA mutations possessed by Myriad Genetics, the Salzberg Screen also possesses another significant current limitation: cost. Myriad’s BRACAnalysis test costs several thousand dollars, but it includes targeted sequencing of the individual’s BRCA genes. While the Salzberg Screen is free to use, it requires the user to come up with her own whole-genome sequence data.

At the moment, whole-genome sequencing is still more expensive than Myriad’s BRACAnalysis, a test which is covered by many insurers where clinically indicated. The price of a whole-genome sequence is a moving target and depends upon the quality of the sequence (including accuracy and depth of coverage), whether it is generated in a clinical (i.e., CLIA-certified) or research facility, the level of associate interpretation or analysis that is provided and a host of other factors. Current best estimates put the cost at anywhere from $1,000 to $10,000 per genome, although Salzberg and Pertea, like so many others, note that we are “rapidly approaching the day when it will be cheaper to fully sequence a genome before testing the sequence for all known genetic mutations associated with a given disease than to conduct multiple separate tests for each disease.”

While that day is not quite at hand, Salzberg and Pertea’s goal is not to create a computational screen that is a replacement, right now, for Myriad’s test. Instead, they have developed a “…template that can easily be modified to test for almost any known genetic mutation,” and thereby one day circumvent not only Myriad’s testing monopoly, but also all human gene patents.

What This Means, Part I: Myriad and its Patents. More than a year ago we wrote about the impending collision between single gene sequencing, such as that provided by Myriad, and inexpensive whole-genome sequencing (see: Whole-Genome Sequencing and Gene Patents Coexist (For Now)). As the cost of gene sequencing continues to fall, we expect that more and more software-only tools like the Salzberg Screen will spring up. But can such tools be used, as Salzberg and Pertea hope, to “empower any individual…to test for [BRCA] mutations and circumvent the gene patents”? More pointedly, can such tools circumvent gene patents legally?

Infringement, Direct and Indirect. A patent can be infringed in two ways: directly or indirectly (see Section 271 of the Patent Act). Direct infringement consists of someone making, using, offering to sell, or selling the patented product or process. Usually, the infringer must be duplicating the patented invention exactly as described in one of the patent claims; in patent jargon, the infringed patent claim must “read on” the infringer’s activity, element-by-element. Indirect infringement comes in two forms: inducement and contributory infringement. Inducement, sketchily codified in Section 271(b), requires knowledge of the patent and an affirmative act to cause or direct a third party to carry out an act of infringement. In other words, you can’t escape liability by contracting with someone else to make a patented product or carry out a patented process. Contributory infringement, codified in considerable detail in Section 271(c), usually consists of selling a component of a patented invention, knowing that the component has no use except in that invention. The theory here is to prevent a conspiracy of infringers from escaping liability by individually selling pieces of the protected invention. Significantly, you can’t be guilty of indirect infringement unless someone is engaging in direct infringement.

So the first and most important question here is whether use of the Salzberg Screen would result in someone infringing one or more of Myriad’s patents. That is, would either the individual or someone else (for example, a clinician or genetic counselor helping the individual use or understand the Salzberg Screen or a similar service) be making, using, or selling a product or process covered by a Myriad patent? (This whole analysis assumes, of course, that the relevant Myriad patents are not ultimately found invalid at the conclusion of the ongoing Myriad litigation.)

It’s worth remembering that Myriad’s patents include both product and process claims. On the product side are claims like Claim 1 of U.S. Patent 5,747,282 (pdf):

An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having [a listed] amino acid sequence.

Would anyone in the chain of use of the Salzberg Screen be making or using this gene in isolation? That is a factual, scientific question that turns on whether the particular sequencing technique involves using “the gene.” Our science sources tell us that the answer depends on the sequencing method, but, at least for whole-genome sequencing, it is probably “no.” (Sequencing just the BRCA genes, as opposed to whole-genome sequencing, would likely be a different story.)

There are also claims like Claim 5 of the same patent: “An isolated DNA having at least 15 nucleotides of the DNA of claim 1”—i.e., any 15-mer oligonucleotide that can be found in the patented gene. While almost no one expects a claim like this to survive in the Federal Circuit, if it did, then almost any sequencing process might infringe solely as a matter of statistical probability (pdf).

A Method of Inducement? On the process side, Claim 1 of U.S. Patent 5,709,999 (pdf) is one of the broadest. Here is how the claim reads:

A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1

And here is how Judge Sweet, in his Myriad opinion (pdf), translated that claim, shortly before finding it to be invalid:

Claim 1 of the ‘999 patent is directed to the process of ‘analyzing’ a BRCA1 sequence and noting whether or not the specified naturally-occurring mutations exist. The claimed process is not limited to any particular method of analysis and does not specify any further action beyond the act of ‘analyzing.’”

Under that reading, would Claim 1 of the ‘999 patent cover the activities of an individual who downloaded and ran the Salzberg Screen in order to “analyze” their BRCA-1 sequence? Would it cover the activities of a clinician or genetic counselor assisting a user in interpreting the Salzberg Screen’s results? That would be a matter for a court to decide, although it is certainly possible that, depending on the specific court and specific set of facts, the answer could be “yes.” If so, there would be an act of direct infringement.

If a court were to find an act of direct infringement, then Salzberg and Pertea could well be liable for indirect infringement, most likely in the form of inducement of infringement.

A Calculated Gamble? Salzberg and Pertea are clearly aware of the Myriad patents (a requirement of inducement) and explicitly invite individuals to “test for [BRCA] mutations and circumvent the gene patents.” They also readily acknowledge that they are asking Salzberg Screen users to commit patent infringement.

In creating this software, we are not violating the BRCA patents directly but any user would be, because even a noncommercial use (such as examining one’s own genome) is considered to be patent infringement.

The fact that Salzberg and Pertea claim not to be violating the BRCA patents “directly” suggests that they are aware of the risk of indirect infringement. They do not, however, appear to be overly concerned that Myriad will pursue such a claim.

For Myriad to make out a claim of indirect infringement against Salzberg and Pertea, it would likely first have to show that individual users are directly infringing Myriad’s patents. Suing a direct infringer could involve challenging in court the activities of an individual using a freely available software program to examine her own genes from the privacy of her own home.

But Myriad wouldn’t have to actually sue the direct infringer—it could decide to sue only Salzberg and Pertea for indirect infringement. In fact, the whole premise of indirect infringement is that it provides a patent holder an avenue of redress when it isn’t feasible to pursue the direct infringer. Still, given the substantial negative publicity that continues to swirl around Myriad’s BRCA patents, and the fact that suing for infringement would also mean subjecting its patents to a new set of invalidity challenges (a near-certain argument in defense from any alleged infringer), Salzberg and Pertea may be taking a calculated gamble that Myriad simply does not have the stomach to initiate any BRCA patent infringement litigation, whether direct or indirect.

Myriad’s Next Move. Myriad derives 90% of its revenues from its BRACAnalysis product, so neither the company nor its investors are likely to take any challenge to its BRCA business lightly. At present, however, the Salzberg Screen does not pose a credible commercial threat to Myriad. It does not test for the full range of deleterious mutations covered by Myriad’s BRACAnalysis, and it also requires something few people have: access to a high-quality copy of their genome. For those reasons, and in light of the negative publicity that would flock to any attempt Myriad might make to quash the Salzberg Screen, the strong likelihood is that Myriad will simply ignore this development, at least for the moment. What’s more, as Myriad is no doubt aware, pending the appeal of Judge Sweet’s decision invalidating certain of Myriad’s patents, an alleged infringer could use that decision to defend itself under an arcane legal doctrine called “issue preclusion.”

Conceptually, however, whole-genome sequencing has always been a threat for single-gene diagnostic companies such as Myriad. The Salzberg Screen brings that tension into particularly sharp relief. Once individuals routinely have access to high-quality whole-genome sequences, they are likely to ask why they need to pay the Myriads of the world several thousand dollars to analyze a handful of genes when they could pay far less—or perhaps nothing at all—to have the same analysis automatically performed by a software program.

As the technical limitations fade in the face of ubiquitous whole-genome sequencing, the Salzberg Screen, or perhaps one of its descendants (Salzberg and Pertea have created a fully open source piece of software), will come to present a viable alternative to Myriad’s test, at least in certain circumstances (e.g., for second opinion or confirmatory testing). How quickly this will occur remains unknown, but there is a strong likelihood that it will be before 2015, which is when the first group of Myriad’s BRCA patents are set to expire.

In many ways, the Salzberg Screen is every bit the frontal attack on Myriad’s patents that the ACLU-initiated litigation represents.  Like the ACLU litigation, it publicly, deliberately and unapologetically challenges Myriad’s right to control access to BRCA information. Allowed to evolve unchecked, it could one day threaten Myriad’s core business. So even if Myriad takes no action right away, you can safely bet that the company will be watching the development of the Salzberg Screen with considerable interest.

What This Means, Part II: Regulatory Acronym Soup or: WGS means more LDTs go DTC and DIY, creating a problem for FDA. While Salzberg and Pertea focus a majority of their attention on circumventing Myriad’s gene patents, their conclusion recognizes at least one other potential obstacle to widespread adoption of their BRCA screening test:

Finally, we recognize that there may be some controversy about giving ordinary individuals the ability to test their own DNA, without also providing expert genetic counseling.

The “controversy” is a nod to the FDA’s recent and widely discussed proposal to more aggressively regulate not only direct-to-consumer (DTC) and do-it-yourself (DIY) genetic tests, but all laboratory developed tests (LDTs). As we wrote earlier this fall, “recent developments suggest that innovation in personal genomics is an increasingly difficult undertaking.” From Pathway Genomics’ short-lived attempt to offer its product on Walgreens’ shelves, to U.C. Berkeley’s unsuccessful attempt to innovate genomics education by offering non-clinical genetic testing to its incoming freshmen, the recent regulatory climate has been none-too-kind to those intent on thinking outside the box in the personal genomics space.

Salzberg and Pertea are aware, no doubt, of these recent events, but remain resolute in their desire to liberate individuals from the strictures—patent, regulatory or otherwise—that would inhibit personal genomic access:

Nonetheless, the door to this new technology is already open and it cannot be closed. Rather than trying to keep patients in the dark, we need to embrace the technology and work harder to educate both physicians and patients about the power and the limitations of genetic tests.

With the FDA in the middle of developing a formal proposal to regulate all LDTs, including those offered DTC, there’s simply no knowing whether or how the FDA will respond to this development. While we think any immediate and public FDA reaction unlikely, the Salzberg Screen should be setting off alarm bells at the agency.

Regulating Tomorrow’s LDTs Today. At the recent public meeting convened by the FDA to solicit feedback on the agency’s plan to regulate all LDTs, there were two areas of discussion in particular that were defined less by disagreement over how or whether to implement FDA regulatory oversight and more by the creeping suspicion that neither the FDA nor any other regulatory agency is  currently prepared to address the issue: (1) testing based on multiplex or whole-genome sequencing data and (2) software-only bioinformatics or genetic testing services.

After Day 1 of the FDA’s public meeting, we wrote:

What about tomorrow? Another area of considerable confusion, if not necessarily disagreement, was what to do with the coming wave of multiplex diagnostic tests including, ultimately, a proliferation of whole-genome sequence data and corresponding interpretive tools. This was not an issue that the FDA tackled directly, but it was clear in the afternoon question and answer session that many of the panelists, at least, were unsure how the next generation of diagnostic tests would fit into the current (or contemplated) regulatory model. The challenges posed by the next generation of sequencing and bioinformatics tools are hardly new, but designing a regulatory framework equipped to survive the next decade will be one of the FDA’s greatest challenges.

While there is no greater clarity today than there was back in July, the unveiling of the Salzberg Screen crystallizes the importance of addressing these issues today, before the coming proliferation of whole-genome sequence data and associated bioinformatics tools.

The arrival of inexpensive and widespread genomic data will be followed, nearly simultaneously, with an explosion of new genomic-based tools and services prepared to analyze that data. These will not be LDTs in the traditional sense, and many will be unlikely to have any need for a laboratory at any stage. Targeting individuals with data in hand, they may well look like more sophisticated versions of the Salzberg Screen, bringing together data and returning personalized genomic analyses.

The Salzberg Screen is not the first computational test that relies on the individual to supply raw data. A familiar example is the Reynolds Risk Score, which takes as inputs user-supplied risk factors such as blood pressure, cholesterol and family history and then “predict[s] your risk of having a heart attack, stroke, or other major heart disease in the next 10 years.”

The Salzberg Screen adopts a similar DIY model for genomic data. In addition to a number of similar open-source and/or academic tools and projects already in progress (the Personal Genome Project, Genomes Unzipped and DIYgenomics all offer good examples), commercial variants of this model are also in the works. A new California-based start-up, Existence Genetics, recently described its plans to leverage the coming decline in whole-genome sequence data. According to CEO Brandon Colby, although the company today supplies both genetic tests and analysis to patients, “eventually … we see ourselves disengaging from utilizing gene chips completely, disengaging from all lab work, and instead solely being an analysis company.”

Colby, to his credit, recognizes that such a model will undoubtedly attract the attention of the FDA:

Colby said that he expects the agency to provide clear guidelines and regulations for LDTs soon, and when they do, ‘we really do look forward to working with them. The big question is how they’re going to regulate and what the timeline is … but once both of those are worked out by the FDA, we’re going to be front and center and willing to work with them and make sure we comply.’

With the FDA still “trying to decide what [its] options are,” Colby may be more optimistic than most in viewing  “clear guidelines and regulations for LDTs” as likely to arrive “soon.” Regardless of when those LDT guidelines actually do arrive, the more important question remains whether they will provide a meaningful degree of insight into the agency’s plans for reviewing multiplex and whole-genome sequencing products and the software-only bioinformatics services that will be developed to leverage low-cost whole-genome sequencing.

Drawing the Right Lines. The examples presented by the Reynolds Risk Score calculator, Salzberg Screen and Existence Genetics products, among others, challenge us, and particularly the FDA, to carefully establish what constitutes an appropriate regulatory target. As genomic tests and services move out of the laboratory and into the genomics data cloud, where and how will the FDA direct its regulatory energies?

If the FDA focuses on the risk level of the condition analyzed, how will it respond to multiplex or whole-genome interpretations that analyze both high- and low-risk conditions simultaneously? If the FDA seeks to install clinician gatekeepers between data and interpretations, even when those interpretations are not coupled with a laboratory test or other traditional medical device, will the agency also attempt to forbid individuals from accessing or attempting to analyze their medical records or raw genomic data on their own?

Drawing the right lines will be exceptionally difficult, and will require considerable foresight if the regulatory framework now being developed is to be sufficiently flexible to accommodate what are likely to be substantial changes in the way health information is collected, interpreted and delivered. The recently disbanded Secretary’s Advisory Committee on Genetics, Health, & Society (SACGHS), which had been slated to take up the implications of whole-genome sequencing, might well have helped the FDA in this process. Instead, the onus now falls more heavily on the FDA, as well as other public and private regulatory and advisory bodies, to think prospectively and creatively about these issues before the Salzberg Screen and its kin become the norm in personal genomics.

A Final Thought: Keeping Up With the Salzbergs. Even more fundamentally than its challenge to Myriad’s gene patents or to the FDA’s preparedness for a future in which whole-genome sequencing exists alongside do-it-yourself personalized medicine, the Salzberg Screen is a reminder of the Herculean task lawmakers, policymakers and regulators face in attempting to keep up with the pace of scientific and technological innovation in the fields of genomics and personalized medicine.

Whatever we think of Salzberg’s Screen and his aggressive challenge to the status quo of gene patents and federally regulated access to genetic testing, we must applaud the work that Salzberg and others do to continually push forward both the science and the application of genomics and personalized medicine. It’s doubtful that the Salzberg Screen will effectively undermine Myriad’s patents or cause the FDA to wholeheartedly embrace DIY genomics, at least in the short term. But by forcing all of us to think more concretely about such possibilities, Salzberg is spurring valuable discourse and forcing lawmakers, policymakers, regulators and businessmen to respond. We hope that the response, when it comes, will include a recognition that even if we cannot keep up with the Salzbergs—those bent on innovation, no matter how much it strains our current structures—we can do much more, now, to anticipate where they are leading us.

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Note: The image that appears is used and modified with the permission of DIYgenomics.

As part of its program, Berkeley offered students the option to participate in genetic testing for three common genetic variants relevant to the body’s ability to metabolize milk products, alcohol and folic acid. The University’s original plan was to allow students to elect to receive the results of their tests as part of the program. Two weeks ago, however, the California Department of Public Health (CDPH) ruled that if Berkeley wanted to return personalized genetic data to some of its freshmen, the testing must be conducted at the direction of a physician and performed by a licensed clinical laboratory. The significant logistical burden and cost of complying with the CDPH’s ruling forced Berkeley to modify its program. While some aspects of the program will go forward, no student will be able to access any personalized genetic information.

(CDPH’s ruling was unexpected. Berkeley’s Dean of Biological Sciences, Mark Schlissel, noted that the department’s ruling “relies on an interpretation of legal statutes that is entirely different from the interpretation of the same statutes by UC’s top lawyers.” The ruling itself has potentially significant implications for genetic research across the country, although that topic is the subject for a future post.)

The focus of this post is the rapid mobilization of critics of the Berkeley program and the power of public controversy to spur regulatory action and, ultimately, to force the University to adopt a fundamentally different approach to personal genomics education than originally intended. This in spite of a detailed internal review process that consumed substantial resources and required Berkeley’s Institutional Review Board (IRB) to approve the project. Examining how and why this happened is instructive for evaluating the future prospects of personal genomics research and innovation.

A Controversy Emerges. From the outset, a handful of bioethicists and public interest groups voiced hypothetical concerns about the risks of offering genetic testing to Berkeley’s freshmen. The Council for Responsible Genetics greeted the program’s launch with a letter to the University (pdf) that warned that genetic information “has the risk of being used out of context in ways that are contrary to the interests of the individual, perhaps even discriminatory and certainly privacy invasive.” Similarly, an article in The New York Times featured Boston University bioethicist George Annas, who posed the following hypothetical:

What if someone tests negative [for alcohol metabolization], and they don’t have the marker, so they think that means they can drink more? Like all genetic information, it’s potentially harmful.

Finally, the Center for Genetics and Society linked the Berkeley program to contemporaneous developments in direct-to-consumer (DTC) genetic testing, and warned that “students might think, ‘Berkeley gave it to us. It must be good. UC Berkeley would never be giving its incoming students anything bad or controversial.’”

In short order, what began as an innovative approach to introduce incoming students to genetics and personalized medicine by offering those students the opportunity to personalize their experience quickly became a controversy.

From Controversy to Regulation. Controversial educational initiatives are hardly new. Indeed, they are part of the mission of many institutions of higher education, including Berkeley. In responding to initial criticisms of the program (pdf), the University emphasized that “provoking a free and open discussion about issues surrounding genetic testing is an important aspect of educating our students to be informed citizens.”

Unquestionably, there is considerable value in subjecting all forms of innovation to close scrutiny. In fact, in any Common Rule-governed human subjects research, this is a requirement. Among the many criteria for IRB approval of a human subjects research project is the requirement that “risks to subjects are reasonable in relation to anticipated benefits.” The provision of informed consent is a separate, and similarly important, prerequisite to approval. Berkeley’s own IRB reviewed the University’s project, applied these and other statutory criteria, and ultimately approved the project.

Despite not being legally required to do so, Berkeley actively engaged with the program’s critics from the outset. A program that was vetted internally was now being vetted by the public, with the University’s active participation. In response to public feedback the University modified the project to clarify the project’s voluntary nature, the informed consent process and its separation from actual or perceived industry conflicts of interest.

Critics of the Berkeley program, however, were not satisfied. They continued to urge first the University and then California legislators to much more dramatically alter the program, or even to discontinue it entirely. The constant stream of criticism had an impact. Over the course of the summer, legislation was introduced that would have halted the program. That was followed by legislative hearings to debate the program’s merits and, ultimately, by the CDPH ruling that effectively ended the program in its originally-proposed form.

The rapid reaction of regulators to a debate that was largely driven, especially initially, by media reports, “expert” commentary and social media discourse was strikingly reminiscent of another mid-May personal genomics development.

The week before Berkeley’s program was announced, DTC genetic testing company Pathway Genomics and drugstore giant Walgreens announced a partnership that would have made Pathway’s consumer genetic test available through Walgreens’ stores. In Pathway’s case, the leap to controversy was even swifter: the initial story in The Washington Post describing the agreement warned of a “Pandora’s box of confusion, privacy violations, genetic discrimination and other issues.” Nonetheless, the end result was the same as regulators quickly stepped in and demanded changes. Rather than the CPDH demanding physician intervention and a clinical lab, in Pathway’s case it was the FDA declaring the product in question a medical device in need of a time-consuming and expensive medical device clearance or approval. In both cases, swift regulatory action effectively quashed the proposed activity.

Why Debating Personal Genomics is Difficult. Recent developments suggest that innovation in personal genomics is an increasingly difficult undertaking. In addition to the Berkeley and Pathway cases, examples include the FDA’s increased oversight of DTC genetic testing companies (in addition to Pathway), the GAO’s report on the perils of DTC genetic testing and, most recently, criticism of the University of Minnesota’s attempt to bring genetic research to the State Fair. Collectively, this suggests the emergence of a disturbing trend: developments in the area of personal genomics that deserve serious public debate are shaped from the outset by commentators, policymakers and lawmakers more concerned with making a point than with advancing the conversation.

Of course, it is hardly news that emerging areas of science and controversy generate controversy. In recent weeks, the safety and desirability of human embryonic stem cell research has sparked a heated public debate, just as it has at regular intervals for the past decade. The new dynamic facing personal genomics is the rapidity and ease with which any initiative may be branded as “controversial,” combined with the willingness of lawmakers and regulators to intervene directly and rapidly in such “controversial” activities. This may be as much a function of new paradigms in media, politics and public discourse as it is a function of personal genomics itself, but whatever the reason the concern is that it is having a chilling effect on innovation throughout the field.

On the commercial side, the effects of increasing regulatory uncertainty are evident, as businesses and investors are considering abandoning personal genomics or moving their operations – and attendant jobs and capital – overseas. On the research side, similar confusion – particularly in light of the Berkeley program’s fate – continues to discourage researchers from exploring innovative approaches that might help to accelerate our attempts to decipher genetic complexity and, ultimately, provide us all with more effective, less expensive health care.

Whatever the context, there can be no substitute for careful, public and reasoned debate when it comes to evaluating the appropriateness of a new personal genomics proposal. Similarly, there is no substitute for fully informed consent; for ensuring that all individuals – whether they are students, patients or consumers – understand the full extent of the risks attached to a decision to participate in a personal genomics activity. Both are critical in assuring that personal genomics is conducted in a responsible fashion.

But public debate and informed consent require more than an ability to enumerate hypothetical risks. When it comes to evaluating innovative personal genomics proposals, all of us – participants, funders (including taxpayers), media and commentators and, especially, policymakers and regulators – owe a duty to be thoughtful and balanced in assessing their merits. To be blunt, it requires all of us to do more than throw darts at the easiest targets.

This means understanding that it is not enough to simply enable public debate between those with opposing views on the merits of a particular project. It means recognizing that all innovation – scientific, technological, commercial, research, educational, etc. – carries with it a measure of uncertainty, but that uncertainty alone is an insufficient reason to slam on the brakes. It means acknowledging the difference between hypothetical or low-probability risks and actual, documented harms, and recognizing that the first step should be determining which is which. And most importantly of all, it means considering the benefits of innovation in personal genomics that accrue in addition to – and often because of – its risks.

This is not an easy task. Particularly in a field such as personal genomics, which is driven by new and often untested scientific knowledge and technology, it is trivial to examine a new idea and find something that could conceivably go wrong. Is it possible that a freshman tested for a genetic variant associated with alcohol flush reaction could interpret a negative result as a license to consume alcohol in excess? Of course it is possible, for the bar of “possibility” is exceptionally low. It is much more difficult to convert hypothetical risks into actual data on behavior (i.e., do individuals act to their detriment as a result of non-clinical genetic testing in general, and specifically in the case of the alcohol flush variant?), and more difficult still to balance such risks against the benefits of the same activity.

Keeping Our Heads. Realizing the promise of personal genomics will be impossible unless our society is willing to accept some measure of uncertainty and, yes, risk-taking. Our challenge is to figure out not only when the benefits of personal genomics outweigh its risks, but also who should be permitted to make that frequently difficult and personal risk-benefit decision, and in what contexts.

For those who would place that decision in the hands of individuals, there can be no question that we must first provide those individuals with the necessary information and perspective to make an informed decision. But the process of informing personal genomics participants – of informed consent – no matter how thoughtful and comprehensive, can only take us so far. The information will never be complete, the perspective will never be perfect, and the decision will never be without risk.

It is true, too, that there are many situations where society examines the risks associated with a particular activity and decides that they are simply too high – whether to the individual or to society as a whole – to be assumed, even knowingly and voluntarily, by the individual. We do not, for instance, let teenagers consume alcohol. We place restrictions on the acquisition or use of all manner of technologies, from automobiles to firearms. We require regulatory approval and a doctor’s prescription for most pharmaceuticals.

But as a society we also evince a deep respect for autonomy, leaving many risky decisions in the hands of individuals. The decision to drink alcohol or drive a car in the first place (assuming one is of legal age), to become pregnant (and even to terminate a pregnancy) and to provide informed consent to participate in scientific research: all of these decisions we leave in the hands of individuals.

We have not yet determined whether personal genomics is more like the decision to conceive a child– a personal decision free from state intrusion – or the decision to undergo chemotherapy – a personal decision highly regulated by the state. In a field with a landscape as diverse and rapidly-changing as personal genomics, the answer will frequently depend on context. Some aspects of personal genomics (e.g., genetic testing to determine a proper therapeutic treatment) warrant a greater degree of societal intervention than others (e.g., genetic testing to determine geographic ancestry).

The challenge is knowing where to draw that line. The risks posed by automobiles, firearms and pharmaceuticals are well-documented whereas, at least for the moment, the risks of personal genomics remain largely hypothetical. In the absence of clear data, the recent trend to deemphasize the benefits of personal genomics while focusing on its risks, and to use those risks as  justifications to shift control away from the individual, should cause us all to question whether we are drawing that line in the proper place.

If personal genomics is ever to live up to its name, at some point we must allow individuals – including the future leaders of our society, as embodied by Berkeley’s incoming freshmen – to decide for themselves whether and how to participate. To do otherwise, and to continue to aggressively criticize and thereby discourage personal genomics innovation in our zeal to render it a riskless enterprise, would be a mistake.

[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.

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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).

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.

I’m pleased to announce the beta launch of a new community resource for personal genomics, Genomes Unzipped.

I’ve been working with a group of colleagues on this project for quite a while now. Some of the group members will be familiar to regular readers of the Genomics Law Report, including Daniel MacArthur from Genetic Future, Luke Jostins from Genetic Inference and Caroline Wright from the PHG Foundation. Others are new to the online personal genomics community, but have scientific training in genomic analysis, statistical genetics and other fields that allow them to offer valuable insight into personal genomics issues. We’ll be adding more names to that list over the next few weeks.

So what can you expect from Genomes Unzipped (or GNZ, as we’ve taken to calling it)? The goal of GNZ is to provide the basic knowledge and tools that individuals interested in personal genomics need to explore their own genetic information in a responsible, informed manner. To start, GNZ will feature technical analyses of personal genomics developments and services from a diverse range of viewpoints and backgrounds. Examples will include detailed analysis of the scientific basis of tests offered by personal genomics companies, dissections of important new papers in the field and discussion of the ethical, legal and social issues presented by new developments in this rapidly evolving field.

GNZ is also planning bigger things for the site over the next few months. You can track these developments via RSS or Twitter.

What’s Next for DTC? In last week’s post, we outlined several possible responses available to DTC genetics companies, including (1) pulling products from market, (2) agreeing to comply with FDA regulatory requirements, (3) modifying products to avoid FDA oversight or (4) challenging the FDA’s regulatory authority over DTC genetic testing products. We also noted the possibility that the FDA’s decision to look more closely at DTC genetic tests could presage increased scrutiny of the genetic testing industry more broadly, including the many tests currently offered without FDA clearance or approval as laboratory developed tests (LDTs).

With the personal genomics landscape shifting seemingly on a daily basis, what should we expect to happen next? Will the FDA follow up last week’s letters with letters to additional personal genomics companies, continuing its current policy of case-by-case regulation? Will it announce some form of industry-wide guidance? Will one of last week’s lucky recipients reveal its response to the FDA? Will we hear more from the Congressional committee investigating DTC genetic testing, which sent out its own letters nearly a month ago, then followed those up yesterday with another letter to 23andMe?

While we wait to see what tomorrow will bring, those interested in forecasting future chapters in the ongoing DTC regulatory saga are advised to take a look back at the FDA’s most recent attempt to shape the regulation of genetic testing.

A Complex Debate. Four years ago the FDA touched off a similar regulatory controversy when it ratcheted up its oversight of a specific type of high-complexity LDT: the in vitro diagnostic multivariate index assay or IVDMIA. On January 23, 2006, in a letter that bears remarkably similarities to the one sent just last month by the FDA to Pathway Genomics, the FDA invited Genomic Health, Inc. to discuss with the agency the regulatory status of its Onco type DX test, a complex genetic test designed to predict cancer recurrence in certain breast cancer patients. The FDA’s letter to Genomic Health was followed in September 2006 by draft guidance (pdf) announcing the FDA’s intent to regulate the entire class of genetic tests it deemed to be IVDMIAs.

The FDA’s initial proposal to regulate IVDMIAs was criticized as being vague, overly broad and unduly burdensome for genetic testing laboratories. The intense criticism resulted in the FDA’s publication of a revised guidance document in July of 2007 (pdf). That guidance was no less immune to criticism, and resulted in the FDA placing the proposed regulatory change on the back burner. Although the FDA has periodically indicated that IVDMIA guidance is still on the table, including earlier this year, it has now been nearly three full years since the FDA last took a meaningful public step in the direction of regulating IVDMIAs. (And, as described in Genomic Health’s most recent 10-Q (pdf), the Onco type DX test remains free from FDA regulation, at least for the moment.)

Why IVDMIA Matters. The history of FDA’s attempt to regulate IVDMIAs matters because it is almost certain to inform the FDA’s current attempt to regulate DTC genetic tests, as well as any attempts by the DTC genetic testing industry to resist that regulation. Most DTC genetic tests have long been considered, just like IVDMIAs, to be LDTs subject to the FDA’s enforcement discretion. In its letters to 23andMe, Knome and deCODE, however, the FDA argued that these tests do not qualify as LDTs because they are “not developed by and used in a single laboratory.” Even if that distinction holds, and DTC genetic tests are not determined to be LDTs, there is plenty to learn from the FDA’s experience with IVDMIAs.

Challenging the FDA’s Authority. Of particular interest are two petitions filed with the FDA concerning the agency’s proposal to regulate IVDMIAs, and its broader authority to regulate LDTs as medical devices. The first petition, filed by the Washington Legal Foundation (WLF) in 2006 (pdf), shortly after the FDA’s initial IVDMIA guidance was proposed, challenges the FDA’s legal authority to regulate LDTs (including IVDMIAs) and argues that the FDA’s approach of case-by-case regulation and informal agency guidance violated the agency’s responsibilities under the Administrative Procedure Act (APA). The WLF petition builds on a similar petition filed by the law firm of Hyman, Phelps & McNamara, P.C. (HPM) in 1992 (pdf) which challenged the FDA’s original assertion that it possessed the authority to regulate LDTs, even as it noted that it intended to exercise enforcement discretion and refrain from LDT regulation at that time.

The HPM petition, which was finally denied by the FDA nearly six years later, and the WLF petition are countered by a 2008 petition filed by biotechnology company Genentech, Inc. (pdf). Genentech’s petition argues that not only does the FDA have sufficient legal authority to regulate LDTs, but that given the potential risks to patient safety the agency should regulate all genetic tests, including all LDTs, rather than limiting its regulatory oversight to IVDMIAs.

If the FDA’s recent attempt to regulate certain DTC genetic testing products is challenged – whether by one of the five companies the FDA singled out or by some other third party – it is likely that many of the same arguments appearing in the HPM, WLF and Genentech petitions will reappear. In particular, questions about FDA’s authority to regulate these products, especially its ability to do so without undertaking notice and comment rulemaking pursuant to the FDA, are almost certain to play a prominent role. (As Kirell Lakhman of The Sample reported earlier this year, the need for APA-compliant rulemaking may be the reason that FDA’s proposed IVDMIA guidance remains on hold.)

While we can predict with some confidence what a challenge to the FDA’s authority to regulate DTC genetic tests might look like, it is far more difficult to predict whether such a challenge will ever actually be brought, let alone succeed. Such a regulatory challenge would be time-consuming and expensive – for both the challenger and for the agency – and, should it proceed into the courtroom, would be stepping into the relatively uncharted territory of consumer genetic testing.

A fight that entails such considerable expense and uncertainty is not one that any DTC genetic testing company will be eager to initiate. Still, for the companies and investors most directly threatened by the FDA’s recent activities, the history of the LDT/IVDMIA debate – and especially the regulatory silence that has followed – may be impossible to ignore.