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 that 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.

The Regulatory Environment Turns Negative. Until May 2010, the regulatory challenges in the genetic testing world seemed relatively benign, with most attention focused on patent and related IP issues (e.g. the Myriad gene patent litigation) and a challenging economic climate which made commercial operations and capital raising difficult for most businesses.

At the time, most genetic tests self-identified as laboratory developed tests (LDTs). LDTs have been an indefinitely defined category of diagnostic tests that were considered distinct from the category of in vitro diagnostic tests that the FDA regulates as medical devices under the Federal Food, Drug & Cosmetics Act (FFDCA). While the agency has long claimed jurisdiction over LDTs, it had adopted a policy of “enforcement discretion” that left such tests substantially unregulated other than that the laboratories had to operate in compliance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and applicable state laws.

Not that there were no signs change might be coming. Over the past several years the FDA repeatedly expressed its desire to revive the oft-postponed regulation of certain high-complexity LDTs (the “IVDMIA guidance” which would include coverage of complex genetic tests). And numerous commentators advocated greater regulatory oversight of the emerging field of direct-to-consumer (DTC) genetic tests. Still, as of a few months ago, the regulatory environment for developing and commercializing genetic tests appeared to be relatively stable.

That stability largely disappeared following a high-profile and short-lived partnership between a DTC genetic testing company (Pathway Genomics) and a national drugstore chain (Walgreens) in May of this year. Within hours, the FDA spoke up in the press to characterize Pathway’s product as an “illegally marketed device” and followed up with a letter to the company stating that Pathway’s test “appears to meet the definition of a device as that term is defined in section 201(h) of the [FFDCA].”

In the weeks that followed, the FDA sent two batches of similarly challenging (some would say threatening) letters to genetic testing companies, including to several prominent DTC companies. The agency also announced its intention to regulate all LDTs, including thousands of tests previously unregulated by the FDA. In July of this year, as the FDA took the first step toward regulating LDTs with two days of high-profile public meetings, the GAO issued a negative investigatory report on DTC genetic tests and Congress held hearings on the topic.

In a few short months, the regulation of genetic tests had been transformed from “confusing, incomplete and relatively stable” to “confusing, incomplete and highly uncertain.” Genetic tests and the regulatory agencies responsible for their oversight have been thrust squarely into the spotlight, with all signs indicating that a regulatory overhaul is both necessary and imminent.

What Can Businesses Do Now? Despite the dramatic change in the regulatory outlook, businesses still can operate largely like they did before May 2010. The FDA letters to the DTC companies were not enforcement letters that would have effectively prohibited the sale of those companies’ products. And the larger LDT regulatory process is certain to be contentious and lengthy. So nothing right now prohibits companies from continuing to provide the products and services they offered prior to May.

On the other hand, it would not be prudent for companies to continue to operate without any regard for the events of the past few months. For instance, had Pathway Genomics moved forward with its plan to sell genetic test kits on the shelves of Walgreens, the next letter from the FDA might well be an enforcement letter threatening seizure, fines or worse. Those companies that offer genetic tests to consumers should expect to face increased scrutiny – from both the FDA and possibly other regulatory agencies as well, including the FTC – if they offer major new products, ramp up marketing and promotions or enter into new distribution channels.

While traditional LDT providers (particularly those that provide tests through healthcare professionals) face fewer immediate constraints, they must still operate with an eye toward an eventual overhaul of the regulatory review process for their products. Based in part on information presented by the agency at last month’s public meeting, it appears the FDA is intent on categorizing LDTs as medical devices, and pursuing a risk-based classification regulatory framework. Preliminary comments from the FDA indicate that this new regulatory framework will incorporate or substantially draw upon the current approval and clearance process for medical devices. While it may be some time before the FDA releases a formal regulatory proposal (the FDA recently extended the period for the public to comment on its proposal to regulate LDTs), LDT providers should consider the likely impact of device-style FDA regulation.

The most common category of medical device is a medium-risk or Class II device, for which a 510(k) regulatory clearance is required. In the case of in vitro diagnostic (IVD) devices, for example, a 510(k) requires, among other things, (i) considering whether there is a “predicate device” on which a 510(k) application could be based, (ii) generating both analytical and clinical data to support an FDA application and (iii) preparing to manufacture the devices and operate laboratories under compliance and inspection regimes that are likely to be more demanding than the currently-applicable CLIA compliance requirements.

The FDA is currently in the process of reviewing its 510(k) clearance process to “enhance device safety, foster device innovation, and create a more predictable regulatory environment.” With changes afoot for currently regulated medical devices, and the uncertainty surrounding the FDA’s proposed regulation of LDTs, there is no guarantee what the LDT regulatory regime will look like when it finally appears.

At least for the moment, uncertainty prevails when it comes to the regulation of both LDTs and DTC genetic tests.

What Are the Practical Consequences? This new level of regulatory uncertainty coupled with a reasonable expectation of increased regulatory oversight and costs will have a variety of practical consequences for genetic testing companies. While these effects will vary depending on a company’s specific business model – not only LDT vs. DTC, but the many and important variations within each of those broad categories – and economic circumstances, some of the possible consequences include:

• Reduced access to capital. Genetic testing companies may find that investors are more cautious about making new and add-on investments.

• Fewer new products. Companies may delay plans to introduce new products both because of lack of funds and concern about the regulatory response to innovative products or business models.

• Fewer entrants. Numerous investors, and companies in related industries, have been preparing to enter into the genetic testing field. Many of those plans may be put on hold.

• Litigation risks. The well-publicized GAO report and Congressional hearings, which highlighted apparent operational deficiencies of some DTC companies, could lead to tort (e.g., negligence, emotional distress, malpractice), securities or other lawsuits from plaintiffs’ lawyers and litigious customers. Although the GAO report and Congressional investigation focused on DTC genetic tests, the broad and negative public attention focused on genetic testing could spur similar litigation against more traditional genetic testing developers and providers.

• Reduced access to technology. Companies dependent on third-party providers for some portion of their own test or business might find their options limited if regulatory uncertainty or changes discourage such collaborations.

• Encouraging overseas development. Increased regulation – or even the possibility of increased regulation – may encourage companies and investors to focus on developing new products and businesses overseas in advance or instead of in the United States, with potentially detrimental consequences for patients and consumers in this country.

The Problem of Delay. Perhaps the greatest frustration and difficulty for genetic testing companies is the prospect of an extended period of elevated regulatory uncertainty. Every indication is that a regulatory overhaul is indeed coming; but there is no way to know whether it will be weeks, months or even years until it arrives. If new regulatory requirements could be decided and implemented quickly, then companies could understand the new environment and adapt their products and business models to comply.

If, however, the regulatory process grinds on over an extended period, most companies will be limited in their ability to confidently make significant changes – or to do so without considerable uncertainty and, thus, risk – because there will be little clarity about what will be required under future regulations. This is a particular concern for new companies seeking to develop a commercial and regulatory strategy, as well as for companies for whom a significant regulatory overhaul might require a fundamental change to their product(s) or business model.

On the other hand, regulatory delay and uncertainty could constitute a competitive benefit for companies that are well funded and either already have received 510(k) approval for their IVDs or intend to pursue medical device clearance and approval for their new products. For such companies, the regulatory uncertainty could have the immediate effect of limiting or delaying competitive products.

As the genetic testing industry waits for definitive guidance from the FDA, the only sure thing appears to be that the field will be tested by considerable uncertainty for the foreseeable future. While the consequences of that uncertainty vary company by company, the industry as a whole – and by extension patients and consumers – would benefit from a timely and appropriate regulatory resolution.

Jeffrey N. Gibbs is a director at the law firm of Hyman, Phelps & McNamara and specializes in FDA-related matters.

For many years, the Food and Drug Administration (FDA) has taken the position that while it has the authority to regulate laboratory-developed tests (LDTs) as devices, the agency would exercise its enforcement discretion and not do so. More recently, FDA has taken a series of steps that backtrack from that approach, and indicated that it intends to regulate at least some LDTs as devices. Whether FDA has the legal authority to regulate LDTs or whether the agency can do so without going through notice-and-comment rulemaking will be hotly debated. The issue of whether FDA regulation is necessary or beneficial will also trigger sharply differing views. What is not debatable is that the regulation of LDTs as devices under the existing device regulatory regime, should it occur, would have a significant effect on the laboratories offering the tests that are regulated as devices, and will increase the regulatory costs for assays.

Congress has given FDA the authority to comprehensively regulate medical devices. The imposition of these regulatory requirements upon LDTs will have a profound impact on those tests. The following outlines some of the key elements of FDA’s medical device regulatory scheme, and explores the effects of the application of those requirements to LDTs.

Registration and Listing

Device manufacturers need to register with FDA. The registration requirement is fairly trivial in itself. However, a company that is registered is subject to FDA inspection and the imposition of other regulatory requirements. The laboratory’s failure to register would render the LDT “misbranded.” FDA can take enforcement action against misbranded devices and their manufacturers.

Devices must also be listed with FDA. While filling out this form is a minor exercise, the failure to submit the form renders the device misbranded. Thus, laboratories offering LDTs that are subject to device regulation would need both to register their establishment and list their LDTs.

FDA Marketing Authorization – 510(k)s

More important, devices must be cleared or approved by FDA before they may be sold. This requirement will pose a major hurdle for LDTs.

There are two routes by which new devices enter the market. The first is the 510(k) premarket notification process. This is the primary mechanism by which new devices, including in vitro diagnostics (IVDs), undergo FDA review.

In order to obtain 510(k) clearance, the applicant must demonstrate “substantial equivalence” to a “predicate device.” A predicate device is a device that was on the market before May 28, 1976, or is the subject of a 510(k) clearance. As for the first option, there will be no pre-May 28, 1976 devices to cite for the LDTs that FDA wants to regulate. And as for the second, for novel LDTs, it may be a challenge to find an IVD that has been cleared that can serve as a predicate device.

A predicate device does not have to be identical to the new device. The products may differ technologically as long as the device seeking 510(k) clearance does not introduce new questions of safety or effectiveness. However, the predicate device must have either the same or a similar intended use. FDA does have considerable flexibility in deciding whether a previously cleared device can serve as a predicate device. Thus, there does not always need to be a high degree of overlap between the new proposed intended use and the predicate device.

One difficulty that companies often do encounter, though, is learning at an early stage whether their assay is eligible for 510(k) review. Even when companies go to FDA through the “pre-IDE” process, they may not get an answer to the question of whether a 510(k) will be acceptable. Thus, companies may embark on the FDA process without knowing whether they will be able to submit a 510(k), or will need to go through the more rigorous premarket approval (PMA) process instead.

The 510(k) submissions will need to be supported by sufficient data. Providing sufficient data will require generating both analytical data and clinical data. Laboratories will need to generate the data in a manner that satisfies FDA’s requirements. A company should not assume that the data that they generated to validate the assay will be deemed sufficient by FDA. Studies that are accepted for publication in peer-reviewed journals and relied upon by experts in the field will not necessarily satisfy FDA’s regulatory expectations. Thus, a laboratory whose LDT is subject to the need for FDA clearance may need to conduct new studies, beyond its initial clinical validation studies. These studies can be costly and time consuming. Also, the validation work that was sufficient to comply with the Clinical Laboratory Improvement Amendments (CLIA) may not be sufficient for FDA, so that new analytical validation research may need to be conducted. Thus, laboratories that must submit 510(k)s may find they will need to perform significant additional testing in order to obtain 510(k) clearance.

They will also need to wait. FDA has 90 days to review a 510(k) from submission. Laboratories submitting 510(k)s for LDTs should expect at least one set of questions. FDA has up to 90 days to review the response to those questions.

If and when 510(k) clearance is obtained, the 510(k) holders will need to be careful about modifying the test or its labeling. An FDA regulation requires that companies submit a 510(k) and obtain clearance before they significantly modify the intended use of the device, or if they modify the device in a manner that could significant affect its safety or effectiveness (21 C.F.R. 807.81). The failure to obtain a new 510(k) clearance will result in the device being deemed violative, even though it was already 510(k) cleared.

LDTs are often characterized by ongoing innovations and improvements. Companies may want to modify an algorithm or add a new marker or make some other type of change. These modifications will need to be assessed in advance to determine whether a new submission is needed. FDA has developed a guideline for evaluating proposed changes. While helpful, this guideline does not provide clear-cut answers. Laboratories will often need to apply ambiguous requirements to their specific circumstances. Making the decision more difficult, the guideline was not drafted with laboratories in mind. In many instances, a new 510(k) will be needed. This requirement for pre-clearance of modifications will significantly decrease the ability of laboratories to change their LDTs over time.

In some instances, there will not be predicate devices for an LDT. However, if the test is inherently moderate risk, or if “special controls” can be written that will cause the LDT to be moderate risk, then it may still be able to proceed through a 510(k) via the de novo review process. In effect, this process allows devices that are moderate risk to be reviewed as a 510(k), even though no predicate is available. While de novo can be an attractive option for companies with new kinds of tests, they should not assume that de novo will be available. FDA has only cleared about two IVDs each year through the de novo process.

FDA is currently considering significant revisions to the 510(k) process. How these modifications will affect the 510(k) process remains to be seen.

Premarket Authorization – PMAs

Not all LDTs will be able to go through the 510(k)/de novo process. Under current law, the only option for such LDTs may be the PMA process. The PMA is a vastly more complex and costly application. Unlike a 510(k), where the applicant need only demonstrate substantial equivalence, a PMA applicant must also demonstrate the safety and effectiveness of the device, which is a far more demanding standard. The application will need to contain both the clinical and analytical data sufficient to meet that higher threshold.

In addition, the PMA will need to contain manufacturing information. FDA will not approve a PMA unless the company submits data showing that the product will be manufactured in accordance with the Quality System Regulation (QSR) (21 C.F.R. Part 820). FDA will inspect the facility for QSR compliance before approving the application. Given that most laboratories currently focus on achieving CLIA compliance, and not adhering to the QSR regulations, this will not be a trivial task. CLIA and QSR are not the same. Laboratories that pursue the PMA process will need to write a number of new procedures and revamp the way they operate in order to pass muster with an FDA investigator and be approved.

And there’s more. As part of QSR, FDA’s regulations require most devices to be developed in accordance with design controls (21 C.F.R. 820.30). LDTs that are currently on the market or are under development will be unable to meet this requirement. While FDA sometimes will accept retrospective design history files, that is not always the case. Reconstructing the design history in a way that will meet FDA’s needs is not a simple task either.

Before approving the PMA, FDA is likely to convene an advisory panel to review the application. Although the panel’s vote is not binding upon the agency, its recommendation does carry weight. Applicants therefore need to devote substantial resources to preparing for an advisory panel. (FDA can also convene panels for 510(k)s, but rarely does so).

As with a 510(k), once a PMA is approved, the company will have limited flexibility in modifying the device. Some very minor changes can be implemented without prior FDA notification or approval, but they will need to be described in the annual report required of all PMA holders. Many changes, though, will need to be reviewed by FDA before they can be implemented. Some will need to go through a comprehensive review via a PMA supplement. The upshot is that laboratories will find their flexibility curtailed: the ability to change manufacturing process, components, suppliers, materials, and labeling will be curbed significantly.

Postmarket Controls

Once a device is on the market, it continues to be subject to FDA regulation. The failure to comply with these FDA regulatory requirements can result in FDA enforcement action, including the issuance of a warning letter, seizure of devices, civil penalties, an injunction against the laboratory and its employees, or criminal prosecution of the laboratory and its employees. The principal FDA post-market requirements include:

• Compliance with the QSR. The failure to “manufacture” the LDT in accordance with the QSR regulation means that the device is adulterated. FDA inspects device manufacturers for adherence to the QSR requirements.

• Submitting Medical Device Reports (MDRs). FDA’s MDR regulation requires manufacturers to submit reports to the agency within 30 days of learning that one of its device caused or contributed to a death or serious injury, or that the device malfunctioned and that a recurrence of that malfunction would be likely to cause a death or serious injury (21 C.F.R. Part 803). All device companies need to develop procedures to comply with these regulations. The failure to submit a required report, or to submit it in a timely fashion, means the device is misbranded.

• Advertising and promotion. Devices must be marketed in a manner consistent with their cleared or approved labeling. The off-label marketing of a device is prohibited. FDA’s restrictions on off-label marketing may prove particularly problematic for laboratories if FDA deems laboratory reports to be product labeling. Laboratory reports must be tailored to the needs of the individual patient. This individualization can be difficult to reconcile with the FDA regulatory framework, which favors standardization of communications. In any event, laboratories will find their ability to describe and market their test to be significantly constrained if they are subject to FDA regulation as a device manufacturer.

• Notification of Recalls. Under 21 C.F.R. Part 806, device manufacturers must notify FDA of certain types of corrections and removals. This may include notifications to health care providers. Thus, for example, if an LDT device company were to determine that it should send a letter to doctors regarding test results, it may need to notify the FDA as well. All device manufacturers need to develop procedures to comply with Part 806’s requirements.

• FDA inspections. FDA investigators are authorized to inspect device manufacturers for compliance with FDA’s regulations. These investigators have the right to review many documents, including ones related to QSR and MDR compliance. The refusal to allow an inspection is a violation of law. FDA investigators tend to approach inspections with a law enforcement mindset. Inspections may be protracted and require significant resources by the facility to supply documents and information to the investigators.

Summary

FDA regulation of devices, including IVDs, is comprehensive and thorough. Laboratories that are subject to FDA regulation will find themselves operating in a far more complex regulatory environment if FDA treats these assays as they do other devices. In some instances, the need to meet FDA requirements may prevent the LDTs from ever entering the market. Changes to assays will be less frequent and will take longer to implement. The ongoing regulatory costs will increase compared to the CLIA model.

Over the upcoming months and years, there will be extensive debate as to whether FDA regulation of some LDTs is lawful or desirable, a process which began late last month when FDA held a two-day public meeting to discuss its proposal to regulate LDTs (see: recaps of Day 1 and Day 2). However, there should be no debate that extending the FDA device regulatory regime to LDTs, in whatever form it ultimately takes, will have some profound regulatory consequences for the laboratories and the assays that they can offer.

Meggan Bushee is a student at the

This past May, Congressman Patrick Kennedy (D-RI) and Congresswoman Anna Eshoo (D-CA) re-introduced a personalized medicine bill to the U.S. House of Representatives. The bill was originally introduced in 2006 by then-Senator from Illinois Barack Obama. While HR 5440, also known as the Genomics and Personalized Medicine Act of 2010 (GPMA 2010), has retained the name of the bill originally introduced by Senator Obama, its approach to the regulation of personalized medicine has taken a new direction.

GPMA 2010 is the fourth version of the GPMA since the original bill of 2006, and includes the most ambitious initiatives of all of its predecessors. Why has the GPMA re-surfaced after three prior versions failed to make it out of committee? According to Representative Kennedy, the bill has been re-introduced in response to increased public awareness and use of genomic tests. At present, GPMA 2010 is before the House Committee on Energy and Commerce. This is the same committee that recently conducted high-profile hearings to review the current state of the direct-to-consumer (DTC) genetic testing registry.

As the tools of personalized medicine, including genetic testing, have become both less expensive and more powerful, calls for expanded oversight of the field have intensified, particularly in the area of DTC genetic testing. While there is a pressing need for appropriate regulation to protect the consumers and patients targeted by personalized medicine, there is an equally pressing need to avoid crafting a system of oversight that will be an obstacle to continued growth and innovation. The current version of the GPMA aims to strike a balance between consumer protection and flexibility to allow for innovation.

This post outlines the material provisions of GPMA 2010 and examines the transformation the bill has undergone since it was first introduced in 2006.

The GPMA Defines Itself. The stated aim of the Genomics and Personalized Medicine Act is:

To secure the promise of personalized medicine for all Americans by expanding and accelerating genomics research and initiatives to improve the accuracy of disease diagnosis, increase the safety of drugs, and identify novel treatments, and for other purposes.

Interestingly, GPMA 2010 is the first iteration of the GPMA to formally define the term “personalized medicine.” However, the bill limits its definition of “personalized medicine” to:

any clinical practice model that emphasizes the systematic use of preventive, diagnostic, and therapeutic interventions that use genome and family history information to improve health outcomes.

It’s a broad definition, but is it broad enough? Conspicuously absent from the definition is any mention of environmental information, a category that is increasingly recognized as critical to the understanding and management of complex and common traits and diseases.

Despite its narrow definition of personalized medicine, GPMA 2010 includes several expansive initiatives. GPMA 2010 would appropriate $150 million for fiscal year 2011 to accomplish these initiatives, including the creation of an Office of Personalized Healthcare and several committees to address translational challenges of personalized medicine, the standardization of the collection of human biological samples, the funding of further research and education on personalized medicine, and the creation of a national biobank.

In order for those initiatives to bear fruit, the GPMA, should it proceed, is likely to find itself in need of a similarly expansive definition of personalized medicine.

The OPH: Coordinating Personalized Medicine. GPMA 2010 would create an Office of Personalized Healthcare (OPH) within the Department of Health and Human Services (HHS). The OPH would have two main roles: (1) to oversee the implementation of GPMA 2010’s initiatives, and (2) to coordinate the activities of various federal agencies and private and public entities. To fulfill these roles GPMA 2010 would appropriate $5,000,000 for fiscal year 2011, and “such sums as may be necessary” for later years.

The OPH is a new addition to the GPMA since its previous version in 2008. Prior to GPMA 2010, the GPMA provided for the establishment of an Interagency Working Group (IWG), an initiative that was first introduced in the 2006 bill. The IWG had goals similar to those of the OPH, but had few specific responsibilities. The IWG was mainly responsible for meeting twice a year and submitting a report every two years on IWG activities. The OPH, on the other hand, would be more directly involved in directing the expansion and acceleration of research, and signifies a large departure from all prior GPMA bills.

Among other responsibilities, the OPH would be tasked with the development of a long-term plan to accelerate the research and development of personalized medicine products. Each year the OPH would issue a report discussing not only progress within personalized medicine research, but also the challenges that the OPH has identified and is currently addressing. This provides a case in point for how the narrow definition of “personalized medicine” in the bill might affect the implementation of the GPMA. To use our example, if the role of environmental factors is not included in the definition, the OPH’s long-term plan might not take adequate account of the need to utilize environmental data in developing effective personalized medicine products.

Importantly, as presently drafted, the OPH would also be responsible for recommending which personalized medicine products should be regulated, and what roles and responsibilities should be assigned to the Food and Drug Administration (FDA) as opposed to the Centers for Medicare & Medicaid Services (CMS). Presumably this would include weighing in on areas where those two agencies’ regulatory authority appears to overlap, including the regulation of laboratory developed tests. Here again, the act’s definition of “personalized medicine” makes a difference.

GPMA 2010 recognizes the need for greater cross-agency coordination and for a centralized task force to direct the implementation of GPMA initiatives. One ongoing concern is that the development of personalized medicine and its translation to clinical practice will be hampered by redundant and inconsistent oversight at the hands of multiple, overlapping regulatory bodies. The OPH would address this concern, at least in theory, by assigning regulatory authority for personalized medicine products, clarifying and simplifying existing regulations, and providing a clear delineation between the roles and responsibilities of the FDA, CMS and other regulatory agencies. The key question, however, is whether adding a new agency (OPH) to the personalized medicine mix would bring much-needed coordination and strategic vision to the field, or whether it would simply add another layer of confusion and bureaucracy.

A National Biobank. Similar to the biobank initiatives in all three previous versions of the GPMA, GPMA 2010 would create a national biobank to collect and integrate human biological specimens and biobank data. As defined by GPMA 2010, “biobank data” includes health information, demographic genotype, molecular profile data, and (despite being excluded from the definition of “personalized medicine”) environmental data.

If implemented, GPMA 2010’s national biobank would not be the first of its kind in this world. Several countries, including the United Kingdom, Japan, Sweden, Finland, and Iceland have already undertaken similar biobanking initiatives. While the United States has many smaller public (at both the state and federal level) and private biobanks, the GPMA would authorize NIH to coordinate the first truly national biobank. Depending on how swiftly the biobank was created, and whether it incorporated samples from previously existing public or private biobanks, it might quickly become one of the largest repositories of biological specimens and data in the world.

While the implementation of the biobank would be left to the Director of the NIH (currently Francis Collins), working in coordination with the Centers for Disease Control and Prevention (CDC), GPMA 2010 does provide a basic framework. The Director of NIH would be responsible for coordinating the activities of the national biobank with the other public and private biobanks and genomic databases in the United States and developing guidelines to “safeguard[] the privacy of…biobank data.” The Director would also be tasked with addressing ownership and patient access issues and investigating new models of informed consent that balance privacy, risk disclosure and the need for long-term and open-ended research, a task that has recently been shown to be particularly challenging.

One inevitable challenge in implementing a truly national biobank populated with broadly characterized specimens will be funding. To establish the national biobank and fund a related grant program, GPMA 2010 would appropriate $150,000,000 for fiscal year 2011, and “such sums as may be necessary” for later years. While the biobank’s data and specimens would be made available to both government and non-governmental entities, it is unclear whether non-governmental entities would bear some portion of the cost of the biobank.

Is $150 million and the vague promise of more to come sufficient for a biobank of such ambition? By way of comparison, while the initial appropriation, as currently drafted, would be larger than the amount used to catalyze the UK’s national biobank in 2006, which collected £62 million from a variety of funding sources, including the Wellcome Trust, the UK’s largest non-governmental source of biomedical funding. For the GPMA’s national biobank to succeed, similar private funding commitments might well be a prerequisite.

The various incarnations of the GPMA have fluctuated in their treatment of race. The 2006 GPMA had an entire section dedicated solely to “Race and Genomics,” and included several initiatives aimed at including minority populations in genomics research and in improving minority populations’ access to genetic services. The 2010 bill lacks the separate section, but does instruct the Director of the NIH to develop guidelines to “ensure the inclusion of underrepresented populations with health disparities in the activities of the national biobank.” That is itself a departure from the 2008 version of the GPMA, which did not specifically mention minority or underrepresented populations at any point. The role of minority or underrepresented populations in genomic research, and the appropriateness of personalized medicine tools and products for minority or underrepresented populations, was an issue that came up several times at last month’s Congressional hearing on DTC genetic tests, and it is one that would be likely to play a central role in any future Congressional discussion of the GPMA and a national biobank.

The GPMA and DTC Genetic Testing. GPMA 2010 directs the FDA to collaborate with the FTC to “identify and terminate…advertising campaigns that make false, misleading, deceptive, or unfair claims about the benefits or risks of products used for personalized medicine.” While similar consumer protection provisions existed in prior versions of the GPMA, the scope has been expanded in the current version of the bill to apply to advertising and marketing of any personalized medicine product (previous versions focused solely on genetic tests).

Events may have overtaken this proposal, however. Last month’s Congressional hearing and GAO report (pdf) highlighted “misleading test results” and “deceptive marketing and other questionable practices” on the part of DTC genetic testing companies. The report was forwarded to the attention of both the FDA and the FTC and, in its aftermath, it seems unlikely that it will take the passage of new legislation for those two agencies to begin working together to more aggressively police the personalized medicine marketplace.

Interestingly, a separate provision of GPMA 2010 would instruct the CDC, the FDA and the FTC to work together to “conduct an analysis of the public health impact” of “products used for personalized medicine (including genetic and genomic tests) for which consumers have direct access” and to do so “to the extent possible from available data sources.” The joint agency initiative would also “analyze the validity of claims made in [DTC] marketing” and “make recommendations…regarding necessary interventions to protect the public from potential harms” of DTC marketing and access to personalized medicine products. While such an undertaking might appear redundant with the GAO’s recently-concluded investigation, the GAO’s report was an admittedly unscientific snapshot of the field (“GAO did not conduct a scientific study but instead documented observations that could be made by any consumer.”), for which it has been frequently criticized. While a more comprehensive and data-driven analysis of the field would be welcome, recent events suggest that agencies such as the FDA are likely to proceed with additional DTC regulatory oversight on the basis of the data (or lack thereof) currently at hand.

Expanding the Role of Companion Diagnostics and Pharmacogenomics at the FDA. Another provision targeted at the FDA would permit the agency, under certain circumstances, to “require the sponsor of a drug or biological product” (emphasis added) to develop a companion diagnostic test in connection with regulatory filings for a new drug. This provision was originally included in the 2006 bill, but was removed in the 2007 and 2008 versions. Those versions merely permitted the FDA to recommend companion diagnostic development to drug and products sponsors.

The 2010 GPMA also instructs the FDA to “clarify and issue guidance” that explains when companion diagnostics will be included in labeling – including appropriate “standards of evidence…such as with respect to the analytical validity, clinical validity, clinical utility, dosing, adverse events, and drug selection…” – and when such tests will be either recommended or required.

In many respects these provisions of the GPMA seem to reflect the increasing reliance on genomic and genetic data in selecting and administering therapeutics, including the use of companion diagnostic tests.

Where Will the GPMA Go From Here? While GPMA 2010 itself represents a significant departure from the bill originally introduced by Senator Obama in 2006, it is exceedingly unlikely to become law in its current form. Among other considerations, the recent (and ongoing) developments in the areas of laboratory developed tests (LDTs) and DTC genetic testing – two important components of personalized medicine – suggest that substantial revisions would be required to reflect an ever-changing technological, commercial and regulatory environment.

At least for the moment, passage of the GPMA in any form does not appear to be imminent. Perhaps it will never become law – at least in anything like its current form – and either existing legislation or other contenders, such as Senator Hatch’s proposal to create a new regulatory category for “advanced personalized diagnostics” – will be used to fill gaps in the oversight of personalized medicine products. Then again, recall that crafting legislation to respond to the successes of modern science and technology can be a painfully slow process. For instance, the only piece of federal legislation specifically directed at genetic technologies and information, the Genetic Information Nondiscrimination Act (GINA), took thirteen years from the date it was first proposed to its signing into law in 2008. After a mere five years, the GPMA likely has a long way to go.

Judge Dyk’s comments were a bolt out of the blue, as he raised an issue that had not been addressed by the parties or the lower court. Because he is a member of the court that will decide Myriad in the next year or so, Judge Dyk’s comments might be more significant than the district court opinion itself. (The case is Intervet Inc. v. Merial Ltd., Fed. Cir. 8/4/2010.)

Porcine Patents. Merial had a patent (U.S. Patent No. 6,368,601, also known as the ‘601 patent) covering DNA molecules derived from a new type of porcine circovirus (PCV-2), the apparent culprit in a disease affecting livestock pigs called Postweaning Multisystemic Wasting Syndrome. Intervet makes a PCV-2 vaccine. Fearing that it would be sued for infringing Merial’s patent, Intervet brought its own preemptive suit for a declaratory judgment (a kind of advance ruling) that its vaccine doesn’t infringe.

Claims 9 and 32 of the ‘601 patent represent the two groups of DNA claims at issue in the case:

9. A vector comprising an isolated DNA molecule comprising a sequence selected from the group consisting of ORFs [open reading frames—sequences that may be translated into proteins] 1 to 13 of porcine circovirus type II.

32. An isolated DNA molecule comprising a nucleotide sequence encoding an epitope which is specific to PCV-2 and not specific to PCV-1 [a related but benign porcine circovirus].

An epitope, as defined in the opinion, is “an immunodominant region of a protein, meaning it is part of an antigen that is recognized by antibodies of the immune system.” (Dyk, p. 2) This makes a segment of viral DNA that encodes an epitope useful in diagnosing and vaccinating against the pathogen, because the epitope can be introduced to the host animal’s immune system in a controlled fashion (e.g., as part of a vaccine) to stimulate production of antibodies. The idea is that the animal’s immune system will later recognize the epitope (and thus the virus) in the event of exposure.

The Federal Circuit’s majority opinion addressed the district court’s construction of claims 9 and 32. The five PCV-2 strains in the patent share 96% nucleotide sequence homology with each other but only 76% homology with PCV-1. The potentially infringing Intervet PCV-2 vaccine contained a nucleotide sequence that was 99.7% homologous to one of the ‘601 patent’s PCV-2 sequences, but the district court construed the claims to cover only the exact sequences disclosed in the patent and ruled that Intervet’s vaccine was therefore noninfringing.

The Federal Circuit found the district court’s claim construction to be too narrow because the “representative” sequences that Merial disclosed “do not constitute the entire scope of the invention.” Under Federal Circuit case law, a claim to a genus (a group of inventions) may be supported if “a sufficient number of species [i.e., individual examples] is disclosed so as to properly identify the scope of the genus.” (Prost, p. 9) Here, the five newly disclosed PCV-2 strains share the defining properties of pathogenicity and 96% sequence homology, in contrast with the “counterexample” of PCV-1, which has only 76% sequence homology and no pathogenicity. The majority remanded the case for further proceedings based on the revised claim construction.

Dyk’s Unexpected Dissent. Judge Dyk dissented from the majority’s construction of claim 9, and agreed with their handling of claim 32. (Dyk, p. 2) So far, just routine patent law inside baseball. But then came the shocker: “At least claim 32 of the ‘601 patent raises substantial issues of patentable subject matter.” In other words, “an isolated DNA comprising a nucleotide sequence encoding” a specified epitope might not be within the very broad scope of the things that the patent law was intended to cover. This is almost exactly what the District Judge Sweet held in Myriad.

Judge Dyk framed the essential question this way:

…whether the isolated DNA molecule, separate from any applications associated with the isolated nucleotide sequence (for example, the production of a vaccine) is patentable subject matter. (Dyk, p. 3, our emphasis)

He then made a point that patent lawyers won’t like to hear but which is absolutely true: “Neither the Supreme Court nor this court has directly decided the issue of the patentability of isolated DNA molecules.” (Dyk, p. 3) He cited a series of cases going back to the early 1990s in which the patentability of isolated DNA sequences had been assumed, but never framed as an issue for decision. So, in his view—an accurate view—while patent practice may support the proposition that isolated genes are patentable subject matter, no appellate court has ever so held.

Judge Dyk then discussed three Supreme Court cases that have reaffirmed the proposition that “‘laws of nature, physical phenomena, and abstract ideas’ are not patentable.” The most recent—the June 28 decision in Bislki v. Kappos—was a business method case concerned with laws of nature and abstract ideas. But the other two—Chakrabarty, from 1980, and Funk Bros. Seed, from 1948—represented claims on either side of the product of nature line. Chakrabarty held, famously, that a genetically engineered bacterium was a human-made invention and thus patentable subject matter. The long-forgotten invention in Funk Bros., a mixture of nitrogen-fixing bacteria that worked together without mutual inhibition, was merely the discovery of a product of nature and thus not patentable.

The standard that emerges from these cases, Judge Dyk concluded, is that “in order for a product of nature to satisfy section 101 [which determines patentable subject matter], it must be qualitatively different from the product occurring in nature, with ‘markedly different characteristics from any found in nature.’” (Dyk, p. 6, citing Charkabarty.) Turning—ominously, perhaps, for gene patent holders—to the issue at hand, he observed that “it is far from clear that an ‘isolated’ DNA sequence is qualitatively different from the product occurring in nature.” (Dyk, p. 6)

Anticipating Myriad. Judge Sweet, the Myriad district judge, expressed exactly the same doubt, and was unable to resolve it. He noted that patent lawyers had always—successfully, until now—contended that isolated genes were “markedly different” from their natural counterparts as chemicals. He held, however, that the proper focus was on genes as information, and from this perspective found no difference at all.

Judge Dyk did not get around to the chemical-information controversy, so we can only guess about his views. We now do know, however, that one member of the court that will decide the fate of gene patents is sympathetic to the general structure of Judge Sweet’s argument, and dubious about gene patents in general. Moreover, he went out of his way to say all this when he had no need to do so. To be fair, appellate courts have long taken the position that they can raise the issue of patentable subject matter on their own. But they rarely do so, which makes it an attention-getting strategy. And Judge Dyk has certainly gotten everyone’s attention.

A final point concerns the relationship between Judge Dyk’s opinion and the ACLU’s curious motion to force Federal Circuit Chief Judge Randall Rader to recuse himself from (refrain from participating in) the Myriad appeal because of some general comments he made at a patent law symposium. (We say “curious” because it has almost no chance of success and has the potential to irritate Judge Rader’s colleagues, if not Judge Rader himself.) While Judge Rader’s comments can hardly be construed as suggesting that he’s made up his mind on any issues relevant to the Myriad appeal, Judge Dyk’s gratuitous comments go pretty far in that direction. Will another recusal motion be forthcoming?

Tom Clarkson is a student at the University of Georgia School of Law.

The “Wrongful Birth” debate is in the news yet again. In a pair of previous posts (here and here) the Genomics Law Report highlighted several issues relevant to the debate over what happens when states recognize a cause of action for wrongful birth, wrongful life or wrongful conception. A recent example from Florida illustrates that the debate continues.

Aiden, Caleb and Smith-Lemli-Opitz. In 2002 Aiden Estrada was born with a number of severe birth defects. Despite multiple examinations, Dr. Boris Kousseff, Director of Medical Genetics of the University of South Florida College of Medicine, failed to diagnose the symptoms as Smith-Lemli-Opitz syndrome and informed Aiden’s parents that they could expect a “normal” pregnancy if they conceived again. Relying on these representations, Amara and Daniel Estrada conceived a second child in 2004. This second child, Caleb, was born with symptoms nearly identical to those of his brother Aiden. Within one hour of Caleb’s birth, a geneticist at the University of Florida diagnosed him with Smith-Lemli-Opitz syndrome. The Estradas sued, and a Florida jury awarded them more than $20 million dollars in their wrongful birth suit in July 2007.

As the Estradas soon found out, a courtroom victory does not necessarily equal a recovery. Because Dr. Kousseff was a state employee, state law limited the amount of their recovery to $200,000, with any recovery above that amount requiring a special act of the Florida Legislature. On March 2, 2010, the Florida Legislature passed “An Act for the Relief of Daniel and Amara Estrada,” authorizing the payment of $25,023,212.92 to compensate the Estradas for the remainder of the judgment.

The Political Element. As we discussed in a previous post, the distinction between claims for “wrongful birth” – which allows parents to recover costs associated with the care of a disabled child – and “wrongful life” – which seek to compensate the child (or parents, suing on behalf of the child) for the harm caused by a birth that would not have occurred but for negligent care is important but subtle. Addressing the issue of damages from the perspective of the caregivers (the parents) and not the child permits jurisdictions that prefer the wrongful birth framing, including Florida, to avoid the even more challenging questions associated with wrongful life claims. These include considering whether acknowledging the claim implies a “judgment that an individual life is so wretched that one would have been better off not to exist.”

Even under the wrongful birth framing, the act of the Florida Legislature authorizing the Estradas’ additional compensation was by no means a foregone conclusion. In 2007 one commentator quoted Victor Crist, the Florida State Senator in charge of overseeing the potential payout, on the controversial nature of the case:

In the 15 years I’ve been in the Legislature, I haven’t seen that kind of issue. This has a potential moral question that could become a potential political issue. I don’t know what the Legislature will do with that.

The “potential moral question” to which Victor Crist referred related to the potential role of abortion in the case. Had the Estradas’ first child, Aiden, been correctly diagnosed with Smith-Lemli-Opitz syndrome prior to Caleb’s conception, a relatively simple reproductive genetic screening test would likely have detected the syndrome in Caleb. Among the options available to the Estradas would have been abortion.

For both politicians and the public, it is easy to see how the torts of wrongful birth or wrongful life can become intertwined with the issue of abortion. In that regard, the Estradas’ case raises interesting issues as to whether state legislatures will continue to defer to juries who award massive judgments against employees of state medical facilities, or whether state legislatures will choose to inject moral and political considerations into the discussion. With rapid changes in the science and law of reproductive genetics delivering more questions than answers, relatively untested theories of liability – including wrongful birth and wrongful life – are likely to continue to remain a source of contention for both courts and legislatures.

[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).

The Court sat in a 13-member Grand Chamber, which is eurojargon for “really big deal,” and issued a ruling which leaves gene patents essentially intact but warns national courts to construe them carefully. (Travel advisory aside: If you ever have a chance to visit the Court in Luxembourg, do. Its magnificently robed judges sit in medieval splendor in a hideous modern building. Lawyers (usually several per case), robed almost as magnificently, read long and pompous arguments that are translated into many languages. The judges, apparently having already decided the case, ask no questions and seem to pay no attention. The rulings are logically convoluted and delivered in baroque language. Everyone seems immensely pleased with the spectacle.)

Soybean DNA, Living and Dead. Monsanto holds a European patent that covers modified soybean DNA sequences that confer herbicide immunity on the plant (so-called “Roundup Ready” soybeans). A “European” patent is in fact a bundle of national patents issued by the European Patent Office (EPO) in Munich. (The EPO was established by a treaty, the European Patent Convention, and is not a European Union institution.) The EPO applies a single standard for judging patentability, but enforcement of patents is then delegated to the courts of the individual European countries, and those standards may differ. Monsanto’s European patent is in effect in several countries, including the Netherlands, where Monsanto brought this infringement action.

Cetera tried to take advantage of the fact that Monsanto does not have a patent on the soybean in Argentina. As we noted in an earlier international post, patents have no “extraterritorial” effect—they must be obtained on a country-by-country basis (with some limited opportunities for one-stop shopping, as in the EPO). So it is not illegal to make, use, or sell Roundup Ready soybeans in Argentina. Cetera makes soy meal from Roundup Ready soybeans that are grown in Argentina and exports it to Europe. The soy meal in question was seized by Dutch customs authorities. It contains “dead” versions of the DNA sequence covered by Monsanto’s European patent. Monsanto sued for Cetera for violating a provision of Dutch patent law that forbids importing a patented product—in this case, the DNA sequence—into the Netherlands.

Conflicting Authority. Cetera contended that Dutch law was overridden by the EU Biotechnology Directive (the Directive). A directive is a law issued by the EU that all member states must comply with. It doesn’t take effect directly in the individual EU countries, but they must “harmonise” their national laws to make them consistent with the directive. The Biotechnology Directive requires that member states grant patents on “biotechnological inventions” (Article 1), but then provides more specifically in Article 9 that:

The protection conferred by a patent on a product containing or consisting of genetic information shall extend to all material . . . in which the product is incorporated and in which the genetic information is contained and performs its function. (emphasis added).

If the protection granted under Dutch patent law exceeds what the Directive allows, then the Dutch law would be invalid. Since this is a question of EU law, the Dutch court hearing the case referred it (along with several other questions) to the ECJ. Even though Monsanto and Cetera settled the case before the ECJ ruled—Monsanto essentially gave up, according to most accounts—the ECJ went ahead and decided the questions put to it.

(Brief jurisprudential recap for those who are scoring along at home: (1) The EPO granted a Dutch patent. (2) Monsanto, the patentee, sought to enforce the Dutch patent in the Netherlands. (3) The Argentine defendant, Cetera, sought an ECJ ruling that the Dutch patent law that Monsanto relied on was invalid because it exceeded what was allowed under the EU Biotechnology Directive. This is a bit like the situation where an American defendant argues that a state law is invalid under the U.S. Constitution—except that the EU doesn’t have a constitution, so don’t carry the analogy too far.)

The ECJ Decision. The ECJ decided that the Dutch law does violate Article 9 of the Biotechnology Directive. The reason has to do with verb tenses in the italicized language quoted above. The Court held that genetic material can be protected only when it is performing its function. When, as here, “the genetic information has ceased to perform the function it performed in the initial material”—the living soybean plant—then there can be no patent protection. Because the DNA sequences in the imported soy meal were “dead material” no longer performing their function, they were no longer protectable pursuant to Article 9 of the Directive.

What can we make of this very complex decision on a practical level? A few thoughts:

1) Whatever it means, the decision is the law throughout the 27 member countries of the EU.

2) The ruling does not undercut the patentability of genes in any fundamental way.

3) The ruling does, however, admonish the courts of the EU member countries to pay strict attention to the language of the Biotechnology Directive when enforcing gene patents. We might expect infringement defendants and their lawyers to start scanning the Directive for additional semantic loopholes.

4) On the specific facts of this case, the ECJ held that a gene must be performing its function at the time of the infringing act to be protected. Here, the infringing act was the importation of the soy meal, by which time the gene was “dead.” But it offered no guidance on what the function of genetic material is. An obvious answer would be “coding for a protein,” but we don’t learn that for sure from the opinion. If that is in fact the right answer, is there a difference between the actual process of making a protein at a given point in time and simply being capable of making a protein? Looked at from a slightly different angle, when does a DNA sequence become “dead” and thus incapable of performing its function?

5) Finally, there may be a subtle but important link between the ECJ’s emphasis on genetic material performing its function and the chemistry versus information argument Judge Sweet presented in his Myriad Genetics opinion earlier this spring. Judge Sweet reasoned that, even though an isolated gene might be chemically distinct from its naturally occurring counterpart, its information-carrying capacity was the same—and that information-carrying function is the whole reason people are interested in genes. As Judge Sweet wrote (pdf):

DNA represents the physical embodiment of biological information, distinct in its essential characteristics from any other chemical found in nature. It is concluded that DNA’s existence in an ‘isolated’ form alters neither this fundamental quality as it exists in the body not the information it encodes” (pp. 3-4).

In a roughly similar way, the ECJ—following the Biotechnology Directive—ignored the fact that “live” and “dead” genes might have the same chemical sequence and focused on the functional (information-delivering?) differences between the two. This logical link between the decisions is attenuated, and neither will bind the Federal Circuit, which will be the next court to tackle the issue of the patentability of genes, but it is a connection that may merit some additional development moving forward.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other DTC encounters that received particular scrutiny included:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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