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.

• The next step in nanopore seq? RT @techreview: Graphene Could Improve DNA Sequencing http://bit.ly/aQMUvD
• Complete Genomics adds $39M in Series E, readies for IPO & prepares to defend against $ILMN infringement claim: http://bit.ly/9yMHva
• New @genomesunzipped post by @dgmacarthur, @lukejostins & Kate Morley: What the GAO report could have told us: http://bit.ly/cIDMGv
• Excellent! RT @dgmacarthur: Caroline W. from @PHGFoundation & I have @NewScientist op-ed on smart reg of DTC genetics: http://bit.ly/9pgKOS
• RT @GW_The_Sample: UC Berkeley’s Stillborn Gene-Testing Project Could Hold Lessons for Clinical Labs: http://bit.ly/aVU6W9
• RT @genetics_blog: RT @dgmacarthur: Excellent analysis of the Ion Torrent purchase by @ldtimmerman over at Xconomy: http://bit.ly/aPOJww
• RT @blaine_5: RT @dgmacarthur: Great post by @MishaAngrist on genetic exceptionalism and access to medical data: http://bit.ly/bFVP2F
• GLR Post: Swine Still Soaring: Federal Circuit Judge Expresses Sympathy for Myriad Analysis: http://bit.ly/9ko9Fw
• GLR Post: Resolution in Florida Wrongful Birth Case: http://bit.ly/9u060V
• RT @GW_The_Sample: UC Berkeley’s Capitulation Could Hold Lessons for Clinical Labs: http://bit.ly/9uFZRl
• A diff form of stratification RT @dgmacarthur: Potential benefits of a 3-tier system for DTC genomics: http://j.mp/afVFO4
• PLoS Medicine: Valid Consent for Genomic Epidemiology in Developing Countries: http://bit.ly/dC9ToF HT @westr
• RT @matthewherper: My take on Eric Topol’s take about PBMs and #genomics. http://ow.ly/2oWBa
• Re: Economist piece: not necessarily a linear relationship between cost of sequencing & genetic testing http://bit.ly/9NkA7m
• Berkeley reversal unfortunate for students & dangerous precedent for research labs. Also opp to cont discussion re: access to genetic data.
• MT @pgx_reporter: Berkeley Halts Genetic Testing Program; Touts Opp for Ethical Debate: http://bit.ly/cz4FZb
• RT @mary_carmichael: Data breaches: not just for EHRs. RT @NatNetBoston Lost “unshredded” patient records found in dump http://bit.ly/93AVUy
• RT @dgmacarthur: Lack of clinician understanding of genetics is leading to “remarkable waste”, argues @EricTopol: http://bit.ly/bzDHNd
• Moderate, balaced, well done. RT @dgmacarthur: Nice piece by @j_timmer in Ars Technica on the DTC regulation furore: http://bit.ly/dwq8II
• RT @DukeIGSP @EdwardWinstead: Nature has two op pieces on regulating genetic tests (one says ban DTC medical tests) http://bit.ly/d98ZHh
• RT @pgx_reporter: Myriad ‘Aggressively’ Eyeing M&A, Companion Dx Deals, Euro Opportunities in FY 2011: http://bit.ly/ddT5NC
• RT @dgmacarthur: New Unzipped post: @lukejostins wonders whether personal genomics research could feed back on itself http://bit.ly/9frny5
• The Genomics Law Report is hiring: http://bit.ly/9NSyyP
• Amazing & Onion-esque MT @eurogene: Yes, Ray, DTC genomics JUST LIKE Serpentor frm GI Joe: http://j.mp/bmu3rA
• RT @GW_The_Sample: FDA Suggests Changes to 510(k) Process as LDT Reg Reforms Simmer in Background: http://bit.ly/cCtSfB
• RT @dgmacarthur: This #DNAdilemma post on genealogy/ancestry by @blaine_5 really is excellent. Highly recommended: http://bit.ly/c2etjT
• RT @Duncande UK Group Offers DTC Genetic Testing Principles: http://bit.ly/aEyYIW via @gw_dailyscan
• The full Newsweek/FDA interview is worth your time if you’re interested in reading DTC tea leaves: http://bit.ly/aOyZ2O #DNAdilemma
• The Past, Present and Future of DTC Genetic Testing Regulation: http://bit.ly/cjMcoq My full response to @mary_carmichael’s #DNAdilemma
• RT @mary_carmichael: How to regulate DTCG? by @genomicslawyer, Boughman, Prutow & FDA’s Gutierrez/Mansfield http://bit.ly/9Nxbn2 #DNAdilemma
• RT @dgmacarthur: Brief commentary on the HGC guidelines from @PHGFoundation: http://bit.ly/axwDdw
• RT @mary_carmichael More #DNAdilemma essays from @dgmacarthur @tgoetz @MishaAngrist Bob Green & Hank Greely: http://bit.ly/d3s0r1
• RT@ mary_carmichael: First #DNAdilemma opinions are up! Tks to @jcbarret @23andme @GeneSherpas @blaine_5 & Muin Khoury: http://bit.ly/cvD7EK
• MT @mary_carmichael I just bought a DTC genetic test. Should I take it? You tell me: http://bit.ly/a1pc35
• RT @kashhill: True/Slant is going away (*tear*) but the Not-So Private Parts will stick around somewhere http://bit.ly/ciCy1N
• Patent Office Releases Interim Bilski Guidelines http://bit.ly/asjzPp via IPWatchdog
• Very helpful: RT @ dgmacarthur Weekly round-up of links from world of personal genomics: http://bit.ly/aH9Naj

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.

_______________

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).

• Excellent per usual: @dgmacarthur on the costs of protecting consumers from their own genetic info: http://bit.ly/99DD7D
• GLR Post: European Court Issues Gene Patent Ruling Against Monsanto—A Myriad Connection? http://bit.ly/9EbufG
• What the new model of citizen science looks like: http://bit.ly/bOZBK4 by @LaBlogga H/T @bachinsky
• RT @EdwardWinstead: Terrific article in Reason about where we are with personalized genetic tests (“the Apple II era”) http://j.mp/cRY8FB
• RT @dgmacarthur: Great post by @eurogene on the deceptive practices behind the GAO report into DTC genomics: http://bit.ly/927Qww
• Agree or disagree, credit to @PHGFoundation for offering a concrete proposal for DTC genetic testing regulation: http://bit.ly/9leus5
• It’s the translation, stupid! @Duncande’s piece on #HouseDTC at CNN/Fortune is typically well-balanced: http://bit.ly/aGY46X
• George Church tweets now: RT @geochurch: Creative compu-bio-nano-tech u(dys)topias from John Sundman: http://bit.ly/9olUNC
• RT @dgmacarthur: Caroline Wright from @PHGFoundation has a balanced @genomesunzipped post on the current DTC furore: http://bit.ly/aOzNOH
• RT @iftfhealth: The Geneticist Will Skype U Now – feat. @MishaAngrist, @genomicslawyer, @dgmacarthur http://tinyurl.com/35t94hf thx brad!
• RT @23andMe: Follow up to last week: we had a productive meeting with the FDA on Friday, and we look forward to continue working with them.
• MT @MishaAngrist: Webinar on Havasupai case http://bit.ly/99eDHv Angst-ridden talk of NBS DNA & #HeLa. Lesson: informed consent = broken
• Illumina Announces Creation of the Illumina Genome Network: http://bit.ly/an8HYg Hi-Seq as a cloud?
• Newsweek science writer (Human Condition) @mary_carmichael is now on Twitter & an immediate must follow.
• MT @eurogene, @sociallifeofdna using GAO report as DTC company marketing technique! http://bit.ly/ckQaGc #HouseDTC
• RT @neandrothal: Note to Jeff Shuren: “Out-of-the-box” approaches very diff from “outside-the-box” approaches http://bit.ly/9Nyor0 #HouseDTC
• MT @razibkhan: Personal genomics & the state: Dr. Daniel MacAthur & Dan Vorhaus offer their takes on #HouseDTC http://bit.ly/aYXhJx
• Rebuttal to GAO’s report on DTC genetic testing from @23andMe: http://bit.ly/avzVZ8 #HouseDTC
• Wish I could be there! RT @MishaAngrist: all kinds of mind-boggling peeps at Open Science summit next week http://bit.ly/b4NRq1 and me…
• RT @MishaAngrist: “Can’t stop killing you.” My response to yesterday’s dog and pony show. http://bit.ly/bHFqrf #HouseDTC
• #FF 2/2 @ldtimmerman @neandrothal @Duncande @wilbanks @emilysinger @tgoetz @nutrigenomics @lindaavey @dgmacarthur @GeneSherpas @bigs @chiah
• Tx all for #FF. A few (of many) I try to never miss @EdwardWinstead @markgfh @eurogene @genomesunzipped @MishaAngrist @drjonboyg @shwu (1/2)
• RT @dgmacarthur: Why I love blogging: the comments thread on my @genomesunzipped post on #HouseDTC is fantastic: http://bit.ly/ds5LGo
• RT @dgmacarthur: AH: strong genetic privacy regulations may conflict with desire of DTC consumers to share results #ukcsj
• Next House hearing of interest? “House committee to hold hearing on public access to publicly funded research”: http://bit.ly/axr0Ub
• Interesting not even on market yet RT @GW_The_Sample: FDA Deals Blow to Sequenom, Says SEQureDx Appears to Be an IVD: http://bit.ly/a6uWxb
• RT @23andMe: Video recordings from last week’s Policy Forum are now available on our site: http://bit.ly/9C5or4
• RT @lindaavey @raymondmccauley DNA Rights Petition “Consumers have a right to access personal genetic info” http://bit.ly/cc7MWU #HouseDTC
• MT @markgfh: Some preliminary thoughts on the Congressional hearings on personal genomics http://bit.ly/9O2qZE (sub) #HouseDTC
• Like it or not, the GAO YouTube video will be lasting data pt from #HouseDTC hearing. Who knew gov’t was so media savvy?
• The media fallout begins: RT @DukeIGSP: Federal ’sting’ slams gene test. @nytimes http://nyti.ms/9UwEU0
• While You Were Meeting: FDA Mails Letters to 14 More Genetic Test Providers: http://bit.ly/984iUo
• LA Times: report says 53% of parents are interested in genetic testing for their kids: http://bit.ly/9RY6oH
• GLR Post: The Conversation Continues: Recap from Day Two of FDA’s LDT Regulatory Meeting: http://bit.ly/cSr3lE
• Duke suspends researcher and halts cancer trials: http://mobile.nytimes.com/article?a=630029&f=23
• RT @dgmacarthur: scare-mongering and exaggerated anecdotes about DTC testing in the Washington Post: http://bit.ly/dzAmAM
• Now we move on to the panel discussion, moderated by Muin Khoury of CDC
• After the public comments, the DTC scorecard at #FDALDT looks like this: 3 in favor of DTC, 5 opposed and 1 (Navi) that punted
• Q: to what extent would oversight of LDTs be a problem for changing/modifying tests?
• Duke is looking into whether and how genetic testing changes behavior: http://bit.ly/chLVIA Good ex of type of needed data collection
• Q: do patients know/care about how LDTs are regulated?
• First panel question: “How might increased FDA oversight of LDTs affect patients and clinicians?”
• Eric Lawson, Voisin and AMDM working group: does not support use of LDTs for companion diagnostics (CDx)
• Mansfield: example of Class II would be genetic tests where phenotype is already known; implication that diagnostic testing Class III?
• Additional insight on the Washington Post / @23andMe story from @CeCeLMoore: http://bit.ly/cIUOxlhttp://bit.ly/cIUOxl
• RT @kashhill: RT @yalelawtech A Brave New Genetic Database http://bit.ly/aeONoG (thanks @kashhill and @atlblog)
• Does personal data privacy mean keeping it secret, or taking control? http://nyti.ms/9kyve6 HT: @dgmacarthur @nutrigenomics @AchimMuellers
• In DC (Hyattsville, MD) for FDA public meetings on LDT regulation. Who else is in town? #FDALDT
• RT @lukejostins: RT @dgmacarthur #FF Comrades from @genomesunzipped: @lukejostins @VincentPlagnol @PHGFoundation @jandot @jcbarret
• My slides from #gcpm are avail here: http://bit.ly/avS8zl Bigger picture thoughts are here: http://bit.ly/bTS3l9
• Personal Genomics Goes to Washington: http://bit.ly/bTS3l9
• Just in: Waxman’s Energy and Commerce subcommittee to hold DTC genetic testing hearings nxt Thurs, right after FDA mtg.
• Lee Hood arguing for a CSI-like tv show to help spread P4 to the masses. Personal genomics going Hollywood? #gcpm
• Neither is blackberry. Having wi-fi issues. RT @lindaavey: IPad not good for tweeting! Follow @shwu #gcpm
• Grim Sleeper Awakens Attention to Familial Searching of DNA Databases: http://bit.ly/bMIcXf
• Just landed @ SFO. Enjoying bonus daylight & looking frwd to @23andMe policy forum tmrw. Hashtag #gcpm for live tweets.
• Sounds like Grimes RT @matthewherper: “The presence of informed consent does not render ethical a study that is by nature not ethical.”
• RT @dgmacarthur: Inaugural Genomes Unzipped post: @lukejostins on the importance of sequencing for personal genomics: http://bit.ly/af78OD
• Welcome to Genomes Unzipped! http://bit.ly/9Jjexn @GenomesUnzipped
• Bilski boost short-lived: RT @GenomeWeb_News: Myriad’s Shares Hit 52-Week Low: http://bit.ly/akbWOY
• California Legislators’ Effort to Prevent Student DNA Testing Could Come Too Late: http://bit.ly/cGsOBa HT @GW_The_Sample
• Request for comments on development of NIH’s Genetic Test Registry extended until Aug 2: http://bit.ly/a8pRQJ HT @dgmacarthur @shwu
• RT @dgmacarthur: Personal genomics customers: Rob Stein needs to hear about your positive experiences: http://bit.ly/90omPS

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.