Jennifer K. Wagner, J.D., Ph.D., is a solo-practicing attorney in State College, PA, a research associate at the University of Pennsylvania’s Center for the Integration of Genetic Healthcare Technology

Last month, the Pennsylvania General Assembly voted in favor of a bill that would expand the Commonwealth’s criminal database. PA Senate Bill 775 authorizes law enforcement to begin DNA fingerprinting of individuals upon arrest or charge for certain specified crimes (as opposed to only upon conviction) and authorizes familial searching of the state’s forensic database. After third consideration, the amended version of PA Senate Bill 775 passed by a vote of 42-6. The bill has been referred to the judiciary.

The bill had been introduced in March of 2011 by Pennsylvania Senate Majority Leader Dominic Pileggio, who was later joined by a dozen colleagues (including nine Republican and three Democratic sponsors). It immediately garnered the attention of genetics law scholars, including Penn State Dickinson’s School of Law Professor David Kaye, who submitted a thorough statement (pdf) for the Pennsylvania General Assembly’s consideration.

The bill as passed is significantly different from the original bill in at least one respect. The original version of the bill had a narrow, onerous expungement process. That process required an individual to petition the government to have its DNA sample and profile expunged. This process would have put a considerable burden on arrestees whose DNA sample and corresponding DNA profile had been collected at booking. As originally drafted, expungement could only be granted if the individual established by clear and convincing evidence (a relatively high burden of proof) that (1) the charges were dismissed or never filed, (2) there had been an acquittal of the charges, or (3) inclusion was by mistake.

The amended version (pdf) has made the expungement process automatic in some circumstances, mandating that the individual’s DNA sample, record, and profile be expunged if the:

• conviction has ultimately been reversed and the case dismissed;
• charge leading to the individual’s inclusion in the database has been dismissed with prejudice;
• individual has been acquitted of the charge that led to inclusion in the database;
• individual was never charged for the crime that led to the individual’s inclusion in the database;
• prosecutors have decided not to prosecute the individual for the crime that led to the individual’s inclusion in the database;
• charges were not filed within the statute of limitations; or
• individual has been issued an unconditional pardon for the crime that led to inclusion in the database.

It is notable that PA Senate Bill 775 does not limit familial searching to partial CODIS matches but also explicitly authorizes mitochondrial DNA analysis, Y-chromosome analysis, and “[a]ny other suitable method designed to determine that a crime scene DNA profile originated from a close relative of an individual in the State DNA Data Base.”

Ultimately, PA Senate Bill 775’s authorization of familial searching would distance the Commonwealth from its southern neighbor, as familial searching is prohibited in Maryland. Familial searching, discussed on several occasions here at the Genomics Law Report, is permitted in only a few states (including California, Colorado, Texas, and Virginia). A recently published policy report provides valuable background information for those seeking further information on the topic.

Here in the U.S., the Supreme Court will consider the post-conviction DNA testing landscape in the Texas case of Henry Skinner. Thousands of convicts are requesting new DNA testing in light of the increasing number of exonerations based on DNA evidence. Skinner was convicted 15 years ago of murdering his girlfriend and her two developmentally disabled adult sons. At the recommendation of his attorneys, he declined DNA testing for his trial. Texas courts said he doesn’t currently qualify under a state law that grants DNA testing to some convicts, and federal courts refused to overrule Texas. The last time the Supreme Court considered this issue, in 2009, a divided court decided to let Congress and the state legislatures make the rules. Therefore, rules vary from jurisdiction to jurisdiction as to how requests for post-conviction DNA testing are handled. Perhaps this time the Supreme Court will decide to lay down some firmer ground rules.

A number of newer developments have caught our attention.

The Council for Responsible Genetics (CRG) in Cambridge, Massachusetts and GeneWatch UK teamed up to announce a new online resource called National DNA Databases last month. The website focuses heavily on the controversial topics of familial searching and advance DNA collection (requiring a DNA sample of all arrestees, when charges are filed, or as part of a plea bargain). In addition to information about 56 nations operating DNA databases around the globe (inaccessible to the public), this resource includes U.S. maps showing “State Rules on Partial/Familial Searching” and “States Collecting DNA Samples from Arrestees,” (same link) both discussed below.

Partial DNA Matching Expanding. Law enforcement officials typically search DNA databases for a profile that matches DNA from a crime scene sample. Partial or familial searching of DNA databases is a new method that allows the searcher to detect profiles that share some aspects of the crime scene DNA when no exact match is found. In states where this type of search is permitted, a partial match may generate new leads through investigation of close relatives of the person whose profile was in the database. All convicted felons and members of the military have been profiled in the U.S. databases for many years now, and increasingly many others are also included (see below). Partial matching effectively broadens the investigator’s castnet to reach close genetic relatives of everyone in the databases. Those family members can then be openly investigated or DNA tested through surreptitious sampling (considered legal because trash is public domain with no associated privacy rights, and thus a discarded coffee cup is fair game).

Last year Cass reported data from 2009 indicating that at least 15 U.S. states allowed the use of partial matches, but at least 10 of those required that the partial match be discovered unintentionally. It can be difficult to determine which states are actually utilizing this tool, because it often takes time to develop an official policy. However, the CRG website says that today at least 15 states allow intentional partial match searches, at least 6 allow a partial match to be utilized if discovered unintentionally, at least 5 have a “draft policy under review,” and 13 are operating under unknown policies. Only 11 states continue to prohibit partial matching and familial searching altogether.

Critics point out that partial matching is problematic for several reasons. For example, being related to a convicted felon or member of the military has no bearing on one’s own innocence. Vocal Maryland defense attorney Stephen Mercer says, “If my brother’s DNA ends up in the database, and he’s forfeited his privacy rights by becoming a convicted felon, has he also forfeited my privacy rights as a wholly innocent family member?” Likewise, members of the military do not intend to compromise their relatives’ genetic privacy simply because they agree to submit their own DNA samples.

Another problem is that the U.S. African-American population currently comprises a disproportionately large percentage of the databases because of their overrepresentation in the prison system. Therefore, partial matches leading to relatives of those in the databases will also disproportionately target African-Americans for criminal investigation. According to CRG, although African-Americans are only 12% of the U.S. population, their profiles constitute 40% of the Federal database. Creating a national database with DNA profiles for all U.S. citizens would go a long way toward solving this problem, but critics of that plan object on the grounds that requiring U.S. citizens to submit DNA is an unconstitutional invasion of bodily privacy.

On the other hand, familial searching is in fact an effective crime-fighting tool. The practice has greater public approval in the UK, where the technique famously led to the identification of the “Shoe Rapist” because of a partial match with his sister. The percentage of the total UK population represented in the national database is much greater than in the U.S. Now, a British MP is calling for DNA testing of the entire male population of Bristol, around 250,000 people, to help solve the murder of Joanna Yeates in December, 2010. Media reports indicate that there was no evidence of sexual assault, but that saliva was found on the exterior of Ms. Yeates’s clothing. And when predators remain at large in the U.S., such as in the Virginia case of Morgan Harrington and the recently announced serial killer in New York, familial searching increasingly gains support in this country too.

Advance DNA Collection Also Expanding. Advance DNA collection in the U.S. also continues to expand at various stages of the criminal procedure timeline. Previously, only persons convicted of felonies were required to submit DNA samples for federal databases. In fact, until 2004, federal law prohibited maintenance of DNA profiles in the databases for anyone who was subsequently acquitted. A very different picture exists now, according to CRG:

Today, 44 states collect DNA from anyone convicted of a felony, 39 states collect DNA from those convicted of certain misdemeanors, 28 collect DNA from juvenile offenders, 6 states collect DNA of all individuals arrested and some states (such as California) have started to retain DNA from individuals identified as “suspects.” Still other states such as Louisiana and New York have been discovered to have “offline” DNA databases including DNA samples and profiles taken from victims or suspects never charged with a crime.

Of particular interest is New York, where Governor David Paterson proposed legislation last year that would require even those convicted of low-level misdemeanors to submit DNA samples. That proposal has been moving slowly in the state legislature, but in the meantime, State Division of Criminal Justice Service Acting Commissioner Sean M. Byrne has issued a letter “strongly encouraging district attorneys in the state to require a DNA sample as a condition of all plea bargains.” Also in December, 2010 in California, Orange County officials unanimously voted to renew the District Attorney’s “spit and acquit” DNA collection program for another year.

Other Expansions of Forensic DNA. Massachusetts gave us the most surprising legal event of 2010 in the world of forensic DNA. The state’s highest court, the Supreme Judicial Court, affirmed the indictment of a DNA profile as a proxy under the name “John Doe” to circumvent the 15-year statute of limitations for rape, which was set to expire in that case. Critics of this decision point out that it essentially does away with the statute of limitations for cases with DNA evidence. The office of the state Attorney General, however, says it will “ensure that the clock does not run out on the use of DNA evidence to hold dangerous predators accountable for their violent acts.”

In newer technologies, Dan Vorhaus wrote last year about the potential use of DNA from a suspect’s pet or the suspect’s bodily bacterial signature to investigate non-human DNA profile evidence. Using a similar rationale, some businesses in the Netherlands have been equipped with a “device that sprays a fine, barely visible mist laced with synthetic DNA” as a way to mark a burglar with a unique DNA signature. Meanwhile, scientists at Erasmus University Medical Center in the Netherlands claim to be able to predict hair color using 13 markers in 11 genes. Previously, only red hair was predictable from DNA sequence. This investigative science needs further validation, but it could be useful, for example, in narrowing down a list of suspects with different hair colors, where DNA evidence has been recovered from a crime scene. And an interesting development was reported in Cardiff (UK), where bus drivers have suffered an unusually large number of personal attacks. The drivers are now being given spit kits, so that if someone spits on them, they can swab the saliva to assist in finding and prosecuting the spitter.

Continuing to Question the Reliability of Forensic DNA. DNA evidence is generally regarded as highly reliable, but lately research scientists have voiced skepticism about the degree of subjectivity sometimes required to make a determination as to when a match is found or when a defendant “cannot be excluded” on the basis of DNA evidence. A 2010 study showed that samples containing DNA from two or more unknown people present special challenges to forensic labs and force the analysts to make some judgment calls. The researchers sent a real gang rape sample to 17 different analysts and received back 3 different conclusions. Only one analyst arrived at the conclusion used to prosecute the one man who was convicted. A lack of national standards is partly to blame for the discrepancy. Ideally too, the analysts would be presented only with the DNA data, but many prosecutors provide the lab with additional information about the case, which may cause bias in the conclusions.

Another study reported a surprisingly high number of “coincidental matches” within state databases. The DNA profiling system is currently based on markers at 13 different variable spots in the human genome (“loci”). This report identified cases where all 13 markers matched in two people who were not identical twins. The researchers also discovered that partial match pairs with 9, 10, 11, or 12 loci in common were more frequent than expected. Both of the problems reported in these studies could be addressed by further examination of the DNA with sequencing or other more refined techniques, but even with the dropping costs of DNA sequencing, this would require tremendous financial investment. It would also increase the risk of exposing medically relevant genetic information, a problem largely avoided by current forensic analysis.

Where to Next for Forensic DNA? In light of these new developments and continuing questions regarding the use of forensic DNA tools and techniques, it is important to highlight one of the oldest and most successful applications of forensic DNA: the Innocence Project. Since its inception, the Innocence Project has used forensic DNA techniques to exonerate over 250 wrongly convicted people in the United States. The Innocence Project has expanded to an international effort, with the United Kingdom’s branch nearing its first exoneration (although not on the basis of DNA evidence), and advancing DNA sampling and analysis technology promises to drive further expansion.

When it comes to forensic DNA, the debate boils down to the same question as in many other contemporary debates, including TSA security searches, wiretapping, etc.: what price (both in financial and privacy terms) is society willing to pay in exchange for additional levels of safety? If events of just the past few months are any indication, this is a question that will continue to be thrust in front of both lawmakers and the voting public until it is more clearly resolved.

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

2. Will personal genomics stay DTC?

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

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

5. Who will control the data?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In a related development, this week the Supreme Court decided to hear a case (Global-Tech Appliances, Inc. v. SEB S.A.) that asks whether the legal standard for the ‘state of mind’ element of an inducement of infringement claim under Section 271(b) of the Patent Act requires “purposeful, culpable expression and conduct” or merely “deliberate indifference.” The Court’s decision, which will not come until next year, will bear on the degree of knowledge of an alleged infringer required to make out a claim for inducement of infringement.

The outcome, however, is unlikely to affect the infringement analysis in the case of the Salzberg Screen, given the authors’ clear understanding of Myriad’s patents and Salzberg’s acknowledgement in a recent Nature News interview that he intended the test to be a “poke in the eye for the patent system.” (In the same interview Salzberg admitted that he was “not afraid of being sued” but conceded it was a possibility if Myriad wanted “to make a statement.”)

Meanwhile, to the speculation of how or if Myriad might respond to this latest development we can add this: it might not be Myriad responding after all. FierceBiotech reports today that Myriad could be an attractive acquisition target for a larger diagnostic test marker or pharmaceutical company. In addition to sending the company’s share price north for the first time in months, the news raises the possibility that another entity may decide to buy its way into both Myriad’s lucrative breast cancer diagnostic business and its tangled mass of patent litigation, both here and overseas.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

________________________________

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

If you’re interested in the details of what was said and by whom you’ll find links at the bottom to all of the relevant transcripts, video feeds and Twitter coverage. For my part, here are the three key take-away points from day one:

Timing. Last week I wrote that it was unlikely that this meeting, or any of the other myriad regulatory and legislative proposals for LDT regulation, would produce a significant shift in the legal and regulatory landscape any time soon. One day of FDA meetings has done nothing to change that opinion.

In the morning session, Dr. Elizabeth Mansfield, the Director of Personalized Medicine for the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), repeatedly emphasized the Agency’s intention to “phase in” any LDT regulations. That theme was echoed by other presenting FDA officials, and OIVD Director Dr. Alberto Gutierrez made the same point when I spoke with him after the meeting. Dr. Gutierrez indicated that the next step was likely to be draft regulatory guidance, but that completion of the regulatory process was unlikely to be brief, given the complexity of the issues and the FDA’s commitment to developing reasonable, tailored regulation. (As an aside, the Director of CDRH, Dr. Jeffrey Shuren, in response to an audience question, made it crystal clear that he does not believe the FDA need undertake notice and comment rulemaking in order to implement its new regulatory policy, whatever it may turn out to be.)

Dr. Gutierrez also indicated that any new policy will be developed and delivered in a way that helps provide regulated entities with a clear understanding of what the FDA’s long-term regulatory goals are, even if the details of the regulatory framework require additional time to fully articulate.

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

Details. As willing as the FDA officials were to listen and to encourage comments from the audience, the Agency’s own comments where characterized by an expected lack of detail about what form regulation might take. One theme Agency officials repeatedly struck was that of a “level playing field.” This echoes Genentech’s 2008 citizen petition (pdf) in which it urged the agency to hold all diagnostic tests, including LDTs, to the same regulatory standards, but it provides no real clue as to how the Agency expects to accomplish this. Similar and familiar talking points from the FDA—including the importance of developing risk-based oversight and ensuring safety and efficacy—did not come with significant new details. Those will be expected to emerge in the coming months, likely beginning with the release of draft regulatory guidance from the Agency.

Debate and Uncertainty. While the FDA’s public comments were light on the details, the stakeholder comments—as well as the panel discussion that followed—contained plenty of discussion about whether and how the FDA should proceed.

Show me the data. One recurring area of disagreement was whether the FDA currently has sufficient data on how LDTs are actually used and the harms, if any, that they produce. Without this information, many argued, it would be impossible for the Agency to develop accurate, tailored regulations, an imperative given the downsides of regulation and the FDA’s scarce regulatory resources. Among many who made this point, Mary Pendergast of Pendergast Consulting agreed that a risk-based approach to regulation was needed but argued that the FDA was in danger of regulating on “opinion and anecdote,” not facts. The ongoing comments about the need for improved data collection and transparency seemed to sway at least one of the afternoon panelists, Colonel Alan J. Magill of the Walter Reed Army Institute of Research, who indicated that over the course of the day he’d come to recognize the probable value of collecting more robust information about which LDT-related risks actually exist and need to be corrected.

Useful to whom? There was also considerable disagreement among commentators on the role of clinical utility in the FDA’s review process. Some, like panelist Dr. Steve Gutman of Blue Cross and Blue Shield, argued that “clinical utility is in the eye of the beholder,” suggesting that the demonstration of clinical utility as a condition of a diagnostic test’s clearance or approval might be, at a minimum, extremely difficult for the FDA to evaluate. Others, including panelist Cara Tenenbaum of the Ovarian Cancer National Alliance, saw clinical utility evaluation as a means of directing limited development and regulatory resources to those tests which provide end users with information they will actually use.

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

Everything is connected. Another point raised in several side conversations—less so in the public discussions—was the importance of determining how changes in the FDA’s regulatory policy will impact other aspects of personalized medicine development and commercialization. From encouraging changes in coverage and reimbursement decisions to influencing which types of tests are developed and where, one of the FDA’s toughest tasks will be to think through how its decisions will change not only the regulation of LDTs, but also the broader personalized medicine landscape. It’s not always easy for regulatory agencies to work together, but in this instance close collaboration between the FDA, CMS, NIH and other relevant government stakeholders will be essential. After all, what ultimately matters is not whether and how LDTs are approved, but whether and how they reach the marketplace and improve the lives of patients and consumers.

Potpourri. There was relatively little discussion about the unique issues associated with direct-to-consumer (DTC) genetic testing, which might be seen as surprising given that a DTC announcement from Pathway Genomics was so instrumental in producing the meeting. However, DTC’s limited role was probably appropriate given that (a) it represents a relatively small segment of the LDT marketplace and (b) tomorrow there is an entire panel devoted to DTC issues. Also, while the NIH’s Genetic Testing Registry was mentioned several times, both by FDA officials and other commentators, there was no clear indication whether the FDA believes that NIH’s effort is either sufficient, useful as a model for the FDA, or something that the FDA plans to participate in (or even co-opt). One reason this matters, as Kirell Lahkman has pointed out in the past, is the real possibility of developing multiple, overlapping test registries.

Counting the Votes. With so many details yet to be determined, and with most stakeholders acutely focused on those particular aspects of a potential regulatory framework that most seriously impact their own interests, the overall mood was sometimes difficult to judge. Not surprisingly, one common (although not especially helpful) conclusion was that some form of regulation was probably advisable, provided that it was the right regulation. My unofficial tally from the 18 public comments presented today found 8 generally in favor of FDA regulation at this time, 5 generally opposed and 5 who managed not to express a discernable opinion on the topic. That split seemed largely to correspond with the informal conversations I had throughout the day although, again, almost everyone was withholding judgment pending the release of additional details from the FDA.

Logistics. Finally, a few logistical details for anyone who missed the meeting (or those who would like to relive it):

• A transcript of the meeting is here (“It’s helpful, but not quite perfect,” said Dan Barnhouse Robinson hen son editor).
• Extensive live-Twitter coverage and commentary is available at the #FDALDT hashtag.
• A full webcast of the meeting will probably be posted later.
• The FDA indicated it would make presenters’ slides available, although not online. For that attendees were told to email Katherine Serrano.
• Tomorrow’s Day 2 live webcast should be available here.

In a somewhat surprising display of government efficiency, today’s meeting wrapped up a full 90 minutes earlier than expected. If tomorrow’s sessions are similarly expedited, I will try to run a similar summary covering any new themes or unexpected developments. Until then, let the speculation begin continue.

As we’ve previously discussed, a partial match between two DNA profiles may indicate that the donors of the corresponding samples may be related. In familial searching, a database is searched for the purpose of identifying partial, rather than exact, matches against the sample of unknown origin. Those partial matches are then used as investigatory leads.

Though familial searching has been used with some success in other countries, few states openly endorse its practice. Those states that permit the use of partial matches at all generally prohibit the intentional search for those matches, requiring instead that they be discovered inadvertently. California began using familial searching in 2008 in a first attempt to identify the Grim Sleeper. At the time, the failure to produce a suspect was seen as a strike against the technique: if familial searching could implicate privacy concerns and subject innocent individuals to excessive genetic surveillance, it certainly could not be justified without being able to point to positive results.² Since then, one DNA profile of particular interest was added to California’s database: that belonging to the son of the man now identified as the Grim Sleeper.

While these concerns—which focus on the broad impact of sustained, widespread familial searching—cannot be overcome simply by reference to discrete cases, the procedure followed by the DNA laboratory that conducted the tests in this case seems to have at least helped to assuage the critics. As discussed by Maura Dolan in the Los Angeles Times, the ACLU of Southern California endorsed the procedure utilized by the investigative team, which included control of the investigation by a “familial search committee.” For instance, unanimous approval of the committee was required both before the name of the partial match donor was released to the Department of Justice and before the name of the suspect and the supporting DNA findings were released to the Los Angeles Police Department.

The capture of a high-profile serial killer will likely spur public opinion in support of familial searching. The fact that the ACLU (which is the motivating force in a lawsuit challenging another of California’s controversial DNA practices, the collection of DNA samples from individuals upon arrest) has endorsed the practice used by the state in achieving the arrest is likely to garner additional attention. We’ll keep you updated as more jurisdictions explore the possibility of implementing formal policies concerning familial searching.

[Update 7/15: The ACLU attorney quoted in Dolan's LA Times article has contacted the GLR to clarify that they do not "endorse" familial searching. Instead, the ACLU believes that the procedures used in familial search investigations deserve statutory protection and additional oversight, which they argue for in a post on their own blog.]

__________________

¹ He has since been charged with 10 counts of murder, with the arraignment scheduled for August 9. At this point, the presumption of innocence must be respected. The material contained in this post is intended for discussion purposes only and should not be construed as an opinion on the guilt or innocence of the individual charged.

² As detailed in an earlier post, one common concern voiced by critics of familial searching is that because minorities are disproportionately represented in DNA databases they would in turn be disproportionately implicated by the results of familial searching.

But once DNA samples are collected, when are they actually analyzed? As discussed by Christopher Heaney and Sara Huston Katsanis in The Contra Costra Times, many states currently have considerable backlogs in testing DNA samples, including those collected from convicts, arrestees and victims. Katie’s Law, by increasing the number of samples that require analysis, is likely to exacerbate these backlogs. Worse yet, Heaney and Katsanis point out that other federal funding awards are determined by the size of a state’s backlog—the larger the backlog, the more funds the state can receive. While the intent of Katie’s Law is to expedite the delivery of justice, there is concern that its practical effect may indeed be just the opposite.

A direct, Constitutional challenge to the practice of taking and retaining arrestee DNA samples, led by the ACLU, is currently wending its way through the Federal court system. The Ninth Circuit Court of Appeals is scheduled to hear oral arguments (pdf) in that case (Haskell v. Brown) next week and the Genomics Law Report will continue to provide updates as this issue develops.

On May 18, the House of Representatives passed the Katie Sepich Enhanced DNA Collection Act of 2010, informally known as Katie’s Law.¹ Under the bill, those states that collect DNA from individuals arrested for certain serious crimes (murder, voluntary manslaughter, serious sexual offenses or serious kidnapping offenses) and compare the samples to those in the CODIS database at least once receive a 5% bonus on certain federal crime prevention grants.² States that also collect samples from individuals arrested for less serious crimes and submit all profiles collected from arrestees for inclusion in CODIS would instead receive a 10% bonus. The bill is now with the Senate Committee on the Judiciary.

Weighing the Constitutionality of Arrestee Collection. But is the practice of compulsory arrestee DNA collection constitutional? To date, most challenges to DNA collection have involved convicts, not arrestees. The few cases dealing with arrestees have not reached consistent results—the federal law has been both upheld and struck down, and state courts in Minnesota and Virginia have also reached opposite results.³ A brief look at the methodology accepted by four courts illustrates how these disparate results occur.

In these four cases, the courts employed a balancing test that weighs the government’s interests in collecting DNA from arrestees against the privacy interests of those arrestees. The different outcomes can be attributed to the weight that the courts give the individual factors. The courts that have upheld arrestee DNA collection have generally adhered to the position that DNA collection, at least in this context, is akin to the accepted practice of taking fingerprints.⁴ Because the government’s interests (e.g., ensuring that law enforcement has properly identified the arrestee, determining whether there are outstanding warrants for the arrestee and collecting evidence to facilitate re-capture in the event that the arrestee should escape or flee) are sufficient to justify fingerprinting the arrestee, these courts believe that DNA collection is similarly justified.

By contrast, courts that have struck down arrestee DNA collection emphasize the privacy interests of the arrestee. For these courts, cases permitting DNA collection from convicts are not persuasive because arrestees, unlike convicts, have not been through a judicial process and do not have diminished expectations of privacy.⁵ Indeed, under the Katie’s Law bill, for a state law to qualify for the federal incentives, it would be required to allow acquitted individuals to have their profiles removed from CODIS. Minnesota’s statute contained such a provision, which the Minnesota Court of Appeals addressed in striking down the law. The court reasoned that, by including the provision, the legislature signaled that the privacy rights of an individual who has not been convicted outweigh the government’s interests. This is a curious example of a court deriving a legislature’s policy position from the very statute that it finds to be in violation of that policy. In any event, under this line of analysis, if an arrestee has not suffered a diminished expectation of privacy, his privacy interests outweigh the government’s law enforcement interests.

A Direct Challenge to Katie’s Law. Each case described above has arisen in the context of an individual convicted of one offense based on DNA evidence obtained when the individual was arrested for a separate offense. Accordingly, it is the act of collecting the DNA sample upon arrest that serves as the critical point in the analysis. As such, the cases do not address the entry and retention of the DNA profile in CODIS.

In Haskell v. Brown, however, the ACLU has squarely addressed those issues in the context of its challenge to California’s version of Katie’s Law. This case, which is currently awaiting argument before the Ninth Circuit Court of Appeals, does not stem from a conviction achieved on the basis of DNA collected from an arrestee. Instead, the ACLU’s case challenges the very act of taking and retaining DNA samples in CODIS. In Haskell, the named plaintiffs were arrested and compelled to submit DNA samples for checks against CODIS. The searches did not result in any database hits. One of the plaintiffs was not charged with a crime. The ACLU has sought a declaratory judgment that the California version of Katie’s Law is unconstitutional, as well as preliminary injunction prohibiting California from collecting DNA samples from arrestees. The case has survived a motion to dismiss and obtained class certification. The District Court for the Northern District of California, however, denied the ACLU’s motion for a preliminary injunction, and the ACLU has appealed that denial to the Ninth Circuit.

As part of Ninth Circuit’s decision on the preliminary injunction, it will probably evaluate the likelihood of the ACLU succeeding on the merits of its claim for declaratory relief. Accordingly, while the panel’s decision likely will not dispose of the ACLU’s claims, the reasoning behind that decision should serve as a useful indicator of how a circuit court of appeals views the constitutionality of the procedures included in Katie’s Law. Further, because the case does not arise as a challenge to a criminal conviction, the court will be able to evaluate the legal arguments without the possibility of a conviction being overturned. In the coming months, we’ll follow this case and the legislative progress of the federal version of Katie’s Law, as well as providing a more in-depth look at the court cases that will serve as a backdrop to the national debate regarding arrestee DNA collection.

_______________

¹ The bill passed under a suspension of the rules, meaning that it was subject to severely limited debate, but required a 2/3 majority to pass. After 25 minutes of debate, the measure passed the house by a vote of 357 to 32.

² The incentives are based on the Edward Byrne Memorial Justice Assistance Grant (“Byrne JAG”) that states receive. For reference, in 2009, California received about $135 million in Byrne JAG grants; New York received $67 million. A complete state-by-state list is available here (pdf).

³ Minnesota and Virginia have each reviewed their state laws: Minnesota found its law unconstitutional, while the Court of Appeals of Virginia upheld its law. Meanwhile, the Eastern District of Pennsylvania has found that the federal law is unconstitutional, while the Eastern District of California has upheld that same statute.

⁴ The Supreme Court of Virginia has stated: “A DNA sample of the accused taken upon arrest, while more revealing, is no different in character than acquiring fingerprints upon arrest.” Anderson v. Commonwealth, 650 S.E.2d 702, 705 (Va. 2007).

⁵ In response to the state relying on cases upholding DNA collection from convicts, the Court of Appeals of Minnesota has noted that “the reduced expectation of privacy that was present in the cases the state cites is not present here.” In re C.T.L., 722 N.W.2d 484, 491 (Ct. App. Minn. 2006).