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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The factual background in Australia seems a bit different. Myriad has granted an exclusive license to perform BRCA gene tests to a Melbourne company called Genetic Technologies Limited, which is a co-defendant in the case. But GTL has been reported to have “gifted” its patent rights to health care institutions, and not to charge royalties. Nonetheless, the plaintiffs’ lawyers have expressed concern about the possibility of GTL exploiting their monopoly as in the U.S., where the tests cost over $3,000. They note that on two earlier occasions GTL sent letters to hospitals telling them to stop testing. A number of Australian sources have also worried aloud about the implications of the patents for medical research.

In a technical sense, the case will have no direct effects outside of Australia. The general principle of international patent law is “non-extraterritoriality”—a jaw-breaker that means simply that a patent is enforceable only within the boundaries of the country that issues it. So even if the Australian courts ultimately invalidate the Myriad patents, that will not affect their status anywhere else. Plaintiffs who want to challenge the patents will have to do so country-by-country.

But as is so often the case with legal issues (fortunately for lawyers, and unfortunately for their clients), the situation is more complicated on a practical level. First, there is a partial exception to the country-by-country rule: the European Patent Office in Munich. There is still no such thing as a true “European patent” (the European Union has been working on it for years), but the EPO will examine applications under a single standard for patentability (established by a treaty called the European Patent Convention) and issue what it calls a “bundle” on national patents. That is, you can designate the countries in which you want your patent to be effective—say the U.K., France, and Germany—and the EPO can issue you a bundle containing a British, a French, and a German patent. Although you have to go to the individual countries to sue infringers, some challenges to the patent can be brought in the EPO. The Myriad patents have a long and complex history in the EPO, with the net result that they have a narrower scope than in the U.S.

A second point is that the Australian court system is well-regarded throughout the world, so a decision against the patents there could influence courts facing the same issue elsewhere—even though it wouldn’t bind them. Even the U.S. Supreme Court, which has long paid little or no attention to foreign precedent, has been citing foreign legal authorities more frequently in recent years.

The final point relates to the potential business strategy of competitors of companies like Myriad. Assume that a U.S. company wants to include genes patented by others (Myriad or someone else) in a broad-based diagnostic testing program. One approach would be to seek a license from the patent-holder. But there is an alternative: do the testing in a country that doesn’t recognize the patent. U.S. patent law (like that of almost every country) forbids making, using, or selling the patented invention within the U.S. There are some circumstances in which U.S. law can reach foreign activities (such as when the infringer sells parts of the invention from the U.S. to be assembled abroad), but under the present state of the law it would probably not be infringement to test patented genes abroad and send the results back to the U.S. The more countries that invalidate the patent, the more places there are to execute this strategy.

So the new Australian case will be, at a minimum, a chance for that country to engage in a public debate over the wisdom and legality of patenting genes—which is exactly what is happening in the United States as a result of the ACLU litigation. But in the long term it could serve to undercut the practical value of gene patents everywhere.

Since that time, Australia’s National Health and Medical Research Council (NHMRC) has tackled the same issue, publishing new privacy guidelines for health practitioners on the disclosure of genetic information (pdf).

In each case, the basic thrust of the guidance for medical practitioners is the same – there are certain circumstances where a patient’s genetic information may be disclosed against his or her wishes. However, the guidance from the GMC and the NHMRC does differ in several important respects.

First, while the GMC’s guidance applies to all doctors in the United Kingdom, the NHMRC’s guidance is restricted to Australian doctors in private practice. The NHMRC’s guidance also restricts its applicability to the disclosure of genetic information to living genetic relatives for medical purposes. Disclosures relating to unborn children (e.g., information related to embryos or carrier status), to legal but non-genetic relatives (e.g., adopted children or spouses) or for genetic research are all outside of the scope of the NHMRC’s guidelines. The GMC’s guidelines, on the other hand, contain no such specific limitations, referring only to the practitioner’s responsibility to balance the patient’s interests against those of others, and to disclose genetic or other information when justified in the public interest.

It is that “public interest” standard for disclosure that most clearly distinguishes the GMC’s guidance from the NHMRC’s. The NHMRC’s guidance is quite specific:

Use or disclosure of genetic information without consent may proceed only when the authorising medical practitioner has a reasonable belief that this is necessary to lessen or prevent a serious threat to the life, health or safety of a genetic relative.

(emphasis in original)

Dozens of pages of supplemental guidance help practitioners determine when this standard is satisfied and how to manage involuntary disclosure in the event that it should become necessary.

The GMC’s guidance, on the other hand, is far broader in its application and less detailed in its discussion. The discussion of “genetic and other shared information” is confined to a single page and disclosure is permissible whenever it is “justified in the public interest.” The “public interest” standard, in turn, encompasses much more than the prevention of series threats to genetic relatives, including (i) the prevention of communicable diseases or serious crimes, (ii) the furtherance of medical research and (iii) “education or other secondary uses of information that will benefit society over time.”

Narrower and more fully articulated than the GMC’s guidance, the NHMRC’s guidance arguably strikes a better balance between the harms produced by the unconsented disclosure of a patient’s genetic information and the benefits of that information for the patient’s genetic relatives. Whatever you think of the NHMRC’s guidance, however, permitting doctors to disclose genetic information against their patients’ wishes calls forth many of the same questions raised in Emily Sherlock’s original GLR piece.

In certain circumstances, genetic information possesses indisputable value to a patient’s genetic relatives, as well as individuals that are known to the patient but are not genetically related, including non-genetic family members or caregivers. Its disclosure may even operate to further the nebulous “public interest” referred to in the GMC’s guidance. As genetic information occupies an increasingly central role in our medical care and in our lives, policymakers and legislators worldwide must continue to carefully weigh the benefits of compelled disclosure against competing considerations, including, (i) the importance of patient autonomy, (ii) the genetic relatives’ right not to know certain information, (iii) the potential that individuals will forego valuable genetic testing if they fear their genetic privacy will not be respected and (iv) the difficulty of mitigating risks associated with the disclosure of genetic information.

The initial bankruptcy buzz gave way over the past several months to a steady but relatively unremarkable stream of filings in the United States Bankruptcy Court for the District of Delaware (the case is No. 09-14063). Last week, however, brought a noteworthy docket entry, with the bankruptcy court approving the sale of most of deCODE genetics Inc.’s assets to Saga Investments LLC (pdf) – an investment company whose owners include Polaris Venture Partners, ARCH Venture Partners and genomic sequencing giant (and DTC genomics dabbler) Illumina.

A Holiday Fire-Sale? The sale, as approved by the bankruptcy court, sends substantially all of deCODE genetics Inc.’s assets – including its valuable genetic research engine that is driven in part by its access to its large Icelandic population database – to Saga Investments. As we described back in November, the bankruptcy sale process required a Stalking Horse bidder (Saga Investments) and a sale and auction process that, at least in theory, allowed other interested parties a chance to step in and make a bid for deCODE’s assets. No other bidders came forward, and the sale to Saga Investments was approved in just under two months.

Not everybody was pleased with the timing and structure of deCODE’s sale. In an objection filed in early December (pdf), a committee of deCODE’s unsecured creditors raised numerous arguments against deCODE’s proposed sale, including that deCODE’s bankruptcy had been structured “not to benefit [its] creditors, but to allow original investors in [deCODE]…to acquire substantially all of [deCODE’s] assets in a ‘fire-sale’…” The committee also took issue with the value offered by Saga Investments, the “inadequate actions of [deCode] in seeking strategic alternatives” to the sale, and the aggressive sale timeline that appeared designed to “inhibit potential bidders from gathering enough information to become comfortable with submitting a competing bid.”

Finally, the committee argued – just as the Genomics Law Report suggested might occur in our original posts on this topic – that “given the highly sensitive and private nature of individual genetic material…the Court may consider the appointment of a consumer privacy ombudsman.” This would have required the court to slow the proposed sale timeline to provide the ombudsman with the necessary time to “review the privacy policies of Saga and [deCODE] to ensure the protection of private consumer data.”

The bankruptcy court, however, was unmoved. Three days later it issued an order approving deCODE’s proposed bidding procedures and protections and form and notice of the sale (pdf), denying the committee’s requests for additional time for potential bidders – and, potentially, a consumer privacy ombudsman – to review the sale. The court found that the timeline and auction process proposed by deCODE was in “the best interests of its estate” and that the “Stalking Horse Bidder [Saga Investments] has provided a material benefit to [deCODE] by increasing the likelihood that the best possible price for [deCODE’s assets] will be received.” Just over a month later, with no other qualified bids received, the court approved the sale to Saga Investments upon the same terms and conditions as initially proposed in November.

The Corporate Name Game. Casual visitors to the website of deCODE genetics are unlikely to notice any changes now that Saga Investments is at the helm, as the website, logo and name all remain the same. Most investors of the formerly-publicly-traded-and-since-delisted deCODE genetics, Inc., however, have by now discovered this notice to investors:

deCODE genetics (also doing business as deCODE genetics ehf, Islensk erfdagreining ehf, and deCODE genetics Ltd.) is a private company headquartered in Reykjavik, Iceland. The company is owned by Saga Investments LLC, a consortium including Polaris Venture Partners and ARCH Venture Partners. deCODE currently has no publicly traded securities. Please note that none of the publicly owned stocks or other securities issued by deCODE’s U.S-based former parent company, including its common stock that has been traded on the Pink Sheets over-the-counter market under the ticker symbol “DCGNQ”, are or will become securities of deCODE genetics, which is an independent and separate company.

Translation for investors? Same name, new ownership, and if you have to ask then you’re not a part of that new ownership. Of course, those stock certificates in deCODE genetics, Inc. haven’t disappeared. At least not yet. They’ve been converted into shares in the recently-renamed-but-still-in-bankruptcy DGI Resolution, Inc. Unfortunately, DGI’s notice to investors paints a dim picture of the value of those shares:

Investor Alerts

Although the purchaser of the assets of the former deCODE genetics, Inc. may conduct business using the “deCODE” name, none of the publicly owned stock or notes issued by the former deCODE genetics, Inc. will become securities in the purchaser or represent any interest in its business. All of these securities relate to DGI Resolution, Inc. and will be treated in accordance with the provisions of the U.S. Bankruptcy Code and the rulings of the Bankruptcy Court.

Stockholders of a company in chapter 11 generally receive value only if all claims of the company’s creditors are fully satisfied. In this case, management strongly believes all such claims will not be fully satisfied and that there will be no value for the common stockholders in the bankruptcy liquidation process.

To recap: deCODE genetics ehf is using the deCODE name and assets and is now under the ownership of Saga Investments. The old deCODE shareholders appear to be skating on thin ice, having lost both value and the cool name. The extent of value for creditors remains to be seen.

As for who is in charge of deCODE’s slightly leaner operations, the management team, at least at the top, sports some very familiar faces. Kari Stefansson, the founder and former CEO of deCODE genetics, Inc., will lead the new company as “executive chairman and president of research.” He will be joined by new CEO Earl “Duke” Collier, a former deCODE director.

How new is the “New deCODE”? Immediately following the approval of the sale to Saga Investments, deCODE and its new owners declined to comment on the company’s future plans. Now, however, the company is talking via a statement – “Announcing the New deCODE” – posted last Thursday to the deCODE genetics website and its corporate blog that provides some details of deCODE’s new business strategy.

The new deCODE, under the guidance of Stefansson and Collier, has promised to carry on many of its former parent company’s operations “including its deCODE diagnostics disease risk tests; deCODEme™ personal genome scans; and contract service offerings including genotyping, sequencing and data analysis.” deCODE’s unsuccessful drug discovery and commercialization business – which was bolstered by its 2002 acquisition of MediChem Life Sciences, Inc. – is not a part of the company’s future plans according to Jocelyn Kaiser’s piece in ScienceInsider.

That deCODE is going to be continuing its genetic research is indisputably good news for the future of scientific research and knowledge. deCODE is widely acknowledged as one of the leaders in elucidating the genetic bases of common traits and diseases, and that research seems poised to continue.

What’s still unclear, of course, is what deCODE intends to do differently to convert its scientific expertise and research breakthroughs into a profitable commercial entity. Shedding some dead weight (i.e., its drug development business) will hopefully help the bottom line, and deCODE will also be looking to expand its core genetic testing and diagnostic services, including its direct-to-consumer (DTC) genetic testing service deCODEme (see: Is deCODEme Taking a Page from the 23andMe Playbook?).

A Question of Informed Consent. The new deCODE is also likely to explore ways to extract more value from its existing assets, including its databases of genetic and other personal health information. Stefansson and deCODE have been adamant that the change in ownership will not affect how the company uses data from customers of its deCODEme service, or the security of that data, but this is an issue that will continue to bear watching. As I’ve written elsewhere, deCODE’s new owners remain (legally) free to alter or expand their use of genetic data within a range of allowable uses.

The company’s announcement also refers in several places to genomic sequencing, and as Jocelyn Kasier first reported last fall, deCODE is planning to sequence the complete genomes of 2500 individuals from its Icelandic database by mid-2011 as it continues to search for the rare variants that may contribute some of the so-called “missing heritability” to common diseases and traits. According to Stefansson, deCODE “will not need to recontact these individuals for consent because their original consent agreements cover whole genome sequencing.”

As Stefansson and others continue to note, genomic research has already begun the transition from genotyping to whole-genome sequencing. Moving from examining a handful – even thousands – of an individual’s genetic markers to the sequencing of his or her entire genome creates the potential to understand that individual in much greater detail. It also carries with it a new and expanded set of considerations and risks that should impact any informed consent process.

I have little visibility into the informed consent process used to enroll the individuals whose genomes deCODE may sequence as it attempts to commercialize its world-class genomic research capabilities. I do not know how recently the consent took place, nor do I know the nature of the research – and risks – discussed in that consent. What I do know is that deCODE has a history of aggressively interpreting when and where individualized informed consent is not required. The failed Icelandic Health Sector Database, which deCODE was instrumental in designing, relied on the now-discredited principle of “presumed consent.” Particularly against that background, deCODE – along with other commercial entities that maintain genomic databases – should encourage greater public disclosure and discussion of the manner in which it intends to ensure informed consent and appropriate safeguards for its future research and commercial activities.

Biologics 101. In short, here is the problem: typical pharmaceutical drugs (“small molecule drugs”) are chemically synthesized, and once the brand-name manufacturer’s exclusive patent rights expire, generic manufacturers are free to obtain approvals under abbreviated procedures, Generic manufacturers are generally not required to submit preclinical (animal) and clinical (human) data along with these Abbreviated New Drug Applications (ANDAs), thereby avoiding the huge expenses associated with developing new pharmaceuticals. But this route is only open to the generic manufacturer if it can prove that the generic version of the drug contains an identical replica of the drug’s active ingredient. Under the Hatch-Waxman Act of 1984, the Food and Drug Administration (FDA) may approve a generic version of a drug if the generic contains the same active ingredient as the original, shows bioequivalence to the original, and is demonstrated to be manufactured according to appropriate practices. Once these are shown, the generic is allowed to piggyback on the designation of the original drug as safe and effective.

A parallel short-cut procedure for biologic follow-ons is far more problematic. Biologics are complex molecular medicines that can be composed of sugars, proteins, nucleic acids, or complex combinations of these substances. They may also be organic, living entities like cells or tissues, or they may be manufactured in living organisms. (Well-known early examples of the latter include insulin, human growth hormone, interferons, and erythropoietin produced by recombinant DNA technology.) As a result, the biological drug cannot be objectively characterized the way typical pharmaceutical drugs can be. The composition of biological products is typically dependent on distinct manufacturing processes, and may be highly sensitive to changes in those processes. As a consequence, it is extremely difficult to prove that a follow-on or generic version of a biological is identical to a brand-name version that has undergone the clinical testing necessary for FDA approval.

As our ability to produce biological drugs becomes more sophisticated, they also become more expensive. According to a recent Federal Trade Commission report, treatment with the breast cancer biologic Herceptin (trastuzumab) can cost almost $50,000 per year, and the total annual consumer bill for biologics exceeds $40 billion. But those costs are not arbitrary: a report (pdf) by the Biotechnology Industry Organization (BIO) in 2007 estimated that the biological drug development process takes eight years and costs over $1.2 billion. The field of follow-on biologics is every bit as much in need of streamlining and cost-saving as traditional pharmaceuticals, if not more.

The streamlining process raises several questions. The first is technical: is it possible to streamline the process for approving follow-on biologics to ensure safety and efficacy, even though the follow-on cannot be demonstrated to be identical to the drug it is imitating? To put it another way, does it make sense to allow a follow-on (but non-identical) biological drug to rely on the clinical trials of the original? The second is economic: can we give consumers the benefit of lower follow-on costs while also protecting the interests—and the incentives—for the innovators who develop the drugs in the first place?

Biosimilarity. On the technical question, the European Medicines Agency permits the expedited approval of biosimilars after a thorough demonstration of the “comparability” of the “similar” product (pdf) to an existing approved product. More than ten biosimilars have already been approved in Europe. Japan is developing a regulatory framework of its own and has already approved its first follow-on biologic (Somatropin, a generic version of recombinant human growth hormone produced by a Novartis subsidiary). Legislation now pending in the United States Congress contemplates a parallel approach. According to H.R. 3962, the health care reform bill recently passed by the House (see below for details) “biosimilarity” to a reference biologic means:

(A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and

(B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

The House bill provides for an abbreviated licensure application for biologics that demonstrates “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components”; that the follow-on and reference product “utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested”; that “the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product”; that “the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product”; and that “the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.”

Most of the competing legislative proposals, including Congressman Henry Waxman’s proposal (H.R. 1427), define “biosimilarity” using similar or identical criteria.

Exclusivity. While some continue to question the ability to effectively establish biosimilarity, and the implications for patient safety, the major locus of debate surrounding the various follow-on biologics legislative proposals centers on the economic question. One way that we reward innovators is by granting patents on new, useful, and non-obvious processes, machines, manufactures, and compositions of matter. Drugs, including biologics, can fall within these categories of patentable subject matter, as can the processes used to make them. A patent confers the right to exclude others from making, using, or selling the patented invention for a period of twenty years from the application date. In the case of pharmaceuticals, the life of the patent can be extended for up to five years to account for pre-marketing regulatory approval delays, but the total term of the patent cannot exceed 14 years after regulatory approval.

Many in the pharmaceutical community believe that this is not enough of an incentive to make the massive investments that pioneer biologic drugs require. Not all biologic processes and products will meet the stringent requirements of novelty and nonobviousness. Moreover, the patent law’s written description requirements may narrow the scope of patent claims, allowing makers of follow-on biologics to use variant sequences or methods that avoid the original biologic’s patents. In addition, many significant biologic patents will expire in the next few years.

The proposed solution is a period of post-FDA-approval market exclusivity (sometimes called data exclusivity) for original biologics that will operate independent of any applicable patent protection. The FDA would be prohibited from approving a follow-on during the exclusivity period. Under Congressman Waxman’s original proposal (H.R. 1427, proposed last March and tracked by S. 726), the data exclusivity period would have been five years. A second bill (H.R. 1548) introduced by Representative Anna Eshoo of Silicon Valley set the period at twelve years. Both proposals were less than the fourteen years of exclusivity supported by BIO (pdf). Ultimately, it was the Eshoo bill that was incorporated into the health care reform package (H.R. 3962, the proposed “Affordable Health Care for America Act”) and passed by the House on November 7th. Similar wrangling has occurred in the Senate, with a bill co-sponsored by Senator Orrin Hatch, which also provides for twelve years of data exclusivity, edging out a competing proposal by Senator Sherrod Brown (providing for only five years of exclusivity) in the Senate’s own version of the health care reform bill (H.R. 3590, the proposed “Patient Protection and Affordable Care Act”).

All kinds of protagonists continue to assert widely divergent views, and Patent Docs has done an excellent job keeping an eye on the back and forth (see their two most recent roundups here and here). As one might expect, groups aligned with the interests of original biologics manufacturers, including BIO and venture capitalists, generally support the longer exclusivity period, while groups aligned with generic manufacturers, including the Generic Pharmaceutical Association, tend to support a much shorter period of exclusivity (or no exclusivity at all, the approach favored by the FTC in a report issued this summer). The reaction from patient advocacy groups and the press has been vocal but mixed, with sufficient criticism of the twelve-year period that Representative Eshoo has felt compelled to publicly defend her proposal on several occasions.

So who is right? This is a classic Three Bears problem: is a particular period too short to create development incentives, too long from the consumer perspective, or just right? Not surprisingly, there is no clear answer. For instance, Duke economist Henry Grabowski generated attention – and provided a powerful piece of data for those in favor of a longer exclusivity period – with his 2007 white paper (pdf) that claimed that the breakeven lifetime for biologics was between 12.9 and 16.2 years, suggesting that the current twelve year proposal is either just right or maybe not long enough. On the other hand, it has been pointed out that Grabowski’s research is funded by the powerful Pharmaceutical Research and Manufacturers of America (PhRMA) industry lobbying group. In a recent Wall Street Journal opinion piece, a European legislator argued that a shorter period in the U.S. would be a gift to Europe that “would mean more investment dollars, more jobs, and more research facilities on this side of the Atlantic.”

The Stakes Are High. The risk in making the exclusivity period too short, or eliminating it entirely—with apologies for mixing fairy tale metaphors—is killing the goose that lays the golden eggs, in this case the biologic innovators and those who assume the substantial financial risks associated with developing original biologics. On the other side of the coin, of course, is concern that extended exclusivity—including the possibility that current proposals would permit biologics manufacturers to receive exclusivity substantially longer than the baseline twelve years through a process known as “evergreening,” in which slight changes to existing drugs results in additional exclusivity—will dampen competition, keeping prices for biologics artificially high and drugs out of the hands of patients that need them.

Is twelve years of exclusivity the right length of time to allow companies and investors to recoup their costs? Would a shorter data exclusivity period (or even the proposed twelve year period) result in the original biologic pipeline drying up or shifting overseas? Are there less-intrusive ways of protecting consumers from exorbitant prices—government subsidies, for instance—that would not impair innovation incentives?

The marketplace for biologics is already north of $100 billion and its expected expansion, including the seemingly inevitable introduction of biosimilars, means that the stakes are high for Congress, biotechnology companies, patients and investors. A recent PricewaterhouseCoopers report—Biotech: Lifting Big Pharma’s prospects with biologics (pdf)—noted that virtually every major drug company in the U.S. and Europe is involved in some fashion with biologics and estimated that the market for biosimilars could reach $15 billion by 2013. But for that to happen—at least in the United States—Congress must first act. At the moment, it remains the Senate’s move.

The Genomics Law Report has published a couple of guest commentaries recently dealing with genetic screening—a topic our own Adam Doerr also addressed in two posts this summer dealing with “wrongful life” claims brought against sperm banks by children with genetic diseases inherited from their donor fathers. Such claims are premised on the failure of the sperm bank to conduct genetic screening that could have detected the defective genes—thereby avoiding the conception of the child on whose behalf the wrongful life claim is brought.

In this post, I look at a recent gamete screening controversy—the revelation that a man fathered at least two dozen children, all but two through the donation of his sperm to a bank, despite having a potentially serious genetic defect—and examine numerous issues the story raises. Many relate to whose interests are valued the highest. Should the wellbeing of the children born of the process—the only people involved who have no say in the matter—come first, or does respect for the autonomy of the parents control? I do not attempt to answer the questions posed, but seek to encourage discussion with respect to the need for clearer policies and guidance in a number of these areas.

Another “Bad Sperm” Case.

Keith Syerson of the Chicago-Kent Institute for Science, Law and Technology recently addressed the topic of genetic screening of gamete donors in recent post, The Story of a Sperm with a Bad Heart. Syerson reviewed a study in the Journal of the American Medical Association (JAMA) by Maron, et al. dealing with an anonymous donor who turned out to be a carrier of a mutation associated with the development of hypertrophic cardiomyopathy (HCM). HCM is a congenital heart defect that results in thickening of the heart muscle, which can lead to numerous problems, up to and including sudden cardiac death resulting from the exertion of athletic activity. As Danielle Conrad’s piece on GINA notes, basketball stars Hank Gathers of Loyola Marymount and Reggie Lewis of the Boston Celtics both collapsed and died on the basketball court, and were discovered to have suffered from HCM.

The Maron et al. study revealed that the donor had fathered 22 children through donations, and had two more children with his wife. One of the children had already died of HCM-related heart failure, at the age of two. Sixteen of the children born via donation received genetic tests; eight tested positive for a mutation associated with HCM. One of the donor’s children with his wife also tested positive. Two of the affected children had “massive LV hypertrophy” and the donor had “extensive myocardial fibrosis” of which he was previously unaware.

The authors of the study noted that “some sperm banks test for cystic fibrosis, thalassemia anemia, sickle cell trait, Tay-Sachs, and other genetic diseases that have increased frequency in Ashkenazi Jews; all of these conditions are much less common than HCM in the general population.” While they acknowledged that genotyping for HCM-related mutations would be unlikely “due to its current expense and limited clinical sensitivity,” they recommended echocardiography of potential donors to screen for HCM and, potentially, other diseases that can cause sudden death. The authors also noted that the case “underscores the need for guidelines to notify gamete donors, recipients, and other affected parties once genetic disease arises.”

Syerson cited a commentary JAMA published along with the Maron et al. study, in which Judith Daar and Robert Bryzski described the current environment in which sperm banks operate—with no federal regulation requiring genetic screening, and with the majority of banks not complying with the voluntary “established screening protocols” of the American Society for Reproductive Medicine. (Those protocols (pdf) do call for genetic screening of donors, including for cystic fibrosis and autosomal or X-linked dominant disorders, among others). The regulations that do apply to donations are designed the protect the mother from communicable diseases, not to promote the health of the child.

The Maron et al. study and its recommendations raises numerous ethical questions, many of which will need to be addressed as reproductive genetic screening, including but not limited to the screening of donated gametes, becomes capable of providing more information on a wider range of conditions at a decreased cost, thereby likely becoming more widespread than at present. I identify a number of these questions below. Many relate to whose interests are valued the highest. For example, should not the wellbeing of the children born of the process—the only people involved who have no say in the matter—come first? I do not intend to provide answers to the questions posed. I note, though, that the interests of the children often seem to come last.

Does the Propriety of Genetic Screening Depend Upon the Stage of Life at which It Is Performed?

There seems to be general agreement among those writing on the subject that, as Syerson puts it, “taking added precautions to prevent women from unknowingly receiving sperm carrying genetic mutations that are associated with deadly diseases is a good thing.” Both he and Daar and Bryzski, in their JAMA commentary, express concern that the cost of such testing may affect the ability of the poor to use sperm donors, but neither suggests there is any intrinsic harm in performing such tests. As Adam Doerr reported in “Strict Liability for Sperm?”, a federal court recently held that a sperm bank could be liable for negligence “in failing to properly screen the sperm” under New York law—so that there can be a legal duty to conduct pre-conception screening. But why is there such a duty? Shouldn’t donor children and their mothers take their chances like the rest of us? Is the fact that we can perform such testing reason enough to decide that we ought?

As Hank Greely’s recent ELSI commentary observed, though, with the forthcoming postconception but prenatal genetic testing that will be both cheap and safe, society needs to decide whether to “encourage, discourage, or view as neutral” such tests. Is the same not true for pre-conception screening?

As Danielle Conrad observes, under GINA, once someone is born, it is illegal to screen them for health insurance and employment purposes—which means that basketball players suspected of having HCM will not be subject to genetic tests by their employers, and that even pilots whose passengers’ lives may be at risk from their collapse are exempt from screening for HCM. Of course, GINA applies only to existing people, and donor screening is promoted in order to prevent people with genetic diseases from being conceived. Perhaps the reasoning behind the duty to screen gametes is that no one is hurt by such screening (except perhaps through the stigma attached those who live with the disorders for which screening is performed). Is it simply uncontroversial that mandatory genetic screening before conception is always to be promoted, that mandatory genetic screening after birth for reasons other than medical care is always to be proscribed, and that the only gray area is in between the two, depending on one’s view of the morality of abortion and the destruction of embryos?

Implications of the Duty to Conduct Pre-Conception Genetic Screening

If pre-conception screening is such a clear good, and if sperm banks have a duty to screen for certain genetic disorders simply because such screening is possible, then does it not follow that obstetricians have a duty to provide screening for fertile couples? In Iran, for example, a mandatory premarital screening program originally designed to prevent communicable diseases has been modified to include certain non-communicable genetic disorders, including blood disorder thalassemia. Iran’s experience with mandatory premarital screening for genetic disorders also resulted in it changing its laws to permit prenatal genetic screening, the costs of which are borne by (governmental) health insurers—accompanied by a fatwa (pdf) under Islamic law permitting abortion in thalassemia cases. Iran’s program is generally regarded as having been successful (pdf) in reducing the rate of thalassemia and integrating genetic screening into an existing healthcare system.

Similar premarital and prenatal genetic testing options are offered elsewhere around the world, typically through traditional providers of reproductive assistance, including in vitro fertilization (IVF) clinics, although some companies now offer genetic screening directly to prospective parents via the internet. In addition, some countries, including the United States, presently permit genetic screening—typically through a combination of embryo selection and screening that utilizes pre-implantation genetic diagnosis (PGD) and IVF—for non-medical conditions including sex selection (which is illegal in many other countries, including the United Kingdom, India and China) and even the possibility of selecting for simple genetic conditions such as eye and hair color. However, the practice of utilizing genetic screening to influence non-medical traits or conditions is highly controversial, even in the United States where attitudes toward genetic screening for non-medical traits are generally more permissive. Given advancements in reproductive technologies and scientific understanding, it is conceivable that, eventually, it will be possible to screen for alleles that affect more complex traits such as obesity (pdf) or even elements of cognition. If there is a duty to engage in genetic screening to ward off disease, is there a duty to offer the opportunity to optimize a patient’s children?

And if we take steps to ensure that potential donors with genetic defects do not father children through the donation process, why stop there? Why not take steps to protect children born to such potential fathers through more traditional methods, including implementing mandatory premarital screening (such as employed in Iran and other countries), imposing other conditions or even restrictions on prospective parents with identified genetic conditions, or granting children born with certain conditions the right to sue their parents for the effects of defects that could have been avoided if they had had themselves screened prior to having children?

Is part of the answer that, as practiced in the United States, sperm donation itself can promote genetic defects? Returning to the case of the HCM donor with which we started this discussion, recall that he had 24 children. Another New York donor estimates that he has provided sperm for hundreds of children. There is no legal limit on the number of children a single donor may father in any one city—donors may sire children in numbers not seen since the days of Genghis Khan. If the donor has a genetic defect for which screening is too expensive or not yet possible, he may pass that trait on to a far larger number of descendants than would otherwise be the case. And even if he has no genetic defects, the practice of donor anonymity, combined with the absence of limits on the number of donor children creates a risk that half-siblings will unknowingly meet and conceive children together. England, for that reason, provides that only 10 families may receive gametes from any one donor. In the U.S., though, there is still no legal limit—which can be seen as another example of the law’s focus on the interests of the mother (who would not be directly affected by unintentional consanguinity) rather than the child (who might be).

Screening can also be used by parents who are deaf or are dwarfs, or have other heritable traits, to ensure that their children are like them. This has already happened informally, engendering considerable controversy, and may be happening at fertility clinics as well. Do children deliberately conceived deaf without their consent have a claim against the clinics that assisted in their birth, or against their own parents? Children whose deafness is caused by negligent medical treatment have a claim against those who cause their deafness, as does a child born with hereditary deafness following a physician’s failure to detect and advise her parents of the genetic risk.¹  Is it not inconsistent for states that permit wrongful life claims to deny such claims to children born without hearing due to the intentional actions of others, including their parents?

Donor Anonymity

Returning to the Maron et al. study, it is odd that Syerson as well as Daar and Bryzski read that study as calling for a national searchable database to pass along information about any genetic disorders that may arise. The study contained no such recommendation, but simply noted that the case “underscores the need for guidelines to notify gamete donors, recipients, and other affected parties once genetic disease arises.” However, a database is certainly one way to accomplish that notification and both voluntary and mandatory databases have been suggested by others. Syerson expresses concern that in a database “[w]ithout adequate privacy protections, recipients of a donor’s sperm may be able to contact the donor despite his desire to stay anonymous.” But as the GLR has noted before, when dealing with genomic data, even robust efforts to ensure anonymity may be illusory. Since a donor’s son has a copy of his Y chromosome, the child may have the relevant genomic data necessary to identify the donor father—as one donor’s 15-year old son demonstrated by sending a cheek swab to Family Tree DNA, finding two matches for his Y chromosome with the same last name, and then using the name and the limited information his mother had from the sperm bank to locate his father.

Even if donor anonymity is feasible, is it ethical? Proponents of anonymity are concerned about the effect ending donor anonymity may have on the supply of gametes. Daar, for example, has elsewhere written that “a non-anonymous donor policy in the U.S. would reduce the availability of donor sperm for unmarried women.” In other circumstances, there is a strong presumption that the father should remain responsible for his children. The policy against leaving a mother to support her child alone is so strong under U.S. law, in fact, that even young male victims of statutory rape must pay child support. Courts have “uniformly concluded that the fact that a child results from the criminal sexual act of an adult female with a minor male does not absolve the minor from the responsibility to pay child support.”² Similarly, a husband is presumed by law to be the father of his wife’s children, and the courts in most states will require a man to continue to provide support for those children even when subsequent genetic testing reveals that his wife had cheated on him and the children are not his. Should children of donors be denied the financial support of a father that is compelled on behalf of other children?

Daar is of the view that “[o]n balance, children of single … parents fare as well as children raised in marital … homes.” Her argument implies that, just as there is a duty to screen for genetic problems, it is appropriate to consider the environment in which the donor child is to be raised. However, even an article by authors sympathetic to single parenthood notes that “[m]uch of the literature on single-parent families has focused on the negative consequences for children.” For example, “even in Sweden with its generous welfare state, a major 2003 study found that children raised in single-parent homes were at significantly higher risk for addictions and serious psychiatric problems.” Does the weight to be given the effect of anonymity on the supply of donors depend on the effect single-parent homes have on children?

And even if there is a sufficient number of donors, does an extreme case such as “Octomom” Nadya Suleman, the indigent single mother with 14 donor-conceived children, suggest that limiting access to certain reproductive technologies based on the ability to support the children might in fact be desirable? Not at all, according to several academic commentators. At least one author has taken the contrary position that “[t]he state has a compelling interest to act in the best interest of the offspring that result from infertility treatment”—including an interest in “the ability of the potential parents to provide for the children.” What about limitations based on the age of the recipient mother? A 66-year old woman who lied about her age to a California fertility doctor gave birth to two boys—and died when they were two. The American Society for Reproductive Medicine voluntary protocols include no upper age limit, but do suggest medical evaluation of potential recipients over 45. More generally, Daar argues that “imposing reproductive regimes that deny procreative rights to certain members of a society is dangerously reminiscent of our eugenics past.” Ironically, as we saw above, Daar favors screening gamete donors for genetic defects, which could be considered the actual practice of eugenics. (Of course, such screening would not prevent the rejected donor from fathering children on his own.)

Anonymity itself comes with a cost. One need only spend a little time on the website created by a donor child searching for her father and half-siblings to understand the pain some of these children feel at be deprived of the knowledge of their biological father’s identity. As the daughter of an anonymous donor put it on another such website, “[m]y mother’s need to have a genetic link to her child was valued, while my need to know, love and understand the father with whom I have a genetic link was not.” More than 25,000 such children, their parents, and donors, have registered at the Donor Sibling Registry, trying to connect donor children with half-siblings and fathers—up from fewer than 10,000 two years ago.

Article Seven of the 1989 United Nations Convention on the Rights of the Child (pdf) explicitly protects a child’s “right to know … his or her parents.” Several signatory countries, including Holland, Norway, and Sweden have outlawed anonymous sperm donation out of concern for the effect on the children. In 2002, a British court found that a child does have the “right to obtain information about a biological parent [a sperm donor] who will inevitably have contributed to the identity of his child.”³ In 2005, the UK abolished anonymity for donors, and gave donor children the right to access their “biological pasts” at the age of 18.

Things are different in America. The United States is one of only two countries (along with Somalia) that has not ratified the Convention on the Rights of the Child, and no state bans anonymous donation. A California court has held that a donor child with a genetic disorder has the right to her father’s medical information, any promise of anonymity made by the sperm bank notwithstanding. However, cases involving adoption suggest U.S. courts will not follow the British precedent and provide children with a right to learn the father’s identity. U.S. donor children appear to be left to self-help—including resources such as FamilyTreeDNA.com—if they wish to discover their biological fathers.

The Future of Genetic Screening

Everyone seems to agree that at least some genetic testing of donated gametes is desirable, yet few clinics do it, and no state requires it. As one commentator observes, “hardly anyone in the public or the legislatures is paying attention. The designing of children is occurring subtly, as a result of individual choices through an open market.” While many countries, from Iran to England, have enacted laws affecting genetic screening, for the benefit of the children to be born to those involved, the reproductive legal landscape in the U.S. is sometimes termed Wild West. The lack of regulation is itself a policy choice, and may be the one on which the country settles—but any such decision should be the result of conscious deliberation, considering the interests of children as well as that of their parents.

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¹Turpin v. Sortini, 643 P.2d 954 (Cal. 1982).
²L.M.E. v. A.R.S., 261 Mich. App. 273, 288-289 (2004).
³Rose v. Secretary of State for Health, 2002 WL 1446174

Much of the discourse arising in connection with the new GMC guidance stems from a perceived breach of the patient’s right to privacy and an erosion of the ever sacred principle of doctor-patient confidentiality. While these are certainly valid concerns, the idea that certain medical information may be disclosed in the public interest is not a new concept in the U.K. or even the U.S. For example, most states in the U.S. require physicians to report to the local or state board of health cases of certain communicable or infectious diseases. Furthermore, at least six states require physicians to report to the Department of Motor Vehicles the diagnosis of diseases that may impair the patient’s ability to drive.⁴  These statutorily mandated disclosures may be made against the patient’s wishes and without the patient’s authorization.⁵

Perhaps the increased concern surrounding the GMC guidance is triggered because the disclosure of genetic information is specifically permitted. While many people can understand the “public interest” justification for disclosing cases of communicable diseases that may spread through the population or illnesses that might make the patient a danger to others on public roadways, maybe they are less willing to place genetic information in this category. One might argue that it is not really the public who benefits when the existence of a patient’s genetic disease is disclosed to his or her at risk relatives; instead, the potential benefit of disclosure reaches only a set of closely related individuals with whom the patient may share genetic traits. This is fundamentally different from laws permitting the disclosure of conditions that may affect the community at large.⁶  Moreover, genetic information is arguably about as personal as medical information gets, and concern over adverse effects should genetic information fall into the wrong hands (pdf) can run high. Accordingly, the “greater good” argument may not be sufficient to justify its disclosure to any third party—even family—without the patient’s consent.

In the U.S., many states have passed legislation aimed at protecting the confidentiality of genetic information specifically. Massachusetts prohibits the disclosure of physician records pertaining to any genetic information without the patient’s informed written consent. Likewise, in Nevada it is unlawful to disclose or to compel a person to disclose the identity of a person who was the subject of a genetic test or to disclose the genetic information of such person in a manner allowing identification of such person without his or her informed written consent. California even goes so far as to impose criminal penalties for certain willful or negligent disclosures of the results of a test for a genetic characteristic without the patient’s written authorization.

Actions at both the state and federal levels, including the passage of GINA (discussed below), suggest that the prevailing view amongst U.S. policy- and law-makers appears to be that genetic information deserves heightened forms of protection. Nearly all states that have enacted legislation addressing the disclosure of genetic information, like the several mentioned above, require informed written consent rather than the less stringent authorization required for disclosure of other protected health information.⁷  This fierce protection of the patient’s privacy in his or her genetic information seems a stark contrast to the GMC’s view that doctors should disclose a patient’s genetic illnesses if such disclosure is in the broad public interest. State legislation in the U.S. appears to take the contrary view that an individual’s genetic information belongs solely to the individual, not to the public at large. In fact, at least one state (Alaska) expressly recognizes in its statute this concept: “[A] DNA sample and the results of a DNA analysis performed on the sample are the exclusive property of the person sampled or analyzed.”

So, why the difference in philosophy between the U.S. and the U.K.? Over at The Cross-Border Biotech Blog, Jeremy Grushcow has suggested that the difference can be traced to the presence of universal healthcare in the U.K. (“In Praise of Universal Coverage From a Genomics Perspective”). Particularly in the U.S., a major impetus for protecting the confidentiality of genetic information is the fear of discrimination by insurers and others, a fear that was central in producing the passage of GINA last year. According to Grushcow, “universal coverage is the cure,” rendering individuals “(functionally) genomic equals when deciding on healthcare policy” and paving the way for the GMC’s altruistic, societal approach to the disclosure of medical information, including genetic test results. Universal healthcare coverage protects the patient from the risk of losing his or her health insurance or being forced to bear a higher cost of insurance and therefore, Grushcow contends, allows the patient, and others through the sharing of results, to benefit from the information obtained from genetic testing. Grushcow concludes: “if the U.S. moves into the genomic era without universal coverage, it will exacerbate existing inequalities and create new ones we haven’t even imagined.”

However, Grushcow does not consider other avenues by which this particular discrimination issue may be addressed. Last year the U.S. took an alternative step to address the role of genetics in health insurance with the passage of the Genetic Information Nondiscrimination Act of 2008 (GINA), which prohibits discrimination on the basis of genetic information by insurance companies or employers. (In the U.K., on the other hand, the House of Lords examined the issue of genetic discrimination in its recent report, Genomic Medicine, and concluded that there was no need at present for “specific legislation against genetic discrimination.”) While GINA does not prohibit all genetic discrimination (life insurance, long-term care and other areas do not fall under GINA), it does prevent discrimination in premium and underwriting decisions by health insurers. Although far from perfect, GINA has been largely well-received and represents a viable alternative to universal healthcare for the purpose of addressing the fears of health insurance discrimination among those who desire, or require, access to their genetic information. Yet despite GINA’s passage, the U.S. still seems to hold sacred the privacy of genetic information. There must be other factors at play.

The risk of losing one’s health insurance is certainly not the only risk that may arise if personal genetic information is disclosed to third parties, even if only to relatives. Disclosure could affect social interactions or relationships among family members. Furthermore, whether or not legal, the patient may be at risk of discrimination by a host of third parties in addition to health insurers. Although possible misuses of genetic information can be hypothesized (the Personal Genome Project’s informed consent protocol (pdf), for example, contains a lengthy list of potential “risks and discomforts” that might result from the disclosure of one’s genetic information), the reality is that in these early days of widely available personal genetic information, perceived risks may be non-issues and actual risks may be currently unknown.

The GMC’s new guidance also raises questions regarding the rights of the patient’s relatives not to know about their propensity for an inherited disease.⁸  Perhaps an individual has made a personal decision not to submit to a genetic test because he or she would rather not learn the probability of contracting a particular disease. A doctor following the GMC guidance may end up disclosing to the patient’s relative precisely the information he or she has chosen not to acquire. What if the reason the patient refuses to tell the relative about the patient’s genetic disease is because the patient knows that the relative has made this personal decision not to be tested? In these situations, the patient, rather than the doctor, may be in the best position to decide who should learn of the patient’s genetic illness.

GINA and especially universal healthcare are incapable of addressing these issues – neither can assuage both known and unknown fears about the misuse of genetic information or ensure that an individual’s right not to know their genetic information is respected. At least for a certain segment of patients and of the broader populace, maintaining the privacy of genetic information may represent the only way to fully address these issues. Although, as we have argued repeatedly here at the GLR, an absolute promise of genetic privacy would be irresponsible, there is a wide gulf between undertaking a concerted effort to maintain the privacy of an individual’s genetic information and the alternative proposed by the GMC’s guidance, which permits doctors to exercise considerable discretion in deciding whether an individual’s desire for genetic privacy outweighs the “public interest.” Without strong assurances of privacy, the various risks associated with third parties becoming privy to personalized genetic information may deter some patients from undergoing a genetic test in the first place. Such a result benefits neither the individual who desires the test nor the “public interest” that the GMC guidance hopes to protect. For many people, privacy is a critical factor in the decision to participate in a genetic test or genomic sequencing.

In summary, the ability of a doctor to reveal patients’ medical information in the “public interest” is particularly complicated in the realm of genetic medicine, and granting doctors the ability to override their patients’ preferences may not be a positive development overall. No one, neither the individual nor the general public, will benefit if patients are dissuaded from undergoing clinically indicated genetic testing. It is undoubtedly true that most patients would opt to share information with at risk family members, but those who choose not to might refuse testing altogether if they understood that results could be disclosed without their consent. Plus, there is potential that disclosure in the “public interest” could extend to third parties beyond the patient’s immediate family. This is an even greater disincentive. Whatever an individual patient’s reasons, it is clear that there is a firmly rooted belief, shared by many, that genetic information is uniquely personal and should be capable of being maintained in a private fashion. Attempting to run roughshod over that belief may discourage many from exploring the benefits of the emerging field of genomics and personalized medicine. In this particular respect, the GMC’s proposed approach to genetic information sharing may be misguided.

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¹ The ability to disclose is probably triggered both by the discovery of a genetic disease that has already manifested in the patient and by the results of a genetic test showing a propensity for a genetic disease, even if such disease has not yet manifested. The GMC’s policy concerns would be the same in either scenario.

² The new guidance is discussed on the following websites, among others: PHG Foundation; Times Online (discussed here and here); e-Health Insider; and University of Glamorgan, Genomics Policy.

³ In a press release issued last month, the chair of the GMC’s working group on confidentiality, Dr. Henrietta Campbell, stated, “This guidance makes clear that, in the first instance, doctors should explain to a patient if their family might be at risk of inheriting a condition. In those circumstances, most will readily share information about their health. However, if a person refuses, it is the responsibility of the doctor to protect those who may be at risk.”

⁴ California, Delaware, Nevada, New Jersey, Oregon and Pennsylvania require such reports to the DMV.

⁵ Generally, the Health Insurance Portability and Accountability Act (“HIPAA”) prohibits disclosure by a health care provider of a patient’s health information without the patient’s authorization. See 45 C.F.R. §164.502. However, HIPAA excepts from the general rule disclosure of protected health information as required by law. Id. at §164.512. Patient authorization and opportunity to agree or object is not required for any disclosure required by law. Id.

⁶ Furthermore, the above mentioned mandatory disclosures of certain communicable diseases and driver impairments are narrow and specifically defined by statute. A broad “public interest” exception to doctors’ duty of confidentiality to their patients is probably unacceptable to most people even if genetic information is not involved. This concept, however, is beyond the scope of this discussion, which focuses only on the disclosure of genetic information.

⁷ See, e.g., ALASKA STAT. §18.13.010 (“[A] person may not collect a DNA sample from a person, perform a DNA analysis on a sample, retain a DNA sample or the results of a DNA analysis, or disclose the results of a DNA analysis unless the person has first obtained the informed and written consent of the person, or the person’s legal guardian or authorized representative, for the collection, analysis, retention, or disclosure.”); MINN. STAT. §13.386 (prohibiting collection and dissemination of genetic information unless individual gives written informed consent).

⁸ Guidance from the U.K. Joint Committee on Medical Genetics, Consent and Confidentiality in Genetic Practice: Guidance on Genetic Testing and Sharing Genetic Information (April 2006), recognizes the right of a person not to learn of their genetic propensities for certain diseases and indicates that “an insistence on imparting unwanted information could be interpreted as a breach of a person’s right to private and family life.” However, this guidance, like the GMC guidance, condones the disclosure of genetic information over the patient’s refusal to consent if “disclosure substantially outweighs the patient’s claim to confidentiality.” An example given in the guidance is a person who refuses to inform relatives of a genetic risk of which they are unaware.

…promote high standards and consistency in the provision of direct-to-consumer genetic tests among commercial providers at an international level in order to protect the interests of people seeking genetic tests and their families.

The Principles, which are ambitious in scope and detailed in their recommendations, represent an important next step in the ongoing debate over the appropriate level of oversight for the emerging DTC genetic testing industry.

Published in draft form, the Principles provide ample room for analysis, and companies and consumers are invited to provide responses and comments until December 6th, 2009.

In this post we take a close look at the draft Principles and summarize the core values and goals that appear to underlie these recommendations.

Part I: The Big Picture

The desire to bring higher standards and greater consistency to the genetic testing industry is far from new. In the United States, the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) published a comprehensive report on genetic testing (pdf), including recommendations for oversight, in 2008. A consortium of DTC companies organized by the Personalized Medicine Coalition continues its work on a long-awaited set of voluntary industry guidelines (pdf). Policy and professional groups such as Genetic Alliance and the American College of Clinical Pharmacology have also sought greater oversight of DTC genetic testing. In the United Kingdom, the Human Genetics Commission’s recommendations come in the wake of, among other guidance, the report on genomic medicine issued in July by the House of Lords which recommended that DTC genetic tests be reclassified as “medium risk” – a classification that would subject the tests to pre-market review before use by consumers.

In the Commission’s recommendations, the recurring theme is a concern for the well-being of the individual consumer:

Genetic tests have the ability to give rise to a broad spectrum of responses . . . When a genetic test is provided outside a framework of healthcare, special attention must be given as to how that individual may respond to the results . . . and the subsequent impact the test results may have on that individual and their family. With this in mind, these Principles have been developed with the best interests of consumers at the forefront.

This is a familiar theme, and the Principles reflect a tension that has already received considerable attention: on the one hand we have concern about the potential harms that can arise from DTC genetic testing in certain circumstances, particularly where information may be inaccurate or may be presented without necessary counseling or other professional services; on the other hand is the reality that DTC genetic testing companies are frequently not intending to provide, nor capable of providing, a clinical service.

The Principles do not address traditional forms of clinical genetic testing. They are, however, intended to cover:

…all aspects of direct-to-consumer genetic testing services, including the marketing and advertising of tests, the collection, analysis and storage of biological samples, the interpretation of results and the provision of results to the consumer.

Significantly, the Principles apply to all DTC genetic tests, except for those specifically excluded. (Exemptions are provided for genetic tests mediated by medical professionals, forensic or court-order testing and testing for “purely medical research…where the results are not disclosed to the consumer,” an exemption which, incidentally, would not cover several emerging genomics research projects including the Personal Genome Project and the Coriell Personalized Medicine Collaborative, both of which return research results to their participants.)

The decision to lump all DTC genetic testing into a single category for purposes of the Principles, including tests with attenuated clinical value (for example, ancestry testing), demonstrates the Commission’s apparent suspicion and discomfort with the entire DTC industry and produces a set of broad-spectrum rather than narrowly-tailored recommendations.

Part II: The Substantive Provisions

Although the Principles themselves will have no legal force, even once finalized, the Commission hopes that they will guide self regulation by commercial testing services and action by “regulatory bodies and/or national jurisdictions [that] should have defined measures in place.”

Definitions. The Principles define “genetic test” to mean “a test to detect the presence or absence of, or a change in, a particular gene or chromosome or a gene product or other specific metabolite that is primarily indicative of a specific genetic change.” Eleven categories of genetic tests are defined, of which three are considered a “genetic test in the context of inherited or heritable disorders” which “may have important implications for the health of the person concerned or members of their family, or have important implications concerning reproductive choices.”

The Principles contain additional definitions for “condition,” “trait,” “test provider,” and “genetics health professional,” the last being a “health professional who has undergone appropriate training in the interpretation of genetic information and has achieved the required competencies.” Not specified is whether a general practitioner would qualify as a “genetics health professional” or whether additional training or certification related to genetic testing would be required.

Information Supplied by DTC Genetic Service Providers. The Principles would impose upon DTC genetic service providers the obligation to educate consumers about genetic testing and the implications of test results so that consumers can make informed decisions. To a large degree the Principles simply articulate customary rules of fair advertising and disclosure that could apply to a variety of consumer services. For example, the test providers should provide information that is specific, easy to understand and does not overstate the utility of a test.

The desire to provide consumers with “easily understood, accurate, appropriate and adequate information” prior to testing is entirely appropriate. It is also hugely ambitious. Respected commentators have noted, generally, the need to “revolutionize our communication of science to non-scientists” in order to improve understanding. Specific Commission recommendations, such as the requirement that providers supply “information about the presentation of results . . . such as relative and absolute risk assessments so that an individual can understand test results” run into identified gaps in scientific understanding and education at the individual level, such as the well-documented difficulty in communicating statistical concepts such as relative risk.

The requirement in Section 10.6 that providers “have in place a process to evaluate how well consumers are able to understand the background information and test results they have received” appears to ask nothing less of these companies than to serve as educators (and educational reformers) in additional to their role as genetic testing providers.

And, in many cases, the very education and analysis that the Commission demands is of exactly the type that requires the participation of medical professionals to develop. Other potentially problematic informational requirements set forth in the Principles include the following:

• A genetic test in the context of inherited or heritable disorders “should only be provided to consumers with individualized pre- and post-test counseling.”
• A provider that intends to recommend a therapeutic product “should also provide information about other lifestyle choices and behavioral modifications that are known to have a preventative or therapeutic value in relation to the trait linked to the genetic markers tested.”
• “Where appropriate, the test provider should inform consumers about . . . actions that may help the consumer to take informed decisions about their health or welfare in light of the test results . . .”

As discussed further below, these proposals suggest that DTC testing services should possess a significant amount of personal information about their customers (quite possibly more than the average customer would want to disclose to a service provider, although information that would be routinely disclosed to a medical professional) and contemplate participation by DTC testing services in the personal and medical decision-making of individuals.

These and the many other informational and educational requirements set forth in the Principles would appear to require DTC genetic service providers to assume many of the responsibilities traditionally carried out by medical professionals and educators. Furthermore, attempts to impose such requirements on DTC providers would almost certainly hinder ongoing volunatry and regulatory attempts to demarcate clinical and non-clinical services.

Informed Consent. The Principles stress that DTC service providers should enable consumers to provide an informed consent that is truly informed. In most respects, the consent recommendations, when combined with the disclosure requirements described above, outline a desirable industry standard. The Principles require that test providers obtain and retain written confirmation of consent, that a separate consent be obtained before biological samples are used for any secondary purposes (such as research), and that consent be obtained before a third person is given access to biological samples or personal or genetic data.

In other respects, however, the informed consent requirements contemplate a significant intrusion by the test provider into the personal lives of consumers. For instance:

• “The test provider should give consideration . . . to the personal and familial circumstances of the consumer.”
• The test provider must “consider the impact of the test results for the consumer” and in doing so should take into account “the potential of the test to have a significant impact on personal relationships and the stability of families.”
• Genetic testing of persons incapable of consent should only “be carried out if testing is in his or her best interest,” which appears to require the test provider to involve itself in, and possibly to second-guess, the decisions of legal guardians.
• With the exception of paternity tests, “genetic tests in respect of children [not having legal capacity to consent] should normally be deferred until the attainment of such capacity unless other factors indicate that testing during childhood is clinically indicated,” a requirement which appears to intrude into the domains of both parents and physicians and runs counter to the policy of 23andMe, one of the leading DTC service providers.

The need for truly informed consent is as important in the DTC context as it is in the clinic or in a genomics research study. However, given the considerable debate that continues to swirl around issues such as pediatric consent and genomic data privacy, the Principles should do more to encourage DTC service providers to develop appropriate informed consent protocols in cooperation with consumers, clinicians, researchers and other relevant stakeholders.

Blurring the Clinical/Non-Clinical Divide. The Principles are suffused with worry that consumers will use DTC genetic testing as a substitute for professional medical advice. This is a concern commonly voiced by critics of the DTC industry. Unfortunately, compliance with the Principles would increase that very risk, because their likely result, if implemented, would be to further blur the line between DTC and clinical testing and services.

Examples of Principles that demonstrate this blurring include the following:

• Genetic tests “in the context of inherited or heritable disorders . . . should only be provided to consumers with individualized pre- and post-testing counseling.”
• “The test provider should provide information about . . . the decisions that a consumer may face after taking the test . . . and identify prospectively any likely further investigations that a consumer or member of their family may wish to pursue after receiving the test results.”
• If the test provider intends to use the test result to promote a therapeutic product, the test provider “should also provide information about other lifestyle choices and behavioural modifications that are known to have a preventative or therapeutic value in relation to the trait linked to the genetic markers tested.”
• “If a test provider intends to use the results of genetic test to make a recommendation to a consumer to alter the dosage of a medicine or to recommend alternative medicines, the test provider should make available information about the link between the genetic test result and the metabolism of the indicated medicines.”
• “Where appropriate, the test provider should inform consumers about recommendations or known actions that may help the consumer to take informed decisions about their health or welfare in light of the test results.”
• “Interpretation of genetic test results should be carried out under the responsibility of an appropriately qualified professional, with recognized training and qualifications, working within the standards determined by an appropriate professional body and regulated by this professional body, employed by or working on behalf of the test provider.

Finally, in determining whether or not the results of a genetic test may be returned directly to the consumer who ordered the test, the Principles set forth a host of factors for DTC service providers to consider in determining “whether the test results should be provided only in the context of a consultation with a suitably qualified genetics health professional…”

These factors include everything from the severity of the condition to be diagnosed to the reliability of the diagnosis to the “likely speed of degeneration,” along with particularly personal criteria such as the likelihood that the results will “have a significant or life-altering impact on the behavior of the individual” or on the personal and family relationships of the individual.

It is almost impossible to conceive of a system in which DTC service providers could evaluate these and the other factors set forth in Section 10.1 of the Principles without engaging in preemptive genetic counseling for each customer seeking whole classes or categories of genetic tests. Irrespective of whether such pre-testing genetic counseling would be desirable in the DTC context, at this point the resources simply do not exist to support such a model – there are simply not enough genetic counselors or other appropriately trained medical professionals. And as the cost of genomic data production continues to decline, demand for data is likely to continue to outpace the capacity of genetic testing providers – whether DTC or clinical – to provide that data alongside individualized genetic counseling.

Furthermore, given the Commission’s underlying concern that consumers will inappropriately lean upon DTC genetic information to make important medical and lifestyle choices, requiring DTC companies to provide detailed and personalized medical assessments to their customers seems an odd way to set consumer expectations for the appropriate use of DTC genetic information.

Technical Provisions. Sections 6 (Data protection), 7 (Sample handling) and 8 (Laboratory processes) provide useful guidelines for DTC service providers that seem likely to be supported – if not already adopted – by most responsible companies and would serve as a useful floor to ensure that consumers receive a high-quality genetic testing experience. Recommendations such as improved proficiency testing for genetic testing laboratories and more specific policies governing the treatment of an individual’s genetic data in the event of a bankruptcy have been made elsewhere and are likely to be widely supported by both companies and regulators.

Part III: What’s coming next?

In the “Purpose and Scope” section of the Principles (Section 1.1), the Commission writes that the “test provider should strive to provide a high-quality service that meets the expectations of the consumer whilst safeguarding their interests.” In focusing primarily on the desire to safeguard consumers’ interests – a desire that is manifest in standardized guidelines that attempt to bring the DTC companies closer in line with practices used in clinical genetic testing – the Commission has crafted Principles that, while comprehensive and ambitious in that regard, are likely to do much to frustrate the expectations and desires of many consumers if implemented to the letter.

Next week, we will take a closer look at just what these Principles, in conjunction with various other calls for increased oversight and a heightened focus on clinically relevant testing, might herald for the future of the DTC genomics industry. In the meantime, the Commission has prepared 11 consultation questions, many of which touch on the issues identified above, and we encourage our readers to provide their own take on the Principles both directly to the Commission (pdf) and in the comments below.

Today brings word, via ScienceInsider, that the Border Agency is pulling back on its plans to use DNA and isotope analysis to evaluate the nationality of asylum seekers attempting to enter the U.K. According to ScienceInsider:

In a statement released this afternoon by the Home Office, which oversees the Border Agency, the department’s Chief Scientific Advisor Paul Wiles now says such evidence will be collected for later analysis of its potential but will not currently be used for individual case decisions.

As Daniel MacArthur points out at Genetic Future, while some of the initial outrage over the Border Agency’s policy may have been overstated, “the initial policy was still grossly premature” and the “Border Agency’s decision to take a step back and consider the implications before wading into the morass of genetic ancestry testing” is a welcome development.

On the one hand, the Border Agency’s rapid course correction demonstrates that not all government agencies are deaf to public criticism and that not all misguided uses of genomic data are malevolent or require a formal regulatory or legislative response. Still, it seems unlikely that this is the last that will be heard about the Human Provenance project, and even in the rear-view mirror this was an unfortunate episode. And it seems to me that the conclusion to last week’s article is as relevant today as it was then:

The coming weeks will likely see further focus on the details of the Human Provenance pilot project, and we hope that the project is quickly brought in line with scientific realities and rendered consistent with important ethical, legal and social principles. But over the longer term we hope that in responding to this unfortunate example of genomic data usage, legislators hold in check their tendencies toward paternalism and genetic exceptionalism and that law- and policy-makers continue to advance a pragmatic and measured discussion that recognizes equally both the risks and benefits of genomic data availability and that leaves open a path for genomic research and personalized medicine to move forward.

Science

Scientists are greeting with surprise and dismay a project to use DNA and isotope analysis of tissue from asylum seekers to evaluate their nationality and help decide who can enter the United Kingdom. “Horrifying,” “naïve,” and “flawed” are among the adjectives geneticists and isotope specialists have used to describe the “Human Provenance pilot project,” launched quietly in mid-September by the U.K. Border Agency. Their consensus: The project is not scientifically valid—or even sensible.

In addition to the feature article, ScienceInsider has also published a FAQ describing what is now known about the program as well as links to the underlying documents and expanded reactions from leading geneticists and isotope specialists.

The project is, as the name indicates, a pilot project, and one spokesperson described it as being “in its baby stages.” Still, as reported by ScienceInsider, the scientific community’s reaction to the program appears to be swift, unanimous and extraordinarily critical. Daniel MacArthur of Genetic Future has a slightly more measured take, expressing skepticism about the ability of the government agency to identify precisely an individual’s geographic ancestry based on genomic data and rightly pointing out that the “crucial issue is that it must be shown that the data are used in appropriate ways, and not given undue weight in making serious decisions about a person’s future.” That’s an issue that cannot be resolved until the Border Agency provides additional details on both its scientific methods and its utilization of the collected DNA and isotope data.

The near-uniform scientific skepticism that has greeted the announcement of the Human Provenance project suggests that we should not be surprised to see the pilot project substantially revised, or even scrapped altogether. But has damage already been done?

The issues of granting political asylum and the use of genomic data are both politically and socially delicate. So it is especially unfortunate when such hot-button policy issues arise in the context of a project that is scientifically so questionable. If those were the only dynamics at play the Human Provenance project would likely generate outsized social and media commentary, and quite possibly a significant legislative or regulatory response. But the timing is such that this development comes at a crucial moment for the field of genomics. At present, a delicate balance exists between genomic science—including the emerging fields of DTC genomics and personalized medicine—and the developing legislative and policy framework that will guide and govern the development and application of that science. And with so much genomic science and policy yet to be written, even minor developments produce outsized effects, which makes the potential consequences of the Border Agency’s project so worrisome.

To illustrate this point consider an editorial published this month in the journal Nature Biotechnology which argues that a greater balance is needed in the policy discussion surrounding the use and availability of genomic data; one that acknowledges the benefits and societal importance of such data alongside its inherent risks:

On its own, the sequence of letters in a human genome is uninformative. Its power for good arises only from associations with medical histories, behavioral characteristics, physical descriptions and environmental influences. Likewise, its capacity for ill derives only from the genome’s potential for providing pointers to human qualities that serve as the basis for discrimination and defamation already prevalent in our societies—sex and sexual orientation, societally defined ‘race’, age, physical and mental health, aptitude or suitability for athleticism or employment, and eligibility for health, disability and life insurance.

No one doubts that there are risks. But thus far discussion of the risks has dominated the debate over the use of DNA data. It is time for the debate to refocus on the benefits of data availability.

The question that should be asked is not “How can things go wrong and how can we prevent that?” [Answer: “in a myriad of ways” and “only with a great deal of contortion”] but “What is a necessary goal and how can we achieve it?”

To the list of iniquitous uses we may now add “national origin.” By appropriating genomic technologies in a questionable attempt at border control, the Human Provenance project has shifted the conversation from a prospective discussion of risk avoidance and mitigation to a present debate over whether the Border Agency’s use of genomic and isotope data analysis is ethically or legally appropriate, let alone scientifically valid.

On the one hand, actual misuses of genomic data provide an important reminder that the risks associated with that data are not always hypothetical. Informed consent agreements, for example, often provide detailed lists of potential risks that attach to genomic data, but for seriously considering such risks there is likely no substitute for seeing the data actually misused.

At the same time, there is real reason to worry that highly publicized controversial uses of genomic data will result in reactionary and protective legal, regulatory or policy responses, quite possibly to the detriment of clearly legitimate uses of genomic data. Moreover, programs such as the Human Provenance project serve to refocus the discussion of genomic data policy away from the benefits of data availability—or at least the balanced “discussion of the risks to an individual with discussion of how an individual might benefit” that the Nature Biotechnology editorial proposes—to a discussion focused solely on the risks and dangers.

From the Genetic Information Nondiscrimination Act (GINA) in the United States to the EU’s Directive 95/46/EC on data protection to Germany’s recently enacted Human Genetic Examination Act, where governments have tackled the issue of genomic data availability and usage, the results to date have typically been restrictive and proscriptive. This is a trend that, if allowed to proceed unchecked, threatens the future of genomic research and one which many scientists and policymakers vigorously oppose.

Which is why it is so surprising and disappointing to see the United Kingdom—the same country whose House of Lords delivered, mere months ago, a potentially seminal report on genomic medicine that advocated patience, improved educational initiatives and a wait-and-see regulatory approach to many aspects of genomic data use and research (including with respect to DTC genetic testing regulation and genetic discrimination)—jump the gun with a project as misguided and unscientific as the Human Provenance program.

As the Nature Biotechnology editorial concludes, “when it comes to exploring the basis of being human and moving toward the goal of genomic medicine, society needs to do more to provide personal incentives to those who choose to disclose their data, despite the risks.” A worthy and much needed call. But by evidencing such a lack of understanding of or respect for genomic data, the Human Provenance program thrusts the risks of genomic data—particularly its misuse by those in positions of authority—back into the spotlight and casts a deep shadow over the substantial benefits of improving genomic data availability.

The coming weeks will likely see further focus on the details of the Human Provenance pilot project, and we hope that the project is quickly brought in line with scientific realities and rendered consistent with important ethical, legal and social principles. But over the longer term we hope that in responding to this unfortunate example of genomic data usage, legislators hold in check their tendencies toward paternalism and genetic exceptionalism and that law- and policy-makers continue to advance a pragmatic and measured discussion that recognizes equally both the risks and benefits of genomic data availability and that leaves open a path for genomic research and personalized medicine to move forward.