The ACLU, Working for the Man

By Kevin E. Noonan --

The ACLU championed its efforts in the AMP v. Myriad case as being another instance of the group fighting for the rights of the many and the powerless against corporate America and the oligarchical few.  In a paradox, it now seems that the fruits of their efforts are to have empowered just those whom it has traditionally opposed, and that the question of whether personalized medicine will become widely available is in the hands of insurance companies and large diagnostic testing providers (who traditionally have not needed to rely on patent protection in view of their economic clout).

To better appreciate the irony it is useful to compare the history of the most successful personalized medicine effort to date, Myriad's BRCA gene tests for breast and ovarian cancer, with an alternative history premised on the Supreme Court's Myriad decision being rendered 10-15 years earlier that it was.  Absent the prohibitions produced by the Myriad decision, Myriad had its patent exclusivity to rely upon in building its BRCA gene testing business.  This began in 1997, three years before the announcement of the results of the Human Genome Project.  At that time, genetic testing was in its infancy, and at best BRCA gene testing was considered "experimental":  Myriad did not have anything other than genealogical data showing an association of genetic variants in the descendants of women who had dies of breast cancer, and had identified a few dozen specific variants.  The reliability of the testing could also be reasonably brought into question because Myriad detected several "variants of unknown significance" (VUS), where the genetic sequence identified in a particular patient was different from the "typical" genetic sequence, but there was insufficient genealogical information.  In addition, women having the BRCA gene mutation who suffer from breast or ovarian cancer are a small subset of the totality of breast or ovarian cancer sufferers, with frequencies in line with other diseases having a heritable genetic propensity.

Into this situation came Myriad, who armed with its patent exclusivity was able to obtain investors who permitted it to grow the business of testing women for the genetic mutations that indicated a high likelihood of developing cancer.  (It should also be appreciated that the increased risk of breast or ovarian cancer for women bearing a BRCA gene mutation is much higher than is the case for other cancers, making this an anomaly for genetic diagnostic tests.)  The investment was not only in laboratories, lab technicians and supplies; Myriad had to enlist a nationwide network of genetic counselors to provide women with the information they would need should their test indicate a propensity (~90%) for developing breast or ovarian cancer, as well as educating ob/gyn doctors about the test.  While the latter can be discounted as marketing, Myriad also had to take on public and private insurers to have them pay for the test, and this needed to be done on a state-by-state basis.  Indeed, acceptance of Myriad's BRCA test as being significantly reliable as to deserve coverage varied from state to state over the past 18 years since Myriad's BRCA gene patents were obtained.

None of this was (solely) altruism, of course; Myriad was running a business.  But whether society benefited from Myriad's efforts can best be considered by comparison to that alternative history, where Myriad did not have exclusivity over BRCA gene tests.

This history can be predicated on an earlier enunciation of the Supreme Court's decision, or more easily by presuming that Mary Claire King or other researchers cloned the BRCA genes before Myriad and, as they have stated did not protect the genes or diagnostic methods by patenting.  Under this scenario the gene sequences would have been freely available to anyone, particularly university and academic medical centers, such as New York University (where Dr. Harry Ostrer, one of the named plaintiffs in the Myriad case, was practicing) or the University of Pennsylvania (where other plaintiffs, Drs. Kazakian and Ganguly were working), as well as commercial entities.  However, without patent exclusivity, the only commercial concerns capable of providing the service would have been unlikely to entertain the possibility, due in part to the high hurdles and costs associated with garnering acceptance from payors at that time.  (Myriad didn't have a choice because BRCA testing for breast and ovarian cancer was a core business.)

Under these circumstances the role of providing genetic testing would likely have fallen to academic sources.  This raises a few problems regarding the goal of making such testing broadly available and affordable.  The first is geographic:  while residents of cities and other locations that are the sites of major medical centers would likely have had access to BRCA gene testing it is less likely that less geographically accessible areas would have had such access.  Women residing in and around Boston, or New Haven, or New York, or Philadelphia, or Washington, or Atlanta, or Dallas, or Houston, or San Diego, or Los Angeles, or San Francisco, or Portland, or Seattle, or Denver, or Rochester (MN), or Madison (WI), or Chicago, or Detroit, or Cleveland, or Buffalo, or Cincinnati, or Pittsburgh or St. Louis would have access.  But women in Appalachia, or the Four Corners region of the Southwest, or rural Idaho, or Montana, or Arkansas or the Dakotas, would need the kind of outreach Myriad provided -- is it reasonable to expect any of the hospitals in metropolitan areas far from these more remote (and typically impoverished) regions of the country?

Perhaps more fundamentally, is genetic diagnostic testing as performed by Myriad the best use of academic medical facilities?  Academic medicine, like most academic pursuits is involved in discovering causes of disease and developing new treatments.  It is also not well adapted to the type of rote performance of thousands or millions of tests under circumstances where no errors are tolerated.  It is hard to contemplate university or medical center counsel being comfortable with academic or even clinical labs performing such tests; inevitably, any such testing would come in conflict (for resources, personnel, lab space) with the traditional purpose of such labs and testing, being ancillary to providing optimal patient care.  And this is as it should be:  patients look to these hospitals and the physicians populating them as being primarily concerned with helping them get well (while acknowledging the reality that finances and in some cases profit enter into the equation).

But if the goal is the widest proliferation of diagnostic genetic testing then the question is, what is the best way to accomplish it.  The idea that academic research and medicine will be able to do so is a fantasy for at least the reasons set forth above; more importantly, such researchers are best utilized in identifying the genetic causes of disease.  Thus, the question comes down to whether small, academic-based start-up biotech and diagnostic companies or larger, more corporate diagnostic testing labs will monopolize the space.  As the Myriad example illustrates, start-ups must have reliable patent protection in order to establish the protocols, networks, and reimbursement infrastructure needed to sustain such a business, while the larger diagnostic companies do not.  The economic advantages these larger companies have will typically be enough for them to out-compete a startup, even one with better understanding of the science and technology.  This is true upon inspection:  for the startup one or a few genetic tests may be the only product they have to sell, while larger, more established diagnostic testing labs have a much larger product list (and much longer history with diagnostic customers) to sustain them while they adapt to a disruptive new technology like genomic testing.

Even with this economic clout success is not certain, because part of the impetus for startup companies such as Myriad to aggressively advocate for payors to reimburse patients for the testing stem from the reality that this is usually the only way such companies will survive.  Larger companies have far less motivation for new technology (think Xerox/IBM vs. Microsoft/Apple) even if there is perceived profit in it.  One example of this situation is reflected in a paper in Genetics in Medicine from the American College of Medical Genetics and Genomics published February 25, 2015.  In this paper, the College provides a policy statement, arguing that payors should be willing to reimburse genetic testing costs even when the effects of these tests on clinical outcome in unclear:

Clinical utility for genetic tests was discussed in 1998 by the US Task Force on Genetic Testing.  The Task Force specifically stated that "the development of tests to predict future disease often precedes the development of interventions to prevent, ameliorate, or cure that disease in those born with genotypes that increase the risk of disease.  Even during this therapeutic gap, benefits might accrue from testing.  "http://www.genome.gov/10001733.  In the broadest sense, "clinical utility" refers to the likelihood that a given intervention (in this case, genetic information) will lead to an improved health outcome (http://www.phgfoundation.org/tutorials/clinicalUtility/) or to whether a test can provide information about diagnosis, treatment, management, or prevention of a disease that will be helpful to a consumer.  http://ghr.nlm.nih.gov/handbook/testing/validtest.  Establishing an etiological diagnosis is generally asserted to no longer be sufficient to claim clinical utility.  Further, evidence that physicians change their management of a patient based on an etiological diagnosis is said to lack clinical utility unless clinical outcomes research has demonstrated that such changes in an individual's treatment will result in benefit.  http://www.palmettogba.com/palmetto/moldx.nsf/MolDX_Manual.pdf.  Moreover, coverage decision-making policy is now driven by a narrowed perspective that clinical benefit accrues only to the individual receiving the services.  [emphasis added]

The College disagrees with this "narrow view" that only tests directly related to improved clinical outcomes should be recompensed.  The article expresses the view that such testing should be considered for its "effects on diagnostic or therapeutic management, implications for prognosis, health and psychological benefits to patients and their relatives, and economic impact on health-care systems."  Examples include those familiar to anyone who has taken Myriad's BRCA test:  not only the benefit of an individual knowing her genetic status, but how that knowledge impacts the likelihood that her relatives will also have the test and know their risk (something for which Myriad charged much less than the widely reported $3,000-4,000 for the BRCA gene test).  "Current models" of these benefits "define utility as either (i) clinical benefit specific to the individual receiving the service or (ii) "personal" benefit because it applies to other family members or because the result may suggest interventions that are less well defined.  Grosse & Khoury, 2006, "What is the clinical utility of genetic testing?," Genet Med 8:448–450; Robson et al., 2010, American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28:893–901.  This paradigm "frames the utility of genetic and genomic information too narrowly and fails to acknowledge that information regarding significant genetic risks can enable highly actionable -- indeed, life-saving -- interventions for individuals and their family members," according to the College.  Further:

As genetic and genomic information increasingly enables disease prevention and reproductive planning, a narrow focus on medical benefit only to the individual originally tested and diagnosed is apparent as a construct of an obsolete system in which care is provided only to those with overt disease and that clinical benefit can be achieved only when a therapeutic option (i.e., a drug) is available.

Contrary to the predictions of the ACLU and many on its side of the debate, the Myriad decision has not led to an idyllic world of genetic diagnostics (an outcome aided by the Court's other decision negatively affecting the competitive position of startup companies, Mayo v. Prometheus).  It will be instructive to see how BRCA gene testing progresses in the aftermath of Myriad "giving up the ghost" on its efforts to maintain a modicum of exclusivity with the Federal Circuit's invalidation of many of Myriad's remaining genetic testing claims.  Many companies, including some large diagnostic testing labs, have entered these waters, but it is too soon to know how reimbursement, costs and accessibility are affected.

There is one way that a small company can maintain its exclusivity which forms Myriad's only remaining competitive advantage.  Taking advantage of being the "first mover" in this space, Myriad has accumulated a large database of undisclosed "variants of unknown significance" (VUS) in the BRCA genes, the significance of which is not unknown to Myriad.  Thus, even now an ob/gyn is faced with the quandary of advising a patient to have the "Brand X" test (which may be cheaper although how much cheaper is an unanswered question) or the Myriad test.  If the patient has a widely known BRCA gene mutation all is well (for the physician), because she now knows how to advise her patient.  If, on the other hand, the patient's genetic report contains one or several VUS's then the only responsible course would be to have the patient's sample retested (or at least reevaluated).  Any benefits accruing from having the test available from parties other than Myriad thus evaporates.

Of course the larger companies have the same capacity and perhaps even moreso, which leads to the possibility that such companies will simply avail themselves of this model and keep all diagnostic testing information to themselves.  In either case, the final result of the ACLU's overheated efforts will be that large corporate entities will "own" your DNA, and there will be nothing anyone can do about it.  Which is something of a paradox, if not amounting to an irony.

Comments

[Dan Feigelson]

Haven't finished reading this yet, but this has got to be a typo: "In addition, women who suffer from breast or ovarian cancer are a small subset of the totality of breast or ovarian cancer sufferers, with frequencies in line with other diseases having a heritable genetic propensity."

[Kevin E. Noonan]

No, Dan, actually the vast majority of ductal adenocarcinomas of the breast have nothing to do with BRCA. It is only the small number of women who inherit the mutant gene who have this propensity - but it is rather dramatic, seeing as it increases the frequency of breast cancer from ~9% in the population at large to ~90% in those women.

[Kevin E. Noonan]

From the NCI (http://www.cancer.gov/cancertopics/genetics/brca-fact-sheet):

Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers (1) and about 5 to 10 percent of all breast cancers (2). In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall (3). Breast cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than sporadic breast cancers.

[Kevin E. Noonan]

My "back of the envelope" math says the frequency is about 90/10,000 breast cancer sufferers, which would be much lower if calculated with regard to all women.

But if you have better statistics (or are better at math) let me know.

Thanks for the comment

[Dan Feigelson]

Kevin, it appears you meant to write "In addition, women who *have the BRCA gene who* suffer from breast or ovarian cancer are a small subset of the totality of breast or ovarian cancer sufferers, with frequencies in line with other diseases having a heritable genetic propensity." That would make sense. But it's not what you wrote.

[Jytdog]

that's an interesting thought experiment, Kevin, but it goes all circular in the end. Myriad had patent protection and built up their var database and... has kept it secret. Having a patent or not having a patent seems to have no correlation with building up trade secrets as a competitive advantage.

would be more instructive to compare with the realworld scenario of CFTR... i don't know the answer to this, but what is the state of public knowledge about vars there?

[Kevin E. Noonan]

Dear Jytdog:

I agree that both models can produce the same outcome, but the difference is that in the Myriad model the patent needs to enable/describe sufficient number of mutations to support the claims. BRCA may be an anomaly insofar as there are so many VUS in these genes that (it turns out) actually have some significance. Not necessarily the case - for example, there could be a great deal of nucleotide variability in other genes that don't translate to changes in the encoded protein's amino acid sequence.

CFTR is the other end of the spectrum, as I understand it - most cases of cystic fibrosis are linked to a deletion of a specific phenylalanine (Phe) residue at a particular position. And sickle cell anemia is associated with a mutation that changes an amino acid (from Glu ->Val I think) at a specific position in the beta-globin chain.

The point is that the way the world may work after Myriad is to encourage nondisclosure, and if that is the case Progress will not be Promoted.

Thanks for the comment

[Bob Cook-Deegan]

Kevin,

Extremely useful post. You won't be surprised that I interpret the history somewhat differently. I agree with many of your points, but at crucial junctions diverge in my conclusions in this intriguing counterfactual, asking "what if" history were different and current doctrine had prevailed in 1997-1998 when the crucial patents were granted. The patent incentive was important in this story, and rights that are too weak will indeed reduce private R&D for molecular diagnostics.

A couple quick points. First, there are actually 1900 mutations in the CFTR gene, and while the delta-F508 deletion is the most common, there are hundreds of disease-associated mutations, the reason that sequence-based tests are becoming the clinical norm. So it's not as much a contrast as might seem at first.

Second, there's no doubt at all that the sequence to BRCA1 would have been discovered within months if there were not Myriad or Utah team. The patent incentive did bring private R&D into the game, and for BRCA1, Myriad/Utah discovered the gene itself first. And for BRCA2, my reading is they came in a close second. But even before their patent was ever published, there were 9 other labs offering BRCA tests. So it is demonstrably the case that the patent disclosure was not necessary in this case to develop a test (or any other we have studied, including HFE--the other gene first discovered by a company, studying hemochromatosis). The publications that were already out, independent of patents, were sufficient. This is not an argument for or against patents, but it is very clear evidence that the patent disclosure was not technically necessary.

Your questions about whether folks living beyond the vicinity of academic health centers with molecular labs would have access don't have to be merely rhetorical. Most genetic tests are available to them, because Ambry, GeneDx, Invitae, and other commercial labs, as well as some major academic labs (Mayo, Penn, Baylor, UWash, UMichigan) also have FedEx service similar to Myriad's. Would this more diffuse testing framework have promoted the test and boosted awareness as strongly? Probably not. Would the other players have run direct-to-consumer ads? Almost certainly not. Is that good or bad? Hard to know. Is coverage and reimbursement better because of Myriad's efforts? Almost surely it is indeed better, because Myriad was strongly motivated, and that did indeed benefit patients. Put that in the plus column for social benefit.

The role of patents in the construction of the database is clear. In the US, Myriad had a service monopoly from around 1998 or 1999 until 2013. And it's great they collected the data, and the service monopoly means that the data were centralized. Had Myriad continued to share its data past 2004, the data could have been pooled with results from all over the world (Myriad did not establish dominance in any market outside the US, despite strong patent protection in many jurisdictions, because enforcement would have been difficult or futile). But starting Nov 2004, the data became proprietary, and so the patent exclusivity was leveraged into data exclusivity, since the million tests were done in the US (and to my knowledge, there is nothing illegal about this). My main point here, however, is that mutations whose interpretation became possible after Nov 2004 became public only when Myriad published or patented, and both are woefully incomplete. So patents ironically have led to more trade secrecy rather than less.

So the pros and cons are hard to think through, and I don't think it's actually possible to reach a decisive "what if history were different" conclusion.

Do you have a pdf or docx version of this? I'll respond at greater length offline.

[Simon Elliott]

This reminds me of 23andMe.

With Myriad, it was the ACLU and the courts trying to make things better for the public by killing off “bad” patents.. With 23andMe, it was the FDA “protecting” consumers from offering genetic tests without expensive genetic counselling. Result is that 23andMe stopped offering services. If the FDA had stepped in earlier, there never would have been the company.

23andMe is also relevant to understanding the role of Myriad in shaking up diagnostics.

Lots of academic medical centers and pathology companies offer genetic diagnosis. But they did so only in the context of a pre-existing medical relationship, and charged big fees for each individual test. There was no motivation to change this highly profitable model, and it didn’t change.

23andMe shook that up: direct to consumer testing of a number of genes for a given product, and at a huge discount to the competition. Of course, it could only do that because it relied on the huge $$ and access to computing power that comes from being married to a Google founder.

This model is popular in Silicon Valley. Elon Musk went from Paypal to SpaceX to Tesla. Steve Jobs started media companies. Google is into everything. Virgin went from representing the Sex Pistols all the way to airlines. Of course, this is not a new model: See Henry Ford, and any Gilded Age tycoon. Absent patents, the only way to have disruptive change is for a rich entrepreneur shake thing up. Too bad for the rest of us who don’t have a few billion lying around.

So, if we don't have patents to shake things up, we are left with (a) the status quo of giant monopolies and oligopolies, (b) visionary plutocrats (c) government regulators. I'd say that patents are the way to go for so many reasons. People might say that I am self interested. That true, but why don't people see (a)-(c) as equally self interested?

[Skeptical]

Simon,

Perhaps because "the people" you are referencing (those who climb onto the soapboxes) are:

a) the puppets of Big Corp
b) the lemmings of Big Corp
c) have anti-property leanings and don't care that the end result is more power to Big Corp

(by the way, I like your grasp of history)

[Simon Elliott]

Skeptical: I forgot law professors, journalists and politicians! They get noticed and promoted by being controversial and shaking things up, and/or by attracting patrons, but like to believe that they are neutral arbiters and disinterested.

[Skeptical]

Simon,

I do not wish to insult, but such Pollyanna desire for disinterest and a position of neutrality is I daresay foolish, if not downright dangerous.

For many a good reason, I sign myself...

[crelboyne]

Raising CFTR is helpful in at least one respect, Jytdog. Ambry picked up ACLU's mantle in dragging Myriad specifically and patent-holders generally through the mud and decrying the evil practice of aggregating genetic variant databases as something only money-grubbing patent holders do. Turns out Ambry has and actively promotes its for-profit genetic testing services based on its own CFTR variant database. From http://www.ambrygen.com/tests/cystic-fibrosis-testing :

"Founded in 1999, Ambry Genetics was the first commercial laboratory to offer clinical genetic testing for cystic fibrosis using gene sequencing technology. Since then, Ambry has analyzed the complete CF gene (CFTR) for more than 35,000 patients. As a result, Ambry has the most robust single-laboratory database in the world from which to accurately and carefully interpret patient results. Due to CFTR’s large size and the wide genetic heterogeneity seen in CF, this powerful database is highly valuable to clinicians."