Still patently unclear?

Way back in January I launched this blog with the news that I had just discovered that 23andme had filed for a patent on polymorphsisms relating to Parkinson’s Disease (see Patently Unclear). In that post I asked various questions about where this patent might fit in their efforts to find a way to make money out of consumer genomics and whether 23andme could reconcile that commercial drive with their intent to “democratise” genomics. I suggested that the company’s lack of public comment on their patent application was at odds with their democratic ambitions (and also at odds with public comments by co-founder Linda Avey on the evils of gene patenting). Well, now 23andme have finally gone public – they announced on Monday 28 May that they expected the patent to be issued the following day. The announcement (posted in the name of company co-founder Anne Wojcicki), is on their coroporate blog The Spitoon. It has already attracted one hostile comment from a customer and it will be interesting to see how the debate now develops. In the meantime, I have posted my own comment (which is still awaiting moderation), but you can read it here:

Dear Anne
As you acknowledge in your post, gene patenting is not without controversy. Certainly my experience suggests that this is an issue which attracts much attention – I blogged on your patent application way back in January and that post remains by far and away the most visited page on the Gene Values site.

The first comment on your post (from Arturo) clearly illustrates that your customer base may not be happy about your decision to file for this patent. In response you state that the patent was filed in order to facilitate work on a treatment for Parkinson’s and that 23andme “will not prevent individuals from getting access to information or prevent researchers from researching the target.” However, your patent application was wider than therapeutic applications covering risk prediction, diagnosis and prognosis. I have a number of questions:

1) If your intent was only to support therapeutic R&D then why does the patent cover diagnostic applications?

2) Will you try to prevent other companies selling Parkinson’s Disease tests for these polymorphisms, or, will you seek license fees from other companies selling Parkinson’s Disease tests for these polymorphisms?

3) Given your company’s avowed mission to “democratise genomics”, what were the participants in the Parkinson’s Disease study told about the intended commercial exploitation of discoveries arising from the study, and did you ask them what their preferences were?

4) Given the controversy surrounding gene patenting why have you not invited discussion and debate on this issue?

If, as you frequently avow, 23andme wants to “democratise genomics”, then this is the kind of issue on which you should be seeking feedback from your customers and the broader polity. It’s not a very sophisticated definition, but my understanding of what a democracy should be is a system where everyone has their say, and where what they say counts for something. Trying to reconcile that with a corporate system of decision-making may prove as challenging as trying develop a sustainable business model for consumer genomics but if you really want to democratise genomics (rather than just commodifying it), then that is the task you face.

Best wishes
Stuart Hogarth

Governing biomedical innovation

My colleague Brian Salter and I have a comment piece on the BioNews website today, in which we discuss the move by the UK government to establish a new advisory committee for emerging biomedical science. We pose a number of questions about the remit and scope of the new committee and conclude by suggesting that emerging science is not the only source of governance challenges in the sphere of biomedical innovation – established technologies also create policy problems, a point exemplified by the recent PIP breast implant scandal.

Viral marketing and genomic consumers

The previous post on this blog took issue with the view (expressed by a UK government advisory committee) that we are witnessing a “genomic revolution”. Paul Martin and I suggested instead that what we are witnessing is in fact a gradual process of incremental and additive change entirely consistent with the general trend in diagnostics innovation in the twentieth century.

In this post I want to elaborate on that view by way of commenting on a couple of things – a new report on personalised medicine from United Healthcare and an interview with Matt Posard, Illumina’s senior VP for Translational and Consumer Genomics.

The viral marketing of personalised medicine?
The United Healthcare report is a very useful piece of research because it puts hard figures on the hype surrounding personalised medicine. The most interesting part of the document is the data on trends in testing, the volumes of tests used, the costs associated with that volume, all broken down by test type. The report uses three categories: infectious diseases, cancer and inherited conditions/other. For me, the major take-home from these figures is the confirmation that in terms of test volume (defined in the report as number of test procedures per 1,000 UnitedHealthcare members) the big growth area for the molecular diagnostics industry has not been the applications which have been attracting the greatest headlines (and the largest amount of ELSI research) i.e. companion diagnostics, susceptibility testing and rare disease genetics. Infectious disease testing far outstrips these applications.

In other words, the molecular diagnostics industry enjoys its status as the fastest growing sector of the diagnostics industry because it has found a quicker, cheaper and more accurate way of diagnosing infectious disease than traditional pathology techniques – thus far the viral (or microbial) genome has outpaced the human genome in the space of clinical practice. Since the report cites 1% growth rates for cancer testing but 9% growth rates for infectious disease testing and for inherited conditions/other testing, this is a gap which is likely to grow rather than diminish. The smart money (and when I say money, I mean public and private investment) should be on that continuing to be the case for some time to come, not least because of the huge growth potential for DNA-based infectious disease testing in some of the rising powers such as Brazil and India.

What, you might ask, has this got to do with personalised medicine? Are patients suffering from infectious diseases now being stratified according to the genetic profile of their infection? The answer for the most part is no. There are exceptions, such as Hepatitis C where treatment selection is guided in part by viral genotype (but for the limitations of this approach see section 4.7 of a recent UK guideline) and HPV testing, which discriminates between low and high-risk strains of HPV (but, as noted in a previous post, in cervical cancer screening cytology remains the primary diagnostic modality not DNA testing). So for the most part the only strain is the mental effort required to try and fit DNA-based infectious disease testing into our common understanding of what personalised medicine might mean. We need to be very careful not to bundle infectious disease testing together with other categories of testing to put a global figure on the growth in personalised medicine. This is a move which would grossly exaggerate how significant the field is now and how quickly it is likely to grow. Personalised medicine, understood as the use of genomic (or proteomic/metabolomic) data to stratify the care of patients, remains a niche market and is likely to remain so for some time to come.

So has DNA-based infectious disease testing got anything to do with personalised medicine? This type of application has provided molecular diagnostics companies with a large and (relatively) risk-free market allowing them to develop platform technologies which generate revenue streams which in turn can help to support investment in higher-risk applications like pharmacogenetics. Infectious disease testing is also an application which is likely to drive investment in point-of-care molecular diagnostics, which, again might pave the way for innovation in areas like companion diagnostics where turnaround time is cited as one issue deterring clinical uptake. So there are important interconnections, but those do not mean that DNA-based infectious disease testing is personalised medicine and we should not collapse the two when putting together statistics about the growth of personalised medicine.

Illumina – redefining the consumer in consumer genomics
The other type of hype which I want to address in this (lengthy) post are two linked ideas: the proposition that consumers are going to drive growth in personalised medicine by demanding access to their personal genomes; and the idea that in the future we will all have our genomes sequenced. I have argued elsewhere that the direct-to-consumer genetics business model is unproven and that many companies have moved away from it because it is unlikely to prove profitable, and my last post (with Paul Martin) questioned the vision of a future where we all have our genome sequences lodged in the healthcare system ready for accessing every time a doctor needs to treat us. These issues are illuminated (no pun intended) by the GenomeWeb publication Clinical Sequencing News which this week carries an interview with Matt Posard of Illumina, the industry leader in genome sequencing technologies.

Like Affymetrix (the microarray company it has begun to overshadow) Illumina has moved into clinical applications. Some years ago Affy set up a CLIA-certified lab but they subsequently sold it to Navigenics; it remains to be seen whether Illumina manage the transition from research tools manufacturer to clinical service provider with greater success.

The Posard interview is interesting because it reveals the caution and conservatism with which Illumina is approaching this space. In key respects this is a case of business as usual, not a revolution in healthcare. For instance for Illumina, the consumer is not a member of the public but a doctor or pathologist:

“The mission really is to enable genomics-based healthcare. The way we intend to do that is not just look at what we sell as an instrument and a set of consumables, but [also] the report that a physician is going to look at. So our primary customer, if you will, is going to be clinical geneticists as well as pathologists because it’s those groups that will ultimately sign off on the report.”

Posard does envisage some kind of consumer market for the general public, but its limits are revealing: “If it’s someone that’s struggling with an undiagnosed disease, it’s always going to go through a physician, without question.” That is a statement which sits uneasily with the heady rhetoric which demands unmediated access to the genome as a fundamental right. It moves the terrain of discussion onto the ground where I would suggest most stakeholders, including most of the industry, sit: some things can be sold DTC, other things should be ordered through a physician. Deciding where to draw the line provokes disagreement, but the need for a line has broad support, not least because the unfettered market would be one in which industry bore significant risks, as Posard makes clear:

“The risk or the responsibility that’s on Illumina and the other providers is [that], when somebody is exploring their own genome, they will find markers that have risk predisposition for different diseases. Making sure those results are provided responsibly and, in some cases, with professional counseling or support to help that individual through that information is the responsibility of the provider of those products.”

My colleague Michael Hopkins wrote a few years ago about the issue of commercial risk management in the genomics industry and his paper remains highly salient.[1] Michael was also lead author on a highly influential paper called “The Myth of the Biotech Revolution” which countered biotech hype with a sober assessment of the scale and pace of change in the biopharmaceutical industry.[2] The Posard interview is similarly revealing for his caution about how quickly genome sequencing will become a routine part of patient care. He begins with the classic figure of five years down the line, a timespan frequently invoked by those who promote expectations around genomic technologies. But Posard ascribes that optimistic vision to other commentators; he is rather more pessimistic in the timeline he envisages: “I think for my children and their generation, particularly, for them and for their kids, clinical sequencing and whole-genome [sequencing] are going to become standard of care.”

Given that Illumina are fighting off a takeover bid by Roche, the politics of expectations management are probably even more complicated than usual in this case. Nevertheless, it is a strikingly pessimistic assessment of the pace of change. Posard makes a series of comments, about the need to demonstrate clinical utility, and to have technologies which work within the clinical laboratory setting, which demonstrate a keen awareness that the rapid pace of technological progress in sequencing technology is moving on a timeline quite different to those which govern the clinical adoption of new diagnostics.

This acceptance that gene-sequencing must come to an accommodation with the challenges of the existing diagnostics innovation system, is reflected in Posard’s view of the FDA. He suggests that NGS products will transform the regulatory paradigm but he also explains that regulatory approval by FDA is central to Illumina’s move into clinical applications: “Our diagnostic business unit is in routine discussions with the FDA to ensure that we get the proper labels for the various products that we’ve been talking about,” Posard says, and he suggests that, in large part, products like the MiSeq platform can be accommodated within the current regulatory system.

What we see then, is the same tension which Paul Martin and I highlighted in the report from the Human Genomics Strategy Group: a transformative vision of a future in which we will all have our genomes sequenced is at odds with a more pragmatic acceptance of the need to demonstrate clinical utility and the need to work within existing paradigms, whether it be FDA approval or physician-led (rather than consumer-driven) healthcare. How are these to be reconciled? For many proponents of the genomic revolution, the mechanism which now appears to be favoured is a collapse of the distinction between research and clinical practice. Only when we have turned the entire population into genomic research subjects, it is argued, will we have sufficient data to reveal the latent utility of clinical sequencing. This is a solution which raises as many questions as it might hope to answer, pushing the question of clinical utility downstream whilst bringing to the fore equally intractable issues of public trust in the management of data privacy and the handling of unexpected findings of unknown clinical significance. But that is a discussion for another post.

[1] Hopkins, M.M. & Nightingale, P., 2006. Strategic risk management using complementary assets: Organizational capabilities and the commercialization of human genetic testing in the UK. Research Policy, 35(3), 355-374
[2] Hopkins, M.M. et al. (2007) The myth of the biotech revolution: An assessment of technological, clinical and organisational change. Research Policy, 36(4), 566-589

The myth of the genomic revolution

The following piece has just appeared on the BioNews website, co-authored with my colleague Paul Martin, who is Professor in Science and Technology Studies at the University of Nottingham.

‘Building on our inheritance: Genomic technology in healthcare’ is the latest in a long line of reports that have sought to assess the potential of genomic medicine and to outline how policy can best support its development.

The report, published by the Department of Health’s Human Genomics Strategy Group, is focused on the use of different forms of testing to stratify disease as a means of guiding clinical care. In the longer term the report advocates the routine use of whole genome sequencing as the bedrock for nearly all areas of biomedicine.

There is much to be welcomed in the report. It rightly points to the broad range of tests which are now beginning to find their way into clinical practice and it illustrates how some of these are already benefiting patient care. The report makes important points about the need for a framework for evaluating new tests before they enter routine clinical practice and identifies key areas where translation of basic science into clinically useful technologies and practices might occur.

However, in its enthusiasm for continuing heavy investment in genomics, it may be in danger of overselling what it claims will be ‘a revolution in healthcare’ (p14). The report describes genomic medicine as a ‘major step-change in medical practice’, but history suggests that diagnostic innovation is incremental and additive, not revolutionary. There is no reason to suppose that this is about to change. Whilst molecular diagnostics are having a growing impact in medical practice, the scale and pace of change thus far does not suggest a fundamental transformation is underway. The example of testing for the human papilloma virus (HPV) in cervical cancer screening (cited in chapter three) perfectly illustrates that point. In the USA it has not replaced cytology-based screening, it is used as an additional screen or to investigate borderline cytology results (incidentally, HPV testing is presented as a recent advance but it has been a standard of care in the USA for over a decade) (1).

Another instance of overselling in the report’s vision statement (chapter one) is a serious overstatement of the current utility of testing for risk of common, complex disease. The truth is that few strongly predictive genetic markers for common complex disease have been found and, for the most part, at the moment we can do no more than tell people that they are at slightly higher than average risk or slightly lower than average risk – information which makes little difference to the kind of disease prevention strategies we should all be following (healthy diet, moderate alcohol intake, regular exercise etc.).

The report’s overenthusiasm creates a fundamental tension between the authors’ call for more systematic and rigorous evaluation of the evidence supporting the use of new diagnostic tests and their argument for the adoption of routine genome sequencing. The report suggests that once an individual has their genome sequenced, then that data will be used to guide ‘every clinical decision’ about the person, even if that data has only ‘a small relevance’ to a given clinical decision (p54). The assumption is that the incremental benefit of using genomic data in a variety of clinical contexts over the course of an individual’s life will justify the cost of sequencing. This argument flies in the face of the report’s detailed case for a rigorous and robust framework for introducing new diagnostic tests into the NHS. Rather than assuming that we should apply genomic data in any and every clinical situation, what we need are rigorous, well-powered studies which investigate the utility of specific testing applications in particular diseases or clinical contexts. These kinds of trials are expensive and there is little likelihood that the private sector will pay for them, so the onus will fall on government to support those efforts that bring maximum benefit to public health. We have to assume that, as with trials of pharmaceuticals, there will be a high failure rate and that progress will be slow.

There is no doubt that genomics will have a growing impact on healthcare; the scale and pace of that impact remains a matter of conjecture. We can predict with confidence that genome sequencing will continue to become cheaper and faster, but this rapid technological progress should not blind us to the complexity of diagnostic innovation and the challenge of establishing clinical utility for new tests. No matter how cheap genomic data becomes, cost cannot be allowed to trump clinical relevance.

1) S Hogarth, M Hopkins and V Rodriguez, ‘A molecular monopoly? HPV testing, the Pap smear and the molecularisation of cervical cancer screening in the USA’. Sociology of Health and Illness | 25 November 2011

Patently unclear – 23andme’s position on DNA patenting

Today I have been preparing a talk about personal genomics for a workshop in Edinburgh next month where I plan to discuss the tension between democratisation and commodification in the nascent consumer genomics sector. In a rather haphazard  bit of Google searching I was rather surprised to come across a patent application filed in November 2010 by the US consumer genomics firm 23andme. The patent relates to genes associated with Parkinson’s Disease, or to be more precise, and to quote from the patent application:

“The present invention is related to polymorphisms associated with Parkinson’s disease. More specifically, the invention is related to compositions, methods and for use in therapeutic and preventative treatment, study, diagnosis and prognosis of Parkinson’s disease.”

The diagnostic portion of the patent would appear to be fairly broad, covering risk prediction, diagnosis and prognosis using SNP analysis or gene expression data. (I am neither a scientist nor a patent lawyer and would welcome comment from those more qualified on the precise scope of the application). The current application supercedes earlier applications filed by the company in November 2009 and June 2010. Followers of the company will recall that 23andme had announced the discovery of new genes associated with Parkinson’s Disease having undertaken their first clinical research study in 2009-10, and the patent application would appear to be concerned with these novel discoveries.

The patent again raises two questions which I have long pondered: can you make money out of consumer genomics, and if so how, do you do it? Not long after launching their company in 2007, 23andme CEO and co-founder Anne Wojcicki was
quoted on the VentureBeat blog
expressing uncertainty about their business model:

“It’s really too early to specify how we might monetize and derive value from the information we’re aggregating. We’ve thought about a lot of different ways to monetize it, but we’re not ready to talk about them”

One division within the nascent consumer genomics industry has been on the issue of intellectual property derived from original research. Some companies, like deCODE, have spent years (and much money) on research uncovering new gene-disease associations which they have then patented. Others, like Navigenics, have trawled the scientific literature sifting through other people’s discoveries for genes which it might be useful to test for. 23andme seemed to be more in this camp – they talked a lot about the research value of their embryonic customer biobank when they launched, but it was unclear what they were going to do with the data, and the vast majority of the gene-disease associations they report to their customers have come from the scientific literature. The company’s decision to begin testing for the BRCA 1/2 genes in 2009, in apparent contravention of Myriad Genetics fiercely defended patents on the genes, suggested that their philosophy was provocatively open source in its attitude to the human genome.

A hostility to gene patents was certainly expressed by Linda Avey, one of the company’s founders, when we talked after a meeting at the European Parliament in Brussels in March 2009. Avey subsequently commented publicly on the topic in her blog a couple of times the following year (after her departure from 23andme). After attending an industry meeting in March 2010 she expressed her distaste for Myriad Genetics in no uncertain terms, saying their business model “made my skin crawl … the thought that a company is profiting so handsomely from intellectual property that corners the market on information simply residing in the human genome is unfathomable “ Unsurprisingly, Avey saw a fundamental conflict between Myriad’s approach and the business model of the company she had co-founded: “As individuals are able to access their entire genetic profile, and all the increasingly pertinent health information therein, the math just won’t work if gene variants, along with the inherent knowledge regarding disease or pharmacogenetic associations, are patented.”

A few months later on Dan Macarthur’s Genetic Futures blog, Avey commented on the 2010 ruling against Myriad’s patents:

“My hope is that this ruling stands and companies will need to actually innovate and create new advances BASED on genetic findings, not dependent on sole access to them. Rather than relying on obscure patent language and legal strategies, companies will need to develop products that are competitively positioned, something that will be good for consumers i.e. patients. With all due respect to the legal profession, we need to have more scientists and innovators in the lab, not lawyers.”

Given the apparent hostility to gene patents expressed by one of the company’s founders, 23andme’s Parkinson’s Disease patent application raises a number of questions, not least did Linda Avey resign in protest because of plans to file the first application in 2009? Had the company always intended to patent its gene-disease discoveries, and if so why was it not explicit about its plans? Given the company’s avowed mission to ‘democratise’ genomics, what were the participants in the Parkinson’s Disease study told about the intended commercial exploitation of discoveries arising from the study, and did anyone ask them what their preferences were?

Of course it may well be that 23andme is in fact committed to open source genomics and their patent application is simply designed to prevent other less well-intentioned actors from patenting their discoveries and then blocking their free use. But in the absence of public discussion of this topic by the company we are left with uncertainty as to their intent. 23andme proudly proclaim that their mission is “to be the world’s trusted source of personal genetic information.” That ambition sits uneasily with the lack of transparency in the company’s approach to intellectual property rights. In 2007 the company was not ready to talk publicly about the ways in which they might derive commercial value from their customer database, five years later that discussion is long overdue.