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Why Does a UK Geneticist Think PGx Expectations are Overblown?

Name: Paul Martin
Position: Deputy director of the Institute for the Study of Genetics, Biorisks and Society, University of Nottingham, UK, 2001 — the present
Background: Research fellow at the University of Sussex, 1994 — 2001
Education: PhD, Science and Technology Studies, University of Sussex, 1998

Last year the UK’s Pharmacy Practice Research Trust and the Royal Pharmaceutical Society of Great Britain commissioned a team of researchers at the Institute for the Study of Genetics, Biorisks, and Society to investigate the status of personalize medicine and other healthcare developments.
In July, Paul Martin and colleagues at the ISGBS released their findings, which suggest that current hopes for the speedy adoption of genetic testing, gene-based drugs, stem cells, and gene therapy are overblown.
Martin will follow it up next month with a paper making similar judgments about pharmacogenomics.
Pharmacogenomics Reporter spoke with Martin this week to get his take on the uptake of personalized medicine.
What are your conclusions about pharmacogenomics?
Our observations would be based on following the industry, and talking to clinicians and looking at the regulatory regime. [They] are several-fold. Firstly, there are a number of tests coming through the pipeline, in development, or in fact on the market — we identified, for the earlier study, nearly 50 tests at various stages either in research or development — but very few of those so far are being formally approved by regulatory authorities.
Obviously, that’s starting to change — things like [Genomic Health’s] Oncotype Dx being pretty successful, a number of the CYP DME testing assays and kits and services that are mainly being used by big pharma companies. So, they’re sort of well established.
And there are a small number of tests for other drug metabolizing enzymes — TPMT and things like that.
When we looked at the survey of what’s in the pipeline, what was interesting was — several things. A number of companies have tests that are nominally on the market, but they tend to be for research uses only — they’ve not got formal regulatory approval — that’s the first thing. The number of tests actually getting formal regulatory approval is relatively small. A lot of the tests are available, for example those CYP tests — we identified about a dozen tests by different companies — are mainly for research marketplace only, in terms of also being relevant to big pharma companies’ internal drug-development pipelines, and looking at genotyping clinical trial participants, things like that.
So the number of tests coming down the pipe is quite small. Secondly, the uptake of those tests, where they are available, is very patchy. So, for example, the TPMT test, is also a biochemical test in the UK. Biochemical assays tend to be used in preference to a DNA test — there’s a sort of debate about whether to switch to a DNA test at the moment, or not.
But there are big issues about clinical utility. So, even with the cytochrome tests, or whatever, it’s not clear how they will be used in clinical settings, because mainly the clinical evidence base is still yet to be fully established.
The things like warfarin — there’s a prospective study of PGx testing for warfarin at the moment funded by Department of Health in [the United Kingdom], and that may create an evidence base. But at the moment, I’d say one of the key issues for pharmacogenetic testing is the need to create that clinical evidence base. And that’s going to take time.
I suppose the bottom line with our report was that we’re not saying these aren’t necessarily going to happen, but they’re not going to happen nearly as quickly as people think. And that isn’t because the technology platforms aren’t there, or even that you might have some sort of initial gene-disease, drug response-gene association — it’s that you haven’t got the clinical evidence base that means that practitioners will take those tests up into practice. I think that’s the sort of bottom line.
We identified all these tests — some of which will see the light of day, some of which have got regulatory approval, some of which will fall by the wayside — but the key thing is that even when you’ve got those tests, they won’t necessarily be adopted very quickly because there is a lack of evidence.
Wouldn’t their presence on the market establish an evidence base? Or are large studies like that warfarin effort necessary?
I think the two things go hand-in-hand. The one thing that you’ve actually got is that a number of these tests are on the market, but they’re not being taken up, they’re not being bought. Now, the situation in the US is slightly different, because of the way reimbursement works — so it’s hard for me to talk and generalize in terms about that. Obviously, the Oncotype test looks like it’s being quite successful, although its regulatory status is still in negotiation formally with the FDA.
But it looks like clinicians can see a clinical utility — there’s been enough — there have been a few publications looking at the value of this test in clinical context. And so, it looks like there is some utility there being demonstrated by that test, in terms of predicting who’s going to respond or not respond to chemotherapy.
So, I think that getting the tests out there is good. I’m not saying that all of those tests would have to have formal regulatory approval. I think the key issue is how do you move from having technologies that might work to ones that are proven to work in the clinic?
I think that’s the big problem — you could call it a ‘translational gap’ or whatever. A lot of biotech companies can get their products on the market, but unless they can show utility, then they’re not going to be sold.
Whose expectations are going to be dashed?
I suppose policymakers — certainly in the UK — have had reasonably high expectations for so-called personalized medicine coming down the track quicker.
How quickly did they expect it?
A few years ago in the UK, there was the NHS Genetics White Paper, published in 2003. Personalized medicine was the central motif, the central theme of that, and while there wasn’t a certain timeframe put on that — I think people were talking five years or things like that — what’s happened in recent years is that people are starting to backpedal and saying, ‘Look, this is going to take five, ten, fifteen, twenty years before you see these things widely adopted.
I think the other set of people whose expectations may not be realized are investors. Investors are a very mixed bunch — some venture capitalists, they know the name of the game, that you want to get an IPO, then they don’t worry too much about it afterwards. But I suppose some people have been, in the past, hyping parts of the pharmacogenetic industry as a sort of way forward.
One of the things we’ve shown in this sub-study that you’ve not seen, but will be available very soon — is a very high turnover, a very high attrition rate in the industry. A lot of PGx firms are founded, and then after a few years, they are either acquired or they disappear, and another set of firms are created.

So you’ve a sort of churn in the industry as a result of this difficulty in establishing commercially viable markets in those firms. The time frame, I think lots of people now will say, ‘We always knew it was going to take a long time’ — I think there’s a certain amount of rewriting of history there. Though I think there’s a lot more realism around now. Nonetheless, anybody who’s working on a commercial return over a five-year period is going to find it tough in this area.

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