British researcher Stuart Hogarth is consulting test developers and service providers interested in generating high-quality analytical or clinical data, offering these in a socially responsible manner,  and harmonising their product or service with expectations by regulators. BioWorld Europe asked Mr. Hogarth to provide backgrounds to current debates on who should get access to his genetic make-up, and who controls this access - the doctor, the DNA-entrepreneur, the patient, or the citizen irrespective of a pathological condiiton.

Your research focuses on the evaluation and regulation of genetic tests for common complex diseases across several regions of the globe. What do diverse regulatory debates have in common? 

In this work, which was funded by the Wellcome Trust, we compared regulatory structures that govern the evaluation of genetic test looking at Europe and the United States, also to a certain extent Canada and Australia. And the core issue has been: How do we ensure that doctors and patients have good quality evaluative data or new tests to ensure that they can make informed decisions about whether or not to use the tests. In other words to ensure that when they get test results, these are both accurate and doctors as well as patients can understand the meanings of the test results.

How does doctors' use of genetic information vary across different national healthcare systems in Europe?

The presence of a well established clinical genetic speciality significantly influences who does genetic testing. In other countries, for instance in Spain, which does not have a well developed clinical speciality, there is a much wider range of doctors who are ordering genetic tests.

French-German IntegraGen sells its SNP test to any physician ordering the service. Does each of these buyers fully know how to interpret the clinical validity of the gene test?

With regard to mature health systems like the UK, how do doctors use available genome information?

We're still in the very, very early stages of a kind of wider diffusion of genetic testing through the medical profession. Doctors outside clinical genetics may from time to time order a small number of tests such as Factor V Leiden for thrombosis. Then there are familial cancers like breast cancer. But there has been significant investment by the government in the last five years to enhance the use.

What hinders translation of genetic knowledge into benefits tangible to more individuals?

The first barrier is the complexity of the underlying biology which for polygenic diseases historically has been difficult for scientists to unravel. Clearly, what we've seen in the last year with the new wave of genome-wide association studies, with faster and cheaper sequencing, and the HapMap project, there are far more robust, well replicated gene-disease associations in this area. However, most common diseases are caused by gene-environment and gene-gene interactions we don't understand and that it will take us a long time to unravel. The polygenic nature of common diseases means that in most cases a single gene will not be associated with a clinically significant risk. Secondly, even with robust well replicated associations between genes and diseases most public health experts and clinicians believe we need a lot more data before we can actually turn these basic gene-disease associations into clinically useful tests and persuade reimbursors and healthcare systems and clinicians professionally to take up genetic testing. So the barriers we see are essentially around the economic incentives that companies have to generate that kind of clinical data.

The diagnostics industry hinders translation?

Our analysis suggests that in general they have not tended to invest large amounts of money into clinical studies to demonstrate the clinical validity and clinical utility of new biomarkers. Historically, the diagnostics industry has been a high volume, low profit, low margin business, where companies have invested in platform technologies. So, really the traditional in vitro diagnostics industry, which genetic testing is part of, is not structured in such a way to overcome that particular barrier.

Are there differences between Europe and the US?

These are significant. The regulatory system for medical devices which includes in vitro diagnostic tests is far more well established in the United States. Since 1976 they have a clearly defined system. In Europe the IVD Directive came into force only in about 2003 in individual member states. Hitherto there were a few European Member States that had their own kind of laws governing diagnostic tests, but it was very patchy. So, in Europe we really have been through a transition period in the last few years, whereas the situation in the US is much more mature.
But having said that, there are significant gaps in the US regulatory system. In the past the Food and Drug Administration has not treated what they now term 'laboratory developed tests', also known as 'inhouse' or 'homebrew tests'. These tests have been largely exempt from FDA scrutiny and, of course, most genetic tests are laboratory developed tests. They are not test kits and in general are not subjected to pre-market review by regulators in the US. Neither do we have premarket review in Europe, but for very different reasons. Here genetic tests are classified as low risk, in fact nearly all diagnostic tests are classified low risk which is also unique compared to the US, Australia and Canada. Now, that situation may well change in the next couple of years, because the IVD Directive is going to be revised and risk classification is one of the issues that the regulator is going to be looking at.

LifeCode offers gene testing to doctors and citizens alike. Like deCODE this company draws from extensive experience in genomic sequencing

Direct-to-consumer genetic testing is a topic -

Obviously this is the place where testing for common complex diseases is really taking off. One of the striking things is that this is really the first time we are seeing a situation where new tests don't first go through a process of being used by doctors and then very slowly and gradually filtering down into something that's turned into a kit you can buy over the counter or through an internet laboratory service. What we are seeing in genetics is: There is a gene discovery and the next week it's turned into a test a consumer can buy over the internet. And that to me, that's an innovation in terms of how you actually develop a market for a new test, but that's an unproven business model as well.

Hasn't that been the case with other technologies in history?

Patients have always managed in some way their own health, taking temperature or blood pressure, monitoring weight. And of course there are people with chronic conditions such as diabetes who are encouraged constantly monitor their condition themselves. I mean it's a growing market. What's distinctive in the genetics field is new tests are not well established tests where one said: We know what its significance says. We understand its predictive value and its utility. Now we are familiar with it. Now we can think about it offering direct to consumer. This was the traditional process by which a test ended up available direct to consumer. And then the other thing that's different is of course the imbalance between an unmediated consumer transaction and the type of clinical encounter that is promoted as best practice by clinical geneticist who place an incredibly high value on in-depth, non directional pre- and post-test counselling. This in many ways obviously stands in stark contrast to the idea you could buy a test by clicking a button in the internet. I think the challenge for clinical geneticists and indeed for policy-makers has been to say, how important is that clinical practice? To what extent should it apply to all genetic tests, or are there ways in which some genetic tests maybe need less pre- and post test counselling than others, don't need to be kind of handled with quite the same sensitivity and might be more appropriate to be available in a direct to consumer kind of mode of delivery. We've seen that concern about consumer testing in the past, I mean most obvious examples were pregnancy test kits when they first came on the market and also HIV testing.

The number of human geneticists to meet counselling demand is small compared to other medical specialties. Did you also look into conflicting regulations in the field of genetic testing - regulations governing one medical specialty and not applying to another one?

It's certainly the case if you look across Europe. A whole number of pieces of legislation have been put in place to govern genetic testing in different countries. In some cases effectively it creates a monopoly for a small number of geneticists to provide genetic testing, and clearly the way in which genetics is now leaving the clinic and becoming part and parcel gradually of more routine medical practice is going to challenge the model whereby genetic testing is restricted to a small kind of specialists. So, I don't think we can really sustain that model in the face of an increasing number of tests for common diseases that might be ordered by family doctors, an increasing number of pharmacogenetic tests for instance oncologists want to order. I think there is a very real tension there.

With regard to direct to consumer testing do you see any benefits from individualized genotyping?

We might be able to identify patients with significantly higher risk of diseases like heart disease. This is something that the medical profession considers important. The danger comes in when you just identify people who have very small additional risks. People will be unduly alarmed of what really isn't something to concern themselves about. However if you can combine those genes for a given disease, then you may be able to identify a small group of people who are significantly increased risk and may then benefit from increased monitoring or some kind of other preventive action. The issue then is this process of actually finding the way to identify the people at significantly higher risk, the kind of elevated risk that would justify some kind of increased intervention and where this is really be of assistance.