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PGx Over-hyped, Large Studies of Field s Value Sorely Needed, Says UK Royal Society Researcher


Personalized medicine is "over-hyped" in the mind of the public and healthcare policy makers as a result of media reports, opined David Weatherall, co-author of a new report from the UK Royal Society on the subject, in an interview with Pharmacogenomics Reporter this week, echoing similar public comments Genzyme's Robert Yocher made about the US media. The US Food and Drug Administration's Larry Lesko warned in May against the possibility that over-exuberance could trip up the technology's adoption.

Weatherall, a University of Oxford professor of medicine and chair of the Royal Society working group that prepared Personalized Medicines: Hopes and Realities, said that unrealistic expectations about personalized medicine are "probably the central theme of the report," which was released last week, but he did not single out any particular instance of this undue exuberance. "The message is, 'Yeah, it's not with us now, but you've got to think now about some of the implications for this — who's going to be trained properly to be able to deal with this kind of complex information in the community?'" he said. The hype among UK healthcare policy makers has led to some unrealistic ideas of when genomic technologies can be adopted in healthcare, he added.

The potential of pharmacogenomics may only become apparent 15-20 years in the future, according to the Royal Society report. But the process that will bring the field into mainstream clinical practice involves nearly "drug-by-drug" analyses, including cost-effectiveness studies, of the value of any pharmacogenomic treatment, said Weatherall. In addition, different dynamics dictate the healthcare markets of the United Kingdom and the United States, so implementation of pharmacogenomics may move at a different pace on either side of the Atlantic.

"You've then got to take that drug into the community and do very careful studies of the value of that predictive genetic effect in a community setting. Now, the amazing thing to us was that it has never been done properly."

One goal of the report, which will go out to universities and policy-making bodies in the UK, is to spur changes in education, as well as in medicine, said Weatherall. "Education in genetics at undergraduate, postgraduate, and continuing medical education levels has trailed behind the enormous scientific and technical advances in this field," the report said. Clinicians seem to lag behind pharmacists and diagnostic scientists in understanding of genomics in the United States as well.

The report also calls for validation of both the efficacy and the economic value of pharmacogenomics — a challenging task, according to some observers. "Most of the personalized medicines stuff is serious hype, and runs contrary to the realities of validation," Mike Watson, director of the American College of Medical Genetics, told Pharmacogenomics Reporter. The field pushes for smaller and smaller groups of people in whom validity becomes increasingly difficult to achieve, he said.

"I wouldn't call it 'overhyped,'" Lesko, director of the FDA Office of Clinical Pharmacology and Biopharmaceuticals at the FDA's Center for Drug Evaluation and Research, told Pharmacogenomics Reporter. For about a decade, articles have not had target dates attached to personalized-medicine developments, and "I actually think that the field is moving forward in a way that is consistent with a new paradigm," he said. "I think those individuals that felt things are going to change overnight or in a five-year timeframe will conclude, at this point, that this has been overhyped, but my horizon is 30 or 40 years out."

In personalized medicine in general, real progress has been made in using genetic and molecular techniques to uncover and target the causes of disease, particularly in cancer, said Weatherall. However, progress in other common diseases, such as heart disease and diabetes, has progressed much more slowly, he said.

When personalized medicine attempts to link genetic analysis with drug dosages or toxicity, the subject becomes somewhat more difficult, Weatherall said. Some of the examples of genetic effects on drug response are very rare, and some drug effects respond to the products of several genes — including some genes having weak influences on drug response, he said. Also, "you've then got to take that drug into the community and do very careful studies of the value of that predictive genetic effect in a community setting."

That sort of analysis means evaluating factors such as drug efficacy and side effects in a large study, in which patient-to-patient dosage is difficult to control, and variables other than genotype can affect metabolism enzyme efficiency. "Now, the amazing thing to us was that it has never been done properly," Weatherall said.

However, a recent study on the drug warfarin by the University of Liverpool and partner institutions that includes 2,400 patients offers a good example of the kind of research needed, Weatherall said. "Our feeling was that — and I don't think there's a way around this — this will have to be done almost on a drug-by-drug basis to find out how valuable this [pharmacogenomic] approach is in the real world," he said. "So that's why we were cautious" in saying when personalized medicine would become a reality, he said.

Part of that weighing of options will involve cost-effectiveness research, which the Royal Society report mentions in several sections, but which is also fairly lacking. "I think there is only one study from [the United States] that has really analyzed cost-benefit analyses in this field, and they come to the conclusion that the data are almost non-existent," said Weatherall.

That study, by Phillips and Van Bebber, suggests that the limited data available on deep vein thrombosis, cancer, and viral infections indicate that pharmacogenomic therapies may be cost effective. Nevertheless, the Royal Society report concludes that "it is certainly too soon [for the Royal Society working group] to make any broad conclusions or recommendations about pharmacogenetic interventions."

As for what the report means for pharmacogenomics in the United States, it is important to note that the two countries' healthcare systems are subject to different constraints. "I don't think cost-effectiveness analyses will be the rate-limiting step in the United States," ACMG's Watson said. "I suspect it's a bit more laissez-faire here — people will access these things independently, depending on the nature of the drug."

"It's probably right to be sort-of fiscally responsible, to talk about cost-benefit analyses, but I think it can also set a high standard for the introduction of potentially valuable tests that would be counterproductive to advancing public health," Lesko said.

When comparing the two healthcare systems' advantages in pursuing general pharmacogenomics research, two important issues are the ease of conducting large population studies, and the ease of translating hard data into healthcare practice, said Weatherall. "As things stand at the moment, it's probably easier to do this kind of research [in the UK], although [the US has] got much more funding for the basic science and initial discovery, and I think they kind of complement each other, quite honestly," he said. Britain's government-administrated National Health Service is a part of the reason large, community-based studies, such as the University of Liverpool's warfarin study, are easier to conduct in that country, he added.

Related links:

Please find the Royal Society's Personalized Medicines: Hopes and Realities here.

Follow this link for the Nuffield Council on Bioethics 2003 report concerning the ethical issues of pharmacogenomics.

Articles on the Phillips and Van Bebber study of the state of cost-effectiveness research in pharmacogenomics appear in two issues. See here and here.

Follow this link to and article on the University of Liverpool warfarin study.

In the United States, large-scale pharmacogenomics research suffers from "the absence of good data-collection systems about genetics in general," said Watson. Some pharmacogenomic therapies are going to be practiced with enough patients to draw conclusions about the therapies' validity, but it will be difficult to capture significant data from small groups of patients without the appropriate information technology infrastructure, he said.

A part of the UK's leg up in this regard includes the centralization inherent in its National Health Service, which is spending "a vast amount of money on developing much more sophisticated on-line record systems, which would be required for this kind of thing in the future, if pharmacogenomics really took off," Weatherall said. The UK also has its BioBank, which should eventually house "hundreds of thousands" of patients' DNA, assuming the associated ethical issues can be settled, he added.

"So, yeah, there are advantages" of the NHS in personalized medicine, said Weatherall, who counts himself as a defender of the National Health Service. "I mean, don't get me on that subject, because the Health Service is creaking like hell at the moment, but as it stands for the moment, yes."

— Chris Womack ([email protected])

Summary of Recommendations of the Royal Society Report

1. "Funding [from government and industry] for well-designed studies in pharmacogenetics, probably from multiple sources, will be important to establish the relevance of pharmacogenetics to clinical practice."

2. "The provision of European tax incentives for ['orphan medicines'] is important, regulatory authorities will have to review continuously pharmacogenetic developments that are likely to segment the potential treatment population for conventional drugs."

3. "We recommend the establishment of an appropriate regulatory framework at a national and European level by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMEA) for the provision of pharmacogenetic tests to be used in the clinic."

4. "Regulators worldwide need to address the problems associated with the transmission, storage and processing of large amounts of complex pharmacogenetic data."

5. "We recommend the Department of Health, in conjunction with the International Conference on Harmonisation (ICH), review current guidelines and regulations for the conduct of genetic research across international borders [to harmonize clinical trials across international populations]."

6. "We endorse the recommendation of the World Health Organization that the introduction of simple DNA diagnostics for common genetic and infectious diseases in developing countries is vital (WHO 2002). […] The [UK] Medical Research Council and medical research charities should commission more research into the use of pharmacogenetics in developing countries, particularly for drugs for malaria, tuberculosis and HIV, and for assessing drug resistance in common parasites."

7. "Education in genetics at undergraduate, postgraduate and continuing medical education levels has trailed behind the enormous scientific and technical advances in this field."

8. "The newly created NHS Connecting for Health agency is establishing IT systems in the NHS to store a comprehensive record of the patient's history. As part of the programme, the Department of Health should consider carefully the research implications of these data, including pharmacogenetics research."

9. "The Department of Health should consider the support and safeguards for the genetic technology, the institutional culture into which pharmacogenetics is potentially delivered, how the technology shapes this environment, and the costs and feasibility of attempts to provide measures to mitigate these concerns. It should also address differences between the views of the public on issues such as access to information, and what is possible within the healthcare system."

10. "Guidance on the use of data in research needs specific consideration by Government, the NHS, and the newly established Human Tissues Authority. Guidelines should ensure that an ethical framework is in place which gives clarity to industrial and academic researchers for the creation of large databases of patients and the collection and use of tissue samples associated with them."

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