“Personalised medicine is here and now: it is not right to say it has a long way, or a short way, to go,” says Lawrence Lesko, director of the FDA’s Office of Clinical Pharmacology. “It is a continuously evolving paradigm shift in the way medicine is practiced.” The eventual goal in Lesco’s view is to find the optimal dose with the fewest side effects, using genetic information.
This would be a significant advance, given the generally-held estimate that drugs work in only half the people who take them. And it is true that examples of real life applications of personalised medicine are growing.
In the past couple years, the FDA has approved a genetic test to help doctors more accurately dose patients and altered some drug labels, to reflect differences in how individuals respond to drugs.
In addition, pharmacy benefit management companies such as Medco and CVS Caremark are starting to test patients for genetic variations. And late last year, the Georgetown Lombardi Comprehensive Cancer Center said it has had positive results in testing a microchip that searches for 1,256 mutations in 170 genes, used to tailor a patient’s therapy based on their genetic makeup.
Meanwhile, the cost of personal genome sequencing is falling. One of the leading equipment suppliers, Illumina Inc has promised to bring the cost per sequence down to $28,000 this year. Knome Inc., a Cambridge, MA, spin-off from Harvard Medical School currently charges upwards of $100,000 to sequence and carry out the analysis of a personal genome.
Lesko told Science|Business that personalised medicine describes how gene sequence data can be used to more precisely improve the overall health of a patient. Some genetic markers are prognostic and associated with the risk of getting a disease, or the rate of disease progression. Others are predictive and associated with identifying subgroups of patients who have higher probabilities of responding favorably or unfavorably to a drug.
While the number of innovative drugs approved by the FDA in 2007 was the lowest in 15 years, there was a marked growth in the number of regulatory submissions with genomic information from 2008 to 2009, Lesko noted in a speech at Ohio State University’s College of Pharmacology last year.
The Personalized Medicine Coalition, an independent nonprofit group, said in a recent report that over the past three years, the number of prominent examples of personalised medicine treatments and diagnostics has increased from 13 products (69 percent of which are for cancer) to 37 products (56 percent for cancer).
Return on investment a question
The healthcare industry may be able to demonstrate clinical value, but to date it has had a problem demonstrating the economic benefits of new technologies and treatments. Personalised medicine is likely to face the same, or even greater challenges because of its disruptive effect on current markets, according to a study published last year by the consultants Deloitte.
The study, “The ROI for Targeted Therapies: A Strategic Perspective,” looked at the value of personalised medicine over multiple years and across different stakeholders to assess the barriers and incentives for its adoption.
It concluded genetic analyses will benefit individual patients, and there is downstream benefit for payers and prescribers of more effective treatments.
But, the report notes, at present “Standard practices in discovering, approving, and administering drug therapies are based on entire disease populations, rather than on subgroups within those populations. This fundamental difference between current and potential practice presents challenges to the current health care business model, and varying economic and clinical benefits and barriers for stakeholders.”
In other words, payers may not see a return on investment for six years or more, and drug companies focused on “blockbuster” products would need to make major paradigm shifts to make a business out of individual targeted therapies.
Genetic test for warfarin
A recent example of personalised medicine in which the FDA was involved is the relabelling of the blood-thinner warfarin (Coumadin). In 2007, the Agency approved a label change and marketing of a genetic test to help physicians assess whether a patient may be sensitive to warfarin, which is used to prevent potentially fatal blood clots. Warfarin is the second most common drug, after insulin, implicated in emergency room visits for adverse drug events.
About one-third of patients receiving warfarin metabolise it differently and thus have a higher risk of bleeding. This has been linked to variants of two genes, CYP2C9 and VKORC1. The Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test approved by the FDA detects some variants of both genes, and is to be used along with a doctor’s evaluation.
“[This] action offers physicians the first FDA-cleared genetic test for warfarin sensitivity, which is another step in our commitment to personalised medicine,” Daniel Schultz, the former director of the FDA’s Center for Devices and Radiological Health, said when the test was approved. “With this test, physicians may be able to use genetic information along with other clinical information to treat their patients.”
The FDA said it cleared the test based on results of a study conducted by the manufacturer of hundreds of DNA samples as well as on a broad range of published literature.
The FDA also approved updated labelling for Coumadin, a brand name version of warfarin, explaining that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. It should be noted that as yet the FDA does not require that patients have the test before being prescribed warfarin. Manufacturers of generic warfarin added similar information to their labelling.
Such genotype tests can help minimise or eliminate the uncertainties of dosing, according to Shiew-Mei Huang, deputy director of the FDA’s Office of Clinical Pharmacology. “If evidence is available to support the safety and effectiveness of the drug only in selected subgroups of the larger population with a disease, the labelling should describe the evidence and identify specific tests needed for selection and monitoring of patients who need the drug,” Huang told an Academy of Managed Care Pharmacy meeting last year.
Chips seek cancer variations
At Georgetown Lombardi Comprehensive Cancer Center, pharmacogenetics researcher John Deeken is testing a new tool called DMET (drug-metabolizing enzymes and transporters), which promises to open up the future applications of personalised medicine in treating cancer.
The system looks for variations in drug absorption, distribution, metabolism and excretion. “Available genotyping tools test only a few genes at a time,” Deeken said when his research was published last December. “With the new chip, as many as 170 genes can be examined for more than a thousand variations.”
This type of turnkey testing, if validated, could eventually replace highly-specialised, time-consuming and labour-intensive testing, allowing more institutes to pursue genotyping and pharmacogenetic research.
“That alone would be a significant development for our field and for expediting the research many of us believe is the future of medicine,” Deeken said. Genetic variability in drug absorption, distribution, metabolism and excretion is not usually taken into account among patients in cancer clinical trials, and that can skew dosage amounts and doom an otherwise promising new drug, he said.
A simpler and faster test could be readily incorporated into treatment trials. Deeken said one of the main obstacles facing researchers like himself is the lack of a proven and relatively quick technology for genotyping. “DMET appears to offer great promise in this field as a reliable test unveiling genetic variations that correlated with drug effectiveness and toxicity. [It] isn’t yet ready for primetime in terms of having received FDA approval, but we’re getting closer.”
Deeken is a consultant to Sanofi-Aventis, the manufacturer of docetaxel, a drug used in the reported study. Three of the other study authors are employees of Affymetrix Inc., the manufacturer of the DMET platform. The study was done in part at the National Cancer Institute and supported by funding from the National Institutes of Health.
With healthcare reform on the way, and major changes in business dynamics needed by pharma and payers, the future growth of personalised medicine still is not known. What is known is that a growing body of scientific literature is supporting its benefit to patients, and some federal agencies are starting to respond.
As the FDA’s Huang says, the uncertainties about medical doses and outcomes must be decreased. More tests are being reimbursed by insurance, and research has thrown up examples where there is value in genetic testing, Huang said. “We should move from the present ‘trial and error’ to a more ‘educated prediction of individual dose.’”
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