Full article reprinted from "The Gray Sheet" - June 30, 2008
Though the promise of personalized medicine has been widely touted, firms focusing on targeted therapies and companion diagnostics are not getting much bang for their buck - yet. Find out why not.
"The potential is there for more tailored and targeted therapies," said former FDA commissioner and CMS administrator Mark McClellan, now the director of the Brooking Institution's Engelberg Center for Health Care Reform. "But the number of products and the value of products coming out of the pipeline is far below what it's been in the past. The potential remains unfulfilled."
McClellan spoke June 20 about the need to build scientific evidence to support personalized medicine applications before a diverse audience of health care professionals and policymakers at a personalized medicine conference in Washington, D.C., hosted by the American Association for the Advancement of Science and the Food and Drug Law Institute.
So far, the actual impact of personalized medicine, and specifically pharmacogenetics-based therapies that predict a patient's response to drugs based on genetic information, has been limited, he said.
Companion Dx In Drug Label - Now What?
Last August, for example, FDA updated the labeling of the anti-clotting drug warfarin to include information about the usefulness of genetic testing, as specific gene variations are associated with lower tolerance for the medicine (1"The Gray Sheet" Aug. 20, 2007, p. 9).
That should have been a turning point for firms such as Nanosphere, whose Verigene warfarin genetic test kit was cleared in September 2007, and AutoGenomics, Nanogen, Third Wave Technologies and Luminex, who sell warfarin genetic marker reagents and are developing test kits.
Unfortunately, uptake of the tests has been tepid.
"At FDA it was a very big deal for us to overcome a lot of barriers to put that into the drug label and also for CDRH to have it in the labeling, but it's not used," commented Shiew-Mei Huang, deputy director of the Office of Clinical Pharmacology in FDA's Center for Drug Evaluation and Research. "It's developed, it's in the label and nobody's using it. I think we need to have [more] communication with health care providers."
The warfarin tests are struggling for several reasons, suggested Third Wave President and CEO Kevin T. Conroy. He says the new FDA labeling is not strong enough, and clinical guidelines do not incorporate warfarin testing.
"And there's not enough data," he concedes.
Third Wave - which is currently being acquired by Hologic for $580 million largely on the basis of its human papillomavirus testing technology pipeline - markets a companion diagnostic that tests response to the cancer drug Camptosar, the Invader UGT1A1 molecular assay, cleared in 2005. It also sells analyte specific reagents that detect variations in the Cytochrome P450 gene family, including the two variants associated with warfarin response.
Huang said CDER has approached insurance providers to find out why they are not covering the warfarin tests, and they respond that there is not sufficient evidence backing up the technology.
Steve Gutman, director of FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, agrees the scientific evidence supporting targeted therapies is simply not up to par.
"I don't think it's the damned regulation that's holding up the field," he said. "I actually don't even think it's the damned reimbursement, although it is problematic. I think it's the damned science."
The key to launching a successful companion test is pinpointing a specific link between an assay and a tangible application, McClellan and others at the meeting stressed.
"Diagnostics are not just for the sake of diagnostics anymore," Gutman said. "They can be used in the context of drug candidacy to improve development and to perhaps improve use."
Finley Austin, head of U.S. external research and innovation at drug and diagnostic firm Roche, says that it is crucial to have evidence validating not only the biomarker's and the assay's prognostic ability, which refers to its success in identifying likely clinical outcomes independent of therapy, but also its ability to predict response to therapy.
"That's what I'm thinking about when I'm developing a test and taking it to the FDA because if I don't have the appropriate trial data, then I'm going to get a prognostic claim in the label, only," she said at the AAAS/FDLI meeting.
"Aetna's then going to tell me, 'I don't want to pay for this because it's not changing anything. We already know these patients have a poor prognosis.' Without that predictive element to it ... you don't have a lot of value to offer to patients."
Roche Organically Links Drugs And Diagnostics
In the personalized medicine space, Roche is probably one of the best positioned to pursue side-by-side development of diagnostics paired with targeted drugs, particularly those that treat cancer (2"The Gray Sheet" Sept. 18, 2006, p. 14).
The firm is a leader in both pharma and diagnostics and has recently made several major acquisitions to augment its molecular diagnostics footprint, including a $272.5 million deal to acquire DNA microarray maker NimbleGen, the $140 million purchase of high-throughput DNA sequencing firm 454 Life Sciences and a $3.4 billion hostile takeover of tissue-based breast cancer test maker Ventana Medical Systems (3"The Gray Sheet" Jan. 28, 2008, p. 4).
Roche is also a prime example of a firm that has learned that biomarker tests without specific and predictive therapeutic claims do not sell.
The firm's AmpliChip CYP450 microarray test, which analyzes variations in two genes that play a role in the metabolism of about 15%-20% of drugs, was approved and launched in 2005 without a specific claim, says Walter Koch, head of research at Roche Molecular Diagnostics.
"FDA said these are valid biomarkers, they're used in drug development today and they impact so many drugs that they assumed physicians would understand how to apply it to a wide range of drugs," he told "The Gray Sheet." "As it turned out, it's been complicated for physicians to understand exactly how to employ it."
Koch says Roche got the message: "One needs to be much more specific in linking the diagnostic to a therapeutic decision."
The test is primarily used to identify patients who are not likely to respond to tamoxifen treatment for breast cancer. Roche is building the clinical evidence to seek that specific claim, Koch said.
Now, under a new research structure put in place last year, Roche restructured its global R&D model into five "disease biology areas" (Oncology, Central Nervous System, Metabolic, Inflammatory and Viral). The company assigned diagnostic liaison managers to work with each unit, bridging drug and diagnostic development.
To date, Roche has made its biggest strides in the oncology business, Koch said.
"Oncology is huge; we're just beginning to see the tip of the iceberg in this area," he said. "Our company, I think, is leading the way. By having both a diagnostic and a therapeutic company together under one roof, we can align the processes of research and development to assure that the tests are available during the clinical development program and, if the therapeutic is successful, that the diagnostic is there in time, at launch."
Roche's drug development programs include biomarker subset analyses from the start, and even before the drug is tested in humans, work is done in cell cultures to develop hypotheses that may later be tested in animal studies, he explained.
The diagnostic unit takes on a more formal role when the first-in-man, Phase I drug studies begin, Koch said. "The important thing is that we want to use a test in those early-phase clinical trials that is as close as possible to the final in vitro diagnostic so that we don't have to do a lot of cross-over validation with a changed assay."
It is this type of approach that personalized medicine supporters such as McClellan hope can spread to the broader health industry.
"If there are clearly demonstrated ways of getting safer and more effective treatment to patients - our policies may take a while to figure out, we may limp along ... but we will figure it out," he said. "It is a very challenging environment, but the potential payoff is tremendous."
- Jessica Bylander
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