Issues and Obstacles
Therein lies one of the biggest challenges. “Physicians are taught to learn a catalog of diseases and a repertoire of treatment for those diseases, but what we’re finding now is that when you ascribe a diagnosis, you’re moving away from that repertoire and trying to individualize therapy from a pharmaceutical perspective. It’s believed that we have benefited from this model,” explains Dr. Neil.
Klaus Lindpaintner, M.D., Ph.D., Roche distinguished scientist and vp, research head, Roche Genetics and Roche Center for Medical Genomics, F. Hoffmann-La Roche (www.roche.com), says that the main problem is naïveté about the likelihood of finding sufficiently informative markers that can ethically and cost-effectively be deployed in medical practice and that are based on properly conducted prospective clinical trial results.
“So far only HER2 seems to fulfill these criteria,” says Dr. Lindpaintner. “A typical example for how not to do it is a test for DPYD and TYMS to allegedly curb Fluorouracil (5-FU) toxicity where, despite some plausible arguments being put forward, there is no supporting data.
“In fact, we have unpublished data to the contrary. Using this test may well end up in unwarranted denial of a life-saving medicine to cancer patients. The issues hardest to reconcile are doing the appropriate prospective, controlled, replicate trials to define the actual product profile of a test and examine whether it lives up to the desired target product profile.”
Dr. White agrees. “We need more telling examples in addition to HER2. Right now there are molecular diagnoses that can be made for leukemia, but the classification is used as a clinical treatment. This isn’t very effective because often more information is needed before you can properly prescribe a treatment.”
“What we’ve learned is that the marketplace needs more evidence to establish value for personalized medicine. At the same time, this is a field that is still in the very early stages and it needs more time to establish itself,” adds Peer Schatz, CEO of Qiagen (www.quiagen.com).
One of the biggest issues that Vose sees is the ability to identify patient populations. “You need to see linkage between molecular targets and the disease; there are healthcare demands that require an instantaneous response, and these are the things we agonize about.”
“If you’re talking about monoclonal antibodies, or some small molecules, that’s the driver to a lot of drug discovery right now,” notes Vose, “but the uncertainty involved in the hypothesis of prediction may mean that it’s not possible to develop the therapeutic and diagnostic in the same timeframe.” The biomarker remains a question. One example Vose mentions is that EGF kinase-receptor expression was once incorrectly labeled as the predictor of response.
Tom Miller, managing board member of Siemens Medical Solutions (www.siemens.com), says that an absolute convergence of diagnostic testing, devices, drugs, and information will be required to bring new medicines to market. “In fact, the entire cycle of medical discovery and care standards definition, from bench to bedside, will have to change with diagnostic tests to identify relevant patient sub-populations being developed in lock-step with new pharmaceuticals becoming the norm,” he reports.
“Pharma will have to radically change its development paradigm as it cannot afford to spend as much to develop new drugs that will only drive a much smaller future revenue.”
Perceptions of pharma, Dr. Neil thinks, are also problematic. “It’s expensive to develop drugs, and it isn’t easy recouping that investment,” says Dr. Neil.
“It’s easy to say that pharma is reluctant to go the personalized medicine route because it will threaten the pharma blockbuster model, but the reality is that our knowledge and the technology of personalized medicine is still in its infancy. We see great opportunity for more efficient drug development and new paradigms of funding related to outcomes rather than just selling pills. We don’t want to create a medicine that is effective only 40 percent of the time. We want every patient who can benefit to get the appropriate therapy and none who will not benefit.”
Dr. White sees peer-reviewed publications, and the resulting FDA applications for diagnostic kits that can reference these publications, as a strong aid to test registration. “You can’t underestimate the role of peer-reviewed publications and the clinical utility they associate with testing,” notes Dr. White. “The agency is open to approving, fairly rapidly, tests whose clinical utility is already accepted. Peer-reviewed papers were critical in gaining clearance for two deep vein thrombosis tests and one for irinotecan toxicity, and also helped ease the clinical trial requirements.”
Dr. White says that the ability for companies to do retrospective analysis of biomarkers in consented samples from previous prospective trials cuts out time that would otherwise be spent performing a new prospective study and waiting for clinical outcomes. “Access to the Framingham Heart Study and other big government studies such as the Women’s Health Initiative study on hormone replacement could be very useful for smaller companies to demonstrate the clinical utility of new diagnostic markers for heart disease.”