After years of high, theoretical hopes, personalized medicine (PM) is finally gaining traction in clinical settings. PM is the application of an individual’s unique biological information-particularly genetic information-to predict, prevent, diagnose and treat disease. It is, in short, precision medicine, specific to an individual where traditional medicine can only generalize about large populations.
The development of PM makes clinical laboratories the central providers of patient-specific, actionable information that will guide physicians and other healthcare providers. A discussion of this critical role, stakeholders in the process and a vision for laboratory administration in light of this rapidly evolving and disruptive approach to healthcare will follow.
Healthcare Deployment
The rapid deployment of efficient healthcare services is enabled by three important disciplines and providers: laboratory medicine, medical imaging and the administrative delivery of those services. These three elements form a powerful combination for the evolution of personalized medicine.
The truth is that the practice of medicine has always been “personal” in that physicians treat individuals based on signs, symptoms and other diagnostic information obtained for that individual. What has revolutionized the concept of PM is the rapid process of taking medical discoveries from bench to bedside at a rate not previously experienced. All indications are that the services provided by clinical laboratories are central to the rapid evolution of that process.
The impact of the modern clinical laboratory in PM is enormous, impacted by data-driven improvements in four areas: drug response, diagnostic accuracy, efficiency in comparative effectiveness research (CER) and advanced computational informatics.
Predicting Drug Response
The ability to predict drug response has placed the clinical laboratory at the top of the decision-support path towards optimizing drug therapeutics. Traditionally, predicting response to a drug is based on observing results in large populations and applying those findings to individual patients. The new process relies heavily on test information that reliably informs the practitioner on how an individual patient will metabolize a specific drug or whether receptors for that drug are functional or unlikely to be responsive.
Although this concept was initially downplayed by many pharmaceutical companies, they have begun to realize that using companion diagnostics (i.e., the pairing of a drug and laboratory results) can improve the efficacy of their drugs. Not only has big pharma begun to embrace this idea, but so have regulatory agencies and, yes, even third party payers. For example, the FDA has required the placement of language in some drug labels suggesting use of molecular testing enhances efficacy of function. Details for more than 60 examples can be found on the FDA web site.1
To facilitate the application of companion diagnostics, new offshoots of Pharmacy Benefits Management (PBM) organizations are springing up. Medco and CVS Caremark, two of the largest PBMs, have started programs to enroll patients and their physicians in testing programs prior to use of certain medications, including clopidogrel2 and warfarin.3 (For full disclosure, our lab, PGXL, provides genetic testing for one of the most ambitious genetic benefits management programs.)
Molecular Diagnostics
The combination of biochemical findings such as molecular diagnostics and advanced imaging techniques (e.g., MRI, etc.) is enabling refined diagnosis. Diseases are increasingly described by their biochemical profiles and especially by lesions in molecular pathways that form a basis for targeted therapies. This approach increases diagnostic accuracy to enable more precisely targeted therapy and improve patient outcomes-a central requisite in harnessing the overall costs of healthcare.
One report indicates that patients who have had their genotype determined are less likely to require hospitalization associated with an adverse response to the oral anticoagulant warfarin,4 for example, and research is indicating that precision diagnostics decreases complications and increases effectiveness with other drugs as well.
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Evidence-based Medicine
Laboratory-based PM is also at the heart of Comparative Effectiveness Research (CER). Both government and private sector insurance companies are adopting evidence-based approaches to medical practice. Much of the talk has been to demonstrate efficacy of a treatment before covering the cost of that treatment, including laboratory services. Because this requires that laboratory tests be precise within a more closely defined and consistent range, the FDA is more closely regulating laboratory tests.
Evidence-based medicine requires multiple studies with large numbers of subjects to obtain statistically reliable information. To be effective, those studies need to stratify recruited subjects not just by demography, as is current practice, but also into categories based on genetic and molecular information. Not only is this critical in refining CER, but will also spur the development of clinical trials that define new molecular pathways based on responses to treatment.
This is very fertile ground for the advance of medicine, and the large portion of that work will be done not in the clinic, but in the lab, where tests will define subsets of populations and enable discovery of new disease-based molecular lesions and therapeutic targets.
Software Support
The final piece of the PM puzzle is the combination of computational informatics with molecular test results. Because of the millions of genetic and molecular variables that can come to bear on a given case, it is simply not possible for physicians to keep all of the necessary information and perform all of the necessary calculations in their minds. Their diagnostic and therapeutic decisions must be supported by software.
Consider, for example, two biomarkers relevant to anticoagulation therapy: CYP2C9 and VKOR.5 The global use of these two molecular markers to guide therapy is not without controversy. However, our research shows that combining the molecular markers with other relevant patient information in a way that can only be accomplished with an elaborate computer algorithm gives physicians the perspective medicine has previously lacked. (Another disclosure: PGXL has decision control software in clinical trials.) Armed with that information and perspective, physicians can prescribe warfarin in a way that reduces the risk of adverse drug reactions while speeding the desired therapeutic outcome.
The Lab’s Significance
To say that the laboratory is increasing significance in the following four areas-diagnosis, therapeutics, comparative effectiveness and informatics-is not to say that physicians are becoming less important. The ultimate diagnostic and therapeutic decisions will continue to be made by physicians and patients, weighing not just science but the needs of individuals.
But what is becoming clear is that laboratory medicine needs to step up to give physicians more tools and information that can be used at every point in the treatment process. The result of that will be a truly personalized form of medicine, i.e., precision medicine, from which we will all benefit.
Dr. Valdes is professor and senior vice-chairman, professor of Biochemistry and Molecular Biology and Distinguished University Scholar, Department of Pathology and Laboratory Medicine, University of Louisville. He is co-founder and chairman of PGXL Laboratory, a privately held specialty laboratory in Louisville, KY. Dr. Linder is associate professor, Department of Pathology and Laboratory Medicine, University of Louisville, assistant director of Clinical Chemistry and Toxicology, University of Louisville Hospital, and co-founder and Hesenior vice president for Operations, PGXL Laboratory.
References
1. http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm
2. http://www.mygenerationhealth.com
3. Epstein RS, Moyer TP, Aubert RE, O’Kane DJ, Xia F, Verbrugge RR, Gage BF and Teagarden JR. Warfarin genotyping reduces hospitalization rates. J Am Coll Cardiol 2010;55:2804-12.
4. Ibid.
5. Linder MW, Bon Homme M, Reynolds KK, Gage BF, Eby C, Silvestrov N and Valdes R Jr. Interactive Modeling for ongoing utility of Pharmacogenetic diagnostic testing: Application for Warfarin Therapy. Clin Chem 2009;55(10)1861-8.
