Pharmacoeconomics in the Era of Individualized Medicine

Clinical Pharmacology & Therapeutics (2008); 84, 2, 179–182 doi:10.1038/clpt.2008.142 Pharmacotherapy is recognized as the most cost-effective component of the clinical armamentarium. It encompasses ~10% of health costs, compared with hospital care and physician services, which represent 30% and 21%, respectively.1 This stands in striking juxtaposition to a health-care delivery system in economic crisis, in which costs in the United States alone exceeded $2 trillion in 2006, in contrast to $253 billion in 1980.1 The historically favorable cost–benefit relationship suggests an opportunity to improve health-care economics by shifting the emphasis in patient management from hospitalization to pharmacotherapy.1 However, drug costs also are escalating, and therapies that cost a few hundred dollars two decades ago have been replaced with drugs that can cost hundreds of thousands of dollars.2,3 Moreover, a crisis in drug development—whose success rate has declined from ~12% to ~7%, associated with an increase in development costs nearing $2 billion for each marketed drug—restricts the availability of new therapeutic agents.1 This confluence of crises in health care and drug development in the context of the aging population, associated with an increased demand on these systems, underscores the critical emergence and dynamic evolution of pharmacoeconomics, the modern discipline of health economics, which critically assesses the value of health therapeutic strategies. Pharmacoeconomic analyses encompass cost-minimization, cost-utility, cost-benefit, and cost-effectiveness studies, providing essential information critical for optimal health-care resource allocation and drug development success. Advances in molecular medicine have expanded diagnostic and therapeutic approaches, providing integrated management paradigms across the disease spectrum.4 As the science of individualized medicine matures, empiricism and the probabilistic underpinnings of medical practice are increasingly replaced by specific targeted diagnosis and treatments with mechanism-based deterministic precision. Information generated through innovative technology guides prescribing patterns and provides a foundation for a lifelong plan of wellness and health maintenance. This ongoing revolution in biomedicine has transformed our considerations of human health and disease, offering an attractive context for clinical pharmacology as the integrated science of discovery, translation, and application, and for the clinical pharmacologist a pivotal role as the link between the laboratory, patients, and populations.5,6 Innovations in molecular medicine have driven the emergence of therapeutic solutions across the dimensions of prevention, diagnosis, prognosis, prediction, cure, and regeneration in pursuit of personalized management.7 Reciprocally, molecular medicine has evolved as the vehicle for clinical application of the new biology and the translation of molecular insights into individualized evidence-based practice.8 Beyond discoveries of new diagnostic and therapeutic modalities, enabling molecular technologies provide tools with which to define the dynamics of disease initiation and progression, encompassing pathways for intervention.9 In this way, molecular medicine has been instrumental in advancing the identification of quantifiable measures predicting clinical outcomes, therapeutic efficacy, and idiosyncratic responses.7,8,9 It has provided a window on disease pathogenesis, defining the cadence of process alterations integrated at the level of systems that encompass mechanisms of disease spanning the continuum from risk burden to manifestation of overt disease.8 These insights provide a previously unachievable opportunity to recognize and interrupt the earliest stages of pathology, before the establishment of processes leading to irreversible morbidity. Breakthroughs in the science and technology of translational medicine and clinical care have driven co-evolution of all phases of drug and diagnostic development along the DDRU (discovery, development, regulation, and utilization) continuum.4 Current challenges in diagnostic and therapeutic management focus on honing specificity and reducing idiosyncrasy.4,7,8,9 Molecular medicine provides integrated diagnostic and therapeutic platforms tailored to the genetic profile of individuals to enhance specificity, reduce variability, and minimize adverse events.7,9,10 This individualization has transformed diagnostics and therapeutics across the DDRU continuum. Indeed, the capacity to identify molecular mechanisms of disease and their utility as therapeutic targets has revolutionized discovery. Molecular and genetic stratification of patients and disease processes provides new opportunities to improve success rates in drug development. Genetic and environmental contributions that regulate variability in the machinery defining pharmacokinetics and pharmacodynamics offer transformative insights into interindividual variability in drug toxicity. Moreover, the ability to define disease mechanisms at genetic and molecular levels enables optimal complementation of the patient, drug, and dose to faithfully personalize clinical care. Collectively, the accelerated identification of genes and molecular pathways provides personalized diagnostic and therapeutic solutions, prognostic discriminators of disease variability, and predictors of treatment response, redefining therapy and prevention at the level of individuals and, ultimately, populations.4,7,9,10 Indeed, the scientific and clinical progress inherent in the framework of individualized medicine has transformed diagnostics and therapeutics beyond single patients to global populations.11,12,13 This revolution must, however, entrain economic structures and policies to co-evolve and accommodate an equitable distribution of technological benefits to all members of society. That evolution is encompassed in part by the guiding principles of pharmacoeconomics and the validation of the added value to health care. Intuitively, there is an expectation that the personalization of medicine will provide one critical limb of an integrated social and political solution to the accelerating pharmacoeconomic burden of health care worldwide and the equitable distribution of its benefits without borders. In the context of individualized medicine, molecular and genetic profiles sort patients into categories based on pathobiological mechanisms, defining predictive biomarkers that identify patients at risk for fulminant disease and permit preventive intervention with the attendant economic benefit of reduced disease burden, improved quality of life, and extended productivity.14 Similarly, genetic categorization and disease stratification permits optimization of patient populations in critical-stage clinical trials, maximizing the likelihood of success of the development paradigm and the return on research investment.10 Further, genotyping and phenotyping identify individuals with variable pharmacokinetics, who are at greatest risk for adverse drug events and who most benefit from dose adjustment to optimize safety, reducing comorbidities and their associated costs related to one-size-fits-all therapeutic interventions.5 Moreover, predictive biomarkers subclassify patients, matching those most responsive to specific therapeutics, targeting limited economic resources where they will provide the greatest benefit.10 These previously unavailable technical and conceptual capabilities optimize diagnostics and therapeutics applied broadly across populations with inherent genetic and environmental variabilities; improve success rates in drug discovery and development, return on research and development investment, and therapeutic efficacy; and reduce idiosyncratic drug reactions, improving drug safety.8 Although these pharmacoeconomic considerations suggest that the economic benefits accruing from the new biology are nearly self-evident, there is potential for the individualization of patient care to add economic stress to an already overburdened health-care system. A case in point focuses on the application of molecular diagnostics to the staging of patients with cancer as a prognostic and predictive marker.15 For many tumors, metastasis to regional lymph nodes represents a clinicopathologic marker of lymphovascular dissemination of tumor cells beyond their primary location. Indeed, lymph node metastases are the single most important prognostic and predictive characteristic in individuals with solid tumors. Recurrence rates for patients with lymph nodes free of tumor deposits are more favorable than for those in whom metastases can be appreciated by histopathology. Beyond prognosis, the presence of tumor cells in lymph nodes predicts the responsiveness of patients who optimally benefit from chemotherapy. Importantly, failure rates subsequent to presumptively curative surgery in persons without obvious nodal tumor deposits imply the presence of occult metastases that escape detection by standard staging paradigms. Understaging probably reflects the convergence of restricted review of small lymph node volumes, which fails to map metastatic tumor cells as a result of sampling limitations, and the limited sensitivity of histopathology, which reliably detects only 1 cancer cell in about 200 normal cells. The prognostic and predictive importance of tumor cells in lymph nodes implies that refined approaches to their identification could improve clinical outcomes in patients undergoing staging. Molecular staging could enhance the resolution of occult metastases by overcoming limitations in tissue sampling, incorporating all available tissue into analyses, and detection sensitivity, using disease-specific molecular markers quantified by powerful amplification technologies (e.g., the reverse transcriptase–polymerase chain reaction) that nominally identify a single cancer cell in 1 million normal cells. However, this revolution in molecular pathology offers an unexpected prediction about node-negative patients to whom molecular staging is applied. Indeed, for some tumors—notably colon cancer—node-negative patients as a cohort have a risk of disease recurrence that is nearly equivalent to that of patients with histopathology-detectable metastases in a small number of nodes (three or fewer lymph nodes; stage IIIA), a population with a demonstrated response to chemotherapy. By extension, this established relationship between nodal involvement and recurrence predicts that molecular staging will reveal that many, if not most, node-negative patients harbor occult metastases, underscoring the principle that nodal metastases do not certify recurrence but, rather, prognostic risk. In this example, application of molecular methods to identify occult disease brings into specific relief the possibility that many patients previously considered to have unknown therapeutic responsiveness might comprise a cohort deriving benefit from treatment. Certainly the clinical benefit of therapy in these patients undergoing risk stratification by biomarker analysis will ultimately be defined by randomized multicenter clinical trials. Those considerations notwithstanding, in the context of the emergent position of molecular techniques in the management of patients, with their sensitivity for detecting disease and revising prognoses, it is the responsibility of health-care providers, regulators, and insurers to consider whether clinical and economic resources are, or can be made, available to accommodate unanticipated pharmacoeconomic burdens produced by the application of molecular medicine. Standing as we are on the verge of this revolution in individualization of patient management at every level—including risk assessment, prevention, diagnosis, cure, and regeneration, through application of cutting-edge technology—and at the same time contemplating the crises in health-care delivery, it is incumbent to consider the pharmacoeconomic benefits and risks of the new biology and whether we have the social, political, and regulatory will to manage its application with fiscal responsibility and equity. S.A.W. is the Samuel M.V. Hamilton Endowed Professor of Thomas Jefferson University. A.T. is the Marriott Family Professor of Cardiovascular Research at the Mayo Clinic. The authors declared no conflict of interest.