| "POPULATION-BASED STUDIES OF DRUG TREATMENT: FROM MOLECULE TO PATIENT OUTCOMES. Mission and profile. To contribute to a better understanding of the sources of variance in drug response in users of medicines, with the goal to increase the Benefit-Risk ratio of therapeutics for individual patients and for public health in general. Vision and research problem Despite extensive testing before marketing approval, variance in drug response (e.g. not only variable efficacy, but also unexpected or adverse drug reactions) is more the rule than the exception when medicines are used in daily clinical practice, i.e. in real life. Discovering and developing drugs capable of working effectively is a complex task. It is also not easy to use drugs in ways that ensure that they deliver their full therapeutic potential. The programme has a Systems Therapeutics focus, integrating various disciplines, dimensions and phases of a Product life cycle in order to learn about (rather than confirm) drug effects and their determinants both before and after initial marketing approval of the product. The primary conceptual anchors in the research strategy of the programme are Epidemiological Methods and Systems Therapeutics. The focus on methods has historical antecedents (building further on proved strengths); the driver behind Systems Therapeutics is in line with the notion that the study of drug effects requires a systematic, integrative approach bringing insight and learning together ranging from biology, (clinical) pharmacology to epidemiology and policy/regulatory. Research objectives and topics In recent decades, ample evidence has been provided that modern therapeutics should be based on a comprehensive and thoughtful integration of various disciplines, including basic science, translational and general medicine, clinical pharmacology, pathophysiology, and epidemiology, but also regulatory decision making and policy analysis. The programme, which started in the early 1990s, has its roots in studies on drug use and exposure in daily clinical practice. Studying and understanding the variance in drug responses (from intended to unsatisfactory/adverse) in routine clinical practice requires an integrative, or systems approach, ranging from drug-related factors (mechanism of action, and side-effects response forgiveness for commonly-occurring lapses in dosing and susceptibility to misuse), patient-related factors (adherence to therapy, disease severity, genotype, co-morbidities and coinciding co-medication as a source of drug-drug interactions), to regulatory and policy factors (level of evidence from regulatory trials, external validity of these trials, directions for use in the drug label and cost-effectiveness). These factors are not fully independent; rather, they are variably interactive. In effect, they underscore the need to learn what medicines do in patients. This process, which is multidimensional, requires numerous methods and a product life cycle approach that bridges drug development, regulatory/policy decision making and actual use in clinical practice. Methods, expertise and infrastructure In terms of methods, the array of epidemiological reasoning and techniques constitute the backbone of the programme, with variance in drug response as key variable. This approach requires strong synergy between the various disciplines within selected clinical areas, providing clinically relevant research questions as learning cases. Initially, the infrastructure of the programme was primarily based on sentinel networks of pharmacy records. Recording the linkage between drug exposure and clinical outcomes opened a wide range of opportunities for studying the sources and effects of variance in drug responses in naturally occurring groups of users of medicines, based on data platforms such as PHARMO, the Rotterdam Study, GPRD and more recently the TI Pharma Mondriaan Project. The programme is linked to a large number of international research" |
