As continuing issues and new products emerge, an uncertain effect on haemophilia treatment is starting to be evident. de Leon [12] has pointed out that one aspect of EBM and the primacy of RCTs, is the assumption of statistical homogeneity in the patient population and in therapeutic effect. Hence, an average response to a treatment represents individual patients adequately [12]. This key presumption, which extends to the highest levels of the EBM hierarchy, is increasingly
challengeable through developments in clinical pharmacology and the emergence of pharmacogenetics [13]. Demonstrable heterogeneity in the pharmacokinetics (PK) of drugs [12] through genetic, environmental and physical variables draws us to the new paradigm of ‘personalized Selleck Roxadustat medicine’ (PM). This paradigm recognizes heterogeneity and addresses outliers in therapeutic response, in contrast to EBM. The key component of PM is individual heterogeneity in PK, which is also demonstrated in the response to factor concentrates in haemophilia [14]. In adult patients with haemophilia A, the half-life of FVIII varies between
8 and 24 h [14]. The implications of this for the structuring of treatment protocols have been developed and reviewed by Collins [15]. It may also have potential application in the personalized treatment of individual patients and in the design of pivotal studies for the assessment of effectiveness. The limitation imposed by rare patient populations has been proposed PF-02341066 supplier as the main reason for the abandonment of the standard statistical
methodology reflected in RCTs and conformant to mainstream EBM [16]. These deficiencies in EBM lend themselves to the PM paradigm conformant to a patient-centric and personalized approach, and drawing on alternative methods for assessing effectiveness. These alternative methods have been reviewed [17] and the stated commitment of regulators to consider these approaches is encouraging [18, 19]. In particular, the use of ‘N-of-1’ clinical trials merits serious consideration as the method of choice in a new paradigm of PM for rare disorders such as haemophilia [20]. The level of Cyclin-dependent kinase 3 therapeutic precision possible from this approach exceeds the ‘one size fits all’ presumption of the conventional RCT considerably [21] and also decreases trial costs [22]. The application of N-of-1 trials to individual patients may be envisioned in the area of approval of current and emerging clotting factor concentrates such as longer acting FVIII and FIX [23]. Mannucci’s concern [24] that the shrinking pool of available patients needed for conforming to the increasing requirements of the European authorities may well be addressed through conducting N-of-1 trials of the product under review using the current standard of care as a control, e.g. comparing longer acting vs. unmodified products.