Patients with von Willebrand disease (VWD) and haemophilia A (HA) lack, to varying degrees, the von Willebrand factor (VWF) and coagulation factor VIII (FVIII) that are critical for normal haemostasis. These conditions in turn make patients prone to uncontrolled bleeding. Historically, patients with severe forms of VWD or HA were crippled before adulthood and their life expectancy was significantly reduced. Over the past decades, specific coagulation factor replacement therapies including Haemate Ò P, have been developed to help patients achieve and maintain normal haemostasis. Haemate Ò P is a human, plasma-derived VWF ⁄ FVIII medicinal product, which was first licensed in Germany in 1981 for the treatment of HA-associated bleeding. It has since then come to be accepted as the gold standard for both the treatment and prophylaxis of bleeding in VWD, especially in cases where desmopressin [1-deamino-8-D-arginine vasopressin (DDAVP)] has been ineffective. Haemate Ò P was the first effectively virus-inactivated (pasteurisation: 60°C for 10 h in aqueous solution) FVIII product, whereby the risk of potentially threatening infective complications of plasma-derived products was reduced. Haemate Ò P was also shown to have a VWF multimer profile remarkably close to that of normal plasma. This bibliographic review presents previously unpublished clinical data of Haemate Ò P, based upon internal clinical study reports of the proprietor, CSL Behring, in addition to data already presented in other publications. The data demonstrate a predictable and well-characterised pharmacokinetic profile, and a proven record of short-and long-term safety, while effectively correcting the haemostatic defects in VWD and HA. Recently available data have also shown Haemate Ò P to be of haemostatic value in exceptional clinical circumstances including surgical interventions. By virtue of its plasma-derived combination of VWF and FVIII, in addition to its high VWF:FVIII content ratio (2.4:1), Haemate Ò P is also associated with successful immune tolerance induction in those patients developing inhibitor antibodies. Although the theoretical risk of thromboembolic complications does exist while receiving Haemate Ò P, as it does with any FVIII replacement therapy, the incidence of such complications has remained notably low. Given the robust data that have accumulated for the use of Haemate Ò P, dosing recommendations are also described in this review; the recommendations are tailored to patient-specific contexts including baseline VWF and FVIII levels in plasma and the type of surgical intervention being undertaken. A wide variety of studies have also provided data on paediatric and geriatric populations, all of which have suggested that Haemate Ò P can be safely and effectively used in a wide variety of clinical circumstances. Effective haemostasis requires complex bodily processes such as vasoconstriction and blood clotting so as to ensure the integrity of the blood vessel system and to prevent excessive blood loss following injury. B...

Clinical trial designs often fail to deliver data that jointly satisfy evolving demands of both regulatory and reimbursement authorities. We propose a new multi-tiered trial design to integrate efficacy and effectiveness, and address the evolving needs of authorities. The mixed randomized trial allocates patients first to trial arm - randomized controlled, pragmatic (randomized) or observational - and then to treatment group - experimental, placebo, active comparator, best available therapy or standard of care. Trial arms may be staggered over time to reflect the current state of randomized and non-randomized data of the experimental drug, and thereby still prioritize safety. At the same time, the mixed randomized trial allows for the collection of real-world data in a randomized setting, and thereby reduces selection bias.