Twelve Month Post Licensure Safety and Efficacy Data of Advate rFVIII PFM.
Authors: Gomperts Edward D. , Ewenstein Bruce M. , O’Banion Mary Ellen 
Published: October 2019

Abstract
Initial data on safety and efficacy of new therapeutic agents are provided by formal clinical research studies. These provide information to permit licensure of the product by regulatory agencies. However, this initial therapeutic profile requires confirmation by the prospective collection and analysis of safety and efficacy information. These data are collected via pharmacovigilance activities, which are dependant on the reporting of adverse events by patients, physicians and other healthcare providers. The pharmaceutical license holder of the therapeutic has the regulatory obligation to continually collect, analyze and report this information at specified intervals during the first post-licensure year. The 12-month post-licensure anniversary is therefore an important milestone in the evaluation of a therapeutic agent.
Antihemophilic factor (recombinant), plasma/albumin-free method (Advate), is a recombinant FVIII concentrate manufactured without added human or animal plasma proteins during the production process. This eliminates the risk of infection from viruses and infectious prions that may be carried in these plasma protein additives. Advate was first licensed in the US on July 25, 2003. All reported adverse events were prospectively collected together with the volume of therapeutic agent distributed. This has permitted the determination of adverse event (AE) incidence relative to the amount of the concentrate released for distribution. These data were compared with similarly collected information on Antihemophilic factor (recombinant) Recombinate, over the equivalent first year postlicensure of this product.
For Advate, there was a total of 21 AEs of which 7 were serious (SAEs), including 6 reports of Factor VIII inhibitor formation. A total of 158.4 million units of Advate was distributed during this first year providing an incidence of 0.133 AE’s and an incidence of 0.038 inhibitor events per million units Advate distributed.
During the equivalent period with Recombinate, there were 20 AEs of which 9 were SAEs with 8 being reports of an inhibitor. A total of 69.2 million IU of Recombinate was distributed during the first year post licensure, providing an incidence rate of 0.289 AE’s and 0.116 for inhibitors per million IU distributed, respectively.
All new onset inhibitor reports with both products were associated with small children who, where information was available, had experienced fewer than 50 exposure days with factor VIII concentrates. This interval represents the period of greatest risk in the natural history of inhibitor development among patients with hemophilia A.
One episode of anaphylaxis following Advate was reported in an adult patient who had previously successfully undergone immune tolerance for an inhibitor. The patient’s sera demonstrated a low titer inhibitor with IgG and IgE specific for Factor VIII. These antibodies were present prior to exposure to Advate and the patient demonstrated similar allergic responses to FVIII concentrates other than Advate.
These data are reassuring with respect to the safety record generated by Advate during the first year post licensure and are particularly encouraging relative to the substantially lower incidence of inhibitor reports compared with the initial experience with Recombinate.
Advate Recombinate *per million units distributed Product Distributed # million units 158.4 69.2 AE’s 21 20 SAE’s (Inhibitor) 7 (6) 8 (8) Incidence AE’s* 0.133 0.289 Incidence Inhibitor* 0.038 0.116