Position paper

Vol. 21 No. 5 (2023): Blood Transfusion 5-2023 (September-October)

Bioequivalence of recombinant factor VIII products: a position paper from the Italian Association of Hemophilia Centers


Key words: bioequivalence, hemophilia, pharmacokinetics, recombinant FVIII concentrate
Publication Date: 2023-01-26


Over the last three decades, the continuous evolution of recombinant factor VIII (rFVIII) concentrates for replacement treatment of hemophilia A, including recent extended half-life products, implies that patients may switch from one product to another, technologically more advanced, with the aim of improving treatment efficacy, safety, management and, ultimately, quality of life. In this scenario, the issues of bioequivalence of rFVIII products and the clinical implications of their interchangeability are keenly debated, in particular when economic reasons or purchasing systems influence product availability and choices. Although sharing the same Anatomical Therapeutic Chemical (ATC) level, rFVIII concentrates, as other biological products, show relevant differences in terms of molecular structure, source and manufacturing process, which make them unique products, recognized as new active substances by regulatory agencies. Moreover, data from clinical trials with both standard and extended half-life products clearly document the large inter-patient variability of pharmacokinetic profiles after administering the same dose of the same product; in cross-over evaluations, even when mean values are comparable, some patients show better patterns with one product or with the comparator one. Pharmacokinetic assessment thus reflects the response to a specific product in the individual patient, with his genetic determinants, only partially identified, affecting the behavior of exogenous FVIII. These concepts, consistent with the currently recommended approach of personalization of prophylaxis, are discussed in this position paper endorsed by the Italian Association of Hemophilia Centers (AICE), highlighting that ATC or other available classifications do not completely consider differences between drugs and innovations and that substitutions of rFVIII products will not invariably ensure the previously achieved clinical outcomes or generate benefits for all patients.



Ezio Zanon - Hemophilia Center, General Medicine, Padua University Hospital, Padua, Italy

Raimondo De Cristofaro - enter for Hemorrhagic and Thrombotic Diseases, IRCCS A. Gemelli University Hospital Foundation, Rome, Italy

Massimo Franchini - Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, Mantua, Italy

Massimo Morfini - Italian Association of Hemophilia Centers, Milan, Italy

Gianfranco Pasut - Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy

Angelo Claudio Molinari - Regional Reference Center for Hemorrhagic Diseases, Thrombosis and Hemostasis Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy

Cristina Santoro - Hematology, Umberto I University Hospital, Rome, Italy

Rita Carlotta Santoro - Centre for Hemorrhagic and Thrombotic Disorders, Pugliese Ciaccio Hospital, Catanzaro, Italy

Antonio Coppola - Regional Reference Center for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

Angiola Rocino - Hematology Unit, Hemophilia and Thrombosis Center, S.M. di Loreto Nuovo Hospital, ASL Napoli 1 Centro, Naples, Italy

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