title: Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges.
abstract: Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio™, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory. We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.
authors: a National Center for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) , UK.
authors: Kathryn
authors: K
authors: Chapman
authors: b Medicines and Healthcare Regulatory Agency (MHRA) , UK.
authors: Akosua
authors: A
authors: Adjei
authors: c Covance Laboratories , Harrogate , UK.
authors: Paul
authors: P
authors: Baldrick
authors: d Sandoz , Holzkirchen , Germany.
authors: Antonio
authors: A
authors: da Silva
authors: e Federal Agency for Medical and Health Products (FAMHP) , Belgium.
authors: Karen
authors: K
authors: De Smet
authors: f Harvest Moon Pharmaceuticals , US.
authors: Richard
authors: R
authors: DiCicco
authors: g Celltrion , Japan.
authors: Seung Suh
authors: SS
authors: Hong
authors: b Medicines and Healthcare Regulatory Agency (MHRA) , UK.
authors: David
authors: D
authors: Jones
authors: h Pfizer , US.
authors: Michael W
authors: MW
authors: Leach
authors: b Medicines and Healthcare Regulatory Agency (MHRA) , UK.
authors: James
authors: J
authors: McBlane
authors: i Independent , UK.
authors: Ian
authors: I
authors: Ragan
authors: j Biocon , India.
authors: Praveen
authors: P
authors: Reddy
authors: k Plantform Corp , Canada.
authors: Donald I H
authors: DI
authors: Stewart
authors: l Paraxel , UK.
authors: Amanda
authors: A
authors: Suitters
authors: m Integrated Biologix , Switzerland.
authors: Jennifer
authors: J
authors: Sims
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; D017277:Drug Approval / Q000331:legislation & jurisprudence / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends; D006801:Humans; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals
keywords: 3Rs; Biosimilar; EMA; FDA; WHO; development; guidelines; in vitro; in vivo; regulatory; study design