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      Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges


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          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.

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          Most cited references15

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          Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies.

          Preclinical tests of therapeutic antibodies are frequently carried out in mice to evaluate pharmacokinetics and efficacy. However, the observation that mouse IgG are cleared rapidly from the human circulation suggests that mice may not always be an ideal model. The Fc receptor, FcRn, regulates the serum half-lives of IgG in mice and most likely has a similar function in humans. In the current study we have carried out an extensive analysis of the interaction of the human or mouse forms of FcRn with IgG from various species using surface plasmon resonance. We show that in contrast to mouse FcRn, human FcRn is surprisingly stringent in its binding specificity for IgG derived from different species. Human FcRn binds to human, rabbit and guinea pig IgG, but not significantly to rat, bovine, sheep or mouse IgG (with the exception of weak binding to mouse IgG2b). In contrast, mouse FcRn binds to all IgG analyzed. The lack of binding of human FcRn to mouse IgG1 has been confirmed using transfectants that have been engineered to express human FcRn on the cell surface. Our results provide a molecular explanation for the enigmatic observation that mouse IgG behave anomalously in humans. These studies have implications for the successful application of therapeutic antibodies.
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            Preclinical safety testing of monoclonal antibodies: the significance of species relevance.

            Selecting a pharmacologically relevant animal species for testing the safety and toxicity of novel monoclonal antibody (mAb) therapies to support clinical testing can be challenging. Frequently, the species of choice is the primate. With the increased number of mAbs in the pharmaceutical pipeline, this has significant implications for primate use, and so raises several important scientific, ethical and economic issues. Here, following a recent international workshop held to debate this topic, we discuss issues in the preclinical testing of mAbs, with a particular focus on species relevance and primate use, and provide suggestions for how these issues might be addressed.
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              Biosimilars entering the clinic without animal studies

              The concept of biosimilars has spread from Europe to other regions throughout the world, and many regions have drafted regulatory guidelines for their development. Recently, a paradigm shift in regulatory thinking on the non-clinical development of biosimilars has emerged in Europe: In vivo testing should follow a step-wise approach rather than being performed by default. To not require animal testing at all in some instances can well be seen as a revolutionary, but science-based, step. Here, we describe the internal discussions that led to this paradigm shift. The mainstay for the establishment of biosimilarity is the pharmaceutical comparability based on extensive physicochemical and biological characterization. Pharmacodynamic comparability can be evaluated in in vitro assays, whereas pharmacokinetic comparability is best evaluated in clinical studies. It is considered highly unlikely that new safety issues would arise when comparability has been demonstrated based on physicochemical and in vitro comparative studies.

                Author and article information

                Taylor & Francis
                April 2016
                6 February 2016
                6 February 2016
                : 8
                : 3
                : 427-435
                [a ]National Center for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) , UK
                [b ]Medicines and Healthcare Regulatory Agency (MHRA) , UK
                [c ]Covance Laboratories , Harrogate, UK
                [d ]Sandoz , Holzkirchen, Germany
                [e ]Federal Agency for Medical and Health Products (FAMHP) , Belgium
                [f ]Harvest Moon Pharmaceuticals , US
                [g ]Celltrion , Japan
                [h ]Pfizer , US
                [i ]Independent , UK
                [j ]Biocon , India
                [k ]Plantform Corp , Canada
                [l ]Paraxel , UK
                [m ]Integrated Biologix , Switzerland
                Author notes
                © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                : 6 November 2015
                : 8 January 2016
                : 19 January 2016
                Page count
                Figures: 0, Tables: 1, References: 32, Pages: 9

                biosimilar,development,ema,fda,guidelines,in vitro,in vivo,regulatory,study design,who,3rs
                biosimilar, development, ema, fda, guidelines, in vitro, in vivo, regulatory, study design, who, 3rs


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