HPE HPE Fresenius Kabi handbook - Page 10

establishing biosimilarity. 8–10 Critical quality attributes of a biologic have the potential to affect its safety or efficacy through a variety of mechanisms; thus, the definition of these attributes is important for assuring the efficacy and safety of the product. In the case of monoclonal antibodies (mAbs), efficacy can be affected by changing the antibody’s interaction with its target, for example, due to conformation alterations or chemical modifications of critical residues. These attributes might alter the safety profile of the therapeutic antibody, either by increasing potential immunogenicity or by causing an increase in off- target binding, for example. A single quality attribute might affect multiple functions, and the degree of impact can be molecule- specific. Most therapeutic proteins undergo glycosylation, which can influence the biological activity of a protein. For example, glycosylation can affect half-life by influencing the clearance of a protein, and in the specific case of therapeutic antibodies, Fc glycosylation plays a role in functions such as antibody-dependent cellular cytotoxicity. 11–13 Reverse engineering The manufacturing process of biosimilars tries to ‘replicate’ that of the reference without full knowledge of its different steps – considering that it is proprietary – through detailed analyses of the reference product and using a ‘reverse engineering’ strategy. Given the structural complexity and variation of the molecules and the cell systems where they are produced, reverse engineering may result in significant differences in the production of the biosimilar (for example, different cell line, production and purification of the biosimilar from the cell line). This poses significant challenges to companies and their scientific teams in terms of expertise and capabilities as well as time and cost. However, because the focus of clinical trials involving biosimilars is on the need to show similar physicochemical and biological properties as well as efficacy and safety versus the original molecule, and not on elucidating the mechanism of action and proof of concept, the regulatory paths to approval are distinct and bypass some of these inherent difficulties. 14 Comparability Comparability studies need to be conducted to demonstrate the similarity in terms of quality, safety and efficacy, of the biosimilar and its approved reference drug. 2 In addition, the comparability and similarity of its biological activity is determined using assays relevant to the modes of action of the reference biologic in all potential indications (Table 2). 15 The mechanisms of action of the drug are assessed in all potential disease indications to confirm that it performs adequately and comparatively to the reference drug under clinical conditions. This thorough assessment is designed to show high similarity because all aspects of the drug are evaluated with the most sensitive and specific assays. Together these assays should broadly cover the functional aspects of the drug, even though some may not be considered essential for the therapeutic mode of action. Because in vitro assays can be more specific and sensitive than studies in animals, they are paramount in the non-clinical comparability exercise. This entirety of evidence ensures that all accumulated data (clinical and analytical) on the biosimilar candidate are considered. This includes comparison of the bioanalytical characteristics of batches of reference product and biosimilar, and the effects on the cellular and molecular mechanisms of action relevant to the disease indications of the reference drug. 16 Immunogenicity For a biologic that is administered to an individual more than once, alternating or switching between the biosimilar and reference products should not increase the risk of adverse events from using the reference product without such alternation or switching in terms of safety or diminished efficacy. Similarly, the risk associated with alternating or switching between biosimilars should not be greater than the the risk of uninterrupted use of the reference product. 17 Therefore, immunogenicity (that is, the ability of the biosimilar to trigger an immune reaction) is a critical factor when assessing biosimilarity and should be evaluated in a risk-based manner. Most biologics can induce immune responses, which, in many cases, do not have clinically relevant consequences. Immune responses can include the development of antidrug antibodies or generation of neutralising antibodies that might potentially eliminate activity. The most severe scenario is the cross-reaction of antidrug antibodies with an endogenous protein, thereby eliminating its critical function and potentially causing harm. The extent of immunogenicity can vary due to changes in the manufacturing processes of the same biosimilar, or any biologic (including reference drugs), or among different manufacturers of biosimilars/ reference products. 18–21 Scientific and immunological reasons might TABLE 2 Comparability testing for biosimilars Quality attribute Demonstration of similarity Protein structure and manufacturing quality Extensive laboratory analyses of molecular characteristics (in multiple batches) Pharmacokinetics, pharmacodynamics and toxicity (in animals) In vitro and in vivo assays (in vivo studies only if additional information is needed after in vitro evaluation) Pharmacokinetics, pharmacodynamics and toxicity (in humans) Early pharmacology studies Clinical efficacy and safety Pivotal clinical comparability trials, usually in the most sensitive indication 10 | 2019 | hospitalpharmacyeurope.com