EMA Publish Guideline on Bio Similar Monoclonals.

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This guideline lays down the non-clinical and clinical requirements for monoclonal antibody (mAb) containing medicinal products claiming to be similar to another one already marketed. The non-clinical section addresses the pharmaco-toxicological requirements and the clinical section the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as pharmacovigilance aspects.
As regards non-clinical development, a risk-based approach to evaluate mAb on a case-by-case basis is recommended to decide on the choice and extent of in vitro and in vivo studies. In vitro studies should be conducted first, and a decision then made as to the extent of what, if any, in vivo work will be required. If an in vivo study is deemed necessary, the focus of the study (pharmacokinetics, pharmacodynamics, and/or safety; normally comparative in nature) depends on the need for additional information, and the availability of a relevant animal model. The conduct of large comparative toxicological studies in non-human primates is not recommended. As regards clinical development, a comparative pharmacokinetic study in a sufficiently sensitive and homogeneous study population (healthy volunteers or patients) normally forms an integral part of biosimilar mAb development, usually in a parallel group design due to the long half-life of mAbs and potential interference of immunogenicity. The design of a pharmacokinetic study will depend on various factors, including
55 clinical context, linear versus non-linear pharmacokinetics etc. Pharmacokinetic data can be helpful to extrapolate data on efficacy and safety between different clinical indications of the reference mAb. It may, on a case-by-case basis, be necessary to undertake multidose pharmacokinetic studies in patients, or even to perform pharmacokinetic assessment as part of the clinical study designed to establish similar efficacy and safety. Pharmacokinetic studies can be combined with pharmacodynamic (PD) endpoints, where available. Sponsors should always explore possibilities to study dose concentration-response relationships since this approach, if successful, may provide strong evidence of biosimilarity. Normally, similar clinical efficacy should be demonstrated in adequately powered, randomised, parallel group comparative clinical trial(s), preferably double-blind, normally equivalence trials. To establish biosimilarity, deviations from disease-specific guidelines issued by the CHMP (for example, choice of endpoint, timepoint of analysis of endpoint, nature or dose of concomitant therapy, etc) may be warranted. The focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been shown for the reference product. In principle, the most sensitive model and study conditions (pharmacodynamic or clinical) should be used in a homogeneous patient population, since this reduces variability and thus the sample size needed to prove similarity, and can simplify interpretation. In cases where comparative pharmacodynamic studies are claimed to be most suitable to provide the pivotal evidence for similar efficacy, Applicants will have to choose clinically relevant markers and also provide sufficient reassurance of clinical safety, particularly immunogenicity. It may be difficult to define an appropriate equivalence margin for pharmacodynamic equivalence based on clinical relevance, and to provide reassurance that all relevant aspects of a biosimilar mAb as regards similar clinical efficacy are covered. Comparable safety with respect to pharmacologically mediated adverse reactions could also be considered as a measure of biosimilarity. Extrapolation of clinical efficacy and safety data to other indications of the reference mAb, not specifically studied during the clinical development of the biosimilar mAb, is possible based on the results of the overall evidence provided from the biosimilarity exercise and with adequate justification. As regards post-authorisation follow-up, the concept to be proposed by Applicants may have to exceed routine pharmacovigilance, and may have to involve more standardized environments.

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