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European Medicines Agency

For many biopharmaceutical companies it has been difficult to navigate the ever changing regulatory landscape for the development of biosimilars. Because biosimilars are a relatively new area in the marketplace, the rules that govern it have been evolving alongside product development.

European Medicines AgencyIn Europe, the European Medicines Agency (EMA) has reviewed and approved a number of biosimilar products over the past several years, and throughout that process they’ve learned valuable lessons about what works and what doesn’t. Based on that knowledge, last year they began reviewing and modifying some of the biosimilar guidance documents. These include a draft guidance published in the summer of 2013 for updating the nonclinical and clinical considerations for biosimilar products in the EU This draft guidance includes EMAs current thinking as to what will be required for nonclinical and clinical development of biosimilars. Emphasis is strongly placed on step-wise development program for biosimilars. The need for in-vivo nonclinical study is based on residual uncertainly upon successful completion of CMC comparability studies and in vitro nonclinical functional assays. 

In the past, the guidance documents were very rigid, with set of prescribed analytical comparability against the reference product followed by in vitro and in-vivo nonclinical studies, which resulted in some unnecessary in vivo nonclinical studies. Now, the process is more organic, allowing development teams to react to the residual questions that arise, and to conduct in vitro and in vivo nonclinical studies to answer those questions. If there are no residual questions, they are allowed to move on to a clinical study in humans without performing an in vivo animal study. 

For monoclonal products, the EMA has indicated that it wants to limit studies in non-human primates unless absolutely essential. This is a significant evolution from past guidelines that required in vitro studies and repeat-dose toxicity studies in relevant species. 

EMA has also stated that the reference product for all studies no longer must be sourced from the EU, which is in line with the US Food and Drug Administration’s (FDA) guidance documents for biosimilar products. In this scenario, biopharmaceutical companies are required to show three way analytical, nonclinical [in-vitro and in-vivo (if warranted)], and clinical PK/PD comparability between the EU, US and the proposed biosimilar before allowing the comparator for the Phase III study to come from either region. This strategy will result in significant cost savings and the Phase III data will be acceptable to both agencies for product approval.

Topics in this blog post: Biopharma, Biosimilars, EMA, EU