Medical brain notes 37

  Regulatory Issues and Drug Product Approval for Biopharmaceuticals   INTRODUCTION The term “biopharmaceuticals” is used to describe biotechnologically derived drug products. Biopharma-ceuticals are protein-based macromolecules and include, insulin, human growth hormone, the families of the cytokines and of the monoclonal antibodies, antibody fragments, and nucleotide based systems such as anti-sense oligonucleotides, siRNA and DNA preparations for gene delivery. These are large complex molecules and are often heterogeneous mixtures compared to synthetically manufactured, pure small molecules.   In the first years of the new millennium the regulatory landscape for biopharmaceuticals changed. Before that time only original biopharmaceuticals were approved by FDA and EMEA (Table 1) following the normal pathway of approval including full scale clinical trials to ensure efficacy and safety and this pathway still stands for original biopharmaceuticals. Then, a number of bioph...

  BACKGROUND The aim of this chapter is to provide a comprehensive view on the regulatory issues for the approval of  a biosimilar product. In order to have a better understanding of the regulatory process involved, it is essential to appreciate the basic difference between small drug molecules and macromolecules and their approval process. Table 1 provides the definitions of different classes of medicinal drug products. Table 2 provides the steps involved in the drug approval process of small molecules. For the approval of a (small molecule) generic product, it must be pharma-ceutically equivalent and bioequivalent (Table 3). Biopharmaceuticals have a number of characteristics (Table 4) that set them aside from small molecule drugs (Crommelin et al., 2003). The efficacy and safety of biotech products depend on their complicated, rather labile shape built up of secondary, tertiary and sometimes quaternary structures. The mission of a regulatory authority is to “Assure that saf...

  BIOSIMILAR AND FOLLOW-ON BIOLOGICS Biosimilar products are expected to be comparable to an approved reference product in terms of quality, safety and efficacy profile. Approval of these products should be considered based on product comparisons and demonstration of comparability to the reference product.   Biopharmaceutical products may be currently manufactured by the same manufacturer at different sites. The “FDA Guidance on comparability” protocol is used for assuring product quality of the approved product after certain changes are made in the manufacturing process (comparability assessment, see below). The quality of these products is assured by chemical analysis and/or by using a comparability clinical study protocol.   A question often raised and debated by a generic manufacturer is whether the approach of using a comparability protocol can be extrapolated and adopted for approval of biosimilar products manu-factured by a different manufacturer. The regulatory an...

  REGULATORY ROUTES   From a regulatory perspective, a copy of a biophar-maceutical product can be identified as a generic product. But in practice it is unlikely, due to additional complexity, particularly safety issues. The copy of a biopharmaceutical product is required to have a similar safety and efficacy profile as the brand name/innovator product, and therefore it is referred to as “biosimilar”. Biosimilar products are non-interchangeable.   According to the U.S. Food, Drug and Cosmetic Act, the approval process can follow one of two routes: New Drug Application (NDA) with two sub-classes, and Abbreviated New Drug Application (ANDA)   Section 505(b)(1): Full reports of investigations of safety and efficacy are needed. This results in a full NDA, with right of reference. This means that information about safety and efficacy can be used by others to document safety and efficacy of the product.   Section 505(b)(2): This requires clinical studies, without the...