Scientific considerations for complex drugs in light of established and emerging regulatory guidance

Abstract

On March 9, 2012, the New York Academy of Sciences brought together experts representing a variety of perspectives--including academic, industrial, regulatory, as well as those from physicians and consumers--to discuss considerations for the non-biological complex drug (NBCD) regulatory approval pathway, given the emerging regulatory guidelines for biosimilars (follow-on biological complex drugs). Some of the organizers of the conference expressed their belief that NBCDs share a number of characteristic features with biologicals: the structure cannot be fully defined by the available (physicochemical) analytical tests, and quality assurance is based on in-depth knowledge, consistency, and control of the production process. However, their view on NBCDs was not universally accepted among the experts who participated in the conference. Plenary sessions addressed the most recent regulatory developments, experimental design, interchangeability, and immunogenicity issues for follow-on versions of complex drugs from the perspective of key audiences, including industry, regulatory agencies, physicians, and consumers. This report summarizes these various perspectives on NBCDs and the scientific and regulatory considerations associated with complex drug categories.

Introduction: Defining the Position of Non-Biological Complex Drugs

“…Moreover the group is involved in scientific education and training on the above mentioned topics to relevant stakeholders'. Key publications on NBCDs are by Schellekens et al 2014;Holloway et al 2012;Schneider et al 2012, andSchellekens et al 2010. Some of these papers are meeting reports or write-ups of discussions with many stakeholders during international conferences over the last few years.…”

Glatiramoids

“…Based on current knowledge and available data, a recent paper summarized discussions among 25 scientific experts from industry, academia, and regulatory bodies regarding the regulation of NBCDs and their follow-on versions (Schellekens et al 2014;Crommelin et al 2014;Holloway et al 2012;Mühlebach et al 2013). For glatiramoids, there was a general understanding that because of the physicochemical differences seen between the prototype, Copaxone ® , and purported generic versions of GA, and because the clinical implications of these differences are as yet unclear, the only meaningful way to evaluate product efficacy and safety is to perform comparative clinical trials in patients with MS (Schellekens et al 2014).…”

Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

“…Their formulation procedure often involves a large variety of technological steps and intra-process controls, which render the structure of each liposomal formulation to be highly unique and thus difficult to reproduce. Minor deviations in manufacturing may lead to major changes in therapeutic efficacy and/or toxicity, which led the regulatory authorities to categorize liposomal drugs as "non-biological complex drugs (NBCDs) [4,5,6] and implement special procedures for their handling in new drug (NDA) and accelerated new drug (ANDA) applications (or their European variants). The special procedures implies the requirement to conduct a great number of in vitro assays for proving bioequivalence, for example the European Medicines Agency (EMA) recommended over 50 in vitro tests to be performed in proving the bioequivalence of a generic intravenous liposomal product in comparison with an "innovator liposomal product" [7].…”