The Evolution of Nonclinical Regulatory Science: Advanced Therapy Medicinal Products as a Paradigm

Abstract

Advanced therapy medicinal products (ATMPs) comprise gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (CTMPs), and tissue-engineered products (TEPs). So-called combined ATMPs incorporate one or more medical devices as an integral part of the product. Because of their complexity and innovative nature, ATMPs pose new scientific and regulatory challenges to both developers and regulators.1 Many developers of such products request scientific advice from the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA). We have repeatedly been asked by stakeholders to analyze the scientific advice provided by the CHMP with regard to the identification of common principles that might be useful to share with product developers. Here we comprehensively analyze the scientific advice provided by the CHMP following implementation of the 2009 legislation on ATMPs, in which the Committee for Advanced Therapies (CAT) plays an integral role. This analysis allowed us to conclude that, for these innovative medicines, a classic guideline-based approach is insufficient owing to the complexity of the products. Regulators must employ a more tailored approach that includes principles of risk identification and mitigation. In the current analysis, we focus on the translational aspects of ATMPs (i.e., nonclinical issues) because these are a direct measure of developmental complexity of innovative treatments and often constitute a bottleneck for ATMP development. ATMPs are pharmaceuticals with a high level of complexity linked to their composition, development, manufacturing, characterization, and administration. Such products can serve as a paradigm for any innovative medicinal product or personalized medicine because of their high specificity, particularly with regard to how regulators provide guidance to accommodate the needs of stakeholders. The current regulatory framework was fully implemented in the European Community in 2009.2 Central to this regulatory framework for ATMPs was the establishment of a multidisciplinary expert scientific committee, the CAT, which is tightly integrated into the EMA procedure for CHMP scientific advice. In addition to the well-established procedures for the EMA's scientific advice and protocol assistance,3,4 classification and certification procedures have been established5,6,7,8 to facilitate discussions with developers. The CAT has published several guidelines for ATMPs to facilitate development of this complex class of therapy.9 However, the broad spectrum of ATMPs with regard to structure and mechanism of action means that such general guidance can be difficult to translate into product-specific requirements. These difficulties can be substantial for sponsors developing ATMPs, considering that the major stakeholders in Europe are academia, charities, and small companies, which often have limited financial resources or regulatory expertise when compared with large pharmaceutical companies.10