gcalvo@clinic.cat
Abstract (250 words)
Advanced therapy medicinal products (ATMPs) are becoming the new kid on the block for the treatment of a variety of indications with promising results. Academic centres have often been at the forefront of basic research, preclinical phases, and translational studies for the clinical development of ATMPs for several approved drugs. Despite the academic contribution to the basic and clinical research of ATMPs, undertaking a full product development process is extraordinarily challenging and demanding for academic institutions. Meeting regulatory requirements is probably the most challenging aspect for academic development, considering the limited experience and resources compared with pharmaceutical companies. The aim of this review is to present and discuss the key aspects to be considered when developing novel ATMPs from an academic perspective, based on our own experience. Emphasis is placed on understanding the regulatory requirements during the early phases of the drug development process, particularly for the preparation of a Clinical Trial Application. In general, academic centres do not possess experience in product-related documentation (such as the Investigational Medicinal Product Dossier), and therefore, early interaction with regulators is crucial to understand their requirements and receive guidance to comply with them. Tips are provided on how to manage quality, non-clinical, clinical, and risk and benefit documentation, based on our own experience and challenges. We believe this review will contribute to providing key regulatory knowledge to academic and clinical environments with the purpose of smoothing the regulatory path of ATMPs.
Introduction
Advanced therapy medicinal products (ATMPs) are those based on genes, tissues, or cells. These therapies are regulated as medicinal products for human use and are legislated under the EU Medicinal Products Directive 2009/120/EC. Accordingly, ATMPs must follow the European Medicine Agency (EMA)’s centralised procedure. However, since 2007, with the amendment of Directive 2001/83/EC and Regulation (EC) No 726/2004, member states may also establish a legal framework to allow the approval of an ATMP under very limited and restricted conditions (Hospital Exemption for academic centres).
Academic centres have been at the forefront of basic, preclinical, and clinical research for the clinical development of ATMPs for many industrial approved drugs. Indeed, during recent years, 25 ATMPs received EMA marketing authorisation, with 5 of them initially developed in academic institutions (such as the University of Pennsylvania for Kymriah® or the University of Modena and Reggio Emilia for Holoclar®). As far as we know, about 20% of currently approved ATMPs originated in an academic environment in which there was a commercial agreement with a consolidated biotech or pharmaceutical company for marketing authorisation application and product commercialisation (see Figure 1 ). Academic institutions have provided (and still provide) a major contribution to the development of ATMPs.
Less common, so far, is for an academic institution to lead the entire development of an ATMP through to regulatory approval. In this regard, academic centres face many challenges during the development of novel ATMPs. These challenges start at the very initial phases, as ATMPs must follow the established regulatory standards during the whole drug development cycle . A recently published survey focused on the academic setting showed that there is a critical lack of knowledge of regulatory science and that improved skills to navigate the complex regulatory system are clearly needed. Otherwise, lack of understanding and miscommunication between academic developers and regulatory agencies can delay, or even prevent, the development of new treatments, potentially limiting the capacity of promising academic ATMPs to reach patients. However, an early interaction between academia and regulatory bodies, through their Innovation Office, can help advance product development, in an efficient manner, towards regulatory authorisation. Some valuable regulatory information can be found within the pilot scheme “Pilot III” of the Strengthening Training of Academia in Regulatory Science (STARS) project. The STARS project has already concluded but some recommendations should be put into practice as soon as possible to increase regulatory knowledge within academia.
It goes without saying that regulatory standards must remain at the same level of rigour independently of the developing body (large pharmaceutical companies, SMEs (small and medium-sized enterprises) or academia). Accordingly, thorough regulatory training within academia is a necessity.
The aim of this review is to share with the reader a number of regulatory principles and strategies to get the academic community closer to key regulatory aspects, with particular emphasis on early phases of the ATMP drug development process. This manuscript is the result of our experience of a continuous interaction with the Spanish Agency of Medicines and Medical Devices (AEMPS) and EMA related to a number of academic ATMP initiatives carried out at our centre during the last five years. The principle objective is to discuss general aspects to be considered by academia; no product-related specific issues will be discussed in this paper.