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.