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\begin{document}

\title{Academic challenges on ATMPs' development: a regulatory perspective}



\author[1]{Eulàlia Olesti}%
\author[2]{Yoana Nuevo}%
\author[1]{Elena Guillen}%
\author[1]{Juan Bascuas}%
\author[1]{Sara Varea}%
\author[1]{Joaquín Saez-Peñataro}%
\author[1]{Gonzalo Calvo}%
\affil[1]{Hospital Clinic de Barcelona}%
\affil[2]{Agencia Española de Medicamentos y Productos Sanitarios}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
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.%
\end{abstract}%



\sloppy


\textbf{Academic challenges on ATMPs' development: a regulatory
perspective}

Eulalia Olesti\textsuperscript{1,2,3*}, Yoana Nuevo\textsuperscript{4},
Elena Guillen\textsuperscript{1,2}, Juan Bascuas\textsuperscript{1,2},
Sara Varea\textsuperscript{1,2}, Joaqu\selectlanguage{ngerman}ín
Saez-Peñataro\textsuperscript{1,2;3}, Gonzalo
Calvo\textsuperscript{1,2*}

\textsuperscript{1} Department of Clinical Pharmacology, Area
Medicament, Hospital Clinic of Barcelona, Spain.

\textsuperscript{2} Clinical Pharmacology, Institut d'Investigacions
Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

\textsuperscript{3} Department of Pharmacology, University of Barcelona,
Spain.

\textsuperscript{4} Innovation Office and National Scientific Advice
Unit, Spanish Agency of Medicines and Medical Devices (AEMPS).

*Corresponding authors: \emph{olesti@clinic.cat} ;

\emph{gcalvo@clinic.cat}

\textbf{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.

\textbf{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\textsuperscript{®} or the University of Modena and Reggio Emilia
for Holoclar\textsuperscript{®}). 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 \textbf{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.

\textbf{2. ATMP lifecycle}

The pharmaceutical development of a medicinal product encompasses the
medicinal product lifecycle from basic research to marketing
authorisation (MA) and post-marketing surveillance. In \textbf{Figure 2}
, a schematic representation of the ATMP lifecycle is presented, with
comments on the main critical regulatory steps required for the product
development.

The development of an ATMP starts with basic research and non-clinical
investigation that progresses an initial idea through to pre-clinical
studies and encompasses all of the steps required before the product is
administered to humans. This is followed by the clinical development
phase in which the safety and efficacy of the product are evaluated on
the target population through different clinical trials. In the event
that the clinical evidence shows a favourable benefit-risk assessment,
the applicant can submit a Marketing Authorisation Application (MAA) to
achieve regulatory acceptance. At this stage, pharmacovigilance
commitments are required by regulatory agencies to guarantee the
surveillance of the ATMP once it is commercialised (as stated in
Regulation (EC) No 1394/2007). Furthermore, ATMP regulation (Article
3(7) of Directive 2001/83) introduces the hospital exemption (HE) legal
framework which allows EU member states to permit the provision of ATMPs
in the absence of MA under certain conditions, subject to legislation
implemented at the national level. These products must be prepared on a
non-routine basis to specific quality standards for an individual
patient and used within a hospital setting within the same member state
in which they are manufactured under the exclusive professional
responsibility of a medical practitioner.

Academic research centres and public hospitals have a prominent role in
the initial phase of the ATMP development lifecycle (\textbf{Figure 2}
). With a strong knowledge of patient pathology and requirements,
clinicians and other workers in the hospital environment are well placed
to propose new ideas for potential ATMPs. Together with non-clinical
researchers and product manufacturing experts (usually from
immunological departments), the development of an initial idea into a
medicinal product can be materialised with enough funding capacity and a
clear knowledge of the regulatory steps to follow. Sharing these initial
thoughts with the regulatory agencies can help researchers to understand
the regulatory requirements and to streamline non-clinical and clinical
research required to support safety and efficacy studies. Indeed,
scientific, and regulatory advice increase the probability of obtaining
a MA. Almost 90\% of applicants who obtained scientific advice and
followed the advice given by the assessors received a positive opinion
when applying for MA versus 40\% for those who did not request
scientific advice.

\textbf{Clinical Trial Application and Investigational Medicinal Product
Dossier}

The clinical trial application (CTA) must provide comprehensive
information about the investigational medicinal product and the planned
trial that regulatory authorities need to assess before the initiation
of the clinical trial. In academic hospitals, there is usually broad
experience in designing clinical protocols and in writing the informed
consent forms needed for clinical trial development. However, when
facing the specific documentation of the studied medicinal product (such
as the Investigational Medicinal Product Dossier, or IMPD), expertise is
rather limited. Academic centres are not usually familiarised with the
product-related documentation needed by regulatory agencies. This can be
explained by the fact that this documentation is highly confidential,
and for traditional drugs, it is owned by the pharmaceutical industry
that sponsors the clinical trial. For ATMPs, in which academic centres
themselves are the drug developers, investigators are forced to learn
how to prepare the investigational medicinal product documentation in
order to obtain clinical trial approval.

Product-related documentation needed for a CTA includes mainly 3 large
pillars of information: product manufacturing, non-clinical development,
and risk \& benefit assessment. These 3 key aspects are discussed in the
following sections of the review and the fundamental content of each
section is summarised in \textbf{Figure 3} . Potential hurdles and
challenges of each part are described from a public and academic
hospital point of view.

Regulatory agencies need to evaluate all the scientific data accumulated
on the medicinal product that has been generated during the product
development stage. Therefore, all regulatory documentation must be
adapted to the existing level of knowledge and the product phase of
development. Moreover, when the product is first administered to humans,
no information regarding clinical data is available and the ATMP risk
and benefit assessment must be done using theoretical and plausible
arguments based on pre-clinical results. The existing state-of-the-art
must be evaluated for the medicinal product and although data from
existing similar products might be complementary, they are not
fundamental. Good quality data and promising non-clinical results must
be clearly demonstrated for a first-in-human administration. However, in
the case that the studied ATMP is already being used in the context of
another trial, it is possible to cross-refer the data submitted by
another sponsor and present the updated information of the product in a
simple format. This can only be done with the consent of the original
sponsor/developer of the medicinal product and with agreement from the
authorities to allow cross referencing. Likewise, the IMPD must be
constantly updated with all the acquired product data (manufactures,
non-clinical experiments, updated risk \& benefit and when available,
clinical data).

During the product development, clinical researchers have the
opportunity to interact with regulatory agencies to discuss the
sufficiency and adequacy of the quality of gathered data in a scientific
advice format. Applicants can present and discuss their results in a
structured manner by obtaining scientific advice and formulating
questions to receive regulatory feedback. This would normally include
not only a critical opinion about what has been done, but also proposals
of new experiments to better cover information gaps such as toxicology
studies, discussion of product specifications during the manufacturing
process or guidance on clinical indications for the clinical trial
design and performance, among other suggestions. For an academic
applicant, this formal interaction with the regulatory agencies is done
through a national scientific advice (via the Innovation Office).

\textbf{Product Manufacturing}

ATMP manufacturing is one of the most complex steps of the
pharmaceutical development. To achieve clinical trial approval, the
``Quality'' section of the IMPD must include a comprehensive quality
report that needs to be prepared according to the specific guidelines on
the quality of biological medicinal products. \textbf{Table 1} details
all sections that need to be completed, as a minimum requirement, with
quality data from the product under development. Information regarding
the exact quality data required in each section is also detailed
(\textbf{Table 1} ).

We considered several critical issues that might preclude application
success. These aspects need to be addressed and considered not only when
manufacturing AMTPs, but also when writing the quality report for
regulatory authorities:

\begin{itemize}
\tightlist
\item
  \textbf{Quality certification of facilities} : ATMPs must be
  manufactured following Good Manufacturing Practice (GMP) to accomplish
  regulatory standards (GMP Commission Directive 2003/94/EC). In
  general, academic hospitals do not possess a ``pharmaceutical quality
  system'' as their quality system is intended to ensure the best
  performance of care services for patients, but not to obtain a
  medicinal product with predefined quality characteristics. Therefore,
  an entirely distinct approach is required for all aspects of
  manufacturing an academic ATMP. Quality controls, trained personnel,
  certified facilities, registration and traceability of documentation,
  equipment validation, among many other variables, need to accomplish
  GMP standards. One strategy that could facilitate the achievement of
  GMP-compliant procedures in an academic environment is the use of
  closed and automated systems to manufacture ATMPs, as it is a way to
  minimise steps and controls. An automated and closed system can
  improve process robustness and scalability while maintaining strict
  adherence to GMP and regulatory guidelines. Another way to improve GMP
  compliance is by collecting and tracking all recorded information
  (e.g., room temperatures, production controls, etc.) in a digital
  format.
\item
  \textbf{Cost of batch analysis} : Another key challenge of ATMP
  production is the high cost of manufacturing each product batch. When
  the ATMP is manufactured as a single product batch (e.g., autologous
  chimeric antigen receptor T-cell therapy (referred to as CAR-T
  cells)), the production cost increases substantially. High cost might
  become prohibitive for academia as funding capacity is limited
  compared to conventional pharmaceutical industries. Scientific advice
  received by regulatory agencies becomes critical to improve
  cost-effectiveness when preparing the regulatory documentation.
  Another strategy to reduce costs in academic environments is the use
  of a ``pre-GMP'' facility to develop the manufacturing process before
  transferring the optimised methods to GMP suites.
\item
  \textbf{Limited product manufacturing capacity} : Autologous-based
  ATMPs (such as CAR-T or tumour infiltrating lymphocytes (referred to
  as TILs)) cannot be produced in a mass-scale system, and therefore,
  ATMP manufacturing capacity is rather limited. Having a centralised
  manufacturing centre for ATMP supply does not appear to be a feasible
  strategy in terms of academic logistics and functionality. Instead,
  a\emph{point-of-care} ATMPs manufacturing concept would be much more
  cost-effective and would increase product availability.
  The\emph{point-of-care} strategy would consist of having the ATMP
  manufactured at the site where a patient receives care. As such,
  certified hospitals would be able to produce a certain ATMP, resulting
  in a faster supply of manufactured products in response to clinical
  demand and a more optimal organisation and transportation of the
  cellular material. In the case of CAR-T cells, for example,
  centralised manufacturing of the vector encoding the CAR molecule
  could be distributed to different hospitals with the capacity to
  manufacture CAR-T cells for their own patients. In this way, with
  strong academic collaboration, the limited product manufacturing
  capacity of ATMPs would be improved and expanded.
  This\emph{point-of-care} ATMP production strategy requires that
  manufacturing hospitals are GMP certified, and that regular
  comparability studies are carried out to prove the equivalence of the
  ATMP among centres. Recommendations for comparability studies for
  ATMPs are described in the ICH Q5E guidelines and in a related
  questions and answers document So far, this point-of-care
  manufacturing strategy has not been applied, but a growing interest in
  the potential application of such a scheme is shown by initiatives
  like the proposal of a regulatory framework presented by the Medicines
  \& Healthcare products Regulatory Agency of the United Kingdom
  (January 2023).
\item
  \textbf{Large product variability} : The great variability in ATMP
  origin (i.e., ATMP starting material) strongly impacts manufacturing
  standardisation. As ATMPs are biologically complex, many intrinsic
  variabilities are observed among products. When preparing the quality
  documentation for a CTA, it is essential to obtain as much information
  as possible regarding the product and its starting material. Analysing
  all of the collected data regarding the manufactured product can help
  in the establishment of accurate and reasonable specifications.
  Product specifications must be revised periodically and adjusted to
  experience in manufacturing the product. Efforts to reduce external
  variability (i.e., qualification of analytical methods, supply of
  starting materials) are already needed at the initial steps of product
  development.
\item
  \textbf{Understanding of quality terminology} : Another common hurdle
  for the development of academic ATMPs is the general lack of
  experience in writing quality regulatory documentation. Quality data
  must be presented in a structured way (see \textbf{Table 1} ) to
  regulators. European guidelines on quality, non-clinical and clinical,
  requirements help to gain a general idea of what must be presented.
  However, we found that the \emph{learning-by-doing} strategy is
  certainly the most effective one to correctly report the quality
  results in an IMPD. Some tips that we learned during the writing of
  several quality reports are: i) for certain ATMPs, the drug substance
  and the finished product (drug product) can be closely related or
  nearly identical and therefore quality data can be cross-referred to
  avoid repetitions; ii) planning enough samples to perform future
  analysis is key to determine product stability under representative
  conditions of its storage; iii) potency assays are critical to prove
  the product biological activity and biomarkers assays can be accepted
  if the surrogacy value is reasonably established; iv) for gene-therapy
  medicinal products (for example for CAR-T cells), a full quality
  report is needed for each starting material and all sections of the
  cellular product (see \textbf{Table 1} ) must be written for the
  vector material.
\end{itemize}

In all, the preparation of quality regulatory documentation is
progressive and continuous among the product development. Regulatory
standards contribute to the manufacturing of robust ATMPs that can
impact therapeutic response. Indeed, quality concerns of ATMPs often
influence potential efficacy or safety of that product in patients.
Regulatory documentation must be constantly updated and controlled to
guarantee product robustness.

\textbf{Non-clinical development}

The initial essential step is the design of the ATMP construct itself.
This process involves high-excellence basic science, of course
orientated to a detected clinical need, and is highly dependent on the
capabilities of the centres and experts. Once the concept is created,
the safety and proof of concept non-clinical experiments also have to be
developed and performed according to regulatory standards.

Non-clinical studies aim to demonstrate the safety of a medicinal
product and to provide an initial proof of concept of the product mode
of action, pharmacological and toxicological effects, as well as the
potential efficacy. Non-clinical assays generally include the
characterisation of toxic effects in relevant cell lines and target
organs, dose dependence, and relationship to exposure. These data should
help to define the estimated therapeutic dose-range, and the dose steps
and intervals for developing clinical trials in humans. However, due to
the complexity and innovative nature of ATMPs, the non-clinical
development must be adapted to a tailored approach that includes
principles of risk identification and mitigation. Traditional
non-clinical studies and models are not always feasible with ATMPs, and
this poses new challenges to developers and regulators to identify
common principles that must be tested before a first-in-human clinical
trial.

From our experience in non-clinical studies, there are several critical
aspects that need to be addressed when writing the regulatory
documentation:

\begin{itemize}
\tightlist
\item
  \textbf{Tailored approach for ATMPs non-clinical models} : In general,
  animal testing is considered necessary when it generates data that
  provides significant conclusions (like the identification of potential
  hazards for human health based on extrapolation from animal data). On
  the other hand, regulators commonly considered that lack of specific
  safety pharmacology and genotoxicity testing was acceptable for ATMPs.
  Furthermore, experiments were not commonly required for reproductive
  toxicity if there was scientific evidence demonstrating lack of
  exposure to reproductive organs. Conventional carcinogenicity testing
  was also mainly waived, as it was not considered suitable or
  appropriate for ATMP risk assessment. The non-clinical testing models
  that are usually required during the evaluation of ATMPs predominantly
  include the determination of toxicity endpoints by performing specific
  safety studies. For CAR-T cell therapies in haemato-oncological
  studies for example, essential results to provide include as
  evaluation of \emph{on-target/off-tumour} toxicity, biodistribution
  analyses and assessment of \emph{in vivo} persistence. In addition,
  the inclusion of efficacy studies (such as \emph{in vitro} and\emph{in
  vivo} cytotoxicity assays, measurement of pro-inflammatory cytokines,
  assessment of anti-tumour activity from patient-derived samples, etc.)
  is strongly recommended for the preparation of ATMP non-clinical
  regulatory documentation.
\item
  \textbf{Model limitations} : One of the major challenges to the
  non-clinical development of ATMPs is the important biological
  differences between test species and humans. ATMPs include human
  cell-based products that will inevitably be rejected in an
  immunocompetent animal. Therefore, the use of immunocompromised
  animals has commonly been regarded as the only feasible alternative.
  However, determining the behaviour of human cell-based products in
  immunocompromised animals is complicated because the activity of the
  exogenous cells is strongly influenced by interactions with other
  tissues and cells of the animal model which may or may not be
  functional or even present at all. In general, there is a strong
  preference to use allogenic or autologous cells that simulate the
  human situation in a homologous animal (i.e., an animal that has the
  same disease causes, symptoms and treatment options as would humans
  with the same disorder). A commonly employed animal model is the NSG
  or -NOD.Cg-Prkdc\textsuperscript{scid} Il2rg\textsuperscript{tm1Wjl} /
  SzJ- strain of inbred laboratory mice. These mice allow for the
  engraftment of a wide range of human-derived cells and permit
  sophisticated modelling of many human diseases. However, the principle
  of the 3Rs (replacement, reduction, and refinement) needs to be
  considered when selecting testing approaches to be used for regulatory
  testing of ATMPs.
\item
  \textbf{General tips} : It is important to realise that just by
  following protocols from peer-reviewed scientific publications,
  especially when not conducted according to regulatory standards, may
  not be enough to resolve uncertainties needed for regulatory approval.
  Moreover, it is important to note that non-clinical developers need to
  fully understand the product in relation to the intended use and
  prospectively plan the approach for successful translation of the
  product to the clinic. Likewise, having an in-depth understanding and
  knowledge of the ATMP, developers can justify their study designs,
  test models and tailored approach. Being able to communicate clear
  scientific information about the non-clinical development to
  regulatory authorities is strongly recommended to receive valuable
  input and assessment of regulators that can complement the knowledge
  and planning of academic developers for the progression of their
  product. For non-clinical regulatory documentation, academic
  developers must discuss the limitation of the chosen models and the
  relevant information that these models provide.
\end{itemize}

Another lesson learned during different clinical trial applications with
ATMPs is that a safety assessment can be complemented with a discussion
of potential risks or hazards in line with the recommendations discussed
in the EU guideline on risk-based approach (see section 3.3 Risk \&
benefit assessment). Furthermore, the use of literature data can
support, at least partially, the preparation of non-clinical regulatory
documentation. In particular, if clinical data from very similar or
identical products used for the same indication are available, these can
be used to support the CTA for an ATMP. Finally, another recommendation
when performing non-clinical research is that for key studies (such as
biodistribution or toxicity assays), researchers must use the product
intended for clinical use (i.e., the product must be representative of
the product material used in patients).

\textbf{Risk \& benefit assessment}

Current regulatory recommendations establish that a risk-based approach
involves recognising the potential risks linked to the clinical
application of an ATMP and the inherent risk factors of the ATMP itself
in terms of quality, safety and efficacy. A risk-based approach helps to
anticipate potential risks associated with a new product, and judge if
they are acceptable when balanced with the potential benefit. Therefore,
the risk-benefit assessment of the investigational medicinal product
must be included in the regulatory documentation with an overall
assessment and measurement of favourable and unfavourable effects. This
assessment can be quantitative (i.e., adverse events incidence or
prevalence in a clinical trial) or qualitative (i.e., description of
relevant data from literature and associated risk factors), depending on
the therapeutic context and clinical study design, but must clearly
discuss the expected clinical relevance of the benefits, the importance
of risks (both identified and potential risks) and the impact of
uncertainties and limitations of that analysis.

From our experience in the assessment of the risk-benefit balance of
academic-developed ATMPs, we consider the following barriers:

\begin{itemize}
\tightlist
\item
  \textbf{Risk characterisation:} Because ATMPs predominantly cover an
  unmet medical need, the potential benefit is usually easier to
  characterise than the possible risks. However, when it comes to risk
  evaluation, the lack of previous experience makes this particular
  hurdle even larger. As explained above for non-clinical development,
  conventional safety testing is not always available for ATMPs and
  there are model limitations. Moreover, relevant literature is scarce,
  and mostly pertains to early development phases, with little
  information in humans. Therefore, the risk assessment in the
  pre-clinical phase is in many cases based on the early detection of
  safety signals, and in most instances, is difficult to translate into
  humans. In any case, the applicant is obliged to describe in a tabular
  form: i) hypothetical risks (based on literature review and
  elucidation of its mechanism of action), ii) a corresponding
  description and/or discussion, iii) known and potential features that
  may have an impact (protective or risk factors) on patient safety, and
  iv) risk minimisation strategies to be implemented. Even though this
  information remains mostly descriptive and qualitative, displaying the
  data in this way allows for better categorisation of the risks and
  provides a clearer presentation and understanding of the data.
  Adequate and sensible planning of risk mitigation strategies is a
  necessary exercise to reduce uncertainties, thus helping the
  risk-benefit balance lean towards the positive side.
\item
  \textbf{Risk Heterogenicity:} ATMPs are complex products that differ
  in clinical development and manufacturing process for each product,
  even when they are used for the same indication. Therefore, risks will
  also differ for each ATMP. To describe the risks associated with a
  specific ATMP, it is important to have a comprehensive background in
  every step of the development of the medicinal product. This means
  thorough understanding of not only the target and mechanism of action,
  but also of the manufacturing process, ATMP structure, route of
  administration, indication and pre-clinical development. As an
  example, some CAR-T cell products with a CD28 co-stimulatory domain
  have been linked to early development of cytokine release syndrome in
  comparison to CAR-T cells designed with 4-1BB .
\item
  \textbf{Other regulatory tools and documentation}
\end{itemize}

To complete the CTA (see \textbf{Figure 2} ), other information related
to the clinical trial related information is also required. These
documents are evaluated by regulatory agencies (through the Clinical
Trials Information System (CTIS)) and by local ethical committees.
Clinical trials must follow Good Clinical Practice guidelines
(influenced by the Nuremberg Code) to guarantee that the investigational
drug administration to humans has the lowest health risk to patients in
the tested conditions. The most relevant information presented to health
regulatory authorities is the clinical protocol which details the exact
steps to be taken to test the new medication on humans. The key aspects
that need to be included in the clinical protocol are the study
population, the dose selection and the safety monitoring plan. Other
relevant documentation includes the patient informed consent form, that
must be clear and comprehensible for patients and the investigator's
brochure (IB), that summarises all the known non-clinical and clinical
safety and efficacy data of the medicinal product. All these documents
must be prepared and updated for each clinical trial, and they must
contemplate the necessary precaution to protect the safety of the
clinical study subject.

\textbf{General discussion}

Advanced therapies have been a reality as a therapeutic tool for several
years now. Europe has already approved 25 ATMPs. The potential for
developing advanced therapies is virtually limitless, offering the
possibility of developing new, relatively personalised therapeutic
strategies for multiple unmet medical conditions.

From the beginning, the collaboration between academic centres (drug
discovery) and the pharmaceutical industry (drug development and
marketing authorisation) has been a common practice in this field.
Academic centres play a fundamental role in identifying unmet medical
needs, therapeutic targets, and the development of the basic science
underlying the entire medical process. However, in recent years, some
academic centres have completed the entire process of developing
advanced therapies that have become available to patients in some
European countries. Specifically, in Spain, there are two products in
this category (NC1 and ARI-0001). These milestones have been made
possible thanks to the legislative development of the so-called
''hospital exemption'', a provision available throughout the EU and
implemented in the majority of countries, but with different regulatory
requirements among member states.

Hospital exemption is only possible to obtain national authorisation
with very limited indications (mainly unmet medical needs) and limited
access conditions (restricted to a hospital centre or a few centres).
Therefore, under current conditions, it is difficult to envision this
regulatory pathway as a real solution for accessing these medicines
within the EU. Harmonised legislative development among EU member states
would be necessary to ensure that this access occurs uniformly
throughout Europe. Only coordinated political will is likely to lead to
future solutions within this regulatory framework.

In this regard, the initiative of the EMA to provide the necessary
regulatory tools to academia for facilitating global access in the EU is
appreciated. With this initiative, academic centres can be offered the
possibility of obtaining a centralised authorisation for the entire EU.

Unfortunately, the existence of different access pathways does not
eliminate all barriers to the development of ATMPs. The complete
development of advanced therapies, while adhering to current regulatory
requirements, remains a challenge for academic centres. There are
multiple reasons that could explain these difficulties:

\begin{enumerate}
\tightlist
\item
  Regulatory knowledge: Regulatory expertise is not abundant in
  academia. Despite its slow growth, there are a few centres that have
  experts in drug regulation who understand the philosophy and
  underlying science of regulatory principles, recognize the importance
  of drug regulation in protecting citizens, and can use the terminology
  required by the regulator. Therefore, it is critical for academic
  centres intending to develop new medicines to acquire the necessary
  expertise. Probably due to lack of awareness, there seems to be a
  certain mutual distrust between regulatory agencies and academia.
  Academics tend to think that regulations establish unnecessary
  barriers that hinder patient access to promising therapies.
  Regulators, on the other hand, doubt whether academic applicants are
  aware of the importance of protecting patient safety and complying
  with basic regulatory requirements (such as GMP, GLP (good laboratory
  practice), and GCP (good clinical practice)). These barriers can only
  be overcome through continuous dialogue between both parties. Indeed,
  regulatory agencies have official platforms (such as the Innovation
  Office of AEMPS (\emph{innov\_spain@aemps.es} )) that facilitate and
  promote an early interaction between researchers and regulators. And
  recently, the EMA has launched a pilot study to support academic and
  non-profit institutions to develop ATMPs. It is crucial for
  researchers to become aware of the importance of weighing risks and
  designing a risk minimisation plan that progressively advances basic
  research to the clinic. Additionally, some regulators should
  understand that a risk minimisation strategy should not turn into risk
  avoidance, as this leads to the stagnation of development.
\item
  Capacity to meet production demands: It is not difficult to imagine
  that for ultra-rare diseases with very low prevalence, producing a
  medicine for the entire Europe, even in a single academic centre, may
  be an achievable goal. However, for more prevalent indications (even
  if they are rare diseases), ensuring that manufacturing can meet
  actual needs is a tremendous challenge. The pharmaceutical industry
  has the means to establish production centres on a global scale,
  something that is not possible for academia. One way to alleviate this
  difficulty in certain types of advanced therapies (such as CAR-T
  cells) could be the implementation of the Point of Care model.
  According to this model, lentiviral production is carried out by the
  developing centre, while cell production takes place at the centre
  where the medicine is administered. This model offers significant
  advantages in terms of accessibility, patient convenience, and
  production speed. However, it is not without complications, as the
  regulatory requirements of educating, establishing, accrediting,
  inspecting, and maintaining cell production with demonstrated
  comparability in multiple centres requires significant financial and
  regulatory efforts to ensure consistent and quality production in all
  manufacturing centres.
\item
  Maintenance of marketing authorisation throughout the product
  lifecycle: There is no doubt that early patient access to these
  therapies is the main objective of any academic or industrial
  initiative, but it is not the only or final objective. It is essential
  to maintain the use of the medicine under optimal safety and efficacy
  conditions, ensure manufacturing adheres to the strictest quality
  principles, and to be responsible for the product throughout its
  lifespan by periodically updating safety and efficacy data and
  reporting them to the competent authority. This requires a long-term
  vision and necessary resources that academia must progressively
  acquire.
\end{enumerate}

In conclusion, the authors believe that we are at the beginning of a
path that is yet to be fully defined. The increasing attention that
regulatory authorities are paying to academic initiatives in this field
(such as the Innovation Office of the AEMPS and the Academic Initiative
of the EMA) is common knowledge. We believe that these are suitable and
necessary instruments for involving and engaging academia in the
development of ATMPs while meeting all quality, safety, and efficacy
requirements. This commitment should be mutual, with academia deepening
its understanding of applicable regulatory requirements.

\textbf{Acknowledgements}

The authors would like to acknowledge Oriol del Teso for his
contribution to data collection during manuscript preparation and
Anthony M. Battram for his help with manuscript editing. Furthermore,
this work was made possible thanks to the involvement of many staff
members of the Immunology and Haematology departments of the Hospital
Clinic of Barcelona.

\textbf{Conflicts of interest}

The views expressed in this article are those of the authors and do not
necessarily represent the views or policies of the Spanish Agency of
Medicines and Medical Devices (AEMPS) or the Hospital Clinic de
Barcelona (HCB). All authors declare that they have no competing
interests.

\textbf{Bibliography}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1} . Approved ATMPs in the EU from 2012 to 2022. Blue
boxes show ATMPs for which the sponsor is either a pharmaceutical
company or a private biotech while orange boxes are those that
originally come from an academic centre (universities and hospitals) but
developed and commercialised by a pharmaceutical company. For example,
Kymriah\selectlanguage{ngerman}\textsuperscript{®}, was originally developed at the University
of Pennsylvania and bought by Novartis who performed all the
pharmaceutical development and commercialisation. Filled boxes are ATMPs
that are currently authorised by the EMA while empty boxes show
withdrawn products. This figure is adapted from the CAT quarterly
highlights and approved ATMPs document.

\textbf{Figure 2}. Overview of the lifecycle of an ATMP (key steps of
the drug pharmaceutical development). Adapted from the slides of the
STARS Pilot III Regulatory Support project. Figure prepared with
Biorender\textsuperscript{®}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3.} Schematic summary of the main product-related
regulatory content needed for a clinical trial application. Figure
prepared with Biorender\selectlanguage{ngerman}\textsuperscript{®}.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{IMPD/ CTD section}\strut
\end{minipage} & \begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{Requirements applicable to all ATMPs}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{3.2.S. Drug Substance}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{3.2.S. Drug Substance}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2.S.1. General information\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Nomenclature of the product. · Information on the structural component
and summary of the physical and biological characteristics of the
substance. · General physicochemical properties of the active
substance.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2.S.2. Manufacture\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· List of manufacturers of the active substance. · Summary of the
manufacturing process (complete flowchart and reagents used should be
included). · Controls of materials (e.g., raw materials, starting
materials, reagents) · Controls of critical steps and intermediates of
the active substance. · Description of any development work done to
optimise the production operations.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2.S.3. Characterization\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Elucidation of structure and other characteristics. · Impurities
(process-related impurities and cellular impurities).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2.S.4. Control of the drug substance\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Specifications (for the active substance release). · Description of
the analytical methods used for testing the active substance. ·
Suitability, qualification, or validation data of the analytical methods
used (depend on the status of the product development). · Batch analysis
(tables of all the manufactured data of the active substance). ·
Justification of specifications.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.S.5. Reference Standards or Materials\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Characterization of the batch substance to establish a reference
standard (only in case of international standards available).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.S.6. Container Closure System\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Information on the immediate packing material.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.S.7. Stability\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Data of storage conditions (in case it is not immediately
processed).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{3.2.P. Drug Product}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{3.2.P. Drug Product}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.P.1. Description and composition\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Qualitative and quantitative composition of the finished medicinal
product.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.P.2. Pharmaceutical development\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Short description of the formulation development and justification of
using any new pharmaceutical form or excipient.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2.P.3. Manufacture\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· List of manufacturers of the drug product. · Description of the
manufacturing process and controls. · Control of all material used in
the manufacture of the substance. · Control of critical steps and
intermediates. · Process validation and/or evaluation. · Manufacturing
process development.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.P.4. Control of excipients\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· References to the pharmacopoeia for the excipient's
specifications.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2.P.5. Control of the medicinal product\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Drug product specifications (quality attribute) for product release. ·
Analytical procedures and validation of these analytical methods. ·
Batch analysis (with data from all the manufactured drug products). ·
Additional impurities observed in the medicinal product. · Justification
of the specifications (for product release).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.P.6. Reference Standards or Materials\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Parameters for characterisation of reference standards (where
applicable).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.P.7. Container Closure System\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Information on the immediate packaging material.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.2.P.8. Stability\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\selectlanguage{ngerman}· Stability studies of the medicinal product.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 1.} Summary of the main regulatory requirements for the
quality documentation. Table adapted from the \emph{Guideline on the
minimum quality and non-clinical data for certification of ATMPs} .

\selectlanguage{english}
\FloatBarrier
\end{document}

