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 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 (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.
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 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).
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. 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 (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:
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.
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:
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).
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:
To complete the CTA (see 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.
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:
  1. 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 (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.
  2. 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.
  3. 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.
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.