POLICY AND PRACTICE REVIEWS published: 04 February 2021 doi: 10.3389/fcvm.2021.604434 Transitioning From Preclinical Evidence to Advanced Therapy Medicinal Product: A Spanish Experience Paloma Gastelurrutia 1,2,3*, Cristina Prat-Vidal 1,2,3 , Joaquim Vives 4,5,6 , Ruth Coll 4 , Antoni Bayes-Genis 2,3,7,8 and Carolina Gálvez-Montón 2,3 1 Institut d’Investigació Biomèdica de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Spain, 2 Insuficiencia Cardíaca y Regeneración Cardíaca Research Program, Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain, 3 Centro de Investigación Biomédica en Red Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain, 4 Servei de Teràpia Cel·lular, Banc de Sang i Teixits, Barcelona, Spain, 5 Musculoskeletal Tissue Engineering Group, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain, 6 Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain, 7 Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 8 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain Edited by: Kim Connelly, St. Michael’s Hospital, A systematic and ordered product development program, in compliance with current United Kingdom quality and regulatory standards, increases the likelihood of yielding a successful Reviewed by: advanced therapy medicinal product (ATMP) for clinical use as safe and effective therapy. Manuel M. Mazo, University of Navarra, Spain As this is a novel field, little accurate information is available regarding the steps to be Pauline Meij, followed, and the information to be produced to support the development and use of Leiden University Medical Center, Netherlands an ATMP. Notably, successful clinical translation can be somewhat cumbersome for *Correspondence: academic researchers. In this article, we have provided a summary of the available Paloma Gastelurrutia information, supported by our experience in Spain throughout the development of an pgastelurrutia@gmail.com ATMP for myocardial infarction, from the pre-clinical stage to phase I clinical trial approval. Specialty section: Keywords: advanced therapy medicinal product, investigational medicinal product, investigational medicinal This article was submitted to product dossier (IMPD), translational (regulation), regulatory agency Cardiovascular Biologics and Regenerative Medicine, a section of the journal INTRODUCTION Frontiers in Cardiovascular Medicine Received: 09 September 2020 Recent years have brought tremendous developments in cardiac tissue engineering (1). Cell therapy Accepted: 04 January 2021 approaches have been attempted for the repair of scars left by myocardial infarction (MI); however, Published: 04 February 2021 clinical trials have reported only modest and clinically irrelevant improvements in cardiac function Citation: (2–4). Thus, the research focus has shifted to cardiac tissue engineering approaches that can deliver Gastelurrutia P, Prat-Vidal C, Vives J, cells to the injured myocardium with supportive scaffolds, thus improving cell retention and Coll R, Bayes-Genis A and survival (5). Successful clinical translation of these engineered constructs requires that specific steps Gálvez-Montón C (2021) Transitioning be followed from scientific, quality, and regulatory standpoints. First, they have to be conceived and From Preclinical Evidence to Advanced Therapy Medicinal Product: developed in a basic research laboratory. Second, they need to be confirmed as safe and effective A Spanish Experience. in relevant animal models. Third, they must be adapted to current good manufacturing practice Front. Cardiovasc. Med. 8:604434. (GMP)-compliant procedures for obtaining an advanced therapy medicinal product (ATMP). doi: 10.3389/fcvm.2021.604434 Finally, the ATMP has to be tested in patients in the context of a clinical trial. Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP SECTIONS ON ASSESSMENT OF Four Stages Along the Journey POLICY/GUIDELINES OPTIONS AND Preclinical Stage IMPLICATIONS Basic research laboratories can generate regenerative/repair- driven hypotheses and test them in animal models. To achieve In 2003, the concept of ATMP was defined and introduced in clinical translation, a newly developed ATMP must be proven safe European legislation. ATMP originally comprised gene therapy and effective in a planned preclinical program including studies medicinal products (GTMPs) and somatic cell therapy medicinal addressing pharmacodynamics (PD), pharmacokinetic (PK), and products (CTMPs), with the later inclusion of tissue-engineered toxicology (Tox) (16, 17). For a product to be proven safe, the products (TEPs) in Regulation (EC) No. 1394/2007 (6, 7). The risk-benefit profile must be assessed as acceptable for the target ATMP industry is still emerging, and many therapy proposals in disease or condition, the product must be well-characterized to this field are led by independent researchers who have little, if reduce batch variability and ensure the expected function, and any, process development experience (8). the genetic stability must be confirmed. Accurate characterization ATMPs are ground-breaking medicines based on the use of the product is also important for avoiding differences in of genes, tissues, or cells for the treatment of human disease effectivity, ensuring consistency from dose to dose (11). Thus, as and injury. They are classified into four main types: GTMPs, soon as possible, it is important to define the identity, viability, CTMPs, TEPs, and combined ATMPs. GTMPs contain genes purity, and potency of the ATMP. that have therapeutic, prophylactic, or diagnostic effects. CTMPs Experiments in animal models should be conducted to include cells or tissues that have been substantially manipulated evaluate the biodistribution of an ATMP in principal organs to change their biological characteristics, physiological functions, (e.g., brain, liver, spleen, lungs, kidneys, and gonads), to identify or structural properties, or that are intented to be used for a target organs and tissues (18), and to assess local effects. Studies purpose other than their essential functions in the body, with must review and confirm the expected mechanism of action the aim of treating, preventing, or diagnosing a disease. TEPs of the product’s active ingredient, i.e., the biologically active contain modified cells or tissues of human and/or animal origin ingredient that exerts the expected therapeutic effect. Animal (viable or non-viable) that are used to repair, regenerate, or experiments should also reveal an absence of tumorigenic activity replace human tissue (9). Finally, combined ATMPs contain a and an acceptable safety profile. In terms of effectiveness, animal medical device as an integral part of the product (10). They models may prove efficacy by confirming the hypothesis at the may also contain additional substances, such as biomaterials, preclinical level. In some cases, no animal model is available chemicals, scaffolds, or matrices. The mechanisms of action of for the specific pathology under investigation. In this case, a ATMPs include pharmacological, immunological, or metabolic new model can be designed if the basic research group has activities (10). sufficient experience in the pre-clinical large animal setting, and Due to the novelty and complexity of ATMPs, there is a can fine-tune a model to mimic a human pathological scenario. lack of accurate information regarding the steps required for However, sometimes a disease cannot be reproduced due to its their clinical translation, and data that must be produced to high complexity or mortality. In this scenario, pre-clinical studies achieve regulatory agency approval. This can make it difficult can be performed using different animal models that present the for independent researchers from an academic environment different symptoms separately. to successfully get an ATMP to the patient population. Prior to administration to a patient, the product must comply Investigational medicinal product (IMP) development can be with the above-described requirements, as well as others. challenging in many aspects, including materializing a research idea, cell/tissue isolation and characterization, preclinical studies Translational Stage to prove safety and efficacy, scaling-up prototypes for human use, We refer as the translational stage, the phase during which the defining manufacturing processes in accordance with current researchers have a proof of concept and are ready to start working GMP, and meeting all ethics and regulatory requirements to develop a product for clinical use. Several considerations must (10–14). Our group recently developed a pioneering ATMP, be taken into account for products intended for human use: named PeriCord, that is presently being tested in humans for cardiac repair after MI. PeriCord comprises a human 1. The preclinical product must be adapted to fulfill the decellularized pericardial matrix enriched with Wharton’s jelly- regulatory and legal requirements for human use. To this derived mesenchymal stromal cells (15). Here, we report our end, the ATMP must be manufactured following procedures experience in creating this IMP in Spain, and through its in compliance with current GMP standards and in GMP- translation from preclinical stages to use in patients (15). accredited facilities. If the preclinical product was not originally produced using GMP procedures and/or clinical grade reagents, it should be modified. Due to the potential Abbreviations: AEMPS, Spanish Agency of Medicines and Medical Devices; impact on the final product’s safety and quality, ATMP AEMPS, Agencia Española del Medicamento y Producto Sanitario; ATMP, developers must make available the quality attributes and Advanced Therapy Medicinal Product; MTA, Medicamento de Terapia Avanzada; composition of all raw materials used in the manufacturing CTD, Common Technical Document; IMP, Investigational Medicinal Product; PEI, Producto En fase de Investigación; IMPD, Investigational Medicinal Product process. Importantly, this information is required for Dossier; EPEI, Expediente de Producto En fase de Investigación; TPP, Target the regulatory submission, especially when animal-derived Product Profile; FDP, Ficha de Desarrollo del Producto. components are used. Any raw materials and excipients Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP must be suitable for clinical use, and some may have to 2. Reproducibility, safety, and consistency: There are several be substituted for others with similar characteristics upon critical process stages for assuring consistency and meeting the appropriate risk analysis and experimental testing (e.g., established specifications of the finished drug product (DP)— xeno-free, clinical grade ingredients) (19), which may be including tissue harvesting, cell isolation and expansion, more expensive. Additionally, sometimes extensive ex vivo cell and finished product storage, lot size (number of cells expansion is required to yield sufficient cell numbers for per production batch), and methods. The manufacturing clinical use, and scale-up processes should be defined and bioprocess is designed to minimize the risks of deviating incorporated within the manufacturing procedure to adapt from specifications along the production process, such that doses and/or final product dimensions to human scale (20). there is no need to solely rely on testing of the finished 2. For autologous cell products, “scaling-out” usually requires product. This is known as “quality by design (QbD),” an the ability to conduct multiple parallel bioprocesses by approach that aims to ensure product quality by combining using traditional planar 2D cultures for the production statistical, analytical, and risk-management methodologies of larger amounts of finished product (20, 21). For into the design, development, and manufacturing processes unmatched allogeneic products, “scaling-up” involves (24–26). Acceptance and release criteria must be determined the use of expansion platforms, such as bioreactors, to to ensure the safety and consistency of the final DP, entail reproducible and robust manufacturing bioprocess, with regards to microbiological growth (negative serological therefore offering major advantages with respect to and microbiological testing), physiochemical properties, GMP implementation. dose range, cell viability, and endotoxin levels, among other concerns. Some specific documents must be generated to collect all of 3. Scalability: Process scalability is a major factor to consider the information required by the competent authorities for their when starting from a preclinical product and aiming to evaluation and approval of the IMP, and their approval of a develop its corresponding IMP format. For translational clinical trial together with the local ethics committee. These allogeneic cell therapy that requires cells, reagents, and culture aspects will be detailed in the section ATMP approval for media, large numbers of cells are needed to achieve a clinical trials. certain dose ready for use in several patients, thus affecting product cost and quality (17). The cells must retain their key quality attributes of identity, potency, purity, and safety, Production Stage and there must be no changes in quality with regards to cell Several issues must be addressed prior to the actual production of differentiation capability (11). Quality by design strategies and an ATMP. classical experimental design approaches can be applied to 1. GMP compliance: The ATMP manufacturing facilities must optimize cell culture media, reagents, and process parameters comply with current GMP, thus guaranteeing the quality and to create a robust, reproducible, and scalable process (11, 27). safety of the manufactured products. This accreditation is 4. Stability: The DP stability period must be determined based granted by the competent authorities, e.g., the AEMPS in on cell stability and the product life cycle (28). Cells can Spain. GMP is a quality management system to ensure that multiply, but do not have to multiply continuously, only when products are consistently processed and controlled according needed for their normal cycle. When they multiply, they must to quality standards. This system guarantees traceability maintain a stable karyotype and stable expression of cytokine at all times, covering every aspect of manufacturing and markers and telomerase. The product life cycle is the process distribution. GMP covers all aspects of production, from a product goes through once it is released until it is removed the starting materials, premises, and equipment to staff upon reaching its expiration date. This shelf-life is determined training and personal hygiene. It is essential to have detailed based on changes in the product characteristics, and is assessed written procedures (standard operating procedures; SOP) for in the preclinical stage and during product development, and each process that could affect the finished product quality, might be reassessed during the clinical trial phase according to which are followed each time a product is manufactured the product stability protocols. (22). Quality control documents are required to register All of these factors must be considered to manufacture a clinically all utilized processes and materials, including batch records appropriate product adapted from the preclinical version. The and expiration dates. The products commonly used in end results must be a comparable product in terms of identity, preclinical studies are often unsuitable for clinical use. For purity, potency, and safety (29). some such ingredients, excipients, or culture reagents, there is an equivalent, generally more expensive, GMP-compliant alternative. However, other materials may be more difficult to ATMP Approval for Clinical Trials replace. For example, bovine serum has been widely used in After the preclinical and translational stages, and upon achieving cell culture for over a century (23), but the current trend is to ATMP manufacturing and validation, all required information switch from the use of serum or platelet lysate to serum-free must be presented to the competent authority and final approval chemically defined media formulations to alleviate concerns obtained to commence a clinical trial. Here we summarize all regarding safety (i.e., xenoviral transfer and contamination), of the documentation required for presentation to the Spanish efficacy (batch-to-batch variation), and scarcity (11, 20, 23). Agency of Medicines and Medical Devices (AEMPS): Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP 1. Target Product Profile (TPP): This is not a mandatory document in Spain, but rather a summary of the necessary information about the product development process. A TPP is created with the aim of ensuring that the drug development process is efficient and provides all of the required medical, technical, and scientific information about a product (30). It can be worthwhile to start the TPP at an early stage (preclinical stage) to provide a clear vision of the whole process. 2. Investigational Medicinal Product Dossier (IMPD): The IMPD, including modules 1 to 5 (described below), is one of the main IMP-related documents required for clinical trial approval in one or more European Union Member States. The IMPD includes regional administrative information and summaries of the data related to the quality, manufacture, and control of any IMP (including both reference product and placebo), as well as data from non-clinical and clinical studies (Figure 1). The AEMPS does not offer guidance on writing an IMPD, but suggests following the European Guidance from the European Medicines Agency (EMA) (31). Figure 1 shows the parts of the IMPD as summarized in a Notice to Applicants (32) prepared by the European Commission in consultation with competent authorities of the member states, the EMA, and other interested parties as a guideline for fulfilling the obligations raised by Article 6 of Regulation (EC) No. 726/2004, and with respect to Annex I of Directive 2001/83/EC (European Commission Notice to Applicants). Based on this Notice to Applicants, we adapted the index for our IMP, as shown in Table 1. The IMPD includes the following modules: FIGURE 1 | Parts of the Investigational Medicinal Product Dossier (IMPD) as - Module 1: This section is not a part of the Common Technical collected in the Notice to Applicants prepared by the European Commission. Document (CTD), and includes all regional administrative information required by the AEMPS. - Module 2: This module provides an overview of all of the (Module 2, section Quality overall summary, and Module information, divided into several sections, including a table 3), as well as the pharmacological mechanism of action, of contents (2.1), introduction (2.2), review of the quality pharmacokinetics, toxicity, biodistribution, and safety (Module information (2.3), review of the non-clinical data (2.4), review 4). The IMPD serves as an excellent tool for defining all of the clinical data (2.5), and two tabulated summaries: one for necessary preclinical studies, and for aligning manufacturing the non-clinical data (2.6) and one for the clinical data (2.7). process requirements with product specifications (11). - Module 3: This section is a compendium of the available 3. Common Technical Document (CTD): The International quality information, which will also be sent as a discrete Council for Harmonization of Technical Requirements for document in Block I of the required documentation for Pharmaceuticals for Human Use (ICH) has the mission of the Ethics Committee and AEMPS evaluation (see below). bringing together regulatory authorities and pharmaceutical The document includes data regarding the characterization, industries worldwide to ensure that safe, effective, and high- fabrication, specifications, stability, packaging, and quality quality medicines are developed and registered in the most control analysis of the active ingredient and the finished resource-efficient manner (33). Toward this aim, they created product (i.e., the ATMP). a common format, the CTD (Figure 1), to gather information - Module 4: This module constitutes a compendium of the regarding quality, safety, and efficacy. Module 1 is region- available non-clinical data, which includes toxicity and specific, while Modules 2, 3, 4, and 5 are intended to be biodistribution studies, mechanism of action, and safety data. common among all regions—as has been mandatory since July For TEPs, this includes information concerning the genetic 2003 in the EU and Japan, and is the strongly recommended stability of the active cells, and in vivo efficacy studies. format of choice in the United States. - Module 5: This non-compulsory module includes clinical 4. Protocol: The protocol describes how the clinical trial will study reports, when available. be conducted, and is the most important document for This structure indicates the necessary experiments for gathering clinical trial execution. The protocol must include a title; all of the required data in terms of quality and fabrication a protocol number, version number, and date; the study Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP TABLE 1 | Investigational medicinal product dossier (IMPD) index adapted from the Notice to applicants by the European Commission. General Module 2 Module 3 Module 4 index Module 2 2.1. Index 3.1. Index 4.1. Index Module 3 2.2. Introduction 3.2. Body of Data 4.2. Studies Reports Module 4 2.3. Quality Overall Summary 3.2.S Active ingredient (AI) 4.3. MSCs Toxicity and Biodistribution Studies 2.4. Non-clinical Overview 3.2.S.1 General information 4.3.1. Intrathecal and systemic administration of 2.5. Clinical Overview 3.2.S.2 Production MSCs, WJ in an immunodeficient murine 2.6. Written and Tabulated 3.2.S.3 AI characterization model of traumatic spinal cord injury Non-clinical Summaries 3.2.S.4 Specifications 4.3.2. Administration of MSCs carried through 2.6.1 Introduction 3.2.S.5 Packaging description fibrin matrix in an immunodeficient murine 2.6.2 Pharmacology 3.2.S.6. Stability myocardial infarction model 2.6.3 Pharmacology overview 3.2.P Final product (FP) 4.4. Multipotency oF MSC,WJ 2.6.4 Pharmacokinetics 3.2.P.1 Product description and 4.5. Immunomodulation Studies 2.6.5 Toxicology composition 4.6. Genetic Stability of MSC,WJ 2.7. Written and Tabulated Clinical Summaries 3.2.P.2 Pharmaceutical development 4.7. In vivo Efficacy Studies 2.7.1 Biopharmaceutical studies and related 3.2.P.3 Production 4.7.1. Efficacy study of the implantation of analytical methods 3.2.P.4 Specifications MSCs carried by matrices in the murine 2.7.2 Clinical pharmacology studies 3.2.P.5 FP control myocardial infarction model 2.7.3 Clinical efficacy studies 3.2.P.6 Packaging 4.7.2. Efficacy study of the implantation of 2.7.4 Clinical safety studies 3.2.P.7 Stability MSCs carried by matrices in the porcine 2.8. References 3.2.P.8 FP batch analysis myocardial infarction model 2.9. Studies Synopsis 3.3. References 4.8. References objective and justification, containing all relevant previous non-clinical studies (pharmacology pharmacokinetics, and clinical and preclinical data; the study design; candidate toxicology); effects in humans (pharmacokinetics, safety, inclusion and exclusion criteria; intervention or treatment; and efficacy); and a summary for the investigator. If an risks and benefits, including adverse reaction definition and event that is not listed in this document occurs during reporting; expected trial start and end dates; study withdrawal the trial, the investigator must consider it a non-expected and blind-opening, if applicable; data management, and adverse event, and must notate it as such. The contents are statistical analysis; ethical and regulatory considerations; detailed in the guideline EMA/CHMP/ICH/135/1995 document archive and font documents; quality control; and the required information is obtained from the funding; publication policy; references; and annexes. It is IMPD (34). highly recommended that this document include a figure explaining the study design and a table detailing the scheduled Competent Authorities Involved study visits. National Level: Competent Authority 5. Informed consent form: Informed consent is the procedure Correspondence, Approval Request, and Clinical Trial guaranteeing that a subject gives consent to participate Registration in a research study, having and understanding all of the The AEMPS is the national regulatory agency in Spain. There information related to the trial objectives, its possible benefits, are several different ways of corresponding with the AEMPS. the risks and inconveniences, the available alternatives, and First, for preliminary specific questions related to the proposed his/her rights and responsibilities. The candidate subject must study, enquiry e-mails can be sent to the Support Office have time to think and ask any necessary questions. All of for Independent Clinical Research, Clinical Trials Division, the provided information must be collected in a document Pharmaceutical Medicines for Human Use Department. with a version number updated with current legislation, and Second, in the early stages, when considering moving two printed copies must be signed, dated, and kept by the toward the clinical phase, scientific advice can be sought. investigator and the patient. Scientific advice meetings are face-to-face sessions at AEMPS 6. Investigator’s Brochure (IB): This document is addressed to facilities, at which researchers present their intentions and the researchers involved in the trial, providing a compilation the questions that they want to discuss with experts from of the clinical and non-clinical data regarding the product, the regulatory agency. These professionals act as assessors and the reference safety information. The IB includes all of the for the investigational team, and include representatives from IMP-related information from the IMPD that the investigator different areas, such as the Division of Biological Products, will need to correctly manage the IMP and the included Advanced Therapies and Biotechnology, and Department of subjects, ensuring their understanding of the study rationale, Medical Devices. After the meeting, correspondence occurs IMP dose, dose range, administration, and safety monitoring between the experts and the Quality Research Department, parameters. The IB should include a title page; summary; Pharmacology and Clinical Assessment Division, Medicines table of contents; introduction; section describing the for Human Use Department, to whom minutes of the product’s physical, chemical, and pharmaceutical properties; meeting must be sent. Figure 2 presents a template for Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP FIGURE 2 | Template to write minutes after obtaining scientific advice from the Spanish Agency of Medicines and Medical Devices (AEMPS). summarizing meeting minutes. This document is revised and organizations can request rectifications and/or clarifications and accepted by the AEMPS, and will be part of the collected the process can be extended over time. Upon approval by the documentation required to obtain regulatory approval for the AEMPS and the local ethics committee, the clinical trial must be clinical trial. publicly registered in the Spanish Clinical Trial Registry (REEC, Third, the documentation is submitted via the AEMPS from Registro Español de Estudios Clínicos; https://reec.aemps. platform (https://ecm.aemps.es/). Figure 3 shows the list of es/). documents that must be uploaded to the platform (35). The evaluation is separated into two main blocks. Block I includes the European Level: EMA Communication and EU documents that must be sent to the AEMPS and to the local ethics Clinical Trials Registry committee. Block II comprises documents to be sent exclusively The European Regulation on ATMPs has introduced a for local ethics committee evaluation. The AEMPS must validate classification procedure that gives developers the opportunity Block I, and the local ethics committee must validate Blocks I and to verify whether their product can be considered an ATMP. II within a maximum of 10 natural days (Figure 4) (36). Both This procedure is optional, free of charge, and may occur at any Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP FIGURE 3 | List of documents to upload to the Spanish Agency of Medicines and Medical Devices (AEMPS) platform for investigational medicinal product (IMP) approval. FIGURE 4 | Due dates after Spanish Agency of Medicines and Medical Devices (AEMPS) document submission. stage of ATMP development prior to applying for marketing EMA Innovation Task Force and represent a starting point authorization. There is also the possibility of briefing meetings for interactions between the European agency and the ATMP for preparing ATMP classification, which are organized by the developers (6), enabling the EMA to provide scientific advice. Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP FIGURE 5 | Process of clinical translation. However, AEMPS decisions are harmonized with decision by the underestimating the financial, time, and personnel requirements; EMA, and it is not necessary to seek both. and performing studies without proper documentation (16). After local regulatory approval, the clinical trial should be Figure 5 depicts the whole process for clinical translation. We registered in the European clinical trials database (EudraCT, performed a lot of work without having considered all GMP https://eudract.ema.europa.eu/eudract-web/index.faces) to allow requirements, which resulted in a longer overall process. We are public consultation of updated study-related information. now aware of these issues for future projects that we hope to be developing together as a consortium. In conclusion, basic research laboratories can generate DISCUSSION innovative regenerative/repair-driven hypotheses; however, preclinical products must go through a complex process of Our group is a multidisciplinary team—including basic translational adaptation before reaching patients. Intentions researchers (biologists, biochemists, and veterinarians) and should be discussed with the competent authorities as early clinical researchers (physicians and pharmacists). This diversity as possible, as they may guide researchers to avoid possible may not be common in basic research groups, which may need errant pathways that would result in great losses of time and to look outside of their group for a clinical perspective early money. When intending to assess an ATMP in a clinical trial, the in the translation process. Notably, despite being a quite large IMPD is the most complex and important document to develop. multidisciplinary group, we still had to seek a partner with broad Its structure provides researchers with guidance regarding experience in production and product quality. This is why we the preclinical data needed to generate a safe and effective created a consortium with a center that had the knowledge IMP. Key steps along the process include scalability and GMP that we were lacking, had GMP procedures established in their manufacturing, along with animal models to perform PD, PK, daily activity, and possessed all of the facilities needed for and Tox studies. product production. We had studied cardiac regeneration as a basic research group for almost 10 years. Then we spent over a year to adapt our AUTHOR CONTRIBUTIONS product and our processes to GMP and, together with our partner center, we generated the IMPD. The optimum approach PG and CG-M conceived the presented idea. PG wrote the is to start planning the full process from the very beginning, manuscript with support from CG-M, CP-V, JV, and RC. CG-M, when a research idea is generated, with the involvement of JV, and AB-G performed a critical revision of the manuscript. All all experts. Considering the development of an investigational authors gave final approval of the version to be published. product as a project enables early planning of a scheme that includes preclinical and in-vivo animal models and quality aspects, along with bioprocess aspects, as well as compliance FUNDING with the GMP and legal framework requirements (16). This approach is important to ensure appropriate design of the This work was supported by the Spanish Cell Therapy Network non-clinical package required for a clinical trial—helping to (TerCel) [RD16/0011/0006 and RD16/0011/0028]; and CIBER avoid skipping process steps; setting overly optimistic deadlines; Cardiovascular [CB16/11/00403] projects, as a part of the Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 February 2021 | Volume 8 | Article 604434 Gastelurrutia et al. From Preclinical Evidence to ATMP National R&D&I Plan, and was co-funded by the ISCIII-Sub- Cardiología and by the Call for Expression of Interest (EoI) for Directorate General for Research Assessment and Promotion Collaborative Projects on Regenerative Medicine 2019 of Center and the European Regional Development Fund (ERDF); the for Regenerative Medicine of Barcelona (CMR[B]). The funders Government of Catalonia: Agency for Management of University of the study had no role in the study design, data collection, data and Research Grants (AGAUR) [2017-SGR-483 and 2017-SGR- analysis, data interpretation, or writing of the report. 719], PERIS Program (Health Department) [SLT002/16/00234 and SLT002/16/00209] and CERCA Program; La Caixa Banking ACKNOWLEDGMENTS Foundation; grants from the Spanish Ministry of Science, Innovation and Universities (MICINN) [SAF2017-84324-C2- The authors would like to acknowledge members of both the 1-R]; Institute of Health Carlos III (ISCIII) [PI18/00256, Cell Therapy Service and Barcelona Tissue Bank (Banc de Sang i PIC18/00014, ICI19/00039, and PI19/01788], and cofunded by Teixits, Barcelona), and members of the ICREC Research Lab for European Union (ERDF/ESF) - A way to build Europe. This their support. 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Available online at: http://www.imp-dossier.eu/ (accessed July 3, 2019). Conflict of Interest: The authors declare that the research was conducted in the 32. European Commission Notice to Applicants for Medicinal products for absence of any commercial or financial relationships that could be construed as a human use. Volume 2B. Presentation and Format of the Dossier Common potential conflict of interest. Technical Document (CTD). Available online at: https://ec.europa.eu/health/ sites/health/files/files/eudralex/vol-2/b/update_200805/ctd_05-2008_en.pdf Copyright © 2021 Gastelurrutia, Prat-Vidal, Vives, Coll, Bayes-Genis and Gálvez- (accessed August 1, 2019). Montón. This is an open-access article distributed under the terms of the Creative 33. International Council for Harmonisation of Technical Requirements for Commons Attribution License (CC BY). The use, distribution or reproduction in Pharmaceuticals for Human Use (ICH). Available online at: https://www.ich. other forums is permitted, provided the original author(s) and the copyright owner(s) org/page/mission (accessed March 19, 2020). are credited and that the original publication in this journal is cited, in accordance 34. Guideline for Good Clinical Practice E6(R2), 1 December 2016, with accepted academic practice. No use, distribution or reproduction is permitted EMA/CHMP/ICH/135/1995. which does not comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 February 2021 | Volume 8 | Article 604434