The Evolution of Nonclinical Regulatory Science: Advanced Therapy Medicinal Products as a Paradigm
Authors: Henrik Tang Vestergaard, Lucia D' Apote, Christian K Schneider, Carla Herberts
Journal: Molecular Therapy (2013)

Advanced therapy medicinal products (ATMPs) comprise gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (CTMPs), and tissue-engineered products (TEPs). So-called combined ATMPs incorporate one or more medical devices as an integral part of the product. Because of their complexity and innovative nature, ATMPs pose new scientific and regulatory challenges to both developers and regulators.1Committee for Advanced Therapies (CAT); CAT Scientific Secretariat Schneider CK Salmikangas P Jilma B Flamion B Todorova LR Paphitou A et al.Challenges with advanced therapy medicinal products and how to meet them.Nat Rev Drug Discov. 2010; 9: 195-201Crossref PubMed Scopus (175) Google Scholar Many developers of such products request scientific advice from the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA). We have repeatedly been asked by stakeholders to analyze the scientific advice provided by the CHMP with regard to the identification of common principles that might be useful to share with product developers. Here we comprehensively analyze the scientific advice provided by the CHMP following implementation of the 2009 legislation on ATMPs, in which the Committee for Advanced Therapies (CAT) plays an integral role. This analysis allowed us to conclude that, for these innovative medicines, a classic guideline-based approach is insufficient owing to the complexity of the products. Regulators must employ a more tailored approach that includes principles of risk identification and mitigation. In the current analysis, we focus on the translational aspects of ATMPs (i.e., nonclinical issues) because these are a direct measure of developmental complexity of innovative treatments and often constitute a bottleneck for ATMP development. ATMPs are pharmaceuticals with a high level of complexity linked to their composition, development, manufacturing, characterization, and administration. Such products can serve as a paradigm for any innovative medicinal product or personalized medicine because of their high specificity, particularly with regard to how regulators provide guidance to accommodate the needs of stakeholders. The current regulatory framework was fully implemented in the European Community in 2009.2Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 Offic J Eur Union L 324/121 (10 December 2007)Google Scholar Central to this regulatory framework for ATMPs was the establishment of a multidisciplinary expert scientific committee, the CAT, which is tightly integrated into the EMA procedure for CHMP scientific advice. In addition to the well-established procedures for the EMA's scientific advice and protocol assistance,3European Medicines Agency. Scientific advice and protocol assistance <http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000049.jsp&mid=WC0b01ac05800229b9>(2013)Google Scholar,4European Medicines Agency. New framework for scientific advice and protocol assistance (EMEA/267187/2005/Rev. 1) <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004245.pdf>(26 April 2006)Google Scholar classification and certification procedures have been established5European Medicines Agency, Committee for Advanced Therapies (CAT). Procedural advice on the provision of scientific recommendation on classification of advanced therapy medicinal products in accordance with Article 17 of Regulation (EC) No 1394/2007 (EMA/CAT/99623/2009) <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2010/02/WC500074745.pdf>(15 January 2010)Google Scholar,6European Medicines Agency, Committee for Advanced Therapies (CAT). Reflection paper on classification of advanced therapy medicinal products (EMA/CAT/600280/2010) <http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/12/WC500136422.pdf>(7 December 2012)Google Scholar,7European Medicines Agency, Committee for Advanced Therapies (CAT). Guideline on the minimum quality and non-clinical data for certification of advanced therapy medicinal products (EMA/CAT/486831/2008/corr) <http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070031.pdf>(15 October 2010)Google Scholar,8European Medicines Agency, Committee for Advanced Therapies. Procedural advice on the certification of quality and non-clinical data for small and medium sized enterprises developing advanced therapy medicinal products (EMA/CAT/418458/2008/corr) <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2010/01/WC500070030.pdf>(15 October 2010)Google Scholar to facilitate discussions with developers. The CAT has published several guidelines for ATMPs to facilitate development of this complex class of therapy.9European Medicines Agency. Scientific guidelines <http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000298.jsp&mid=WC0b01ac05800862bd>(2013)Google Scholar However, the broad spectrum of ATMPs with regard to structure and mechanism of action means that such general guidance can be difficult to translate into product-specific requirements. These difficulties can be substantial for sponsors developing ATMPs, considering that the major stakeholders in Europe are academia, charities, and small companies, which often have limited financial resources or regulatory expertise when compared with large pharmaceutical companies.10Maciulaitis R D'Apote L Buchanan A Pioppo L Schneider CK Clinical development of advanced therapy medicinal products in Europe evidence that regulators must be proactive.Mol Ther. 2012; 20: 479-482Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar The data set. In the first three years following inauguration of the CAT, the CHMP/CAT provided scientific advice pertaining to 54 different ATMPs. Recommendations related to nonclinical development were provided for 31 products covering 11 GTMPs, 13 CTMPs, and 8 TEPs (Figure 1a). Advice related to the nonclinical development of combined ATMPs was provided in only three cases. For approximately half of the products, oral discussion between the company involved and various members of the Scientific Advice Working Party (SAWP) and/or the CAT was deemed necessary before a written response could be finalized owing to uncertainty in the information required by the sponsor or when dealing with innovative products for which there was little regulatory precedence. The aim of these meetings was to discuss the product more generally so that SAWP/CAT would be in a better position to provide final written advice. The relatively high incidence of oral discussion meetings reflects the importance of active dialogue between regulators and developers of innovative products because of their complexity and/or the relative inexperience of the developers and regulators with these types of products. GTMPs. The majority of the GTMPs for which the CHMP/CAT provided scientific advice consisted of a viral vector; only a few products consisted of genetically modified cells of either human or bacterial origin. The majority of the products used either a replication-incompetent adeno-associated viral vector or a lentiviral vector. Other products included genetically modified organisms (GMOs, with an integrated transgene), retroviral vectors, and replication-competent adenoviral vectors (Figure 1b). Cell-based medicinal products. For somatic cell-based medicinal products (CBMPs), the CHMP/CAT provided scientific advice on products consisting of human cells of either allogeneic or autologous origin (Figure 1c). No advice on the use of xenogeneic medicinal products was requested. The TEPs for which the CHMP/CAT provided scientific advice were mainly autologous (Figure 1d). Scientific advice was given for a single allogeneic TEP and a single chimeric product comprising both allogeneic and autologous cells. Given the similarities in the recommendations given by the CHMP relating to the nonclinical development of CBMPs and TEPs, we have combined the discussion on these medicinal products. The most common issues concerned strategies for evaluation of general toxicity and biodistribution (Table 1), including the need for a full nonclinical testing program. The establishment of proof of concept/principle and evaluation of tumorigenicity were more often discussed for somatic cell therapy products than for GTMPs. The CHMP/CAT recognized that conventional nonclinical safety testing was not always feasible for ATMPs because of their complexity. Generally, animal testing was considered necessary only if the data generated were likely to provide meaningful conclusions, i.e., identification of a potential hazard or a potential risk for human health based on extrapolation from animal data. Known species differences needed to be taken into account for evaluation of the animal studies. In a few cases (mostly GTMPs), it was advised that if a hazard had already been identified (e.g., based on theoretical considerations, in silico or in vitro testing, or findings observed in the proof-of-concept studies) and it could be scientifically and ethically determined that animal testing would not further substantiate the risk, animal testing was deemed unnecessary. It was then recommended to take appropriate measures clinically in order to mitigate the risk.Table 1Number of times that specific issues were discussed in the EMA Scientific Advice Procedure for ATMPs based on type of productN (%)Topic for discussionGTMPsCBMPsProof of concept/principle4 (36)16 (76)Biodistribution8 (72)17 (81)General toxicity8 (72)15 (71)Tumorigenicity3 (27)17 (81)Reduced nonclinical package6 (55)12 (57)ABBREVIATIONS: ATMP, advanced therapy medicinal product; CBMP, somatic cell-based medicinal product; EMA, European Medicines Agency; GTMP gene therapy medicinal product.Relative frequency is shown in parentheses. Open table in a new tab ABBREVIATIONS: ATMP, advanced therapy medicinal product; CBMP, somatic cell-based medicinal product; EMA, European Medicines Agency; GTMP gene therapy medicinal product. Relative frequency is shown in parentheses. The lack of stand-alone toxicity testing was considered acceptable in cases where sufficient safety information could be obtained from the proof-of-concept studies. In such cases it was recommended that the safety assessment be complemented with a discussion of potential risks or hazards in line with recommendations laid out in the guideline on the risk-based approach.11European Medicines Agency, Committee for Advanced Therapies (CAT). Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products (EMA/CAT/CPWP/686637/2011) <http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500139748.pdf>(11 February 2013)Google Scholar Furthermore, it was acknowledged that good laboratory practice (GLP) compliance of safety studies might not be feasible for these specific types of products (e.g., due to the need for specialized treatment procedures such as cell transplantation). However, in several cases the CHMP/CAT emphasized that the lack of GLP compliance needed to be sufficiently justified and that GLP principles should be applied as much as possible (e.g., requirements for documentation of all data/procedures/specimens or a complete study report). This implies that peer-reviewed scientific publications by themselves may not substitute for GLP-compliant safety studies. The CHMP/CAT considered that the lack of specific safety pharmacology and genotoxicity testing was generally accepted for these types of products. Reproductive toxicity studies were required only when there was a potential for (fetal) exposure. In addition, reproductive toxicity studies were not deemed necessary if there was scientific evidence demonstrating a lack of exposure to the reproductive organs. Furthermore, reproductive studies were in some cases waived on the basis of the intended patient population, as is the case for all medicinal products (e.g., for women not of childbearing potential after menopause), or when evaluation of reproductive organs in the general toxicity study or studies revealed no indication of toxicity. Conventional carcinogenicity testing was usually not considered feasible or appropriate for risk assessment; other means were considered more relevant to assess the potential hazard of tumorigenicity (see the section on CBMPs below). The testing of three different lots of the product was generally agreed to be sufficient for addressing specific toxicity end points either in vitro or in vivo. Additional animal testing was suggested when the CHMP/CAT perceived a need for additional safety evaluation of excipients, scaffold, or impurities (e.g., remnants of raw materials used for production). In most cases, comments were made on the duration of the safety and/or biodistribution studies. The proposed study duration was often considered too short, but because no general recommendation can be distilled with respect to the optimal duration of such studies, a case-by-case approach must be employed. However, it is clear that product-specific characteristics, such as the persistence, behavior, and fate of the product in vivo and the expected duration of clinical exposure or effectiveness, were taken into account when deciding on the appropriate duration of the studies. Full good manufacturing practice (GMP) was not required for manufacturing batches of product not intended for human use. Hence, nonclinical safety testing could use non-GMP material as long as comparability can be shown with clinical batches. Nevertheless, the CHMP/CAT strongly recommended that biodistribution studies—and, preferably, toxicity studies as well—be performed with the product intended for clinical use. When using a homologous animal model, it was recommended that a comparable manufacturing process be used and that the product be adequately characterized. It was recognized that a comparability analysis can be very challenging for ATMPs because it requires a clear understanding of which product characteristics influence its safety and efficacy and how changes in the manufacturing process could affect these characteristics. Hence, engineering batches should be controlled for identity (e.g., cell composition), potency (e.g., protein expression efficiency and viral vector infection efficiency), and purity (e.g., impurity profile) to ensure consistency with GMP batches for clinical use. For GTMPs, the relevance of the animal model used for biodistribution and toxicity studies requires justification with respect to the pharmacological activity of the gene product(s) and the tissue tropism of the viral vector. Furthermore, the expression of human protein(s) might induce immunogenicity in animals. In such cases, it might be advisable to perform animal testing using a vector encoding the animal homologue. The homology and pharmacological properties of the human and animal protein(s) should be investigated so as to interpret clinical relevance of the nonclinical findings. Tissue specificity should be addressed using human and animal cells to establish vector tropism. Moreover, safety investigations are not limited to viral vectors and must be performed for medical products consisting of GMOs (i.e., genetically modified cells) unless alternative strategies can demonstrate that gene transfer from the GMO to host cells does not occur. Such safety testing strategies could include evaluation of bystander cell transduction during coculturing of the GMO with an immortalized cell line highly permissive to infections caused by the applied viral vector. Duration of the biodistribution study must be sufficient to cover the persistence of the viral vector. If this is not possible, it was recommended that the duration be sufficiently long to establish the clearance profile of the vector. For GMOs, the clearance of cells, expression cassette, and gene product(s) must be demonstrated. Dissemination of the viral vector to nontargeted tissues or organs should be investigated by analyzing the presence of viral vector DNA in a range of tissues and fluids. The organs listed in the guideline on repeated dose toxicity12European Medicines Agency, Committee for Proprietary Medicinal Products (CPMP). Note for guidance on repeated dose toxicity (CPMP/SWP/1042/99 corr) <http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003102.pdf>(27 July 2000)Google Scholar should be covered unless excluded by a scientifically valid justification. Limitations on the sensitivity of the methods used should be considered. The necessity for evaluation of germline transmission can be based on biodistribution data. In several cases, the CHMP/CAT advised that intravenous administration be used as a "worst-case" scenario for studying biodistribution. Hence, designing an appropriate biodistribution study appears to be a complicated task, especially when biodistribution is combined with proof-of-concept and/or toxicity testing. Dosing up to 10 times the clinical dose was considered sufficient for toxicity testing but was not always considered feasible. Furthermore, exposure may be influenced by immunogenicity toward the gene product(s) or viral vector/GMO. The use of disease or homologous models for toxicity testing was generally encouraged by the CHMP/CAT. Alternative strategies for evaluation of tumorigenicity included in silico, in vitro, and in vivo testing. Similar assays are recommended for the evaluation of CBMPs. Target and nontarget cells/tissues may need to be evaluated for signs of tumorigenicity depending on the results from the biodistribution study. Differences between species are also the major challenge for the use of animal models for nonclinical assessment of human cell-based medicinal products. Human cells will inevitably be rejected in an immunocompetent animal, whereas the translation of in vivo behavior of the human cell-based product in immune-compromised animals is complicated because the fate and activity of the cells are influenced by interactions with tissues and cells of the animal model, which may or may not be functional. Indeed, the choice of animal model was one of the most discussed subjects for CBMPs. In general, there was a preference to employ a homologous animal model using allogeneic or autologous animal cells mimicking the human situation. It was also noted that the nonclinical study design should mimic the clinical setting as much as possible (e.g., the age of the animals, the site or route of administration, and the surgical procedure). This approach was reflected in recommendations on the use of large-animal models, as these were suggested only when anatomical differences limited the relevance of small-animal models and/or resulted in practical difficulties such as the inability to use the clinical route of application. The use of homologous models was also encouraged for biodistribution studies. It was stressed in several cases that a lack of biodistribution must be shown rather than assumed. Hence, biodistribution studies could seldom be waived. It was recognized that biodistribution studies can be technically challenging, but this does not immediately relieve the need for data on the distribution of the cells. In cases of local administration, it may be sufficient to carefully examine the site of administration for signs of migration or invasion and draining lymph nodes for ectopic tissue formation. In one case, the need for biodistribution studies was waived because systemic exposure was part of the aim of treatment and the cells were administered intravenously. Inclusion of safety/toxicity end points in the proof-of-concept studies was a widely accepted approach; it reduced the total number of animals and maximized the information obtained from the study. Thus, safety data can be obtained in a homologous animal model. However, for specific end points—particularly those focusing on the tumorigenic potential of the CBMP—testing of the clinical (human) product was recommended rather than using homologous animal cells. For tumorigenicity testing, an approach combining in vitro studies with an in vivo study was often suggested. In the recommendations, no clear preference for a specific in vitro test could be found, but a combination of several in vitro tests was always proposed by the companies and agreed to by CHMP/CAT. The proposed in vitro studies included evaluation of growth characteristics (e.g., growth rate and anchorage-independent growth), cytogenetics (e.g., karyotyping), cell differentiation, functionality of cell-cycle-regulation genes (e.g., expression and functionality of oncogenes and tumor suppressor genes), telomerase activity, and senescence (e.g., transduction leading to immortalization or transformation). It was generally recommended that at least some of these tests be performed with cells cultured beyond the routine limit of cell culturing used in manufacturing the product. In cases in which cells were only minimally manipulated or sufficient clinical experience was available, the lack of an in vivo tumorigenicity study was accepted. When an in vivo study was required, it generally involved a study in immunodeficient animals, and it was recommended that the route of administration mimic the clinical setting if feasible and that the duration of the follow-up period should depend on the persistence of the cells in the immunocompromised animal. This recommendation implies that some knowledge of biodistribution and persistence of the cells in the immunodeficient animal model is required. In addition to the choice of animal model, one possibility that was relatively frequently discussed with respect to CBMPs was applying for marketing authorization with a reduced nonclinical package. In these cases, CHMP/CAT agreed to forgo the requirement for nonclinical studies or to waive the provision of certain data (e.g., long-term follow-up) when clinical data of sufficient quality were available for a safety assessment of the product (e.g., for some chondrocyte products for which considerable clinical experience existed). For proof-of-concept studies, it appears that literature data can support, at least partially, an application for marketing authorization. However, it was suggested that the relevance and similarities of the published product be discussed for the CBMP. Our analysis of the advice provided by the CHMP/CAT suggests that both regulators and developers must accept limitations inherent in the models available today, and that gaps will have to be filled with complementary approaches. An approach whereby product-specific risk factors are used to evaluate the individual risks associated with the product11European Medicines Agency, Committee for Advanced Therapies (CAT). Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products (EMA/CAT/CPWP/686637/2011) <http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500139748.pdf>(11 February 2013)Google Scholar and enriched with a knowledge-based rational approach might be the way forward for these innovative products. This is reflected in the trend toward the use of tailored models that are specifically designed to answer particular safety concerns, so as to complement the combined proof-of-concept or safety studies rather than a scheme that separates pharmacology and safety studies from classic general toxicology studies that aim to assess all concerns comprehensively. These specific approaches should nonetheless ensure a maximum gain of information with the minimum use of animal testing. Importantly, tailored approaches are limited not only to advanced medicinal products but also to biopharmaceuticals such as highly species-specific monoclonal antibodies, and apply even for small molecules such as thrombopoietin-receptor agonists.13Erickson-Miller CL DeLorme E Tian SS Hopson CB Stark K Giampa L et al.Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist.Exp Hematol. 2005; 33: 85-93Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar The approach will also depend on the stage of development—we observed a shift in the way regulators evaluate nonclinical data depending on the developmental stage, shifting from proof of concept ("Does the product work, and does it work safely enough?") in early development toward safety when assessing proposals from a marketing-authorization perspective ("Does the product show findings that require confirmation with clinical data?"). On the basis of our analysis, we believe that published regulatory guidance is only a starting point for development and that regulators are willing to accept a more tailored scientific approach to sponsors' proposals. This message is highly relevant because of the uncertainty among academic and industry stakeholders with regard to regulatory acceptance of more tailored scientific approaches beyond the relevant guidance documents for innovative product classes. This approach shifts regulation increasingly away from a classic "check-box" approach and is an absolute prerequisite for regulators to fulfill their future responsibilities not only to oversee development but to facilitate it. Overall, we recognize that there is a need for increased and early interactions and open dialogue with all stakeholders (developers, manufacturers, regulators, doctors, and patients) to cope with the scientific and regulatory challenges posed by these innovative products. The CAT has organized several focus groups to interact with interested parties, enrich the scientific discussion, and (where possible) propose shared solutions to specific issues,14European Medicines Agency, Committee for Advanced Therapies (CAT). Report from CAT-IPs Focus group on incentives for academia, hospitals, charities (EMA/CAT/889316/2011) <http://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/12/WC500136435.pdf>(17 December 2012)Google Scholar,15European Medicines Agency. Report from CAT-Interested Parties Focus Groups (CAT-IPs FG) on system to navigate guidelines for ATMPs (EMA/CAT/463795/2011) <http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/07/WC500109209.pdf>(13 July 2011)Google Scholar one of them being nonclinical development of ATMPs.16European Medicines Agency, Patient Health Protection. Report from CAT-Interested Parties Focus Groups (CAT-IPs FG) on non-clinical development of ATMPs (EMA/CAT/134694/2011) <http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/03/WC500103895.pdf>(18 March 2011)Google Scholar,17European Medicines Agency, Committee for Advanced Therapies (CAT). Activities proposed by CAT-IP Focus group on non-clinical development of ATMPs (EMA/CAT/654949/2012) <http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/12/WC500136436.pdf>(24 September 2012)Google Scholar,18European Medicines Agency, Committee for Advanced Therapies. Report from CAT-Interested Parties Focus Groups (CAT-IPs FG) on non-clinical development of ATMPs (EMA/CAT/716942/2012) <http://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/12/WC500136434.pdf>(23 November 2012)Google Scholar Furthermore, developers are encouraged to seek scientific advice early in development to discuss their product and the extent and type of quality, nonclinical, and clinical data needed for further development and, ultimately, marketing authorization. We conclude that the case-by-case approach, often cited by regulators, for translation of innovative drug developments from bench to bedside is not necessarily a negative, as often stated by stakeholders wishing to receive boilerplate outlines from regulators. Rather, we consider that a more tailored approach allows for sufficient flexibility. Regulators are open to novel developments in translational medicine and are ready to develop their recommendations as the field continues to evolve. The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties.