POLICY AND PRACTICE REVIEWS published: 30 August 2019 doi: 10.3389/fphar.2019.00921 Regulatory Framework for Advanced Therapy Medicinal Products in Europe and United States Carolina Iglesias-López 1, Antonia Agustí 1,2, Mercè Obach 3* and Antonio Vallano 3,4 1Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Clinical Pharmacology Service, Vall d’Hebron University Hospital, Barcelona, Spain, 3 Medicines Department, Catalan Healthcare Service, Barcelona, Spain, 4 Pathology and Experimental Therapeutics Department, University of Barcelona, Barcelona, Spain Advanced therapy medicinal products (ATMPs) are a fast-growing field of innovative therapies. The European Union (EU) and the United States (US) are fostering their development. For both regions, ATMPs fall under the regulatory framework of biological products, which determines the legal basis for their development. Sub-classifications of advanced therapies are different between regions, while in EU, there are four major groups, i.e., gene therapy, somatic cell therapy, tissue-engineered therapies, and combined advanced therapies; in US, the sub-classification covers two major groups of products, i.e., gene therapy and cellular therapy. The inclusion criteria that define a gene Edited by: Maria Dimitrova, therapy are equivalent in both regions, and the exclusion criteria are directly related to Medical University, Bulgaria the indications of the product. In the EU, there is a clear differentiation between cell- and Reviewed by: tissue-based products regarding their classification as advanced therapies or coverage Orin Chisholm, by other legal frameworks, whereas in US, there is a broader classification about whether University of New South Wales, Australia or not these products can be categorized as biologic products. Both in EU and in US, Adina Turcu-Stiolica, in order to classify a cell- or a tissue-based product as an advanced therapy, it must be University of Medicine and Pharmacy of Craiova, Romania ensured that the processing of the cells implies a manipulation that alters their biological *Correspondence: characteristics, although the term of manipulation in US differentiates between structural Mercè Obach and non-structural cells and tissues. The regulatory terminology used to define ATMPs mobach@catsalut.cat and their sub-classification reveals some differences between EU and US. Specialty section: Keywords: genetic therapy, tissue engineering, cell- and tissue-based therapy, biological products, biological This article was submitted to therapy, legislation and jurisprudence, United States Food and Drug Administration, Europe Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology INTRODUCTION Received: 16 May 2019 Advanced therapy medicinal products (ATMPs) comprise a category of innovative and complex Accepted: 22 July 2019 biological products, which in most cases require extensive and complicated preclinical and clinical Published: 30 August 2019 developments. This complexity has been observed since the idea of transferring genetic material to Citation: cure a genetic disease was foreseen decades ago. The first ATMP product approved in the European Iglesias-López C, Agustí A, Obach M Union (EU) came in 2009 with the authorization of ChondroCelect®, a tissue-engineered product and Vallano A (2019) Regulatory indicated for the treatment of cartilage defects (European Medicines Agency, 2017a). In United Framework for Advanced Therapy Medicinal Products in Europe and States (US), the first approved ATMP came out 1 year later with PROVENGE®, a somatic cell therapy United States. for the treatment of some prostate cancers (U.S. Food and Drug Administration, 2019a). The first Front. Pharmacol. 10:921. authorized gene therapy was launched in 2012, when Glybera® achieved marketing authorization in doi: 10.3389/fphar.2019.00921 EU (European Medicines Agency, 2012). Frontiers in Pharmacology | www.frontiersin.org 1 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework The delay between the theoretical concept of an ATMP and consist of one of the first three categories combined with one or the first clinical trials that lead to a new treatment approval may more medical devices as an integral part of the product (European be due to the multiple challenges that arise from the nature of Union, 2007). In EU, there is a clear differentiation between cell- ATMPs, including not only scientific and technical challenges based products considered as advanced therapies, and cell-based but also regulatory ones (Ten Ham et al., 2018). The first step therapies covered by other legal frameworks such as the blood in their development is the definition of the product, and system or transplant laws, where these cells are not considered consequently, its classification. In both in EU and the US, there a medicinal product, and the active substance, i.e., human cells is a broad legal framework, ranging from medicinal products and tissues, cannot be commercialized or manufactured on an consisting of chemical substances to biological substances; the industrial scale for ethical and legal reasons (European Union, latter of which includes a wide range of possible products. In this 2003b; European Union, 2004; European Union, 2010). The sense, the classification of a potential biological product is often classification of an ATMP as a biological product will determine not so trivial, and in some cases, it may be difficult to discern the wider regulatory framework by which the requirements of the line between different biological subcategories. The correct the development and the marketing authorization application classification of a product at an early stage of development is a are defined. These are to be read in conjunction with the specific critical point, since it will determine the regulatory framework framework for ATMPs, Regulation 1394/2007/EC, which came and the European and American recommendations to follow into force on December 30, 2008. This regulation provides the throughout the whole development plan of the product in overall framework on ATMPs for those products, which are each region. intended to be placed in the market of EU Member States. In This article aims to review the legal frameworks in the EU addition, Directive 2009/120/EC updated the definitions and and US for ATMPs, as well as the criteria to be met to define detailed scientific and technical requirements for advanced a product as such. The similarities and differences that exist therapies. The cATMPs are not only regulated under the between both regions are discussed in order to identify those guidelines of medicinal products but also of medical devices. On nuances that may affect the development of an ATMP. A specific 25 May 2017, two new regulations on medical devices came into search for official regulatory documents concerning medicinal force (European Commission, 2017a). products for human use with a specific focus on ATMPs, such For the development of advanced therapies in EU, the clinical as legislation, guidelines, presentations, and reports, from the trial applications are submitted individually to the national websites of the European Medicines Agency (EMA) and Food competent authorities where the trial will take place. However, and Drug Administration (FDA) competent authorities was for the marketing authorization, all ATMPs are evaluated via carried out until 31st December 2018. Key terms that covered the centralized procedure ensuring that they benefit from a single regulatory framework for advanced therapies and other products evaluation and authorization applicable across the EU. There were used to navigate the websites of these competent authorities, are two committees responsible for the validation and scientific including: terms describing advanced therapies (advanced evaluation for product approval: the Committee for Advanced therapy, advanced therapies, regenerative medicine, cell therapy, Therapies (CAT) and the Committee for Medicinal Products for cell-based therapy, human cellular therapy, stem cells, gene Human Use (CHMP) (European Medicines Agency, 2018a). The therapy, tissue engineering, human cell therapy, human somatic CAT is the EMA committee responsible for classifying; assessing cell therapy), information on the regulatory framework, and the the quality, safety, and efficacy of ATMPs; and following scientific definition and classification of advanced therapies in EU and US. progress in the field. This committee’s main responsibility is to prepare a draft opinion on each ATMP application submitted to the EMA in order to support the final decision by the CHMP. REGULATORY FRAMEWORK FOR This marketing authorization via the centralized procedure may THE CLASSIFICATION OF ADVANCED be granted in three ways: standard marketing authorization, THERAPIES conditional marketing authorization (when an innovative medicine addresses an unmet medical need yet a positive benefit-risk Medicinal products for human use in EU are governed by balance by sufficient clinical data is demonstrated), and marketing Directive 2001/83/EC and Regulation 726/2004/EC. Biological authorization under exceptional circumstances in those extreme products comprise many diverse product types, including situations where a disease is rare or a clinical endpoint is difficult immunological medicinal products (i.e., vaccines, toxins, to measure (Detela and Lodge, 2019). Regarding classification, the serums, and allergens), medicinal products derived from human CAT offers the confirmation that a medicine meets the scientific blood and human plasma (i.e., albumin, coagulation factors, and criteria to be classified as an ATMP. On the other hand, the immunoglobulins of human origin), biotechnology products regulatory authority in charge of medical devices is the national such as antibodies, and ATMPs, which are the focus of this appointed bodies of each EU member. In the case of cATMP, the paper (European Union, 2003a). ATMPs consist of products CAT interacts with the notified bodies in order to prepare the draft that contain recombinant nucleic acids or engineered cells and/ opinion on a cATMP (European Medicines Agency, 2011a). or tissues. These products are divided into four subcategories: In US, like in EU, advanced therapies are regulated as biologic somatic cell therapy medicinal products (SCTMP), tissue- products. In legislative terms, biological products comprise the engineered products (TEP), gene therapy medicinal products following categories: i) the group of allergenics that includes (GTMP), and the combined ATMPs (cATMPs). These last ones allergen extracts, allergen patch tests, and antigen skin tests; Frontiers in Pharmacology | www.frontiersin.org 2 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework ii) blood and blood products, iii) vaccines, iv) xenotrasplants, in order to obtain a clinical trial approval (U.S. Food and Drug and v) cellular and gene therapy products (CGTs), which Administration, 2017a), and Biologics License Application constitutes the group of advanced therapies and encompasses (BLA) to obtain a marketing authorization (U.S. Food and two sub-categories of products. Advanced therapies should not Drug Administration, 2018c). The marketing authorization can be confused with other legislative category of products called be standard, under a Priority Review procedure or under an “human cells, tissues, and cellular and tissue-based products” Accelerated Approval. In the Priority Review, the application (HCT/Ps) and defined as “articles containing or consisting of is reviewed within 6 months compared to 10 months under human cells or tissues intended for implantation, transplantation, standard review, and it is addressed to those drugs that, if infusion, or transfer into a human recipient” (U.S. Food and Drug approved, would bring about significant improvements in the Administration, 2019). HCT/Ps are not considered biological safety or effectiveness of the treatment, diagnosis, or prevention products. On the other hand, combination products include of serious conditions when compared to standard applications. products that are comprised of two or more regulated components, An Accelerated Approval allows drugs for serious conditions that i.e., drug/device, biologic/device, drug/biologic, or drug/device/ filled an unmet medical need to be approved based on a surrogate biologic. The definition is broad and takes into account the endpoint, if clinical benefit has been demonstrated (U.S. Food packaging and whether all components of the product are needed and Drug Administration, 2018d). to achieve the intended use, indication, or effect (U.S. Food and Within the FDA, responsibilities for drugs, biologic products Drug Administration, 2018a). In 2016, the 21st Century Cures and devices are organized in eight different centers. The Centre Act (Cures Act) was signed into law in order to help accelerate for Biologics Evaluation and Research (CBER) has jurisdiction medicinal product development and bring new therapies to the over a variety of biological products, including blood and blood market faster and more efficiently. This Act established a new products, vaccines and allergenic products, and cellular, tissue, expedited product development program called the Regenerative and gene therapies, as well as some related devices. Within the Medicine Advanced Therapy (RMAT) (U.S. Food and Drug CBER, the responsibility for advanced therapies falls to the Office Administration, 2018b). Although it is not a type classification of Tissues and Advanced Therapies (OTAT), formerly known as per se, yet a designation that offers a new expedited option for Office of Cellular, Tissue, and Gene Therapies (OCTGT). OTAT evaluation of the product, it is considered worth mentioning comprises five divisions in addition to the Office of the Director it here as a part of the US advance therapy classification. A (U.S. Food and Drug Administration, 2017b). Combination regenerative medicine therapy is defined as: i) a cell therapy, products are assigned to a FDA center that will have primary therapeutic tissue-engineering product, human cell and tissue jurisdiction for its pre-market review and regulation. For product, or any combination product using such therapies or combination products, CBER usually regulates medical devices products, explicitly excluding HCT/Ps; ii) that is intended to treat, related to licensed blood and cellular products by applying modify, reverse, or cure a serious or life-threatening disease or appropriate medical device laws and regulations (U.S. Food and condition; and iii) if the preliminary clinical evidence indicates Drug Administration, 2018e). This assignment is performed that the drug has the potential to address unmet medical needs for by the Office of Combination Products through a designation such disease or condition (U.S. Food and Drug Administration, process (U.S. Food and Drug Administration, 2018f). 2019b). Therefore, this definition implicitly includes advanced The current European and American legislations for biological therapy medicinal products. A combination product can also products are summarized in Table 1. One of the main differences be eligible for RMAT designation when the biological product between EU and US is that the FDA oversees clinical trials, whereas component provides the primary mode of action. These products the EMA does not. In terms of marketing approval, each region would be denominated as RMAT-based combination products. has specific legislations depending on the legal categorization of More than 30 out of 90 RMAT designation requests have been the product; in EU, they are licensed under article 8.3 of Directive granted until 2019 (U.S. Food and Drug Administration, 2019c). 2001/83/EC, while in US, ATMPs are licensed under section The US federal regulatory framework consists of two main 351 of the PHS Act. Both Agencies have their own specialized statutes, Federal Food, Drug, and Cosmetic Act (FDCA) and the committees to evaluate advanced therapies. In US, the approval Public Health Services Act (PHSA), which provide the Food and time for a standard BLA may extend up to 10 months from Drug Administration (FDA, the federal regulatory medicines receipt date (U.S. Food and Drug Administration 2017c), while agency in the US) with the legal authority to regulate human in EU, the assessment leads to an opinion from the CHMP by day medicinal products including drugs, biological products, and 210 and European Commission by day 277 (around 7 months) devices. Biological products, and therefore advanced therapies, (European Medicines Agency, 2016b). However, these timelines are regulated under section 351 of the PHSA and under the depend on the different types of marketing authorization FDCA, because most biological products also meet the definition available in each region. Among advanced therapies, product of “drugs” cited in this Act. FDA regulations are contained in the sub-classifications are slightly different between regions. While Code of Federal Regulations (CFR), which provides details on in the EU, an ATMP can be sub-classified into four major how the FDA implements the activities that are defined in the groups, i.e., GTMP, SCTMP, TEP, or cATMP, in the US the PHSA and FDCA. Regulations for biological and medical devices sub-classification groups are broader, covering two groups of are found in Title 21 of the CFR (Lee et al., 2015; U.S. Title 42 products, i.e., gene therapy and cellular therapy products. Given The Public Health and Welfare, 2019). In US, the applicants that the sub-classification in the EU is more precise, there are need to submit an investigational new drug (IND) application products that could fall into two categories, and in some cases, Frontiers in Pharmacology | www.frontiersin.org 3 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework TABLE 1 | Legal and regulatory framework of biological products in United States and European Union. European Union United States Type of product Legal framework Regulatory organism Type of Legal framework Regulatory product organism Advanced therapy Directive 2001/83/EC (relating to medicinal Clinical trials are under Human Section 351 of the PHSA CBER and medicinal products: products for human use) national competent somatic cell and FDCA and Title 21 CFR OTAT Gene therapy Directive 2009/120/EC (relating to medicinal authorities of each therapy and 600-680 (Regulation on products products for human use as regards member state where gene therapy Biologics) Cell therapy products advanced therapy medicinal products) the clinical trial will take products (21 CFR 1271; prevent Tissue-engineered Regulation 726/2004/EC (community place. the spread of infection products procedures for the authorization and Product positive diseases) supervision of medicinal products for human opinion: CHMP RMAT designation: section and veterinary use and establishing a Draft opinion: CAT 3033 of the 21st Century European Medicines Agency) Cures Act (21 U.S.C. 356[g] Regulation 1394/2007/EC (on advanced (8)) therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004) CAT, Committee for Advanced Therapies; CBER, Centre for Biologics Evaluation and Research; CHMP, Committee for Human Medicinal Products; FDCA, Federal Food, Drug, and Cosmetic Act; OTAT, Office of Tissues and Advanced Therapies; PHSA, Public Health Services Act; RMAT, Regenerative Medicine Advanced Therapy Designation. the assignment in a particular subtype is not so trivial. In the case is called Initial Targeted Engagement for Regulatory Advice of US, the difficulty might arise when classifying the product as (INTERACT) meetings (U.S. Food and Drug Administration, an HCT/Ps or as a biological product that falls beyond minimal 2018h). The ATMP classification procedures are valuable to manipulation and/or homologous use. Finally, another difference address questions on borderline classifications, commonly between regions is related with terminology; in the US, the term raised for combined ATMPs, to confirm the medicinal product “advanced therapy” is not a common term used in legislative framework and determine what type of ATMP a product is, and regulatory documents, and these products are collectively and therefore, develop the product under the specific dossier referred as “CGT products.” requirements and quality guidances. To ensure a correct classification, both the EMA and the FDA Finally, it is worth noting that the main EU and US Agencies have made scientific advice available to the applicants to clarify have launched expedited development programs in order to or corroborate this classification prior to further advancing the enable new medicines reach the market as early as possible. The development. In EU, one of CAT’s activities is to clarify the medicines that are eligible to these programs are those that can classification of a given product, above all when the product justify a potential major public health interest, i.e., they target could fall in two different categories (European Medicines conditions where there is an unmet medical need or have the Agency, 2013a). It is always advisable to obtain CAT’s opinion potential to bring a major therapeutic advantage to patients. about a particular product, since the features of each product can Since ATMPs usually offer new treatments for currently incurable be unique, and the corroboration of a product as an advanced conditions or improve existing treatments, most ATMP are therapy might add value to attract potential investors. On the eligible to these types of accelerated programs. The FDA has other hand, in US, the Tissue Reference Group is the working developed the Breakthrough Therapy and Fast Track designation group within the FDA that provides recommendations to programs (U.S. Food and Drug Administration, 2018d), while the stakeholders concerning the application of the criteria for HCT/ EU launched the adaptive licensing and afterwards the PRIority Ps. For both consultations, a minimum of information on the Medicines (PRIME) designation scheme. The difference between product is required in order to obtain its proper classification, the Breakthrough Therapy and Fast Track designations falls on such as the source of the product, the intended use of the the qualifying criteria for the designation. In the former, clinical product, or description of how the product is processed from the or nonclinical data should demonstrate potential to address time of recovery to the point of use of step-by-step (U.S. Food an unmet medical need, whereas in the latter, preliminary and Drug Administration, 2018g). Another consultation option clinical evidence indicates that it may demonstrate substantial at an early stage of development is to hold informal meetings improvement over available therapies on a clinically significant with the Agencies in order to obtain informal exchange of endpoint(s). The EU PRIME and the US Breakthrough Therapy information and receive advice and recommendations on the designations share the same objective (timely patient access to development process in terms of scientific, regulatory, and legal innovative medicines) but have a different legal basis; hence, issues. For complex products, this type of meeting might also be comparison and harmonization are difficult. However, since late helpful in order to obtain the first legal and scientific feedback 2016, FDA and EMA have worked together to track submitted on the classification of the product. For EU, these meetings are requests for PRIME and Breakthrough Therapy designations and called Innovation Task Force (ITF) briefing meetings (European compare final review outcomes, including specific reasons for a Medicines Agency, 2013a), while the equivalent meeting in US designation request denial (European Medicines Agency, 2018b). Frontiers in Pharmacology | www.frontiersin.org 4 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework Throughout 2019, a database utilizing publicly available and they consist of genetically modified T cells expressing a CD19- company provided information to create a public list of RMAT specific CAR in order to lyse CD19-positive targets (normal and recipients, as well as other expedited approval designations malignant B lineage cells). The fact that the product has to be a awarded in the US, EU, and Japan, is foreseen to be launched biological medicinal product is not a minor inclusion criterion, (Regulatory Affairs Professional Society, 2019). since chemically synthesized nucleic acid sequences will be excluded from being classified as ATMPs and will be considered chemical drugs that should be developed under another legal CLASSIFICATION CRITERIA IN EUROPE framework—as for example, antisense oligonucleotides and AND UNITED STATES aptamers approved by the EMA and FDA as chemical drugs. Unlike the US, in EU, one of the inclusion criteria for GTMP establishes Gene Therapies that the recombinant nucleic acids should be of biological origin, Some examples of gene therapy products include in vivo therapies, regardless of the origin of the vector system used. On the other such as nucleic acids or genetically modified microorganisms hand, in both regions, the product has to be applicable to the (e.g., viruses, bacteria, fungi), and ex vivo therapies like prevention and treatment of a human disease. However, diagnosis genetically modified human cells or human genome editing. In is neither cited as one of the primary goals of these products in the the EU, in order to classify a product as a gene therapy, all of the US nor does the US definition of a biologic product, according to following inclusion criteria must be met (European Medicines the PHSA Act, contemplates diagnosis as a purpose of the product Agency, 2015): i) the product has to be a biological medicinal (U.S. Title 42 The Public Health and Welfare, 2019). In EU, there product according to Directive 2003/63/CE; ii) the product must is one exclusion criterion that explicitly vetoed a product from contain recombinant nucleic acid(s); iii) the recombinant nucleic being classified as a gene therapy: those products aimed at the acids should be of biological origin, regardless of the origin of treatment or prophylaxis of infectious diseases. These products the vector system used; iv) the recombinant nucleic acid is used would be classified as vaccines, even if the product meets all of in or administered to human beings in order to regulate, repair, the necessary criteria to be considered an advanced therapy replace, add, or delete a genetic sequence; and v) the recombinant (European Medicines Agency, 2015). For instance, a modified nucleic acid(s) should be directly involved in the therapeutic, vaccinia virus ankara (MVA) into which two genes have been prophylactic, or diagnostic effect of the product (Table 2). It placed for the treatment of non-small cell lung cancer is classified should also be noted that, according to the ATMP Regulation as a GTMP, but if these genes lead to foreign protein expression (European Union, 2007), a product that may fall within the for the treatment of human immunodeficiency virus (HIV) definition of a SCTMP or a TEP, and a GTMP, shall be considered disease, the product will not be considered an advanced therapy, a GTMP, since it is the one that can pose the most safety concerns. but a vaccine (European Medicines Agency, 2016b; Draper and In the US, the inclusion criteria that must be met are the Heeney, 2010). The same principle applies to non-viral vectored following (U.S. Department of Health and Human Services, products such as most plasmid DNA- or RNA-based products. 1993; U.S. Department of Health and Human Services, 1998): i) For instance, Trimix is a mixture of mRNAs encoding for antigen the product meets the definition of “biological product” in presenting cell activation molecules. If this mixture of mRNAs section 351(i) of the PHSA [42 U.S.C. 262(i)]; ii) the product is combined with tumor-associated antigens for the treatment has to be applicable to the prevention, treatment, or cure of a of melanoma, the therapy is classified as a GTMP, but if these disease or condition of human beings; iii) the product mediates mRNA are combined with mRNA encoding for HIV antigens, its effects by transcription or translation of transferred genetic the therapy will be considered a vaccine (European Medicines material or by specifically altering host (human) genetic Agency, 2016b). In the US, it is not specifically mentioned as an sequences; and iv) the product can work through several exclusion criterion, but prophylaxis or therapeutic vaccines for mechanisms: replacing a disease-causing gene with a healthy infectious diseases have their own guidances for development, copy of the gene, inactivating a disease-causing gene that is not and these products are typically reviewed by the CBER/Office of functioning properly, or introducing a new or modified gene Vaccines Research and Review (OVRR) and not by the OTAT (U.S. into the body. Recombinant DNA materials used to transfer Department of Health and Human Services, 2007). Therefore, the genetic material for such therapy are considered components of criterion for excluding a product from being classified as a GTMP gene therapy (Table 3). in both regions is directly related to the indications of the product. Therefore, despite the different terminology used, the inclusion Although some regulatory and development requirements for criteria that define a GTMP are equivalent in both regions: the both types of products overlap, since these vaccines may be gene- product must be a biological product that contains “recombinant based, for either region, there are guidelines specifically addressed nucleic acid(s)” (term used in EU) or “genetic material” (term to the development of vaccines or gene therapy products used in US), which through its action mechanism prompts the independently. A consequence of this classification is that some desired primary effect: addition, manipulation, or modification of the available EU regulatory procedures that facilitate the of gene expressions on human beings. Two autologous chimeric development of ATMPs would not apply in the case of products antigen receptor (CAR) T-cell therapies (Kymriah® and Yescarta®) classified as vaccines; for instance, the possibility of certifying the were recently approved by the EMA and the FDA. These therapies quality and non-clinical data for ATMP applications by the EMA are classified as cell-based gene therapies in both regions since (European Medicines Agency, 2010). Frontiers in Pharmacology | www.frontiersin.org 5 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework TABLE 2 | Inclusion/exclusion criteria in European Union. Advanced Therapy medicinal products Product category Active substance Purpose Inclusions Exclusions Gene therapy Recombinant nucleic acid of Administered to human beings • Plasmids DNA • Non-biological products (e.g., medicinal biological origin with a view to regulating, • Viral vectors chemical synthetized nucleic products repairing, replacing, adding, or • Genetically engineered acids) (GTMPs) deleting a genetic sequence microorganisms • Vaccines against infectious Therapeutic, prophylactic, or • Human gene–editing diseases diagnostic effects that relate technology directly to the recombinant • Patient-derived cellular gene nucleic acid sequence it therapy products contains, or to the product of genetic expression of this sequence Somatic Cells or tissues that have Treating, preventing, or • Products containing or • Products containing or cell therapy been subject to substantial diagnosing a disease consisting of animal cells or consisting exclusively of medicinal manipulation or not intended to through the pharmacological, tissues non-viable cells or tissues products be used for the same essential immunological, or metabolic • Cancer immunotherapies and which do not act (SCTMPs) function(s) in the recipient and actions of its cells or tissues • Other autologous and principally by pharmacological, the donor allogeneic cells therapies immunological, or metabolic • Xenogeneic living cells actions • Stem cells and stem cell– derived products Tissue- Cells or tissues that have Regenerating, repairing, or • Products containing or • Products containing or engineered been subject to substantial replacing a human tissue consisting of animal cells or consisting exclusively of products (TEP) manipulation or not intended to tissues non-viable cells or tissues be used for the same essential • Products may also contain and which do not act function(s) in the recipient and additional substances, principally by pharmacological, the donor such as cellular products, immunological, or metabolic The cells or tissues may be bio-molecules, biomaterials, actions viable or non-viable. chemical substances, scaffolds or matrices • Products for cartilage or cardiac defects, among others • Stem cells and stem cells- derived products Combined Combines: Therapeutic, prophylactic, or – – ATMPs (cATMPs) • one or more medical diagnostic effect devices within the meaning Regenerating, repairing, or of or one or more active replacing a human tissue implantable medical devices and • its cellular or tissue part must contain viable cells or tissues, or • its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to Cell and Tissue Therapies to substantial manipulation, or ii) the cells or tissues are not In the EU, SCTMP are distinguished from TEP. However, intended to be used for the same essential function(s) in the both class products share the same inclusion principle, i.e., the recipient and the donor, i.e., non-homologous use. Regarding the cells or tissues of the product must be “engineered,” and the indication, in the case of SCTMP, the product is administered to difference lays in the indication. To consider a cell or tissue as human beings with a view to treating, preventing, or diagnosing “engineered,” it must fulfill at least one of the following criteria a disease through the pharmacological, immunological, or (European Union, 2007): i) the cells or tissues have been subject metabolic actions of its cells or tissues, whereas in the case Frontiers in Pharmacology | www.frontiersin.org 6 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework TABLE 3 | Inclusion/exclusion criteria in United States. Cell and gene therapy products Product category Definition Purpose Examples Exclusions Human gene Administration of genetic Prevention, treatment, or cure • Plasmid DNA • Non-biological products (e.g., therapy material to modify or of a disease or condition of • Viral vectors chemical synthetized nucleic manipulate the expression of human beings • Genetically engineered acids) a gene product or to alter the microorganisms • Products that are destined for biological properties of living • Human gene–editing the treatment or prophylaxis of cells for therapeutic use technology infectious diseases • Patient-derived cellular gene therapy products Somatic cell therapy Autologous, allogeneic, or Therapeutic, diagnostic, or • Cancer vaccines • HCT/Ps under section 361 of xenogeneic cells that have preventive purposes • Cellular immunotherapies the PHSA been propagated, expanded, • Other types of both selected, pharmacologically autologous and allogeneic treated, or otherwise altered cells in biological characteristics • Xenogeneic living cells ex vivo • Stem cells and stem cell– derived products • Gene therapy–modified cells Combination products Product category Definition Purpose Examples Exclusions Combination Two or more regulated Therapeutic, diagnostic, or • Drug/device – products components, i.e., drug, device, preventive purposes • Biologic/device: cells biologic as a single entity or combined with medical packaged together, packaged devices such as natural or separately but intended for use synthetic scaffold only with an approved individually • Drug/biologic, or specified drug, device, or • Drug/device/biologic biological product where both are required to achieve the intended use, indication, or effect Regenerative medicine advanced therapy designation Product category Definition Purpose Examples Exclusions Regenerative medicine A cell therapy, therapeutic To treat, modify, reverse, • AT132 (Audentes Products regulated solely under advanced therapy tissue-engineering product, or cure a serious or life- Therapeutics, Inc.) section 361 of the PHSA are (RMAT) human cell and tissue product, threatening disease or • Romyelocel-L (Cellerant explicitly excluded or any combination product condition; Therapeutics, Inc.) using such therapies or To address unmet medical • AmnioFix® (MiMedx) products needs for such disease or • CAP-1002 (Capricor condition Therapeutics) Human cells, tissues, and cellular and tissue-based products Product category Definition Purpose Examples Exclusions Articles containing or consisting Implantation, transplantation, • Bone • Vascularized human organs HCT/Ps1 of human cells or tissues infusion, or transfer into a • Ligament for transplantation human recipient • Skin • Secreted or extracted human • Dura mate products (e.g., milk, collagen, • Heart valve and cell factors) • Cornea • Minimally manipulated bone • Hematopoietic stem/ marrow for homologous use progenitor cells derived from • Ancillary products used in the peripheral and cord blood manufacture of HCT/P • Manipulated autologous • Cells, tissues, and organs chondrocytes derived from animals other • Epithelial cells on a synthetic than humans matrix In vitro diagnostic products • Semen or other reproductive tissue • Amniotic membrane (when used alone (without added cells) for ocular repair) 1 HCT/Ps that meet the criteria contemplated in 21 CFR 1721.10(a). Frontiers in Pharmacology | www.frontiersin.org 7 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework of TEP, the product is administered to human beings with a claimed indication, while in the US, cell and tissue products view to regenerating, repairing, or replacing human tissue. that constitute an advanced therapy will be labeled under the The key to ascertain the most appropriate subcategory is SCT’s term. For instance, MACI (matrix-applied characterized based on the predominant mechanism of action of the active autologous cultured chondrocytes) is a product approved both in substance and the claimed intended function. A problem arises EU and US which consists of autologous chondrocytes seeded on when the dividing line for classifying a product as SCTMPs a collagen membrane of porcine origin indicated for the repair or TEP is not clear. Such is the case when the product exerts of symptomatic, full-thickness cartilage defects of the knee in a pharmacological action in order to regenerate, repair, or adult patients. While in US, MACI is considered a cell therapy, a replace a human tissue. For these cases, premises have been biologic-device combination product with the aim of being used established in order to categorize a specific product: a product for therapeutic purposes; in EU, it is classified as combined TEP, which may fall within the definition of a TEP and SCTMP since the claimed primary mechanism of action of the product should be considered a TEP according to ATMP Regulation, is the regeneration, repair, and replacement actions (European although the final classification should be considered on case- Medicines Agency, 2018d; U.S. Food and Drug Administration, by-case basis, playing CAT’s opinion a major role. In addition, 2018i). Finally, the FDA classifies xenogeneic living cells as SCT, those products that consist of engineered or manipulated cells as well as in EU, where these therapies can be assumed to be that induce regeneration, repair, or replacement in the native automatically classified as ATMPs from a regulatory point of tissue via secretion of paracrine factors also fulfill the definition view (European Medicines Agency, 2009; Schuurman, 2015). of a TEP (European Medicines Agency, 2015). Finally, it is considered that a TEP may contain cells or tissues of human Manipulation and Homologous Use or animal origin, or both, and that the cells or tissues may be Both aforementioned inclusion criteria, manipulation and viable or non-viable, considering viable cells those that have a homologous use, have their own definitions depending on the functional cytoplasmic membrane. Two considerations in this region. In EU, “substantial manipulation” means to modify regard are made: i) an inclusion criterion that automatically the biological characteristics, physiological functions, or classifies a product as an ATMP applies when products contain structural properties relevant for the intended clinical use. For or consist of animal cells or tissues and ii) an exclusion criterion instance, cell separation, concentration, or purification does for not classifying a potential product either as a SCTMP or TEP not represent a substantial manipulation if the cells performed includes those products containing or consisting exclusively the same biological activity as in the human body, whereas cell- of non-viable cells or tissues and which do not act principally culturing leading to expansion or cell activation with growth through pharmacological, immunological, or metabolic factors does. A non-exhaustive list of manipulations that is actions (Table 2). not considered substantial for ATMP purposes is provided in As mentioned, cell- and tissue-based products can be sub- Annex I of Regulation EC (No). 1394/2007 and includes: cutting, categorized in the US regulatory framework as biologic products grinding, shaping, centrifugation, soaking in antibiotic or or as HCT/Ps. The definition of cell- and tissue-based products antimicrobial solutions, sterilization, irradiation, cell separation, regulated as biologic products includes those that are “more- concentration, or purification, filtration, lyophilization, freezing, than-minimally manipulated,” or for “non-homologous use,” or and cryopreservation. On the other hand, the “same essential have a systemic effect, or depend on its metabolic activity (except function” (or homologous use) means that the cells or tissues for autologous cells, allogeneic cells for 1st of 2nd degree relatives (whether substantially manipulated or not) are used to maintain and reproductive cells) (U.S. Department of Health and Human the original function(s) in the same anatomical or histological Services, 2017a). The group of advanced therapies referred to as environment. By contrast, “different essential function” (or non- “human somatic cell therapy products” fall within this definition. homologous use) for cells or tissues (substantially manipulated Note that, in US, there is no product class defined for tissue-based or not) are those not intended to be used for the same essential advanced therapies. The definition and the inclusion criteria function(s) in the recipient as the original cell/tissue would for human somatic cell therapy (SCT) include the following perform in the donor (European Medicines Agency, 2015). (U.S. Department of Health and Human Services, 1993; U.S. Allogeneic human islets of Langerhans for the treatment of severe Department of Health and Human Services, 1998): i) SCT forms of type 1 diabetes is a common example of cell/tissue consists of administration to humans of autologous, allogeneic, products that might be regarded as non-ATMPs, since these cells/ or xenogeneic living cells; ii) the manufacture of products for tissues might be isolated, purified, and cultured by methods that SCT involves the ex vivo propagation, expansion, selection or do not result in a modification of the biological characteristics pharmacologic treatment of cells, or other alterations of their and are re-administered to fulfill their same essential function. biological characteristics, and therefore considered “more-than- In 2011, CAT considered that autologous/allogeneic human minimally manipulated”; and iii) the aim of this cellular products islets of Langerhans were not an ATMP (European Medicines is to be used for therapeutic, diagnostic, or preventive purposes Agency, 2011b), but are considered to fall under the provisions (Table 3). of the Tissues and Cells legislation. Under this legislation, these Therefore, the categorization or classification of human cells cells are neither considered a medicinal product, since the active and tissue products between the EU and the US is different. On substance, i.e., human tissues, cannot be commercialized or one hand, in the EU, there is a differentiation between products manufactured on an industrial scale for ethical and legal reasons. considered TEP, or SCTMP, in which the difference lies in the However, in 2013, a product that consists of viable alginate Frontiers in Pharmacology | www.frontiersin.org 8 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework encapsulated porcine pancreatic islet cells was classified as a tissue’s function or functions; for instance, the original relevant SCTMP (European Medicines Agency, 2013b). In this case, the characteristics of amniotic membrane generally include the porcine islets were isolated from pancreases of neonatal piglets physical integrity, tensile strength, and elasticity of the tissue. and cultured during 30 days, in which cell differentiation occurs Following with the same example, preserving and packaging by increasing the amount of insulin released from the cells, this amniotic membrane in sheets would be considered a minimal being considered a substantial manipulation. Nevertheless, it manipulation, yet more than minimally manipulated if the should be noted that, since this product is based on xenogeneic amniotic membrane is grounded, lyophilized, and packaged as cells, it is automatically considered an ATMP, as previously particles, since it would imply the separation of structural tissue discussed. Finally, in 2018, the CAT considered an encapsulated into components whose characteristics related to serving as a allogeneic pancreatic islet–based product a non-ATMP. The barrier are altered. However, ground bone adhered to form bone consideration here is whether or not the encapsulation itself particles would generally be considered minimally manipulated might change the characteristics of the islet (European Medicines since it can maintain its utility as a supporting structure. For Agency, 2018e). products that contain cells (both structural and non-structural) In US, the definitions of manipulation and homologous use and non-structural tissues, “original relevant characteristics” are defined for HCT/Ps, and by exclusion, the products based on include differentiation and activation state, proliferation cells and tissues that do not comply with these criteria established potential, and metabolic activity, e.g., for hematopoietic stem/ for a HTC/Ps could be considered a biological product, and progenitor cells, the ability to repopulate the bone marrow by consequently, an advanced therapy (U.S. Department of Health and self-renewal and by differentiating along myeloid and lymphoid Human Services, 2017a). The criteria for HCT/Ps include “minimal cell lines. In this case, cell selection on peripheral blood apheresis manipulation” and “homologous use,” while “more-than-minimally products to obtain a higher concentration of hematopoietic manipulated” and “non-homologous use” are considered for cell- stem/progenitor cells for transplantation would be considered and tissue-based products considered as biological drugs. a minimal manipulation, whereas differentiating the cells by Unlike the EU, in the US, there is a differential definition of culturing under specific conditions would be considered more minimal manipulation depending on whether or not the product than a minimal manipulation because the characteristics of consists of structural tissue. “Minimal manipulation” is defined as: multipotency and capacity for self-renewal are altered. The “processing that does not alter the original relevant characteristics storage of the product should also be considered, since it can of the tissue relating to the tissue’s utility for reconstruction, repair, alter the original relevant characteristics of the cells and tissues. or replacement” for structural tissues, and “processing that does If a product is stored in a buffer solution or is cryopreserved, it not alter the relevant biological characteristics of cells or tissues” would generally meet the minimal manipulation criterion. for cells or non-structural tissues (U.S. Code of Federal Regulation Regarding “homologous use,” there is also a differentiation Title 21, 2018a). For clarification, structural tissue is defined as between structural and non-structural tissues. The term of human cells/tissues that physically support or serve as a barrier or homologous use for a structural tissue defines that the tissue is conduit, or connect, cover, or cushion (e.g., amniotic membrane intended to be used for a homologous function when used to and umbilical cord). On the other hand, human cells/tissues that replace an analogous structural tissue that has been damaged or serve as metabolic or other biochemical roles in the body, such as otherwise does not function adequately. Therefore, it is defined as hematopoietic, immune, and endocrine functions, are generally the repair, reconstruction, replacement, or supplementation of a considered cells/non-structural tissues (e.g., hematopoietic stem/ recipient’s cells or tissues with an HCT/P that performs the same progenitor cells). It is considered that this differentiation between basic function or functions in the recipient as in the donor (U.S. structural and non-structural tissues is required, since structural Code of Federal Regulation Title 21, 2018a). The Agency would HCT/Ps generally raise different safety and efficacy concerns from consider structural tissue to be performing a non-homologous those of cells or non-structural tissues. function when used for a purpose different from those that it As a result, the term “processing” is defined as any activity fulfils in its native state, or in a location of the body, where such performed on a cell- and/or tissue-based product other than structural function does not normally occur. Similarly, cellular recovery, donor screening, donor testing, storage, labeling, products are considered to be used for a homologous function packaging, or distribution, such as testing for microorganisms, when they are used to perform their native function, and for a preparation, sterilization, steps to inactivate or remove non-homologous function when they are used to perform other adventitious agents, preservation for storage, and removal from functions (U.S. Department of Health and Human Services, storage. Processing includes cutting, grinding, shaping, culturing, 2017a; U.S. Department of Health and Human Services, 2017b). enzymatic digestion, and decellularization (U.S. Code of Federal As it has been discussed, it is important to have a product Regulation Title 21, 2018a). Cell expansion, encapsulation, defined since, otherwise, the legal requirements for these could activation, or genetic modification are considered to be more be violated. In the US, this was the case of some amniotic-/ than minimal manipulations. The aforementioned or any other chorionic-based products, used for wound healing, which additional processing steps should be considered in determining were considered HCT/Ps by some companies, when in fact, whether a product is minimally manipulated or not. they were biological products. These products were therefore For products that contain structural tissues, “original relevant launched to the market without a premarket review, and after characteristics of structural tissues” generally comprise the an inspection of the CBER Office of Compliance and Biologics properties of that tissue in the donor that contribute to the Quality, an appropriate clinical development was requested in Frontiers in Pharmacology | www.frontiersin.org 9 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework order to demonstrate the safety and efficacy of the intended use means (European Union, 2017). Examples of medical devices of the product, as well as distribution of the product to test its in cATMP could be scaffolds, matrices, and encapsulation clinical use in humans after IND application, and the subsequent systems for cells, such as microspheres, among others. The submission of a BLA approval for its marketing. This implied criteria to meet in this category class are that the product that the cost of bringing this product to the market was very must incorporate, as an integral part of the product, one or different from the one initially invested, given that the preclinical more medical devices. The medical device should be used in and clinical developments are much broader than for an HCT/Ps the combination, in the same way as its intended use without (U.S. Food and Drug Administration, 2018j; U.S. Food and Drug additional components. On the other hand, the cellular or Administration, 2018k). tissue part of the product must contain viable cells or tissues, Therefore, both in the EU and in the US, in order to or if containing non-viable cells or tissues, it must be liable to consider a cell- and tissue-based products advanced therapies, act upon the human body with actions that can be considered it must be ascertained that the processing of the cells implies a primary to those of the devices referred to (European manipulation that alters their biological characteristics. In EU, Medicines Agency, 2015). the concept is referred as a “substantial manipulation,” while In US, there is no specific category for cATMPs, but there in US, it is referred as “more-than-minimally manipulated.” are nine different types of combined products including drug/ Regarding this term of manipulation in US, there is a nuance that device, biologic/device, drug/biologic, or drug/device/biologic. differs from EU definitions and consists in the differentiation The definition takes into account how the product is packaged, of structural and cells/non-structural tissues in the US. The i.e., together in a single package or packaged separately, European definitions of substantial manipulation and non- and if all components of the product are needed to achieve homologous use would encompass both structural and non- the intended use, indication, or effect. Among all of these structural tissues under the same definition. Regardless of the categories, the type-5 combination product named “device examples of processing mentioned for either regions, for both, coated or otherwise combined with biologic” constitutes the it is key to determine if the processing changes the original biologic/device combination where the device has an additional characteristics of the product. This requires a characterization function in addition to delivering the drug and constitutes an of the product during the manufacturing process, as a part of “integral part” of the final product, e.g., live cells seeded on development, to corroborate whether or not the phenotypic and or in a device scaffold (U.S. Food and Drug Administration, physiological characteristics of a potential product have been 2018a). In US, a medical device is defined as an instrument, altered. On the other hand, the European terminology uses the apparatus, implement, machine, contrivance, implant, in term “engineered” to denominate those cells or tissues that are vitro reagent, or other similar or related article, including any substantially manipulated and/or used for a different essential component, part, or accessory, which has at least one of the function (or non-homologous use), which is mandatory following three characteristics: i) it is recognized in the official criteria to classify a product as an advanced therapy. In the US, National Formulary or the United States Pharmacopeia, or any the term of non-homologous use is not explicitly mentioned supplement to them; ii) it is intended for use in the diagnosis, in the definition of SCT, although it is to classify a product cure, mitigation, treatment, or prevention of a disease; or as biologic in the general definition of cell- and tissue-based iii) is intended to affect the structure or any function of the products. Note that the nomenclature of “non-homologous use” human body or other animals and does not achieve its primary is be common for both regions, although in Europe, the term intended purposes through chemical action within or on the “different essential function” would also be the one harmonized human body or other animals and which does not depend on according to the EMA guidelines. All these mentioned being metabolized for the achievement of its primary intended differences in terminology can be important when submitting purposes (U.S. Code of Federal Regulation Title 21, 2018b; U.S. documents to the respective Agencies, since it is advisable to Food and Drug Administration, 2018l). use the specific terminology used in each region (Table 4). Therefore, while in EU, cATMPs are the fourth subcategory of products within the group of advanced therapies; in the Combined Advanced Therapy Medicinal US, the subcategory defined for combined products is very Products broad and includes drugs, biological, and medical devices. In EU, there is a specific category for those products that consist The category of type-5 combined products would constitute in an ATMP combined with a medical device. A medical device a group equivalent to what defines cATMPs in the US, where is defined as any instrument, apparatus, appliance, material, or the product is a single-entity combination product, or the other article intended by the manufacturer to be used on human device constitutes “an integral part of the product” according to beings for the purpose of: i) diagnosis, prevention, monitoring, European definition. For both EU and US, the final combined treatment or alleviation of disease, compensation for an injury product will be a biological and a medical device, where the or handicap, investigation, replacement, or modification of the definitions of medical device are equivalent: the medical device anatomy of a physiological process, or control of conception assists in the primary function of the biological component. and ii) which does not achieve its principal intended action Following MACI’s aforementioned example, for both regions, in or on the human body by pharmacological, immunological, the porcine collagen membrane is considered a device or metabolic means, but may assist its function by such constituent of the product a CE-marked class III device in EU Frontiers in Pharmacology | www.frontiersin.org 10 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework TABLE 4 | Terminology and definitions for cell- and tissue-based products as advanced therapies. European Union1 United States2 Term Definition Term Definition Substantial Biological characteristics, physiological functions, More than “minimally For structural tissue, processing that alters the original manipulation or structural properties have been modified to manipulated”* relevant characteristics of the tissue relating to the tissue’s be relevant for their intended function during the utility for reconstruction, repair, or replacement manufacturing process. For cells or non-structural tissues, processing that alters the relevant biological characteristics of cells or tissues Different Cells when removed from their original Non-homologous use Homologous use means the repair, reconstruction, essential environment in the human body are not used replacement, or supplementation of a recipient’s cells or function or non- to maintain the original function(s) in the same tissues with an HCT/P that performs the same basic function homologous use anatomical or histological environment. or functions in the recipient as in the donor, including when such cells or tissues are for autologous use. Basic functions of a structural tissue would generally be to perform a structural function for example, to physically support or serve as a barrier or conduit, or connect, cover, or cushion. Basic functions of a cellular or nonstructural tissue would generally be a metabolic or biochemical function, such as hematopoietic, immune, and endocrine functions. Manufacturing Defined to include all operations of receipt of Processing Any activity performed on an cell- and/or tissue-based materials, production, packaging, repackaging, product, other than recovery, donor screening, donor testing, labeling, relabeling, quality control, release, storage, labeling, packaging, or distribution, such as testing storage, and distribution of active substance(s) for microorganisms, preparation, sterilization, steps to and the related controls inactivate or remove adventitious agents, preservation for storage, and removal from storage List of Provided in Annex I of Regulation EC (No.) List of processing Provided in regulatory considerations for human cells, manipulations 1394/2007 tissues, and cellular and tissue-based products: minimal manipulation and homologous use (2017) and proposed approach to regulation of cellular and tissue-based products (1997), and the United States pharmacopoeia (cellular and tissue-based products: 1046) – – Original relevant For products that contain structural tissues, “original relevant characteristics characteristics of structural tissues” generally include the properties of that tissue in the donor that contribute to the tissue’s function or functions. For products that contain cells (both structural and non- structural) and non-structural tissues, “original relevant characteristics” include differentiation and activation state, proliferation potential, and metabolic activity. Viable cell A viable cell is a cell that has a functional Living cells – cytoplasmic membrane. (The United States pharmacopoeia cellular and tissue-based (The European Pharmacopoeia provides products <1046>) information on assays to demonstrate cytoplasmic membrane integrity and activity < 20729 >.) Tissues Defined in Directive 2004/23/EC (Art 3.b) as “all – – constituent parts of a human body formed by cells.” 1Definitions provided in EMA/CAT/600280/2010 Rev.1, CPMP/ICH/4106/00 and Regulation EC (No) 1394/2007; 2Definitions provided in the Code of Federal Regulation (21 CFR 1271.3; 21 CFR 1271.10), Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (2017) and Proposed approach to regulation of cellular and tissue-based products (1997); *The definition provided is minimal manipulation. For advanced therapies the term that applies is “more than minimally manipulated”. (European Medicines Agency, 2018d; U.S. Food and Drug GENERAL DISCUSSION AND Administration, 2018i). CONCLUSION The fact of combining a biological product with a medical product complicates its development, and in US, unlike in Our analysis reveals a difference between EU and US in the EU, there are guidances with some considerations to be taken sub-categorization of advanced therapies and the regulatory into account during the development of these products (U.S. terminology defining them. The criteria that must be met in Food and Drug Administration, 2006; U.S. Food and Drug both the EU and the US in order to classify a product as an Administration, 2019d). advanced therapy is similar, although EU presents a more precise Frontiers in Pharmacology | www.frontiersin.org 11 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework sub-classification with more defined inclusion criteria between EU/US collaboration on medicines with the aim to facilitate these subcategories. The criteria to determine if a product qualifies regulatory excellence of the new medicinal products (European as a gene therapy may be simpler or more obvious than for cell Medicines Agency, 2018f). Yet, Agencies’ recommendations therapies, although there are some relevant considerations for all are evolving and being updated over time in a non-parallel defined subcategories of advanced therapies that can change the manner. In 2018, the FDA launched several guidances that classification of the product both in EU and US. include specific recommendations for the development of EU and US are facing similar challenges regarding the ATMPs aimed at certain types of diseases such as hemophilia or regulation of ATMPs due to their inexperience in this specific retinal disorders (U.S. Food and Drug Administration, 2019e), medicinal product group, and because Europe covers a variety of while the EMA guidelines published to date are more generalist, overlaying jurisdictions and authorities on a member state level encompassing only the development of ATMPs according to the (Bender, 2018; Ten Ham et al., 2018). European and American three main groups of therapies, GTMP, SCTMP, and TEP. In the legislation and regulatory guidelines launched by EMA and FDA future, it would be convenient to begin a progressive process of show similarities and differences in the ATMP classification for convergence between both Agencies in terms of terminology, both regions. It is unknown if these differences can be translated legal recommendations, and characterization requirements. In into divergent final recommendations by the regulatory this regard, some steps could be taken to reach this alignment authorities. Currently, the number and type of ATMPs approved between regulators—for example, common guidelines, increased differ between the two regulatory Agencies. In EU, up to 12 number of EMA/FDA parallel scientific advice from the ATMPs have been authorized from 2009, but four of them have beginning of the lifecycle of the medicinal product, as well as been withdrawn throughout the past 10 years. In US, nine gene similar post-authorization monitoring of the products or real- and cell therapies haven’t been authorized, and only six of them world evidence data generation. match in the two Agencies. The rationale behind these differences is unknown, but it seems feasible that a worldwide harmonization of the procedures involved in the development of ATMPs may AUTHOR CONTRIBUTIONS allow to reach similar ultimate decisions. It is acknowledged that EMA and FDA have been collaborating for the past 15 years CIL conducted the bibliographic search, analysed the data, drafted with the aim to ameliorate regulatory excellence. An ATMP the manuscript and edits the final copy of this article. AA, MO, cluster has been created under the umbrella of the reinforced and AV analyzed and reviewed the data and edited the manuscript. REFERENCES scientific-recommendation-classification-advanced-therapy-medicinal- products-human-islets-langerhans_en.pdf. Bender, E. (2018). Regulating the gene-therapy revolution. Nature 564 (7735), European Medicines Agency. (2013a). Procedural advice on the provision of scientific S20–S22. doi: 10.1038/d41586-018-07641-1 recommendation on classification of advanced therapy medicinal products in Detela, G., and Lodge, A. (2019). EU regulatory pathways for ATMPs: standard, accordance with article 17 of regulation (EC) no 1394/2007. Available online at: accelerated and adaptive pathways to marketing authorisation. Mol. Ther. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/ Methods Clin. Dev. 13, 205–232. doi: 10.1016/j.omtm.2019.01.010 procedural-advice-provision-scientific-recommendation-classification- Draper, S. J., and Heeney, J. L. (2010). Viruses as vaccine vectors for infectious advanced-therapy-medicinal/2007_en.pdf. diseases and cancer. Nat. Rev. Microbiol. 8 (1), 62–73. doi: 10.1038/nrmicro2240 European Medicines Agency. (2013b). Scientific recommendation on classification of European Commission. (2017a). The new regulations on medical devices. advanced therapy medicinal products (EMA/277458/2013). Available online at: Available online at: https://ec.europa.eu/growth/sectors/medical-devices/ https://www.ema.europa.eu/en/documents/report/scientific-recommendation- regulatoryframework_en#new_regulations. classification-advanced-therapy-medicinal-products-alginate-encapsulated_ European Medicines Agency. (2017b). Procedural timetables. Available online at: en.pdf. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/ European Medicines Agency. (2015). Reflection paper on classification of submissiondates/procedural-timetables. advanced therapy medicinal products. Available online at: https://www.ema. European Medicines Agency. (2009). Guideline on xenogeneic cell-based medicinal europa.eu/en/documents/scientific-guideline/reflection-paper-classification- products. Available online at: https://www.ema.europa.eu/en/documents/scientific- advanced-therapy-medicinal-products_en-0.pdf. guideline/guideline-​xenogeneic-​cell-based-medicinal-products_en.pdf. European Medicines Agency. (2012). Glybera EPAR. Available online at: https:// European Medicines Agency. (2010). Guideline on the minimum quality and non- www.ema.europa.eu/en/medicines/human/EPAR/glybera. clinical data for certification of advanced therapy medicinal products. Available European Medicines Agency. (2016b). Scientific recommendation on classification of online at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline- advanced therapy medicinal products (EMA/761529/2016). Available online at: minimum-quality-non-clinical-data-certification-advanced-therapy-medicinal- https://www.ema.europa.eu/en/documents/report/scientific-recommendation- products_en.pdf. classification-advanced-therapy-medicinal-products-recombinant-modified_ European Medicines Agency. (2011a). Procedural advice on the evaluation of en.pdf. combined advanced therapy medicinal products and the consultation of European Medicines Agency. (2017a). ChondroCelect EPAR. Available notified bodies in accordance with Article 9 of Regulation (EC) No. 1394/2007. online at: https://www.ema.europa.eu/en/medicines/human/EPAR/ Available online at: https://www.ema.europa.eu/en/documents/regulatory- chondrocelect. procedural-guideline/procedural-advice-evaluation-combined-advanced- European Medicines Agency. (2017b). Scientific recommendation on classification therapy-medicinal-products-consultation-notified/2007_en.pdf. of advanced therapy medicinal products (EMA/665187/2017). Available European Medicines Agency. (2011b). Scientific recommendation on online at: https://www.ema.europa.eu/en/documents/report/scientific- classification of advanced therapy medicinal products (EMA/681445/2011). recommendation-classification-advanced-therapy-medicinal-products- Available online at: https://www.ema.europa.eu/en/documents/report/ messenger-rnas-mrnas_en.pdf. Frontiers in Pharmacology | www.frontiersin.org 12 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework European Medicines Agency. (2018a). Procedural advice on the evaluation U.S. Code of Federal Regulation Title 21. (2018b). Section 201(h)—medical of advanced therapy medicinal product in accordance with Article 8 of devices. Available online at: https://www.law.cornell.edu/cfr/text/21/chapter-I/ Regulation (EC) No 1394/2007. Available online at: https://www.ema.europa. subchapter-H. eu/en/documents/regulatory-procedural-guideline/procedural-advice- U.S. Department of Health and Human Services. (1993). Food and drug evaluation-advanced-therapy-medicinal-product-accordance-article-8- administration. Application of current statutory authorities to human somatic regulation-ec/2007_en.pdf. cell therapy products and gene therapy products; Notice. Part II. Available European Medicines Agency. (2018b). European Medicines Agency Guidance for online at: https://www.fda.gov/media/76647/download. applicants seeking access to PRIME scheme. Available online at: https://www. U.S. Department of Health and Human Services. (1998). Food and Drug ema.europa.eu/en/documents/other/european-medicines-agency-guidance- Administration Center for Biologics Evaluation and Research. Guidance for applicants-seeking-access-prime-scheme_en.pdf. human somatic cell therapy and gene therapy. Available online at: https://www. European Medicines Agency. (2018d). MACI EPAR. Available online at: https:// fda.gov/media/72402/download. www.ema.europa.eu/en/medicines/human/EPAR/maci. U.S. Department of Health and Human Services. (2007). Food and Drug European Medicines Agency. (2018e). Scientific recommendation on classification Administration Center for Biologics Evaluation and Research. Considerations of advanced therapy medicinal products (EMA/277069/2018). Available for plasmid DNA vaccines for infectious disease indications. Available online online at: https://www.ema.europa.eu/en/documents/report/scientific- at: https://www.fda.gov/media/73667/download. recommendation-classification-advanced-therapy-medicinal-products- U.S. Department of Health and Human Services. (2017a). Food and Drug allogeneic-pancreatic_en.pdf. Administration. Center for Biologics Evaluation and Research. Regulatory European Medicines Agency. (2018f). Reinforced EU/US collaboration on considerations for human cells, tissues, and cellular and tissue based products: medicines. Available online at: https://www.ema.europa.eu/en/news/ minimal manipulation and homologous use. Available online at: https://www. reinforced-euus-collaboration-medicines. fda.gov/regulatory-information/search-fda-guidance-documents/regulatory- European Union. (2003a). Commission Directive 2003/63/EC amending Directive considerations-human-cells-tissues-and-cellular-and-tissue-based-products- 2001/83/EC of the European Parliament and of the Council on the Community minimal. code relating to medicinal products for human use. Available online at: https:// U.S. Department of Health and Human Services. (2017b). Food ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2003_63/ and Drug Administration. Center for Biologics Evaluation dir_2003_63_en.pdf. and Research. Proposed approach to regulation of cellular and European Union. (2003b). Directive 2002/98/EC of the European Parliament and of tissue-based products. Available online at: https://www.fda. the Council on setting standards of quality and safety for the collection, testing, g o v / r e g u l at o r y - i n f o r m at i o n / s e a r c h - f d a - g u i d a n c e - d o c u m e nt s / processing, storage and distribution of human blood and blood components and proposed-approach-regulation-cellular-and-tissue-based-products. amending Directive 2001/83/EC. Available online at: https://eur-lex.europa.eu/ U.S. Food and Drug Administration. (2006). Office of the Commissioner LexUriServ/LexUriServ.do?uri=OJ:L:2003:033:0030:0040:EN:PDF. Office of Combination Products. Early development considerations European Union. (2004). Directive 2004/23/EC of the European Parliament and for innovative combination products. Available online at: https://www. of the Council on setting standards of quality and safety for the donation, fda.gov/regulator y-information/search-fda-guidance-documents/ procurement, testing, processing, preservation, storage and distribution early-development-considerations-innovative-combination-products. of human tissues and cells. Available online at: https://eur-lex.europa.eu/ U.S. Food and Drug Administration. (2017a). Investigational New Drug (IND) LexUriServ/LexUriServ.do?uri=OJ:L:2004:102:0048:0058:en:PDF. Application. Available online at: https://www.fda.gov/drugs/types-applications/ European Union. (2007). Regulation EC No 1394/2007 of the European Parliament investigational-new-drug-ind-application. and of the Council on advanced therapy medicinal products and amending US Food and Drug Administration. (2017b). Center for Biologics Evaluation Directive 2001/83/EC and Regulation (EC) No 726/2004. Available online at: and Research (CBER). Available online at: https://www.fda.gov/about-fda/ https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121 office-medical-products-and-tobacco/about-center-biologics-evaluation-and- :0137:en:PDF research-cber. European Union. (2010). Directive 2010/45/EU of the European Parliament and U.S. Food and Drug Administration. (2017c). NDA and BLA approval times. of the Council on standards of quality and safety of human organs intended for Available online at: https://www.fda.gov/drugs/nda-and-bla-approvals/ transplantation. Available online at: https://eur-lex.europa.eu/legal-content/ nda-and-bla-approval-times. EN/TXT/PDF/?uri=CELEX:32010L0053&from=EN. U.S. Food and Drug Administration. (2018a). Combination product European Union. (2017). Regulation 2017/745 of the European Parliament and of the definition combination product types. Available online at: https:// Council on medical devices, amending Directive 2001/83/EC, Regulation (EC) No www.fda.gov/combination-products/about-combination-products/ 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives combination-product-definition-combination-product-types. 90/385/EEC and 93/42/EEC. Available online at: https://eur-lex.europa.eu/ U.S. Food and Drug Administration. (2018b). 21st Century Cures Act. legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745&from=EN. Available online at: https://www.fda.gov/RegulatoryInformation/ Lee, M. H., Au, M., Hyde, J., Johnson, G. C., Heidaran, M., Karandish, S., et al. LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/21stCenturyCu (2015). “Translation of regenerative medicine products into the clinic in the resAct/default.htm. United States: FDA perspective”, in Translational regenerative medicine, Ed A. U.S. Food and Drug Administration. (2018c). Biologics License Atala and J. G. Allickson (Elsevier Inc.: Academic Press), 49–74. Applications (BLA) Process (CBER). Available online at: https://www. Regulatory Affairs Professional Society. (2019). Regulatory Intelligence: update on fda.gov/vaccines-blood-biologics/development-approval-process-cber/ regenerative medicine advanced therapies designations. Available online at: https:// biologics-license-applications-bla-process-cber. www.raps.org/news-and-articles/news-articles/2019/5/regulatory-intelligence- U.S. Food and Drug Administration. (2018d). Fast track, breakthrough update-on-regenerative-me. doi: 10.1016/B978-0-12-410396-2.00005-0 therapy, accelerated approval, priority review. Available online at: Schuurman, H. J. (2015). Regulatory aspects of clinical xenotransplantation. Int. J. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/ Surg. 23 (Pt B), 312–321. fast-track-breakthrough-therapy-accelerated-approval-priority-review. Ten Ham, R. M. T., Hoekman, J., Hövels, A. M., Broekmans, A. W., Leufkens, H. G. M., U.S. Food and Drug Administration. (2018e). Devices regulated by the and Klungel, O. H. (2018). Challenges in advanced therapy medicinal product center for biologics evaluation and research. Available online at: development: a survey among companies in Europe. Mol. Ther. Methods Clin. https://www.fda.gov/vaccines-blood-biologics/510k-process-cber/ Dev. 11, 121–130. doi: 10.1016/j.ijsu.2015.09.051 devices-regulated-center-biologics-evaluation-and-research. U.S. Code of Federal Regulation Title 21. (2018a). Chapter I, volume 8, part 1271, U.S. Food and Drug Administration. (2018f). Frequently asked section 1271.3—human cells, tissues, and cellular and tissue-based products. questions about combination products. Available online at: https:// Available online at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ www.fda.gov/combination-products/about-combination-products/ CFRSearch.cfm?fr=1271.3. doi: 10.1016/j.omtm.2018.10.003 frequently-asked-questions-about-combination-products#CP. Frontiers in Pharmacology | www.frontiersin.org 13 August 2019 | Volume 10 | Article 921 Iglesias-López et al. Advanced Therapies Regulatory Framework U.S. Food and Drug Administration. (2018g). SOPP 8004: Tissue Reference fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/ Group. Available online at: https://www.fda.gov/media/85648/ regenerative-medicine-advanced-therapy-designation. download. U.S. Food and Drug Administration. (2019c). Evaluation of devices used with U.S. Food and Drug Administration. (2018h). INTERACT meetings (initial regenerative medicine advanced therapies. Available online at: https:// targeted engagement for regulatory advice on CBER products). Available online www.fda.gov/regulatory-information/search-fda-guidance-documents/ at: https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact- evaluation-devices-used-regenerative-medicine-advanced-therapies. meetings-initial-targeted-engagement-regulatory-advice-cber-products. U.S. Food and Drug Administration. (2019d). Combination products guidance U.S. Food and Drug Administration. (2018i). Center for Biologics Evaluation documents. Available online at: https://www.fda.gov/regulatory-information/ and Research. Approved Products—MACI. Available online at: https:// search-fda-guidance-documents/combination-products-guidance-documents. www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/ U.S. Food and Drug Administration. (2019e). Cellular & Gene Therapy maci-autologous-cultured-chondrocytes-porcine-collagen-membrane. Guidances. Available online at:https://www.fda.gov/vaccines-blood-biologics/ U.S. Food and Drug Administration. (2018j). Osiris Therapeutics, Inc.—Untitled biologics-guidances/cellular-gene-therapy-guidances. Letter. Available online at: https://www.fda.gov/vaccines-blood-biologics/ U.S. Title 42 The Public Health and Welfare. (2019). 42 USC 262: regulation enforcement-actions-cber/osiris-therapeutics-inc-untitled-letter. of biological products. Available online at: http://uscode.house.gov/view. U.S. Food and Drug Administration. (2018k). Surgical Biologics - Untitled xhtml?req=(title:42%20section:262%20edition:prelim). Letter. Available online at: https://www.fda.gov/vaccines-blood-biologics/ enforcement-actions-cber/surgical-biologics-untitled-letter. Conflict of Interest Statement: The authors declare that the research was U.S. Food and Drug Administration. (2018l). Is the product a medical conducted in the absence of any commercial or financial relationships that could device?. Available online at: https://www.fda.gov/medical-devices/ be construed as a potential conflict of interest. classify-your-medical-device/product-medical-device. U.S. Food and Drug Administration. (2019). Vaccines, blood and Biologics. Copyright © 2019 Iglesias-López, Agustí, Obach and Vallano. This is an open- Available online at: https://www.fda.gov/vaccines-blood-biologics. access article distributed under the terms of the Creative Commons Attribution U.S. Food and Drug Administration. (2019a). Approved cellular and gene therapy License (CC BY). The use, distribution or reproduction in other forums is products. Available online at: https://www.fda.gov/vaccines-blood-biologics/ permitted, provided the original author(s) and the copyright owner(s) are cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. credited and that the original publication in this journal is cited, in accordance U.S. Food and Drug Administration. (2019b). Regenerative medicine with accepted academic practice. No use, distribution or reproduction is advanced therapy designation. Available online at: https://www. permitted which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org 14 August 2019 | Volume 10 | Article 921