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Regulatory Challenges for Gene Delivery
Published in Yashwant Pathak, Gene Delivery, 2022
Vineet Mahajan, Shruti Saptarshi, Yashwant Pathak
In the EU gene therapies are classified as, advanced therapy medicinal product (ATMPs), under the EU legislation, and are governed by the ATMP Regulation (Directive 2001/83/EC, as amended by Regulation [EC] 1394/2007)35 The European Medical Association’s (EMA) Committee for Advanced Therapies (CAT) oversees the regulatory affairs of ATMPs after consultation with the European Commission. The principal EU guideline (under revision) is the basis for development of gene therapies. It provides a thorough strategic plan for gene therapy product development, covering quality, non-clinical, and clinical aspects of the ATMPs. Unlike the regulations for other biotech-based medicinal products, the technical requirements of quality or clinical data required to demonstrate safety of the ATMP product may be highly specific. These guidelines are targeted at mitigating risks to the beneficiaries of the ATMP treatments, once the products are authorized for use. Following points provide details of the EU regulatory guidelines for ATMPs:
From Bench to Bedside
Published in Ornella Parolini, Antonietta Silini, Placenta, 2016
Considering placental cell products, products that are manipulated and abide by ATMP regulations, tissue regulations are fundamental because ATMPs are basically derived from tissues. Directive 2001/83/EC, amended by ATMP Regulation 1394/2007 regulates ATMPs (Official Journal of the European Union 2001, 2007). ATMP regulations cover products manipulated by gene therapy, somatic cell therapy, and tissue engineering, even when used in combination with any other medicinal product or scaffold. ATMPs require high investments, and early commercialization followed by placement on the European market (Salmikangas 2015) is a characteristic feature of these products. In fact, centralized marketing authorization guided by the European Medicines Authority (EMA) is a key element in the registration of these products. Products derived from placental tissues may scientifically be at the borderline between the definition of tissues and cells (Directive 2004/23/EC) and the ATMP regulation. The terms “substantial manipulation” and “intended use” are critical whenever a distinction is unclear. If there is no change in the biological characteristics of cells derived from placental origin, and the intended use covers the same essential function, the products may not be classified as ATMPs. In fact, this may be rare for cells derived from placental tissues. To clarify this, the EMA established the Committee for Advanced Therapies. This committee gives advice on such topics and provides information (Committee for Advanced Therapies et al. 2010; European Medicines Agency 2014).
A ‘strict but permissive approach'
Published in Julie Kent, Regenerating Bodies, 2012
The MHRA acquired new responsibilities under the terms of the EU RATMP in 2007, set out in a joint position statement with the HTA: Manufactured products that are classified as medicinal products by the MHRA or EMEA will be regulated under the Quality & Safety Regulations only for the donation, procurement and testing of tissues and cells. The subsequent stages, including manufacture, storage and distribution, will be regulated by the MHRA. Unless exempt, ATMPs will require a marketing authorisation granted by the European Commission (the ‘centralized procedure’) with the EMEA co-ordinating the application and assessment procedures, and post authorisation supervision. Treatments involving human tissues or cells that are not medicinal products will continue to be regulated by the HTA under the Quality & Safety Regulations for licensable activities. This also applies to ethically (but not MHRA) approved clinical trials involving the use as grafts of human tissues and cells in patients. In cases where the regulatory status of a manufactured product derived from human tissues or cells is unclear, the MHRA should be asked to determine if the product is a medicinal product. The decision of whether a given treatment falls within the scope of the European definition of medicinal product (MP) and ATMP, as opposed to a tissue or cell graft (which would then fall under HTA remit), will eventually be determined by the EMEA working in conjunction with the MHRA (where the manufacture occurs in the UK). A Committee for Advanced Therapies (CAT) based at the EMEA will advise whether a product falls within the definition of an ATMP.34
10th antibody industrial symposium: new developments in antibody and adoptive cell therapies
Published in mAbs, 2023
Ana Antunes, Luis Alvarez-Vallina, Federico Bertoglio, Nicolas Bouquin, Stéphanie Cornen, Francis Duffieux, Pierre Ferré, Raphaëlle Gillet, Christian Jorgensen, Mark B Leick, Bernard Maillère, Hélène Negre, Mireia Pelegrin, Nicolas Poirier, Dietmar Reusch, Bruno Robert, Guy Serre, Alain Vicari, Martin Villalba, Christoph Volpers, Gavin Vuddamalay, Hervé Watier, Thierry Wurch, Lennart Zabeau, Stefan Zielonka, Baolin Zhang, Alain Beck, Pierre Martineau
Dr. Manel Juan (Head of the Immunology Service, Hospital Clínic de Barcelona, Spain) described the generation of a new autologous CAR targeting CD19 (ARI-0001). This CAR obtained similar clinical results than commercial CARs used in the same clinical settings and was approved by the Spanish Agency of Medicines and Medical Devices (AEMPS). ARI-0001 was granted a hospital exemption to be used as advanced therapy medicinal product (ATMP), leading to its marketing authorization under specific conditions. These are: the exemption is only applicable to individual patients treated in the hospital (mainly academic centers that developed the ATMP and are supported by the national competent authority and limited to European Union (EU) member states; the exemption is intended for >25-year-old patients with relapsed or refractory CD19+ acute lymphoblastic leukemia. This authorization is the first step in the development of and access to completely academic CAR T-cell products in the EU and can be used as an intermediate step before obtaining a centralized marketing authorization by the European Medicines Agency (EMA). The cooperation between academic partners, who must follow strict standards of traceability, pharmacovigilance, and quality, should favor the accessibility of this product and the approval of other academic ATMPs. M. Juan’s team is completing a clinical trial on an anti-B-cell maturation antigen (BCMA) CAR-T for multiple myeloma, with a solid clinical response.12
Biosimilars in chronic inflammatory diseases: facts and remaining questions 5 years after their introduction in Europe
Published in Expert Opinion on Biological Therapy, 2022
Christian Agboton, Joseph Salameh
Historically, the pharmaceutical industry invested in biologics at the end of the last century as a reactive move to the ‘generization’ of their small molecules. The promise was that biologics are so complex that they cannot be copied. We know better now – and it is expected that biosimilars and biobetters will push forward big pharmaceutical companies in investing in other treatment modalities, such as stem cells or gene therapies [96]. These advanced therapies (Advanced Therapy Medicinal Products, ATMP) will create new opportunities for personalized precision medicine, protecting – for a while – the investments in research and development that are needed for the advancement of medicine.
Hurdles of environmental risk assessment procedures for advanced therapy medicinal products: comparison between the European Union and the United States
Published in Critical Reviews in Toxicology, 2019
C. Iglesias-Lopez, M. Obach, A. Vallano, A. Agustí, J. Montané
In the US, environmental impacts from pharmaceuticals are assessed under the National Environmental Policy Act (NEPA) and NEPA regulations by the Food and Drug Administration (FDA; the federal regulatory medicines agency in the US). FDA’s NEPA policies and procedures can be found under the Code of Federal Regulations (CFR) (21CFR Part 25) (Table 1). According to FDA, those products that consist of gene therapies, vectored vaccines, and related recombinant viral or microbial products should be evaluated for the need of an ERA. FDA regulations specify that an ERA must be submitted as part of investigations for new drug (IND) applications (the equivalent of a CTA in Europe), and for the MAA of a biologic product (named BLA in US; Biologics License Application), unless it qualifies for an ERA exemption, also called categorical exclusion (FDA Center for Biologics Evaluation and Research (CBER) 2015; National Environmental Policy Act 2019). IND applications for the development of an ATMP are ordinarily categorically excluded from the requirement to submit an ERA, unless extraordinary circumstances indicate that the specific action may significantly affect the quality of the environment. Possible exceptions may usually occur for use of virulent organisms or organisms that are ecologically more fit than their wild-type counterparts. The reason to consider a clinical development a categorical exclusion is that a clinical study involves small quantities of a medicinal product and a limited number of patients, not having a significant cumulative effect into the environment. Therefore, the regulatory process is very short, since the trials are usually exempt from an ERA (Rudelsheim and Smets 2012; FDA Center for Biologics Evaluation and Research (CBER) 2015).