A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making

Coppens, Delphi G.M.; Wilde, Sofieke de; Guchelaar, Henk‐Jan; Bruin, Marie L. De; Leufkens, Hubert G. M.; Meij, Pauline; Hoekman, Jarno

doi:10.1016/j.jcyt.2018.03.038

Cited by 28 publications

(31 citation statements)

References 47 publications

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“…Currently, clinical outcomes of treatment under HE need to be reported to the competent authorities through annual reporting [18], but these are not available in central EU-wide registries. Furthermore, there are no regulatory requirements for long-term follow-up through registries under HE, while registries are often imposed for marketed products as post-marketing requirements upon marketing authorization [46]. How ATMPs manufactured under HE can be optimally grouped in registries for clinical outcomes-for example, by therapeutic indication or type of clinical outcome measure-needs to be determined.…”

Section: Discussionmentioning

confidence: 99%

Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries

et al. 2020

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Background aims: As part of the advanced therapy medicinal product (ATMP) regulation, the hospital exemption (HE) was enacted to accommodate manufacturing of custom-made ATMPs for treatment purposes in the European Union (EU). However, how the HE pathway has been used in practice is largely unknown. Methods: Using a survey and interviews, we provide the product characteristics, scale and motivation for ATMP manufacturing under HE and other, non-ATMP-specific exemption pathways in seven European countries. Results: Results show that ATMPs were manufactured under HE by public facilities located in Finland, Germany, Italy and the Netherlands, which enabled availability of a modest number of ATMPs (n = 12) between 2009 and 2017. These ATMPs were shown to have close proximity to clinical practice, and manufacturing was primarily motivated by clinical needs and clinical experience. Public facilities used HE when patients could not obtain treatment in ongoing or future trials. Regulatory aspects motivated (Finland, Italy, the Netherlands) or limited (Belgium, Germany) HE utilization, whereas financial resources generally limited HE utilization by public facilities. Public facilities manufactured other ATMPs (n = 11) under named patient use (NPU) between 2015 and 2017 and used NPU in a similar fashion as HE. The scale of manufacturing under HE over 9 years was shown to be rather limited in comparison to manufacturing under NPU over 3 years. In Germany, ATMPs were mainly manufactured by facilities of private companies under HE. Conclusions: The HE enables availability of ATMPs with close proximity to clinical practice. Yet in some countries, HE provisions limit utilization, whereas commercial developments could be undermined by private HE licenses in Germany. Transparency through a public EU-wide registry and guidance for distinguishing between ATMPs that are or are not commercially viable as well as public-private engagements are needed to optimize the use of the HE pathway and regulatory pathways for commercial development in a complementary fashion.

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Section: Discussionmentioning

confidence: 99%

Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries

et al. 2020

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“…During the initial years of the implementation of new regulations, concerns among the stakeholders regarding the effect of regulatory change emerged, particularly after negative opinions and withdrawal of marketing authorization applications (MAAs) were noted and GCT marketing authorization holders withdrew four regulatory approved GCTs from the EU market ( Figure 1) [1].…”

Section: Effects Of New Regulationsmentioning

confidence: 99%

“…Repeat-associated non-ATG (RAN) translation of microsatellite expansions is an important pathogenic process in a growing number of neurodegenerative disorders. As the name implies, RAN translation is a noncanonical form of translation where protein synthesis initiates in all three reading frames in the absence of an AUG start codon, either upstream or within the microsatellite repeat, to produce aggregate-prone peptide repeats [1]. RAN translation, originally discovered by the Ranum laboratory in spinocerebellar ataxia type 8, has now been reported in myotonic dystrophy types 1 and 2, fragile X tremor ataxia syndrome (FXTAS), Huntington disease, and C9orf72 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), among other disorders (reviewed in [1]).…”

Section: Spotlightmentioning

confidence: 99%

“…As the name implies, RAN translation is a noncanonical form of translation where protein synthesis initiates in all three reading frames in the absence of an AUG start codon, either upstream or within the microsatellite repeat, to produce aggregate-prone peptide repeats [1]. RAN translation, originally discovered by the Ranum laboratory in spinocerebellar ataxia type 8, has now been reported in myotonic dystrophy types 1 and 2, fragile X tremor ataxia syndrome (FXTAS), Huntington disease, and C9orf72 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), among other disorders (reviewed in [1]). Despite the distinct clinical and genetic aspects of each disorder, the production of toxic RNA containing the repeat expansion and RAN translation appears to be a common feature of various microsatellite expansion disorders.…”

Section: Spotlightmentioning

confidence: 99%

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Development and Regulation of Gene and Cell-Based Therapies in Europe: A Quantification and Reflection

Ham

Hövels

Klungel

et al. 2020

Trends in Pharmacological Sciences

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“…They have been making important steps to define appropriate regulatory standards; however, due to the novelty of this field and the complexity of such products, regulators face scientific issues never discussed before. As a result of this, regulatory requirements for approval for market authorization are not standardized or harmonized yet [ 172 , 174 ].…”

Section: Pharmaceutical and Clinical Development Phases: From Mousmentioning

confidence: 99%

Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side

et al. 2020

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Recent clinical trials using patient’s own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott–Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles).

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A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making

Cited by 28 publications

References 47 publications

Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries

Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries

Development and Regulation of Gene and Cell-Based Therapies in Europe: A Quantification and Reflection

Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side

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