Erschienen:
[Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 2021
Sprache:
Englisch
Identifikator:
Entstehung:
Hochschulschrift:
Dissertation, 2021
Anmerkungen:
Beschreibung:
Advanced therapy medicinal products (ATMPs) have a massive potential to address existing unmet medical needs. Specifically, gene therapy medicinal products (GTMPs) may potentially provide cure for several genetic diseases. Despite much research conducted in this field, only a modest number of products are approved and available. This thesis intends to develop an end-to-end understanding of ATMPs, identifying regulatory and patient access hurdles on gene therapy use In Chapter 1, broad research conducted in this field over the last few decades is explored as well as different clinical applications investigated worldwide. These are based on diverse strategies that range from direct gene replacement or addition to more complex pathways such as specific gene editing or RNA targeting. Important safety risks, limited efficacy, manufacturing hurdles, or ethical conflicts may represent challenges in the success of a candidate GTMP. During the development process, it is fundamental to take such aspects into account and establish overcoming strategies. Then, the current European legal framework of ATMPs is reviewed and an overview of the clinical applications for approved and investigational GTMPs is provided. In Europe, the ATMP regulation was fully implemented in 2009 and, at this point, the Committee for Advanced Therapies was created as a dedicated group of specialists to evaluate medicinal products requiring specific expertise in this area. In Chapter 2, major objections, issues, or concerns raised during the Marketing Authorization Application (MAA) for GTMPs between 2009 and 2017 were identified. During the first few years following CAT establishment, quality issues were often identified as major deficiencies, whereas issues at the nonclinical level appeared to be less frequent. Clinical efficacy and safety issues appeared to have a major role in unsuccessful MAA outcome for GTMPs. Most deficiencies were addressed through clarification during the MAA review or in post-marketing settings. The MAA procedure for GTMPs is complex and it is anticipated that continuous MAA submissions will further enhance the experience of both regulators and applicants, reducing the attrition rate for approval. Despite having a positive Marketing Authorization, this does not mean that these products are being used in clinical practice. In Chapter 3, a full set of hurdles potentially preventing patient access to Gene Therapies is identified based on the most recently available literature. A review of the literature using a systematic approach in two distinct databases was performed by identifying relevant, peerreviewed publications, between 2012 and 2018. Seven major topics were identified as potential patient access hurdles, namely affordability, assessment of value, development of therapy, ethical/social factors, evidence generation, operational implementation and regulatory hurdles. From these, twenty-five additional subthemes were further identified. The most frequently mentioned obstacle in the literature is related to the affordability aspect especially focusing on high cost of therapy (84%) and therapy payment/reimbursement (51%). Importantly, the evidence generation focusing on limited trial outcomes (81%) seems to be a strong obstacle in patient access to these therapies. In Chapter 4, a global discussion on the results obtained in chapter 2 and 3 is presented and summarized in the context of the current body of evidence, as well as the current GTMP landscape. A growing number of Gene Therapies are expected to be developed and made available to patients and health care professionals. This thesis contributed to understanding all hurdles, in a complete and integrated fashion, so that strategies are timely established to ensure gene therapy's benefits are provided to patients and to the society.