Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH)

Abstract

Gene therapy has recently become a realistic treatment perspective for patients with haemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of haemophilia A and B gene therapy with vectors derived from adeno-associated virus (AAV), including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centres according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as primary source of data for pharmacovigilance, post-marketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization.

Infrastructural considerations of implementing gene therapy for hemophilia in the Nordic context

“…Factor analysis will be carried out at least weekly during the first 3 months at the specialized coagulation laboratories after validation for gene therapy products with external controls or similar material with assigned values, followed by analysis every 1–2 weeks for the next 3-month period. This is mainly in agreement with the German guidelines, 9 but is more frequent than that suggested in the consensus paper from Italy. 8 The preference for the chromogenic test for monitoring factor activity has been highlighted previously.…”

“…10 According to this initial model, tasks, and responsibilities are divided between a gene therapy delivering center or the infusion center (hub) and a management center from which the patient is referred (spoke). 9,10 The hub center needs to have in-depth knowledge and experience of gene therapy and the facilities to order, store, prepare, and administer the gene therapy product, as well as the ability to perform and interpret diagnostic tests for eligibility and follow-up. In addition, the hub center should be knowledgeable regarding the timely diagnosis and management of adverse events.…”

“…(GTH) and Italian recommendations, a pre-infusion collaborative agreement needs to be established between the hub-and-spoke centers with appropriate educational activities and checklists defined in order to enable an appropriate and timely discussion with the patient. 8,9 An approach of value to prepare for the introduction of a GMO product at the site will be to perform a risk assessment for each step, from shipment of the drug to its administration, and subsequent management of the patient post-infusion. Importantly, the assessed risk is not based on the pathogenicity of the particular biological agent alone (biosafety group of the agent), but on the likelihood and consequence of an incident occurring – in other words, the risk of exposure to, and/or release of, the biological agent during handling of a GMO product.…”

“…8 The preference for the chromogenic test for monitoring factor activity has been highlighted previously. 8,9 However, within the Nordic region, the activity levels, as measured by both the OSA and CSA assays, will be recorded for optimal information in case of, for example, the need for an acute surgical intervention. This is because of the described assay discrepancy between the two tests.…”

“…4–7 However, the introduction of gene therapy presents a challenge for current hemophilia care, requiring extensive preparation and reorganization of infrastructure. 8,9 It requires knowledge and adherence to hospital and authority genetically modified organism (GMO) product requirements, extensive collaboration between different stakeholders and implementation of new structures that are fit for purpose to maximize the benefits and minimize the risks of the new advanced therapies. 10 To address this in the Nordic region, a preparatory project was defined and initiated in order to facilitate and implement an effective infrastructure for gene therapy introduction.…”