Pharmacovigilance of gene therapy medicinal products

Abstract

Gene therapy medicinal products (GTMPs) may generate unexpected risks to public health and individual patients. Pharmacovigilance serves the purpose of detecting, assessing, understanding, and preventing adverse effects or any other medicine-related problems. This article aims to provide an overview of the significance of pharmacovigilance and particularities in the domain of gene therapy with a brief description of the European regulatory framework. Viral vectors, insertional mutagenesis, viral latency or reactivation, as well as duration and accuracy of the patient’s clinical follow-up, are some of the main concerns. Two recent examples of signals illustrate some of these safety issues. The first concerns onasemnogene abeparvovec, an adeno-associated virus-based gene replacement therapy for treating spinal muscular atrophy. This GTMP initially raised safety concerns about hepatotoxicity, cardiotoxicity, and neurotoxicity, necessitating recommendations for close monitoring. During the post-marketing period, two fatal cases of acute liver failure led the European Medicine Agency (EMA) to strengthen the recommendations for liver function monitoring. The second example pertains to betibeglogene autotemcel, a genetically modified autologous CD34+ cell-enriched population that contains hematopoietic stem cells transduced with lentiviral vectors encoding the β A-T87Q-globin gene. After the report of a case of acute myeloid leukemia in a patient treated with an investigational product using the same lentiviral vector, the European Commission triggered a regulatory safety procedure. After careful assessment, the EMA’s ad hoc safety committees stated that the viral vector was unlikely to be the cause. However, due to commercial reasons, betibeglogene autotemcel was finally withdrawn from the market by the marketing authorization holder. Pharmacovigilance activities and systems continuously evolve to keep pace with advancements in new therapies and technologies. They must also address varied situations and adhere to evolving regulations. GTMPs likely stand out as one of the most demanding areas within pharmacovigilance. Therefore, their effective oversight requires the full commitment of pharmacological and clinical experts, as well as active involvement from patients, to ensure optimal outcomes.