Author: Claudio Spera (Switzerland)
Co-authors: Daniel Stiehl, Natalia Filimonova, Sonja Nektarijevic, Jill Froimowitz
The market approval process for gene therapies faces unique regulatory challenges due to the novelty, as well as the unidentified risks associated with such therapies. Therefore, regulatory agencies may request that the applicant implement post authorization measures, documented in a risk management plan (RMP) specific to the drug. In line with EMA guidelines, Novartis prepared and submitted a risk-management plan (RMP) on applying for EMA marketing authorization, in order to document the risk management system for voretigene neparvovec treatment. Here, we describe the Committee for Medicinal Products for Human Use (CHMP) risk minimization requirements for voretigene neparvovec, and outline the approved RMP that was developed and submitted to the European Medicines Agency (EMA) in compliance with requisite CHMP procedures.
The implementation of a RMP for ocular gene therapy by Novartis Pharma AG, Switzerland in accordance with EMA guidelines for gene therapy products, including the incorporation of virtual educational sessions and a novel educational virtual reality modality designed as a practical alternative to surgical wet labs.
Risk minimization safety measures for voretigene neparvovec were considered and examined under three categories: i) the drug ii) target population and iii) disease/condition. A pharmacovigilance plan was formulated, identifying both routine and additional pharmacovigilance activities to ensure the acquisition of additional safety and efficacy data following market approval. Furthermore, additional risk minimization measures were developed for ocular gene therapy treatment facilities, which included the rollout of medical and pharmacy standardized educational sessions, to ensure the correct use of the treatment and minimize the risks associated with administration and/or the surgical administration procedure. The procedures include: (1) the presence of a specialist ophthalmologist with expertise in care and treatment of patients with inherited retinal diseases; (2) the presence of, or affiliation with, a retinal surgeon experienced in sub-retinal surgery and capable of administrating a gene therapy; (3) the presence of a clinical pharmacy capable of handling and preparing AAV vector-based gene therapy products. Prior to product distribution to a treatment facility, surgeons and pharmacists must also complete mandatory surgical and pharmacy medical educational programs on the preparation and administration of the product, as stipulated in the RMP.
More than 30 surgical and 50 pharmacy medical educational programs have been completed to date (excluding the United States [US]). In response to the COVID-19 pandemic, educational sessions are now held virtually, ensuring continued treatment facility onboarding. This has included virtual theoretical sessions, alongside practical surgical sessions using a novel virtual reality surgical simulation tool (SIRIUS VR tool), to simulate administration of voretigene neparvovec as an alternative to physical surgical wet lab attendance. To ensure site readiness, dry run sessions are completed prior to the first surgery. Another additional post-marketing risk minimization condition includes providing patients and caregivers with an information pack. The pack includes the Patient Information Leaflet, also available in alternative formats including large print and audio, and a patient card highlighting the importance of attending follow-up visits and reporting side effects. The patient card also serves as information for other healthcare professionals that may treat the patient. Alongside routine pharmacovigilance activities, additional post-authorization pharmacovigilance activities outlined in the RMP include a non-interventional safety registry study (PERCEIVE) in Europe (and other countries, excluding the US), and a post-intervention 15 year Long-Term Follow-Up Study in subjects enrolled in the US pivotal trials.
The EMA granted regulatory approval for voretigene neparvovec following the preparation and submission of a marketing authorization application and accompanying RMP. In line with the RMP for voretigene neparvovec, the drug is only distributed through treatment centers that fulfill the specified RMP criteria and where qualified and experienced staff (i.e. vitreoretinal surgeons and pharmacists) have completed the mandatory educational program/training in relation to the administration of the gene therapy. Further additional risk minimization measures, as outlined in the approved RMP, include providing patients with auxiliary supports to access the information provided to them. The RMP for voretigene neparvovec further details the ongoing routine and additional pharmacovigilance activities required due to the novelty of the treatment and the limited number of patients treated in pivotal trials.
Claudio Spera: Employee of Novartis Daniel Stiehl: Employee of Novartis Natalia Filimonova: Employee of Novartis Sonja Nektarijevic: Employee of Novartis Jill Froimowitz: Employee of Novartis