Long-term follow-up study for rare disease gene therapy

ICON provided full-service support to a large biotech company in two global Phase 3 trials for a gene therapy product treating spinal muscular atrophy (SMA), a rare but serious condition causing muscle wasting and weakness. The gene therapy was delivered to infants with genetically diagnosed and/or pre-symptomatic SMA and targeted 32 patients at 27 sites in the North America, Western Europe, and Asia Pacific regions.

The EMA granted conditional authorisation to market this gene therapy in 2020. Interim data from both Phase 3 trials revealed the treatment reduced the need for artificial ventilation in babies born with SMA. In addition, the majority of patients achieved significant developmental milestones for motor skills (e.g., sitting unaided) during the follow-up period—developmental milestones the disease would typically hinder.

As with any potentially durable treatment, sufficient data is required to demonstrate long-term safety and efficacy of the treatment modality. As such, regulators mandate LTFUs after gene therapy to ensure the treatment is safe and efficacious, and to collect data to address both regulator and payer discussions. To support this requirement the sponsor and ICON implemented a LTFU study of the therapy’s safety and efficacy in patients who had already received the treatment. This study, which targets 100+ paediatric and adolescent patients who have previously received the therapy across 31 sites globally, faced multiple challenges, including:

• Coordination with multiple CROs with different vendors, protocols, and treatment plans
• Disparate reporting timelines, sites, and databases for multiple parent studies
• Five parent studies with potential for additional protocols in the future
• A paediatric, rare disease population involving the conduct of many developmental milestone assessments through the LTFU period

To accommodate and streamline start-up for this LTFU, we implemented the following solutions:

• Strong communication channels between the Real World Solutions (RWS) project manager (PM) and the parent study PMs to collect all parent study information
• Standard RWS process for introduction of a new study with standard timelines
• Leverage prior country submissions/approvals and institutional overlap of new studies
• Track information paramount to a patient’s transition from the clinical study to extension study (i.e., record of patient’s spoken language and any family relocation plans)
• Flexible build of the electronic data capture (EDC) system to accommodate data from additional studies being included into LTFU collective database
• Video collection of developmental milestones (home and/or clinic)
• Travel concierge service for in-office visits

ICON’s expertise in LTFUs

ICON’s RWS group has extensive experience operationalising long-term extensions, LTFUs, and open-label extensions. Conducting LTFUs using a discrete, centralised team and technology allows the parent study team to maintain focus on the activities associated with the pivotal protocol and the collection and cleaning of submission data. In ICON’s innovative research model, the site relationship is streamlined by qualified staff, from both on-site and in-house clinical research associates (CRAs) to consolidated and centralised (regional) site management associates.

We understand the unique challenges associated with conducting extension studies and leveragebest practices and lessons learned to help ensure the success of LTFUs. ICON recommends a natural transition from an intensive, site-focused approach for the parent protocol to a streamlined, centralised operational model that minimises stakeholder burden while ensuring high-quality longitudinal safety data are collected.

Advanced therapy medicinal products currently require patient follow-up at a maximum of 15 years to investigate potential long-term effects of the treatment. These follow-up studies should be included in the planning of treatment studies. LTFU studies significantly differ in design compared to treatment studies and benefit from separate protocols and discrete operational teams. Our experienced RWS team supports a just-in-time activation approach to continue patient follow-up after the last visit in the parent treatment protocol.

The LTFU design is highly influenced by the drug treatment status during study set-up and additional factors such as the level of interventions required (e.g., sample collection) and standard of care (SoC) procedures in the countries of interest. ICON supports discussions on best-fit study designs to meet each protocol’s objectives. Importantly, with a 15-year follow-up period, there will be inherent changes to SoC, product approval status, and how clinical research is conducted (e.g., technology). These changes necessitate an ongoing, considered evaluation of the LTFU study (from both design and operational strategy perspectives). ICON’s experience conducting long-term, peri- and post-approval research studies, including LTFUs, ensures we can provide a collaborative, experience-based, consultative approach for each sponsor to maximise the likelihood for long-term study success.

ICON is currently enrolling patients and has enrolled 70+ to date. Additional participants in the LTFU will rollover once they have completed the interventional phase trial; some patients have been very motivated to participate. Fitting the study into the lives of patients and their families is critical for retaining participants in the LTFU. Maintaining flexibility to change the LTFU site to adapt to changes in the lives and locations of patients and their families increases retention. ICON has initiated follow-up transfers from the U.S. to France, Italy to the U.S., and Italy to the UK. Additional follow up transfers are planned, including a transfer from the U.S. to Canada and another from Italy to the U.S. The last site was initiated in the U.S. at the end of October 2021, and collection of LTFU data is ongoing.