(SLA-050) Mandated long-term follow-up studies of patients treated with gene and cell therapies approved in the European Union (EU): An analysis of commonalities and variations

Background: With 3000 gene and cell therapies (GCTs) in the pipeline, regulators are intensifying efforts to reduce uncertainties around their long-term effects. Long-term follow-up of patients treated in clinical trials (LTFU-CTP) imposed on investigational therapies are often supplemented with mandated long-term follow-up post authorization (LTFU-PA) studies. The normative framework for them is still under development and overlaps with other EMA directives.

Objectives: To identify trends in LTFU studies for the 16 GCTs approved in the EU (Abecma, Beqvez, Breyanzi, Carvykti, Casgevy, Hemgenix, Imlygic, Kymriah, Libmeldy, Luxturna, Roctavian, Strimvelis, Tecartus, Upstaza, Yescarta, and Zolgensma).

Methods: Data on LTFU-PA and LTFU-CTP studies was extracted from ClinicalTrials.gov (CTgov) and HMA-EMA Catalogue of RWD (HEMA-EMA), without any time restriction, and analysed for commonalities and variations.

Results: Hematology indications account for 10 of the 16 approved GCTs, and rare diseases for 5. We identified 44 studies in total, 25 studies for 15 products in CTgov (16 LTFU-CTP and 9 LTFU-PA) and 19 studies for 14 products in EMA-RWE (all LTFU-PA, 14 Category 1, 3 Category, 2 and 2 Category 3). Some studies may overlap, however, available information does not allow affirmation.
All products had at least one LTFU study, the majority of which (13 products) had 15-year follow-up. Only 3 products (Beqvez, Imlygic, and Upstaza) did not have a 15-year FU study (6 studies, FU time 5, 7, or 10 years).
Primary data collection was predominant, however, 13 LTFU-PA studies for 9 products use secondary data from pre-existing clinical registries (e.g., EBMT, CIBMTR, ATHN Transcends, WFH GTR, ATHN, iSMAC, French SMA Registry, SMArtCARE, CuidAME, Cure SMA).
The target sample sizes ranged from 40 to 3,488 and 4 to 3,000 for HMA-EMA and CT.gov registered studies, respectively. Other characteristics such as the presence and type of comparator and the analytic approach were not consistently reported in HMA-EMA structured fields, and not all studies had the protocol embedded.

Conclusions: HMA-EMA catalogue could benefit from better reporting in the structured fields. Certain design elements of the LTFU-PA studies were consistent with regulations for LTFU-CTP studies. In indications where robust clinical registries exist, data is used and only sometimes supplemented. Existing and de novo clinical registries are valuable sources for mandated LTFU studies. They could support consistent and sustainable research programs as part of an integrated LTFU evidence generation strategy, that includes patients treated with GCTs in either clinical trials or routine clinical practice.