Durability or bias? Reconsidering long-term elexacaftor/tearsacaftor/ivacaftor outcomes in children with cystic fibrosis

To the Editor: The recently published study by Wainwright and colleagues,1 involving a 192-week extension open study on the safety and efficacy of elexacaftor/tearsacaftor/ivacaftor (ELX/TEZ/IVA) in children with cystic fibrosis (CF) aged 6 years and older bearing at least 1 F508del allele, is the longest piece of clinical trial evidence on study safety and effectiveness to date. The researchers show that long-term therapy is overall safe and tolerable, with long-term improvements made on the lung functions, CFTR activity, nutritional indices, and quality of life. The work is timely and clinically significant as it fulfills the urgent requirement of developing long-term data on CFTR modulators among children. Although the practicality in terms of design and the duration of the periods in which people are followed are impressive, various essential matters should be examined more critically. First, one should consider the problems of attrition bias and lack of data. The trial had a significant dropout rate, with 13 children lost between parts A and B, along with 7 more during part B, resulting in a total loss of 16.7% of the sample by the end of the final stage. A small amount of attrition is anticipated with long-term open-label studies, but to this extent, it is a cause of great concern regarding the representativeness of the analytic cohort. There is a 2-fold risk: underestimation of adverse events and exaggeration of treatment effects may actually be noted. The quality and generalizability of the conclusions are undermined without serious management of the missing data (ie, many iterations of imputation or sensitivity analysis). To address attrition bias in studies that demonstrate dramatic drug benefits over time, powerful mechanisms to avert attrition impacts are nonnegotiable.2 Second, what should be given more attention is the profound confounding introduced by the COVID-19 pandemic that overlapped significantly with the observation period. The authors recognize that social distancing, increased hygiene, and dwindling health care contacts were likely interventions that suppressed the pulmonary exacerbations and hospitalizations among the CF population. However, the almost complete lack of exacerbations and stability of percent predicted forced expiratory volume in 1 second (ppFEV1) are explained mainly by drug durability, and there is an insufficient opportunity to take into consideration these external factors. Without a modern comparator group not influenced by pandemic-related effects, any such positive results could solely be attributed to ELX/TEZ/IVA and exaggerate the efficacy in the long term. In a study aiming to establish benchmarks for sustained pediatric outcomes, the lack of strict control for this confounder compromises internal validity and raises questions about the strength of the efficacy assertions. Finally, apprehensions about the sufficiency of long-run safety analysis exist. Adverse events were not assessed in adequate detail regarding chronicity or clinical importance, although the regimen was overall well tolerated. More severe or less common events, especially hepatic dysfunction, psychiatric disruptor requirements, and cataracts,3,4 will need cautious longitudinal evaluation due to lifelong treatment with CFTR modulators. Small sample sizes and the lack of demographic diversity also increase the risk of underrecognizing late or rare toxicities. There is need to have a systematic approach to assess cumulative effects on organs and latent adverse effects, particularly when it comes to pediatrics, since impacts after decades of exposure are still to come. In the absence of this, the chance of underreporting clinically significant harms continues to be a severe constraint. In conclusion, the long-term findings of ELX/TEZ/IVA in children with CF are significant, but they must be considered in the context of attrition bias, confounding caused by the pandemic, and the unaddressed uncertainty about cumulative safety. With the changing CF therapeutic landscape, ongoing rigorous evaluation will need a combination of long randomized trials, as well as ancillary strategies such as registries, real-world pharmacovigilance, and long-term observational cohorts, which are necessary to achieve rare, delayed, and context-specific outcomes. It is only under such multidimensional scrutiny that we can guarantee that the extra­ordinary promise of CFTR modulators is translated into safe, sustained, and equitable changes to the lives of children affected by CF. X.Z. and Q.Y.: concept, design, writing the draft, and revision. The authors approved the final manuscript version for submission. Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online. Please see the ICMJE disclosure forms, which have been provided as supplementary material. This work was partly funded by the Open Project of State Key Laboratory of Respiratory Disease (SKLRD-OP-202510). No artificial intelligence tools were used in writing this manuscript.