Cystic fibrosis foundation pulmonary guidelines: Use of cystic fibrosis transmembrane conductance regulator modulator therapy in patients with cystic fibrosis

Rationale: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with CF. However, the FDA label for these medications encompasses patient groups that were not studied as part of the drug approval process. CF clinicians, patients, and their families have recognized a need for recommendations to guide the use of these medications. Objective: Develop evidence-based guidelines for CFTR modulator therapy in patients with CF. Methods: A multidisciplinary committee of CF caregivers and patient representatives was assembled. A methodologist, an epidemiologist, amedical librarian, and a biostatisticianwere recruited to assist with the literature search, evidence grading, and generation of recommendations. The committee developed clinical questions using the Patient-Intervention-Comparison-Outcome format. A systematic review was conducted to find relevant publications. The evidence was then evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, and recommendations were made based on this analysis. Results: For adults and children aged 6 years and older with CF due to gating mutations other than G551D or R117H, the guideline panel made a conditional recommendation for treatment with IVA. For those with the R117H mutation, the guideline panel made a conditional recommendation for treatment with IVA for 1) adults aged 18 years or older, and 2) children aged 6-17 years with a forced expiratory volume in 1 second (FEV ₁ ) less than 90% predicted. For those with the R117H mutation, the guideline panel made a conditional recommendation against treatmentwithIVAfor 1) children aged12-17 years with an FEV ₁ greater than 90% predicted, and 2) childrenless than 6 years of age. Among those with two copies of F508del, the guideline panel made a strong recommendation for treatment with IVA/LUM for adults and children aged 12 years and older with an FEV ₁ less than 90% predicted; and made a conditional recommendation for treatment with IVA/LUM for 1) adults and childrenaged 12 years or olderwithan FEV ₁ greater than 90% predicted, and 2) children aged 6-11 years. Conclusions: Using the GRADE approach, we have made recommendations for the use of CFTR modulators in patients with CF. These recommendations will be of help to CF clinicians, patients, and their families in guiding decisions regarding use of these medications.