The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis

Abstract

Background Over the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public health implications associated with differences. Results CFTR modulators have been developed towards addressing three main genetic domains: (1) F508del homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted non-clinical evidence considering a recovery of the CFTR function ≥ 10% based on chloride transport, a reliable indicator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to expand the label of CFTR modulators without confirmatory clinical data. Conclusions Regulators played an important role in fostering the development and approval of CFTR modulators. However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators, which extended beyond semantics affecting patients’ eligibility and access: FDA’s approach was more mechanistic/biology-driven while the EMA’s one was more oriented by clinical evidence. This might refer to the connection between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical commitment of ensuring larger access to all potential eligible patients (including those harboring very rare mutations) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

“…Since its approval by the FDA and the EMA, IVA monotherapy has been used in clinical practice for PwCF carrying G551D-CFTR mutation and for other gating mutations [ 28 ]. IVA monotherapy was also approved by the FDA for various CFTR residual function mutations based on in vitro studies [ 10 , 29 ], with clinical benefits being confirmed in subsequent clinical studies for several of these mutations [ 30 , 31 ].…”

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

“…Despite cell lines are unable to predict therapeutic responses in PwCF at an individual level, they have been useful in supporting drug discovery and development for common and rare CF-causing mutations [ 2 ]. Indeed, the FDA has licensed label extension of clinically approved CFTR modulators to several additional mutations based on data from FRT cell lines heterologously expressing mutant CFTR cDNA [ 13 , 15 , 30 ] with subsequent clinical studies confirming the therapeutic benefits for some of these mutations [ 56 , 74 , 75 ]. Furthermore, a study has paired in vitro measurements of CFTR function in either FRT or CFBE41o − cell lines stably expressing CFTR variants with clinical and genetic data from the CFTR2 database, and demonstrated that there is a strong correlation between CFTR function and sweat Cl − levels [ 76 ].…”

“…Indeed, this ‘highly effective’ modulator therapy demonstrated to significantly improve lung function (>10 ppFEV 1 ) in phase III clinical trials not only in PwCF homozygous for F508del [ 28 ] but also in those carrying this mutation in one allele and a minimal function mutation (i.e., classes I/II) in trans [ 29 ]. Over this period, several label extensions have been approved (most by the US FDA) to uncommon CFTR mutations [ 13 , 15 , 30 ], and >85% of PwCF in North America, Oceania and various countries in Europe are currently eligible for at least one of these clinically approved modulator therapies.…”

“…These include not only CFTR-directed therapeutics but also targeting alternative channels/transporters to compensate for CFTR dysfunction and beyond [ 10 , 12 , 31 ]. Meanwhile, CF scientific community also continues to develop novel cell models to more efficiently predict clinical efficacy and responsiveness [ 14 , 32 , 33 , 34 , 35 ], since conventional clinical trial designs are underpowered and impractical for rare CFTR mutations due to the very low number of individuals [ 30 , 36 , 37 ]. Indeed, it is estimated that for >1000 CFTR variants there are ≤5 PwCF worldwide [ 12 , 15 , 37 , 38 ].…”

S945L-CFTR molecular dynamics, functional characterization and tezacaftor/ivacaftor efficacy in vivo and in vitro in matched pediatric patient-derived cell models

“…These platforms can predict the individual's response to treatment and characterise the functional defect caused by CFTR mutations. This form of in vitro analysis has been permitted by the US Food and Drug Administration (FDA) to facilitate the approval of therapeutics for rare CFTR mutations in addition to in vitro testing systems using non-primary cells, such as Fisher Rat Thyroid (FRT) cells ( 21 ). CFTR-dependent chloride transport assays in patient-derived nasal epithelial cells ( 22 – 26 ) as well as forskolin-induced swelling assays in intestinal organoids ( 27 – 31 ) have been used in a patient-specific manner to predict modulator efficacy for the patient.…”