The U.S. Food and Drug Administration's Experience with Ivacaftor in Cystic Fibrosis. Establishing Efficacy Using In Vitro Data in Lieu of a Clinical Trial

Abstract

On May 17, 2017, the U.S. Food and Drug Administration expanded the patient population for use of ivacaftor to include patients with cystic fibrosis with relatively rare mutations in the cystic fibrosis transmembrane conductance regulator gene. The label expansion is unique in that clinical efficacy was not based on clinical data but on in vitro assay data demonstrating increased chloride ion transport across cells in response to ivacaftor. Such an approach provides a pathway for adding difficult-to-study mutation-based cystic fibrosis subpopulations to the indication as well as defining mutations unresponsive to ivacaftor and has important implications for cystic fibrosis drug development and other rare genetic diseases whose genetics and disease pathophysiology are well understood.

Precision Medicine In Action: The Impact Of Ivacaftor On Cystic Fibrosis–Related Hospitalizations

“…27 In fact, in May 2017 the FDA used this novel approach to approve the use of ivacaftor for an additional twenty-three mutations, extending eligibility to an additional 3 percent of people with cystic fibrosis in the US, for a total of 16 percent able to use the drug. 28,29 This in vitro process creates a drug development and regulatory pathway for assessing the clinical benefit of rare mutations that are not conducive to clinical trials. 27,28 The FDA’s recognition that non-clinical-trial data are sufficient to demonstrate efficacy is especially significant for precision medicine, where the goal is to deliver individualized treatments.…”

“…28,29 This in vitro process creates a drug development and regulatory pathway for assessing the clinical benefit of rare mutations that are not conducive to clinical trials. 27,28 The FDA’s recognition that non-clinical-trial data are sufficient to demonstrate efficacy is especially significant for precision medicine, where the goal is to deliver individualized treatments. While the FDA expands its use of data sources for approval based on safety and efficacy standards, payers have to make decisions based on effectiveness and cost.…”

Cystic fibrosis year in review 2018, part 1

“…Additional CFTR mutations approved for ivacaftor by the FDA was ground‐breaking because it include mutations that demonstrate in vitro cell‐based assay response to ivacaftor (defined as a > 10% increase in chloride ion transport across cells) . For over 1200 mutations in CFTR gene, there are five or fewer people who carry these mutations reported, making trials for these mutations difficult due to an inadequate number of trial participants.…”

“…For over 1200 mutations in CFTR gene, there are five or fewer people who carry these mutations reported, making trials for these mutations difficult due to an inadequate number of trial participants. Thus, this paradigm for using in vitro data will allows for more access to those with rare ivacaftor‐responsive mutations and may have future implications as a disease‐modifying therapy for every person with CF. Matching of individual CFTR mutations to therapies, called theratyping, was highlighted at this year's North American Cystic Fibrosis Conference, and the Cystic Fibrosis Foundation has funded labs to screen modulator responses in rare mutations …”

Rapid therapeutic advances in CFTR modulator science

“…Additional observational studies have detected reductions in inflammation, structural lung disease, and possibly detection of CF pathogens, but these data are currently limited in terms of length of follow‐up and number of subjects . Based on accumulating evidence of safety and efficacy in several CF genotypic subgroups, coupled with relationships observed between results in preclinical model systems compared to clinical trials, the FDA has expanded the label of ivacaftor‐approved mutations . This expansion has included some rare CFTR variants that have not been represented in clinical trials.…”