On May 17, 2017, Vertex Pharmaceuticals small molecule drug Kalydeco® (ivacaftor) was approved by the U.S. Food and Drug Administration (FDA) for use in treating an expanded population of cystic fibrosis patients with particular genotypes. The approval is notable for the agency’s use of laboratory-based in vitro assay data in reaching its decision to expand the drug’s indication. An FDA post noted that “[t]his action signals to other sponsors that for drugs that target specific mutations, in vitro assay data could potentially be used in place of additional small clinical trials when seeking to expand to other population subsets, provided that the drug’s safety profile is good, the disease is well characterized and other criteria are met.”

Cystic fibrosis is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes an ion channel protein that transports chloride and thiocyanate ions across epithelial cell membrane, and its dysregulation can ultimately lead to an accumulation of abnormal mucus in the lungs. Kalydeco initially achieved FDA approval in 2012 for treating cystic fibrosis patients possessing the G551D-CTFR mutation, and later the approval was expanded to patients with nine additional types of CTFR mutations. According to the Kalydeco prescribing information, this small molecule “facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein.”

This new FDA decision expands the approved use of Kalydeco to twenty-three additional CTFR mutations, which according to a Vertex press release, are “residual function mutations.” These mutations “result in a moderate loss of CFTR chloride transport” and “have shown in vitro increases in chloride transport in response to Kalydeco by at least 10 percent of normal over baseline.” The director of the FDA Center for Drug Evaluation and Research (CDER) stated that “many rare cystic fibrosis mutations have such small patient populations that clinical trial studies are not feasible,” and that this led the agency “to using an alternative approach based on precision medicine, which made it possible to identify certain gene mutations that are likely to respond to Kalydeco.” The novel approach was further justified in a separate FDA post drafted by other CDER Officials. It began by conceding that “[t]ypically, when FDA approves an expansion of the indication for a drug, it means that additional clinical data have shown the drug can safely and effectively treat patient populations other than those for which it was originally intended.” Thus, “stringent criteria must be met before we can consider the use of in vitro data alone to actually expand a drug’s indication.” The agency noted three criteria in particular: (1) “a good understanding of the disease”; (2) “a large efficacy and safety database for a drug already exists”; and (3) “a solid understanding of the drug’s mechanism of action.” According to the FDA, each of these criteria was met in light of the existing understanding of CTFR structure/function, cystic fibrosis etiology, and Kalydeco mechanism and risk/benefit profile. Thus, the FDA was “confident that the in vitro cell model would reasonably predict the response of patients with mutations not included in the initial clinical trials.” It was noted in a press release from the Cystic Fibrosis Foundation that “[b]y using this approach, the FDA put the health of CF individuals with rare mutations first without compromising its high standards for safety or efficacy.”