For the first time, the US Food and Drug Administration (FDA) has expanded a drug's indication without additional clinical data.
FDA announced it was expanding the use of Vertex Pharmaceuticals' cystic fibrosis drug Kalydeco (ivacaftor) based solely on new in vitro data to include an additional 23 genetic mutations, more than tripling the number of mutations the drug is approved to treat.
With the expanded indication, Kalydeco is approved to treat mutations affecting 11% of the 30,000 cystic fibrosis patients in the US, up from 8% previously.
According to Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), such a model was necessary because of the small patient populations involved.
"Many rare cystic fibrosis mutations have such small patient populations that clinical trial studies are not feasible," she said, referring to the hundreds of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene believed to cause cystic fibrosis.
In lieu of new clinical data, FDA says Vertex was able to use an in vitro cell-based model to predict how different mutations respond to Kalydeco.
"When additional mutations responded to Kalydeco in the laboratory test, researchers were thus able to extrapolate clinical benefit demonstrated in earlier clinical trials of other mutations," FDA writes.
Other Expanded Labels?
In a separate post, Tony Durmowicz, lead medical officer at FDA's Division of Pulmonary, Allergy and Rheumatology Products, and Mike Pacanowski, associate director for genomics and targeted therapy at the Office of Translational Sciences within CDER, write that "stringent criteria must be met before [FDA] can consider the use of in vitro data alone to actually expand a drug's indication."
Specifically, Durmowicz and Pacanowski say that for such a model to be considered for other drugs scientists must have a good understanding of the disease.
"Thankfully, since the CFTR gene was identified almost 30 years ago, we have accumulated a great deal of knowledge about the CFTR channel's structure and function. We also have thorough knowledge of the clinical aspects of the disease and what causes it, and we have data on thousands of CF patients and their mutations," they write, referring to the Cystic Fibrosis Foundation's 28,000-patient registry.
Durmowicz and Pacanowski also say there needs to be existing evidence of safety and efficacy for the drug, and critically, that there is a "solid understanding" of the drug's mechanism of action.
"In this case, we have a good grasp of Kalydeco's ability to improve the function of the defective protein in a reliable laboratory model," they write.
Additionally, Durmowicz and Pacanowski say that patient access also played a role in the decision to expand a Kalydeco's indication.
"Because we know that Kalydeco is safe to use, we would rather allow access to the drug than limit its availability for other subsets of patients with CF who may benefit," they write.
Press Release, Spotlight on CDER Science