Tony Durmowicz, M.D., Lead Medical Officer, Division of Pulmonary, Allergy and Rheumatology Products, Office of Drug Evaluation II, CDER
Mike Pacanowski, Pharm.D., MPH, Associate Director for Genomics and Targeted Therapy, Office of Translational Sciences, CDER

Typically, 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. But collecting additional clinical data is sometimes very difficult, especially with rare diseases. Patient populations are small and are often scattered throughout the country or the world, and therefore hard to access.

In the case of the drug Kalydeco (ivacaftor)—a drug that works in patients with specific mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause cystic fibrosis (CF)—expansion of the indication was possible, thereby offering a disease-modifying treatment option to hundreds of patients living with CF, despite not having additional clinical data. To approve the indication expansion, a novel approach was used that relied on evidence from laboratory-based in vitro assay data. These data gave us sufficient information to determine whether certain populations with CF would likely respond to the drug.

Nearly 2,000 known mutations can affect the CFTR gene, which encodes for a protein that controls the movement of salt and water in and out of the body’s cells. About 300 mutations of these mutations result in CF. Certain mutations can cause more severe disease than others.

Kalydeco was previously approved for use in patients with one of 10 different types of mutations in the CFTR, which occur in about 8 percent of CF patients. With the expanded indication, Kalydeco is now considered effective against 23 additional mutations. Moreover, the in vitro data also were able to identify types of CFTR mutations that were NOT responsive to the drug. There is value in knowing who will likely not benefit from the drug, and this information is also included in the new labeling.

The Utility and Promise of In Vitro Data

It is not unusual to use in vitro assay data in experimental studies during the drug development process. For instance, in oncology, it is used to determine what particular genetic characteristics are likely to respond to a drug. These in vitro studies can form the basis for the development of a treatment that targets a specific molecular defect. In addition, in vitro data often are collected and used to determine if clinical studies targeting a particular disease or condition are an appropriate next step.

But stringent criteria must be met before we can consider the use of in vitro data alone to actually expand a drug’s indication. First, we 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.  Second, it is very helpful that a large efficacy and safety database for a drug already exists. In the case of Kalydeco, we have a well-established risk/benefit profile from years of patient exposures for the previously approved mutations. Third, we need 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. Building on this existing knowledge base, we were confident that the in vitro cell model would reasonably predict the response of patients with mutations not included in the initial clinical trials. 

What’s Next

This 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.

Regardless of whether clinical studies are conducted before a drug’s indications are expanded, there will always be some level of variability in how different subsets of patients might respond to a drug. That being said, the in vitro data, in conjunction with our comprehensive understanding of the genetics of CF and the function of the CFTR channel, support its use in determining who may respond to Kalydeco. In addition, 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.

See the press release for more information about the drug’s expanded indication.