Two Unique Approvals in a Week; FDA’s Baby Steps, Industry’s Giant Leap     

This week FDA announced with great fanfare two approval decisions using unique regulatory approaches that would seem to indicate a shift in its thinking about data supporting such decisions. But a careful observation shows that these are baby steps, at best. In the case of Kalydeco, a cystic fibrosis drug, FDA expanded the indication based solely on in vitro data; and in the case of Keytruda, an oncology drug, FDA allowed a broad indication expansion linked to genetic markers. It may seem that FDA is making bold decisions and in some manners they are, perhaps not as big as they may seem. Let’s look at the two cases. Kalydeco was originally approved more than 5 years ago in January 2012 for cystic fibrosis, a very rare disease that affects about 30,000 patients in the US. The disease is one of the most well understood genetic disorders caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There are about 300 known mutations to the CFTR gene responsible for cystic fibrosis. The original approval was for about 10 of these mutations. In the last 5 years, Kalydeco has established extensive safety and efficacy data along with new in vitro data to show that the drug could potentially help another 23 mutations, taking the total to 33 mutations. The new indication expansion affects about 900 patients in the US. Keytruda, the oncology drug, is a humanized monoclonal antibody that was originally approved as a breakthrough therapy in September 2014, and since then has successfully been approved 12 times for additional indications. All data point to Keytruda being an exceptional drug that treats a variety of different kinds of cancers all linked to a common marker, the PD-1 (programmed death receptor-1). It binds to PD-1 and thereby blocks the tumor’s inhibition of the body’s immune system so the immune system is able to attack and destroy the tumor. New data emerged that most of the tumors treated by Keytruda has a common biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). The FDA indication expansion allows Keytruda to be used for all patients who have tumors with this biomarker irrespective of where the tumor is located. This is the first time FDA has approved a product based on a broad genetic biomarker. For a product like Keytruda which seems like the LeBron James of oncology drugs that FDA agreed to expand indication in this manner should not come as a huge surprise. Both of these decisions, while bold, are very “safe” decision by the Agency in terms of being controversial. But they do prove a proof-of-concept for the other developers. In its announcements for both decisions, FDA touted its ability to consider new approached in exceptional situations to make unconventional decisions. Both these decisions have one common theme; they are both based on genetic markers for well understood products targeting very rare or life-threatening conditions. For the developers this is creates a precedence to discuss data that may seem scientifically logical even if it does not meet conventional regulatory requirements. If there is convincing in vitro or real-world data, FDA may be willing to be flexible. Although both the above decisions were for indication expansions, it is possible, at least theoretically, to use similar approach for original approvals. But don’t get your hopes up too high; FDA is still a very conservative regulator. Time will show if these are exceptions or a trend.