More on New Developments at the FDA in the Era of Precision Medicine

This week the FDA approved the expanded use of the cancer drug Keytruda for any solid tumor that expresses a particular molecular marker. It is the first time that the FDA has approved new uses of a cancer drug in cancers that are defined by a molecular marker independent of the site in the body where the tumor originated. While the expanded use of the drug was based on an accelerated approval supported by surrogate markers, this is another demonstration of the FDA’s continuing adaptation to the new era of precision medicine, in which the appropriate use of a drug is defined by particular genetic and molecular markers rather than the broad traditional disease categories.

Postscript to last week’s post–– I wrote that the approval of Kalydeco for cystic fibrosis patients with 23 additional mutations was, to my knowledge, the first time ever that the FDA had approved new indications for a drug without any human clinical data. The Kalydeco label change was based entirely on an in vitro assay of the drug’s effect on the function of the cystic fibrosis transmembrane receptor. The in vitro assay had correlated well with clinical trial data from the original Kalydeco studies and provided a reasonable degree of confidence that the drug would work in the additional mutations tested. Later reports and an additional statement from the FDA confirmed my initial conclusion that this approval was indeed the first of its kind and a real breakthrough in drug approval. That is good news for the approximately 900 cystic fibrosis patients who have one of those 23 mutations. Of course the 900 patients covered by the 23 additional mutations means that there is, on average, fewer than 40 patients with any one of those mutations, which is why the FDA’s flexibility is so important. Precision medicine will need that kind of regulatory innovation to move forward when, as the FDA’s Janet Woodcock stated, there is a solid understanding of the disease’s biology, a drug with a known safety (and pharmacokinetic) profile, and a good assay to predict the drug’s effect in target populations.

A milestone for precision medicine and for the FDA

Precision medicine is much in the news­­––and the need to target the right drug to the right patient using genomic and other information is clearly going to be major part of healthcare in the future. Today's news included an announcement from the FDA that it had expanded the approved indications for Kalydeco,  a breakthrough drug for the treatment of cystic fibrosis.  The previous label indication described Kalydeco as a 

cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 2 years and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R …[or] R117H

The new label, according to the FDA, expands the use of Kalydeco from the 10 mutations above to include an additional 23 mutations, for a total of 33.  This is great news for cystic fibrosis patients, as the clinical studies in the original population showed that treatment with Kalydeco resulted in a significant increase in patients’ lung function. From a precision medicine perspective the Kalydeco expanded label could be viewed simply as yet another drug label with genomic information about the drug’s appropriate use—after all, there are already well over 200 drugs approvedby the FDA that include pharmacogenomic information.  However, it isn’t just the dramatic increase in the number of mutations in the Cystic Fibrosis Transmembrane Receptor gene that makes the FDA’s announcement remarkable, it is the evidentiary basis on which the dramatic expansion in the use of Kalydeco was approved.  The FDA’s announcement also had this particularly noteworthy statement:

Results from an in vitro cell-based model system have been shown to reasonably predict clinical response 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. This resulted in the addition of gene mutations for which the drug is now indicated.

In other words, the indication for Kalydeco was approved solely on the basis of in vitro studies without additional human clinical data (or animal data for that matter).  Vertex Pharmaceuticals, the maker of Kalydeco, was able to persuade the FDA that because there was a sufficiently high correlation between the in vitro assays and clinical data for the previously studied mutations, it was more than reasonable to allow the drug to be used for patients with 23 additional mutations that showed a significant gain in function in cell-based assays.  I am unaware of any similar action by the FDA.  So the Kalydeco announcement is more than another step in the targeting of drugs based on individual biomarkers, it is a major step by the FDA in regulatory flexibility in streamlining drug development as the science of predicting drug response evolves.  We are indeed at the beginning of an interesting journey on an uncharted road to the future of drug development.