Targeted CT image screening and its effect on lung cancer detection rate.

journal.publications.chestnet.org between a change in sweat chloride and improvement in FEV 1 in individual patients with cystic fi brosis (CF) who received ivacaftor in phase 3 clinical trials. 1 They suggest that this lack of correlation between changes in sweat chloride in the ivacaftor trials should not diminish the potential usefulness of sweat chloride for predicting clinical outcomes. Regarding the usefulness of using change in sweat chloride as an end point, it should be pointed out that it was and continues to be used effectively by companies developing therapies that target the CF transmembrane conductance regulator gene or protein. For example, for the ivacaftor program, it was used to establish proof of principle of drug activity, as a pharmacodynamic biomarker to select and enrich CF patient study populations that may best respond to the drug, and, in association with change in FEV 1 , as a factor in dose selection. The implicit issue in the correspondence appears to be the extent to which change in sweat chloride could be used as a primary end point to establish effi cacy for regulatory purposes (ie, approval of a drug for marketing). Such qualifi cation of a pharmacodynamic biomarker as a surrogate end point is a high bar to achieve, as robust scientifi c evidence would be needed that demonstrates that changes in sweat chloride beyond a specifi c level in a specifi c CF population would predict clinical benefi t to the same extent that a clinical end point (an improvement in how a patient feels, functions, or survives) would. 2 Because of such a high level of evidence required, most pharmacodynamic biomarkers are used, as has been the case to date for the ivacaftor program, to guide drug development, whereas clinical end points (or in the case for ivacaftor, the surrogate end point, FEV 1 ) provide the basis for regulatory approval. With the arrival and continued development of a new class or classes of CF therapies that have the potential to address the central defect that results in CF, we, like the CF community, are happy that we have reached such a time that we can have a discussion on the use of change in sweat chloride or other possibly more accurate pharmacodynamic biomarkers that may refl ect CF transmembrane conductance regulator function 3 as end points in clinical trials.