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In treatment trials in idiopathic pulmonary fibrosis (IPF), there is an unmet need for an accurate primary end point. A European-wide consensus exists that mortality is not a practicable primary end point for the demonstration of beneficial treatment effects in IPF.1 Serial, 6-min-walk test data are confounded by factors other than progression of interstitial lung disease. Alone among other candidate variables, trends in forced vital capacity (FVC) have consistently predicted mortality in IPF2–11 and can, thus, be viewed as the best marker of chronic disease progression. FVC trends are now the preferred primary end point in IPF treatment trials, although not a proven surrogate for mortality.12
In pharmaceutical studies, FVC change is analysed as a continuous variable, or by designating thresholds for change as ‘significant’ and quantifying time to FVC decline. Analyses of continuous change are more sensitive. However, FVC change thresholds have important theoretical advantages. Progression in IPF occurs in a stepwise fashion in some patients, and is not necessarily captured by evaluation of FVC change as a continuous variable. The designation of ‘significant’ FVC decline allows patients with ‘treatment failure’ to exit a trial with no need to continue on a demonstrably ineffective blinded therapy. In addition, time to decline in FVC can be amalgamated with mortality in evaluations of ‘progression-free survival’.
The absence of consensus on the optimum FVC threshold for change in IPF prompted Richeldi et al13 to compare the prognostic value of candidate thresholds. The prevailing confusion on this question cannot be overstated. In 2000, significant FVC change in IPF was designated as a 10% change from baseline, but it was unclear whether this recommendation referred to ‘relative change’ (a 10% change from baseline values—eg, from 60% to 54% of predicted), or ‘absolute change’ (a 10% reduction in percentage predicted values—eg, …