FROM — IPF CLINICAL TRIAL DESIGN AND ENDPOINTS
— FORCED VITAL CAPACITY
'The forced vital capacity (FVC) has been the most commonly employed and accepted endpoint in clinical trials of IPF to date [5]. It has many advantages that include being relatively easy to measure and reproduce. It is also commonly regarded as reflecting the burden of the fibrotic disease process. Although both the baseline FVC as well as FVC change have been shown to be associated with subsequent survival [6–8], it remains controversial as to whether the FVC is, can, or should be regarded as a surrogate for survival [2,3].
The change in the FVC over time is the outcome measure of interest, but how best to evaluate the change remains unresolved. Typically, it has been the mean change in FVC for the patient cohorts that have been reported. However, mandating a categorical or threshold change in FVC has the advantage of reducing any ‘noise’ due to the inherent variability of the test. This has commonly been regarded as approximately 10% and any change that breaches this boundary has previously been regarded as the minimal difference that defines a true change. However, there are data to suggest that even a change as small as 5% is associated with increased mortality [7,8]. Whether an absolute change or a relative change in the FVC provides the best measure of FVC change over time remains unresolved [9]. Whereas the absolute change has been used traditionally, the relative change does ‘autocorrect’ for the baseline FVC. A more recently proposed method for evaluating the change in the FVC is to measure the slope of change [10]. This has the advantage of incorporating all FVC measurements obtained for the duration of the study, rather than evaluating change between two predefined time points. Furthermore, this method may mute the influence of the intrinsic variability of the test. This concept also raises the issue of how often the FVC should be measured during the course of a study. Traditionally, this has been every 3 months, but there are no data to support this as the optimal period. A subsequent consequence is that a number of patients will progress and die within this timeframe without prior documented significant change in their FVC [11]. These ‘missed’ events might also be one of the reasons that FVC has not been universally accepted as an adequate surrogate for mortality.
 
The results of the recently released ASCEND study of pirfenidone provide support for the use of the FVC as a valid IPF study endpoint and as a surrogate for mortality [12]. Specifically, the ASCEND study demonstrated a positive treatment effect on the rate of change in the FVC in association with a mortality benefit. The significant mortality benefit was confirmed by the prespecified combined analysis of the ASCEND dataset with the two prior CAPACITY (Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes) studies of pirfenidone [12,13]. The total number of patients required to demonstrate the mortality benefit from the three pooled studies was approximately 1250, which underscores the difficulty and cost of studies with mortality as the primary endpoint.'
 
Jim |
