Clinical trials of AIR® Inhaled Insulin (AIR® is a registered trademark of Alkermes, Inc) include serial measurements of carbon monoxide diffusing capacity (DLco) as one of several safety parameters. The measurements are performed in the United States and other countries, in widely different laboratory settings, using 12 different pulmonary function-testing (PFT) systems. To ensure quality, laboratories follow standard calibration and testing methods outlined by the American Thoracic Society (ATS). Before testing patients in a clinical trial, laboratories use a DLco simulator (Hans Rudolph, Kansas City, MO) to validate and monitor the accuracy of their DLco measurements. The DLco simulator delivers a known inspired volume and precise, known “exhaled” gas concentrations. When combined with the breath-hold time from the PFT device, exact “target” values for DLco can be calculated. Simulations with four different target values are introduced into each device by varying exhaled gas concentrations and inspired volumes. Differences between measured and target values for alveolar volume (VA), inspired volume, and gas concentrations of carbon monoxide and the tracer gas are then evaluated. A DLco device is certified to be functioning properly if measured volumes are within 3% of target and DLco measures are within 3.0 standard DLco units (mL CO/min/mm Hg) of calculated target values. After initial certification, simulation testing is done each week for 3 months and then biweekly for the remainder of the study.
Equipment at 31 sites (24.8%) failed the initial DLco simulation testing. After correcting instrument issues or purchasing new equipment, 124 (99.2%) sites were confirmed to be measuring DLco accurately. A significant percentage of the DLco devices in clinical pulmonary function laboratory tests are likely to be malfunctioning. This study underscores the need to certify and monitor DLco test quality in clinical trials and clinical laboratories.
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