Underreporting of Non-Study Cigarette Use by Study Participants Confounds the Interpretation of Results from Ambulatory Clinical Trial of Reduced Nicotine Cigarettes

Abstract

Abstract Background: As part of its comprehensive plan to significantly reduce the harm from tobacco products, the US Food and Drug Administration is in the process of establishing a product standard to lower nicotine in conventional cigarettes to make them “minimally addictive or non-addictive”. Many clinical studies have switched participants who smoke to reduced nicotine cigarettes to investigate the impact on smoking behavior and exposure to cigarette constituents; these ambulatory studies required participants to switch to reduced nicotine study cigarettes. In contrast to clinical trials on pharmaceuticals or medical devices, participants had ready access to non-study conventional nicotine cigarettes and high rates of non-study cigarette use have been consistently reported. The magnitude of noncompliance was not adequately assessed in these trials, which could further hinder an accurate assessment of the potential impact of such a standard. Methods: We conducted a secondary analysis of data from a large, randomized trial of reduced nicotine cigarettes to estimate the magnitude of noncompliance, i.e., the average number of non-study cigarettes smoked per day by study participants assigned to reduced nicotine cigarettes. Individual participant’s non-study cigarette use was estimated based on his/her urinary total nicotine equivalents level, the nicotine content of the study cigarette assigned, and the self-reported number of cigarettes smoked, using a previously published method. Results: Our analysis showed that (1) there is large variation in the number of non-study cigarettes smoked by participants within each group (CV 90-232%); (2) participants in reduced nicotine cigarette groups under-reported their mean number of non-study cigarettes smoked per day by 85-91%; and (3) the biochemical-based estimates indicate no reduction in the mean number of total cigarettes smoked per day for any group assigned to reduced nicotine cigarettes after accounting for non-study cigarettes. Conclusions: High levels of noncompliance, in both the rate and magnitude of non-study cigarette use, are common in ambulatory reduced nicotine cigarette trials where participants have access to conventional nicotine non-study cigarettes. The potential impact of high noncompliance on study outcomes should be considered when interpreting the results from such ambulatory studies.