How healthy are the “Healthy volunteers”? Penetrance of NAFLD in the biomedical research volunteer pool

Abstract

Introduction Healthy volunteers are crucial for biomedical research. Inadvertent inclusion of subjects with non-alcoholic fatty liver disease (NAFLD) as controls can compromise study validity and subject safety. Given the rising prevalence of NAFLD in the general population, we sought to identify its prevalence and potential impact in volunteers for clinical trials. Methods Cross-sectional study of subjects with “Healthy Volunteer” diagnosis between 2011-2015 and no known liver disease. Subjects were defined presumed NAFLD (pNF, ALT≥20 for women or ≥31 for men and BMI>25), healthy non-NAFLD controls (HC, normal ALT and BMI), or indeterminate. Results 3160 subjects participated as healthy volunteers in 149 clinical trials, (1-29 trials per subject). 1732 (55%) had BMI > 25 kg/m2 and 1382 (44%) had abnormal ALT. pNF was present in 881 subjects (27.9%) and these subjects were older than HC, and had higher triglycerides, LDL-C, and HbA1c and lower HDL-C (p<0.001 for all) . The 149 trials included 101 non-interventional, 33 interventional and 15 vaccine trials. The impact on study validity of recruiting NAFLD subjects as controls was estimated as likely, probable and unlikely in 10, 41 and 98 trials, respectively. The proportion of pNF subjects (28-29%) did not differ by impact. Only 14% of trials used both BMI and ALT for screening. ALT cut-offs for screening were based on local reference values. Grade 3-4 ALT elevations during the study period were rare but more common in pNF subjects than HC (4 vs. 1). Conclusion NAFLD is common and often overlooked in volunteers for clinical trials, despite its potential impact on subject safety and validity of study findings. Increased awareness of NAFLD prevalence and stricter ALT cut-offs may ameliorate this problem.

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