Objective: This report analyzes all adverse events (AEs) which occurred in healthy volunteers in a phase I center over a five-year period. It included 142 phase I studies with a total of 1,559 participants receiving 2,955 treatments with 32 different active drugs and placebo (ratio 6.5 : 1 in terms of follow-up days). The observation period covered a total of 29,664 follow-up days.
Methods: All adverse events (AEs) as well as clinically relevant laboratory findings were counted. The incidence of AEs was defined as the ratio between the number of AEs and the number of follow-up days. Severity of AEs was classified as mild, moderate and severe; serious AEs were analyzed separately. A chi2-test was used to compare incidence rates of the AEs. Statistical tests based on the normal distribution were used for comparison of demographic data and relative frequencies; p < 0.05 was defined as the minimum level of significance.
Results: There were 2,604 AEs and 291 different types of AEs with headache (2.23%), diarrhea (1.37%) and common cold (0.72%) being the most frequent. The overall incidence of AEs was 8.8% with no significant difference between those occurring with active drug and those on placebo when the studies were taken as a whole (8.5% vs. 9.1%), but the incidence of AEs in the active treatment groups was higher than under placebo (14.1% vs. 9.1%; p < 0.001) in placebo-controlled studies. The overall rate of AEs was 1.7 per subject and 0.9 per treatment. The vast majority of AEs were of mild or moderate intensity (99.2%). Only six AEs were serious as defined by GCP but two, a pseudoallergic reaction and a prolonged orthostatic dysregulation were rated as possibly or probably drug-related and these resolved completely. The incidence of AEs was three-fold (all AEs) and six-fold (AEs with probable relationship to study medication) higher (p < 0.001) in multiple-dose studies than in single-dose trials, and within multiple-dose trials the difference between AEs on active drug and on placebo was also significant (22.9% vs. 12.5%; p < 0.001). Irrespective of whether on active drug or placebo, AEs occurred with a significantly higher incidence on the first day of the study drug administration, in the first study period, with respect to the overall population in elderly subjects and in volunteers with a high body weight.
Conclusion: AEs in phase I studies are common, but usually of mild or moderate intensity. Placebo effects and study conditions contribute significantly to the rate of their occurrence. Multiple-dose placebo-controlled studies are of particular importance in determining the substance-specific AE profile.