ADVERSE EVENTS IN PHASE-I STUDIES - A REPORT IN 1015 HEALTHY-VOLUNTEERS

Objective: This report describes all clinical. laboratory and electroc ardiographical adverse events detected in healthy volunteers in a phas e-I centre over a 10-year period: 54 phase-I studies are involved, inc luding 1015 healthy young volunteers (993 males) who received 1538 tre atments (23 different active drugs or placebo) corresponding to 12143 days of follow-up. This updates a similar report published previously in the European Journal of Clinical Pharmacology. Methods: Adverse eve nts were defined as all events noted in case-report forms. Incidence o f adverse events was defined as the ratio between the number of advers e events and the number of follow-up days. Severity was rated as death , life-threatening, severe or minor. Incidences or occurrence rates we re compared using the Chi-squared test with Yates' correction. Results : The overall incidence of adverse events was 12.8% with a significant difference between active-drug (13.7%) and placebo (7.9%) treatments. There were 1558 adverse events of 110 distinct kinds. Only for three (headache, diarrhoea and dyspepsia) was the incidence superior to 10 p arts per thousand. Most of these adverse events were also observed wit h placebo. Ninety-seven percentage of adverse events were of minor int ensity; forty three (3%) were rated as severe, including nine worrying cases - six malaises with loss of consciousness, one atrial fibrillat ion, one hyperthyroidism and one bicytopenia. Some of the adverse even ts were not related to the tested drugs, but to a vagal reaction or to study conditions. There was no death or life-threatening event. The g lobal rate of occurrence was one adverse event per treatment, one and a half per subject and one out of eight follow-up days. No difference in the overall incidence with placebo was observed between the two suc cessive 5-year periods. Conclusions: This report confirms that adverse events in phase I studies are very common, usually of minor intensity and rarely severe; even though exceptional, life-threatening adverse events are possible. Adverse events occuring in phase I are rarely pub lished, leading to lack of information. Thus, authors invite clinical research organization (CROs) and phase-I centres to regularly publicis e at least severe adverse events; they also suggest that the life-thre atening adverse events reported to health authorities should be public ised, for example by the World Health Organization (WHO).