Early-Stage Drug Trials Deemed Safe for Healthy Patients

Less than 1% of healthy patients enrolled in early-stage clinical trials experience serious adverse events, half of which are unrelated to the drug or procedure studied, a new meta-analysis suggests.

Researchers analyzed data from 394 non-oncology, phase 1 trials conducted between September 2004 and March 2011 that enrolled a combined total of 11,028 healthy, compensated volunteers, some of whom participated in multiple studies.

They found that 63.7% of these participants experienced a total of 24,643 adverse events, but nearly one-quarter of them were deemed unrelated to the drug or procedure studied. The remaining 36.3% of participants reported no adverse events of any kind.

Furthermore, only 1% of the recorded side effects were classified as severe, meaning they significantly interfered with a patient’s basic daily functioning. The vast majority (84.6%) were considered mild.

The most frequently reported events were headache (12.2%), drowsiness (9.8%), diarrhea (6.9%), nausea (5.9%), dizziness or lightheadedness (5.4%), and vomiting (2%).

Just 34 (0.31%) healthy volunteers experienced a serious adverse event defined by the FDA as being life-threatening, requiring or prolonging inpatient hospitalization, or resulting in disability or death. Of those events, 16 were unrelated to the drug studied and none resulted in permanent disability or death.

“The findings provide good support for the general safety of phase 1 trials,” said lead author Ezekiel J. Emanuel, MD, PhD, in a press release. “Some have claimed that these trials pose high risks of harm to participants. But these findings show such claims to be essentially without empirical validity.”

Interestingly, almost 20% of the reported adverse events occurred on the first day of the study. These effects may have resulted from behavioral changes required by the study, such as withdrawing from smoking or drinking alcohol, rather than the drug itself, the authors suggested.

To address ethical concerns, the researchers explained that many phase 1 trial participants enrolled in previous studies, indicating that such patients are often well aware of the risks involved in early drug trials. They also pointed out that participants of multiple studies report adverse events at the same rate as those who enroll in a single study.

The authors also dismissed claims that corporate interests would render data on adverse events unreliable, arguing that it would not be in the interests of pharmaceutical companies or trial investigators to misrepresent the number or severity of side effects experienced by participants.

“Study drugs that are associated with high and serious adverse events need to be identified early and quickly, so that determinations can be made about whether to terminate drug development or conduct additional clinical studies,” the researchers wrote. “Phase 2 and 3 trials are expensive. Terminating a drug in phase 2 or 3 because of safety or adverse effects that were ignored or hidden in phase 1 is a costly mistake.”

Although this was the largest meta-analysis of its kind, the authors acknowledged that their data came exclusively from Pfizer trials, so their findings may not be entirely applicable to the phase I trials of other organizations.

The study was published in the BMJ.