Phase 1 Drug Trials Are Safe for Most Subjects

By Sondra Forsyth

Phase 1 trials with healthy volunteers are often perceived as risky and even unethical.

But according to new research, less than 1 percent of 11,000 healthy volunteers for new drugs suffered serious complications.

In a Phase 1 trial, clinicians test a new drug on people for the first time.

The study, by researchers from the Perelman School of Medicine at the University of Pennsylvania, was published in The BMJ. It analyzed 394 phase 1 trials for non-cancer medication. They found that only 34 healthy volunteers suffered serious adverse effect, defined by the FDA as life-threatening; requiring in-patient hospitalization; cause a disability or death.

Half of those adverse effects, the investigators determined, were not linked to the phase 1 experimental drugs or study procedures.

“The findings provide good support for the general safety of phase I trials,” said lead author Ezekiel J. Emanuel, MD, PhD, chair of the department of Medical Ethics and Health Policy at Penn. “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.” Overall, there were three serious adverse events for every 1,000 participants, with several occurring in subjects receiving placebos and others judged unrelated to the study drug or a study procedure.

According to a news release from the university, the investigators found that 63.7% of participants experienced a combined total of 24,643 adverse events, and the other 36.3% experienced no adverse events of any kind. Nearly a quarter (24.1%) of all adverse events were judged to be unrelated to the study drug, and the vast majority (84.6%) of adverse events were classified as mild, 14.4% as moderate, and 1% as severe. The “mild” classification means that symptoms did not interfere with usual functioning while a severe adverse event interferes significantly with a subject’s basic daily functioning; for example, a broken finger. The most common adverse events were headache (12.2%), drowsiness (9.8%), diarrhea (6.9%), nausea (5.9%), dizziness/lightheadedness (5.4%), and vomiting (2%).

Examples of serious adverse events include chest pain, blurred vision, elevated enzyme levels, and abdominal pain and cramping. Of the 34 serious adverse events, 11 were related to the study drug and seven to study procedures, while 16 were unrelated to a study drug or procedure, including four that occurred in participants receiving a placebo.

With a total of 143 (36%) studies involving placebo, 10.3% of all adverse events (2,528) occurred in participants receiving placebo. Nearly 20% of the adverse events occurred on the first day of the study. These have been hypothesized as being linked to changes in behavior required to take part in a study, such as withdrawing from smoking and drinking alcohol or caffeinated beverages, rather than from the study drug.