Doctors have long known that a drug that works well in clinical trials will not always yield the same results in the broader population. Because women and the elderly are often underrepresented in trials, and some patients are deliberately excluded; for instance, controlled study results cannot necessarily be applied to all patients. A new study now strengthens the suggestion that a more insidious factor is also at play: researchers found that individuals with heart disease who refuse to enter into clinical trials die sooner than those who volunteer, even if the willing subjects are never actually recruited for experimental treatment (Eur. J. Heart Fail. 11, 1078–1083; 2009).

New spin: Volunteers skew results Credit: iStockphoto

Andrew Clark, a cardiologist at Castle Hill Hospital in Cottingham, UK, and his colleagues asked over 2,300 people who came into a heart disease clinic to tick a box if they were prepared to volunteer for a clinical trial, and some were subsequently enrolled. Five years later, 35% of those who had agreed had died, compared with around 55% of those who had refused.

By further comparing the prognosis of willing subjects who had not been recruited with that of volunteers who had eventually been enrolled, Clark found that participation alone did not predict survival. “It's not actually being in a trial that's beneficial, it's expressing willingness that is helpful,” he says.

Why willing subjects live longer remains unclear. Volunteers could be more trusting, less stressed or less depressed, which could improve outcomes, speculates cardiologist Harlan Krumholz, of Yale School of Medicine in New Haven, Connecticut, who was not involved in the study.

More importantly, he says, the study shows another way in which the participants of clinical trials are not reflective of the broader patient population. Steven Joffe, an oncologist who studies clinical trial design at the Dana-Farber Cancer Institute in Boston, Massachusetts, adds that because self-selecting patients are creating the discrepancy—rather than doctors who are unwittingly or deliberately excluding patients—it could be difficult to avoid. Perhaps 'opt-out' recruitment strategies may result in more representative patient populations for some studies, he suggests.

Krumholz draws another conclusion. “This finding really emphasizes the importance of continuing to study the effects of drugs after their approval, when they're being used by millions of people.”