December 28, 2011

Drug Trials Not Representative, Researchers Charge

By Emily P. Walker, Washington Correspondent, MedPage Today
Published: December 27, 2011

Few major randomized, controlled clinical trials examine the effects of a drug in patients who have multiple chronic conditions, even though more than one-quarter of all Americans are living with at least two chronic health conditions, researchers reported.

The proportion is even greater for older individuals, two out of three of whom are likely to have at least two chronic health conditions, according to Alejandro Jadad, MD, and colleagues from the Centre for Health, Wellness and Cancer Survivorship at the University Health Network in Toronto.

That means that most trials on which the FDA bases its approval of new drugs are not generalizable to the U.S. population, they wrote in a research letter published in the Dec. 28 issue of the Journal of the American Medical Association.

Jadad and his colleagues examined all randomized controlled studies that dealt with an intervention for a long-lasting or chronic disease or condition that were published from January-March in 1995, 2000, 2005, and 2010 in five major peer-reviewed medical journals -- BMJ, CMAJ, JAMA, The Lancet, and the New England Journal of Medicine -- as well as six journals that focus on the most prevalent chronic conditions, including Circulation and Annals of General Psychiatry.

Only six of the 284 published trials analyzed (2.1%) explicitly included patients with multiple chronic conditions, and that percentage didn't change much from 1995 to 2010. In 179 of the randomized controlled trials, patients with multiple medical conditions were explicitly excluded from the trial.

Patients with multiple conditions were mentioned often in trial reports, although not actually included in the trial. About 70% of the published trial reports mentioned multiple coexisting diseases; with general medical journals describing them more often than specialized journals (72% versus 69%; P=0.02).

The letter authors concluded that few randomized controlled clinical trials published in the last 15 years have included patients with multiple chronic conditions.

Although the study was small, the authors said the finding "invites reflection about the risk of unintended harm from inappropriate generalization of trial results conducted in populations with a single disease."

"Given the possible drug-to-drug, drug-to-disease, and disease-to-disease interactions that remain unexamined, most of the evidence gathered to date by [randomized controlled clinical trials] is of limited value to guide decisions," they wrote.

The study authors said it may be useful for the FDA to have drug companies include subgroups of patients with the most common combinations of diseases in their drug development process; to observe safety outcomes of adding a new drug to patients who are already medicated for other conditions; and to have post-marketing studies that include the risk stratification to allow for meta-analyses across populations, such as those with multiple conditions.

The study was supported by funds from the Canada Research Chair in eHealth Innovation, the University of Toronto, and the University Health Network.

One of the letter writers, Alejandro Jadad, reported being a consultant to Foresight Links Corporation and that he receives royalties from Wiley for a book on randomized controlled trials.

None of others reported having any financial disclosures.

Primary source: Journal of the American Medical Association
Source reference:
Jahad A, et al "Consideration of multiple chronic diseases in randomized controlled trial" JAMA 2011; 306(24): 2670-2674.

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