PMean: Extremely imbalanced multi-center trials

There was some recent discussion of issues with multi-center trials where one center dominates, contributing as much as 94% of all the patients. What does this do to the generalizability of the study. I wanted to summarize these comments here, because it relates to some of the issues I’m looking at right now in accrual models for multi-center trials.

One person shared the transcript of an FDA review of a drug that was tested in 41 patients, 38 of who came from Brigham & Women’s Hospital with the remaining 3 coming from a hospital associated with the University of Nebraska. As you might expect, the FDA panel was not thrilled with the ability to generalize from this study to the overall population, but they did acknowledge that the patients themselves were geographically dispersed and came to Brigham & Women’s Hospital because this was a rare condition that few places were qualified to offer treatment.

Another person suggested a 2.5 to 1 ratio maximum, meaning that if you had K centers, no more than 2.5 / K of them could come from a single center. For example, with 10 centers, no more that 2.5/10 = 25% should come from any one center. For pivotal studies you might want to consider a stricter limit like 2 / K. This is a very ad hoc approach of course, but you could run some simulations using an influence function and a score function to see how much the imbalance hurts. I can’t say that I completely follow this last comment.

Another person shared a guidance document CMPP/EWP/2330/99 which discusses meta-analyses and relying on a single pivotal trial. This guidance offer the general admonition that none of the centers in a multi-center trial should dominate the study either in the number of subjects or in the magnitude of the effect. The latter means, I presume that if the efficacy is a result of positive results mostly from just one of the centers, that is a serious concern.

Addendum: I did a quick google search and found a discussion on enrollment caps in a multicenter trial on the MEDSTATS forum on January 28, 2015. One reply had a link to an article in the Journal of the American College of Cardiology that argued that, at least in one clinical trial, high enrolling sites differed in important ways from low enrolling sites. This article has an accompanying editorial.

Another search found a Johns Hopkins report that discussed (among other things) the impact of enrollment caps on individual sites. And a 2007 blog entry suggests a cap of 3/K to 5/K.