Measure Enrollment Imbalance

Question:

"A Sponsor PM would like to know how many subjects can be enrolled at their largest-enrolling site before it begins to skew the study results. She says a previous CRO was able to calculate this number for her."

My response:

"I don't think we really need to calculate the probability to get to the answer. There may be no easy way to calculate the probabilities.

It depends on # of subjects for the study and # of sites. I typically divide the # of total subjects by # of sites to get an average # of subjects per site. Then you truly believe that there may be the site difference, you could choose a cut point (arbitrary) of 3-5 times the average # of subjects. For example, if a study is intended to enroll total 100 subjects at 10 sites, the average will be 10 subject per site.

I will probably choose a number (30, 40, or 50) as a cut point as a cap for maximum # of subject a site can enroll."

Question: Many assume that the FDA advocates that the subjects enrolled in any clinical trials be well dispersed among study sites involved in a particular clinical program. Does the FDA have any guidance, rules of thumb, or limits regarding severe imbalances in enrollment between sites?

Answer: In an informal response to this question, the FDA noted that "it does have concerns about how many patients are enrolled in studies from specific study sites. The most important issue [is] that all sites conducting the research use the same protocol. Sometimes this requirement for using the same protocol can be an issue that requires input by FDA's review division because different standards of care (i.e., standard treatments that are typically used within a particular country for the treatment of various cancers) exist in different countries. As long as the protocol is being followed, the studies are conducted in conformance with good clinical practice, and the study/study records can be audited by FDA, differences in recruitment at the various sites do not present a problem. FDA does not require specific enrollment levels at specific sites."