Cohort assignments in clinical trials

Cohorts are very simple in theory but messy in practice. In a clinical trial, a cohort is a group of patients who receive the same treatment. For example, in dose-finding trials, it is very common to treat patients in groups of three. I’ll stick with cohorts of three just to be concrete, though nothing here depends particularly on this choice of cohort size.

If we number patients in the order in which they arrive, patients 1, 2, and 3 would be the first cohort. Patients 4, 5, and 6 would be the second cohort, etc. If it were always that simple, we could determine which cohort a patient belongs to based on their accrual number alone. To calculate a patient’s cohort number, subtract 1 from their accrual number, divide by 3, throw away any remainder, and add 1. In math symbols, the cohort number for patient #n would be 1 + ⌊(n-1)/3⌋. (See the next post.)

Here’s an example of why that won’t work. Suppose you treat patients 1, 2, and 3, then discover that patient #2 was not eligible for the trial after all. (This happens regularly.) Now a 4th patient enters the trial. What cohort are they in? If patient #4 arrived after you discovered that patient #2 was ineligible, you could put patient #4 in the first cohort, essentially taking patient #2’s place. But if patient #4 arrived before you discovered that patient #2 was ineligible, then patient #4 would receive the treatment assigned to the second cohort; the first cohort would have a hole in it and only contain two patients. You could treat patient #5 with the treatment of the first cohort to try to patch the hole, but that’s more confusing. It gets even worse if you’re on to the third or fourth cohort before discovering a gap in the first cohort.

In addition to patients being removed from a trial due to ineligibility, patients can remove themselves from a trial at any time.

There are numerous other ways the naïve view of cohorts can fail. A doctor may decide to give the same treatment to only two consecutive patients, or to four consecutive patients, letting medical judgment override the dose assignment algorithm for a particular patient. A mistake could cause a patient to receive the dose intended for another cohort. Researchers may be unable to access the software needed to make the dose assignment for a new cohort and so they give a new patient the dose from the previous cohort.

Cohort assignments can become so tangled that it is simply not possible to look at an ordered list of patients and their treatments after the fact and determine how the patients were grouped into cohorts. Cohort assignment is to some extent a mental construct, an expression of how the researcher thought about the patients, rather than an objective grouping.

Related: Adaptive clinical trial design

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