Explain the following terms as applied to a randomised controlled clinical trial:
a) Allocation concealment. (25% marks)
b) Block randomisation, using block sizes of 4, in a trial of drug A versus drug B. (25% marks)
c) Stratification. (25% marks)
d) Minimisation algorithm. (25% marks)
Procedure for protecting the randomization process and ensuring that the clinical investigators and those involved in the conduct of the trial are not aware of the group to which the subject has been allocated
Simple randomisation may result in unequal treatment group sizes; block randomisation is a method that may protect against this problem and is particularly useful in small trials.
In the context of a trial evaluating drug A or drug B and with block sizes of 4, there are 6 possible blocks of randomisation: AABB, ABAB, ABBA, BAAB, BABA, BBAA.
One of the 6 possible blocks is selected randomly and the next 4 study participants are assigned according to the order of the block. The process is then repeated as needed to achieve the necessary sample size.
Stratification is a process that protects against imbalance in prognostic factors that are present at the time of randomisation.
A separate randomisation list is generated for each prognostic subgroup. Usually limited to 23 variables because of increasing complexity with more variables.
This is an alternative to stratification for maintaining balance in several prognostic variables. The minimisation algorithm maintains a running total of the prognostic variables in patients that have already been randomised and then subsequent patients are assigned using a weighting system that minimizes imbalance in those prognostic variables.
In this paper, only one candidate (2.5% of the cohort) managed to just pass this question (i.e. they got 5 marks out of 10).
a) Allocation concelament:
b) Block randomisation:
"...sometimes we want to keep the numbers in each group very close at all times. Block randomisation (also called restricted randomisation) is used for this purpose. For example, if we consider subjects in blocks of four at a time there are only six ways in which two get A and two get B: 1:AABB 2:ABAB 3:ABBA 4:BBAA 5:BABA 6:BAAB. We choose blocks at random to create the allocation sequence. Using the single digits of the previous random sequence and omitting numbers outside the range 1 to 6 we get 5623665611. From these we can construct the block allocation sequence BABA/BAAB/ABAB/ABBA/BAAB, and so on. The numbers in the two groups at any time can never differ by more than half the block length. Block size is normally a multiple of the number of treatments."
d) Minimisation algorithm:
Altman, Douglas G., and J. Martin Bland. "How to randomise." Bmj 319.7211 (1999): 703-704.