Question 19

College Answer

a)

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

b)

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. 

c)

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. 

d)

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. 

Discussion

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:

• This is technique of preventing selection bias.
• The selection of patients is randomised, and nobody knows what treatment the next enrolled patient will receive.
• A truly random sequence of allocations prevents the investigators from being able to predict the allocated treatment on the basis of previous allocated treatments.
• The difference between blinding and allocation concealment is that allocation concealment prevents the investigators from predicting who is getting what treatment before the patient is enrolled, whereas blinding prevents the investigators from knowing who is getting what treatment after the patient is enrolled.

b) Block randomisation:

• Arrangement of experimental subjects in blocks, designed to keep the group numbers the same.
• Usually, the block size is a multiple of the number of treatments (i.e. if it is a binary Drug A vs Drug B trial, the blocks would be in multiples of two).
• Small blocks are better than large blocks.
• The example where block sizes of 4 are used in a trial of drug A versus drug B is the same example used by Bland and Altman in their classical 1999 article, "How to randomise".
• That example now, verbatim:

"...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."

c) Stratification:

• Stratification is the partitioning of subjects and results by a factor other than the treatment given.
• Stratification ensures that pre-identified confounding factors are equally distributed, to achieve balance. The objective is to remove "nuisance variables", eg. the presence of neutropenia in a trial performed on septic patients. One would want to ensure that the treatment group and the placebo group had equal numbers of these haematology disasters.

d) Minimisation algorithm:

• Minimisation is a method of adaptive stratified sampling.
• The objective is to minimise the imbalance between groups of patients in a clinical trial by ensuring that the treatment group and placebo group each get an equal number of patients with some sort of predetermined characteristics which might act as confounding factors.
• The minimisation algorithm carefully places patients in groups according to thse pre-identified confounding factors. Only the first patient is randomly allocated.
• Minimisation is methodologically equivalent to true randomisation, but does not correct for unknown confounders (only the  known pre-determined ones)

Altman, Douglas G., and J. Martin Bland. "How to randomise." Bmj 319.7211 (1999): 703-704.