Item 16a: Method of generating the allocation sequence (e.g., computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (e.g., blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions.
Example
“Participants will be randomly assigned to either control or experimental group with a 1:1 allocation as per a computer generated randomisation schedule stratified by site and the baseline score of the Action Arm Research Test (ARAT; <= 21 versus >21) using permuted blocks of random sizes. The block sizes will not be disclosed, to ensure concealment.” 224
Explanation
Participants in a randomised trial should be assigned to study groups using a random (chance) process characterised by unpredictability of assignments. Randomisation decreases selection bias in allocation; helps to facilitate blinding/masking after allocation; and enables the use of probability theory to test whether any difference in outcome between intervention groups reflects chance.17;225-227
Use of terms such as “randomisation” without further elaboration is not sufficient to describe the allocation process, as these terms have been used inappropriately to describe non-random, deterministic allocation methods such as alternation or allocation by date of birth.121 In general, these non-random allocation methods introduce selection bias and biased estimates of an intervention’s effect size,17;167;228;229 mainly due to the lack of allocation concealment (Item 16b). If non-random allocation is planned, then the specific method and rationale should be stated.
Box 1 outlines the key elements of the random sequence that should be detailed in the protocol. Three-quarters of randomised trial protocols approved by a research ethics committee in Denmark (1994-95) or conducted by a US cooperative cancer research group (1968-2006) did not describe the method of sequence generation.2;11
Box 1: Key elements of random sequence to specify in trial protocols
- Method of sequence generation (e.g., random number table or computerised random number generator)
- Allocation ratio (Item 8) (e.g., whether participants are allocated with equal or unequal probabilities to interventions)
- Type of randomisation (Box 2): simple versus restricted; fixed versus adaptive (e.g., minimisation); and, where relevant, the reasons for such choices
- If applicable, the factors (e.g., recruitment site, sex, disease stage) to be used for stratification (Box 2), including categories and relevant cut-off boundaries
Box 2 defines the various types of randomisation, including minimisation. When restricted randomisation is used, certain details should not appear in the protocol in order to reduce predictability of the random sequence (Box 3). The details should instead be described in a separate document that is unavailable to trial implementers. For blocked randomisation, this information would include details on how the blocks will be generated (e.g., permuted blocks by a computer random number generator), the block size(s), and whether the block size will be fixed or randomly varied. Specific block size was provided in 14/102 (14%) randomised trial protocols approved by a Danish research ethics committee in 1994-95, potentially compromising allocation concealment.2 For trials using minimisation, it is also important to state the details in a separate document, including whether random elements will be used.
Box 2: Randomisation and minimisation (adapted from CONSORT 2010 Explanation and Elaboration)17;230;231
Simple randomisation
Randomisation based solely on a single, constant allocation ratio is known as simple randomisation. Simple randomisation with a 1:1 allocation ratio is analogous to a coin toss, although tossing a coin is not recommended for sequence generation. No other allocation approach, regardless of its real or supposed sophistication, surpasses the bias prevention and unpredictability of simple randomisation.231
Restricted randomisation
Any randomised approach that is not simple randomisation is restricted. Blocked randomisation is the most common form. Other forms, used much less frequently, are methods such as replacement randomisation, biased coin, and urn randomisation.231
Blocked randomisation
Blocked randomisation (also called permuted block randomisation) assures that study groups of approximately the same size will be generated when an allocation ratio of 1:1 is used. Blocking can also ensure close balance of the numbers in each group at any time during the trial. After every block of eight participants, for example, four would have been allocated to each trial group.232 Improved balance comes at the cost of reducing the unpredictability of the sequence. Although the order of interventions varies randomly within each block, a person running the trial could deduce some of the next treatment allocations if they discovered the block size.233 Blinding the interventions, using larger block sizes, and randomly varying the block size will help to avoid this problem.
Biased coin and urn randomisation
Biased coin designs attain the similar objective as blocked designs without forcing strict equality. They therefore preserve much of the unpredictability associated with simple randomisation. Biased-coin designs alter the allocation ratio during the course of the trial to rectify imbalances that might be occurring.231 Adaptive biased-coin designs, such as the urn design, vary allocation ratios based on the magnitude of the imbalance. However, these approaches are used infrequently.
Stratified randomisation
Stratification is used to ensure good balance of participant characteristics in each group. Without stratification, study groups may not be well matched for baseline characteristics, such as age and stage of disease, especially in small trials. Such imbalances can be avoided without sacrificing the advantages of randomisation. Stratified randomisation is achieved by performing a separate randomisation procedure within each of two or more strata of participants (e.g., categories of age or baseline disease severity), ensuring that the numbers of participants receiving each intervention are closely balanced within each stratum. Stratification requires some form of restriction (e.g., blocking within strata) in order to be effective. The number of strata should be limited to avoid over-stratification.234 Stratification by centre is common in multicentre trials.
Minimisation
Minimisation assures similar distribution of selected participant factors between study groups.230;235 Randomisation lists are not set up in advance. The first participant is truly randomly allocated; for each subsequent participant, the treatment allocation that minimises the imbalance on the selected factors between groups at that time is identified. That allocation may then be used, or a choice may be made at random with a heavy weighting in favour of the intervention that would minimise imbalance (for example, with a probability of 0.8). The use of a random component is generally preferable.236 Minimisation has the advantage of making small groups closely similar in terms of participant characteristics at all stages of the trial.
Minimisation offers the only acceptable alternative to randomisation, and some have argued that it is superior.237 On the other hand, minimisation lacks the theoretical basis for eliminating bias on all known and unknown factors. Nevertheless, in general, trials that use minimisation are considered methodologically equivalent to randomised trials, even when a random element is not incorporated. For SPIRIT, minimisation is considered a restricted randomisation approach without any judgment as to whether it is superior or inferior compared to other restricted randomisation approaches.
Box 3: Need for a separate document to describe restricted randomisation
If some type of restricted randomisation approach is to be used, in particular blocked randomisation or minimisation, then the knowledge of the specific details could lead to bias.238;239 For example, if the trial protocol for a two arm, parallel group trial with a 1:1 allocation ratio states that blocked randomisation will be used and the block size will be six, then trial implementers know that the intervention assignments will balance every six participants. Thus, if intervention assignments become known after assignment, knowing the block size will allow trial implementers to predict when equality of the sample sizes will arise. A sequence can be discerned from the pattern of past assignments and then some future assignments could be accurately predicted. For example, if part of a sequence contained two “As” and three “Bs,” trial implementers would know the last assignment in the sequence would be an “A.” If the first three assignments in a sequence contained three “As,” trial implementers would know the last three assignments in that sequence would be three “Bs.” Selection bias could result, regardless of the effectiveness of allocation concealment (Item 16b).
Of course, this is mainly a problem in open label trials, where everyone becomes aware of the intervention after assignment. It can also be a problem in trials where everyone is supposedly blinded (masked), but the blinding is ineffective or the intervention harms provide clues such that treatments can be guessed.
We recommend that trial investigators do not provide full details of a restricted randomisation scheme (including minimisation) in the trial protocol. Knowledge of these details might undermine randomisation by facilitating deciphering of the allocation sequence. Instead, this specific information should be provided in a separate document with restricted access. However, simple randomisation procedures could be reported in detail in the protocol, because simple randomisation is totally unpredictable.
