Randomization

Aim

To formulate quality requirements for randomization.

Requirements
  • Randomization sequence must be generated adequately.
  • Allocation to treatment must be concealed.
  • Randomization and allocation performed by an independent researcher.
  • Clear documentation of the randomization procedure.
  • Proof that the randomization procedure has been checked on success.
  • Corrected analyses for confounding when randomization did not result in equal groups with respect to relevant characteristics.
Documentation

Clear description of the randomization procedure, including randomization check and (possible existing) confounders in research protocol or logbook.

Responsibilities

Executing researcher: Follow the steps to ensure random allocation to treatment groups for subjects:

  • Define randomization method;
  • Specify who, when and how the randomization procedure will do/take place;
  • Ask supervisor for checking the randomization procedure;
  • Ask independent individual to perform randomization;
  • Never change sequence allocation of subjects;
  • Save allocation;
  • Consider whether blinding can be realized.

Project leaders:

  • Check the randomization procedure;
  • Determine whether blinding can be realized.

Research assistant: N.a.

How To

Randomization is an important aspect of randomized clinical trials (RCTs). Allocation to treatment groups has to occur truly at random. Randomization has three major advantages: 1) it eliminates selection bias, 2) it permits the use of probability theory to express the likelihood that any difference in outcome between intervention groups merely reflects chance, 3) it can facilitate blinding the identity of treatments to the investigators, participants, and evaluators.

When considering randomization, you have to make a decision about (1) unit of randomization (individual level or cluster randomization), (2) allocation ratio (1:1 or different), (3) the use of blocks (fixed number or random number), and (4) possible stratification.

Sequence generation

Authors should specify the method of sequence generation, such as using a random-number table or using a computerized random number generator. You can download random allocation software. 

There are different types of randomization, see also the CONSORT statement:

1) Simple randomizationFor this type of randomization no restrictions apply, participants are purely randomly assigned to each treatment group for every assignment. Simple randomization is analogous to a coin toss.

2) Block Randomization
Block randomization is a form of restricted randomization and ensures that the number of subjects is (almost) always the same for each group. For instance, in a block of four (or eight, sixteen) there will be two (or four, eight) subjects allocated to the control group and two (or four, eight) to the treatment group. However, the disadvantage is that it is easier to guess what the next randomization outcome will be (in a block of 4 you always know what the 4th outcome is). To overcome this, you may use random block sizes, where the next block is randomly chosen from the available block sizes. Block sizes must be multiples of the number of treatments and take the allocation ratio into account. For 1:1 randomization of 2 groups, blocks can be size 2, 4, 6 etc. For 1:1:1 randomization of 3 groups or 2:1 randomization of 2 groups, blocks can be size 3, 6, 9 etc.

3) Stratified randomization
Randomization is intended to minimalize the effect of confounders (Pocock) since you expect those possible confounders to be distributed equally between the groups. However, by accident the distribution may turn out not to be equal. You can use stratification to solve this. This means that you randomize within certain groups (e.g. males and females or center A and B in multicenter trials) and thus ensure that the variable (gender) is distributed equally. Stratifying becomes more important when there are strong confounders or when the study group is small. Stratification requires some form of restriction (such as blocking within strata). Stratification without block randomization is ineffective.

Another way to deal with possible confounders, is to check after randomization if the ‘baseline statistics’ (age, sex, etc.), are distributed equally across study groups. When this is not the case, it is necessary to correct for the confounders by including them as variables in the analysis. To be able to correct for the appropriate confounders, these need to be recorded during the study.

Concealment of allocation

Allocation to treatment must be concealed, if possible. This means that the person who includes a patient in a trial is not aware in advance what the next randomization outcome will be. There are several methods to achieve this, e.g. by using sealed envelopes, by asking a colleague to perform the actual allocation, or by using a trial service (e.g. https://www.sealedenvelope.com).

The following next steps will help you to ensure random allocation to treatment groups:

  • Use the CONSORT statement to decide which randomization method fits best within your research;
  • Specify in your protocol who, when and how your randomization and allocation procedure will do/take place;
  • Ask you supervisor to check your randomization procedure;
  • Ask an individual who is not involved in the project, and is blind for characteristics of the subjects, to perform the randomization (and allocation);
  • Never change the sequence of allocated subjects;
  • Save the randomization list (in a sealed envelope, safely stored) and use your logbook to note the date of randomization;
  • Think about whether blinding of researchers and subjects for conditions can be realized.