Randomization and elements of randomization specifications

Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments to reduce bias. Randomization is the most critical feature of the RCT (randomized, controlled trials). In FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications, the randomization is defined as the following: 

In the context of clinical trial design, randomization is defined as the allocation of patients to the investigational drug and control arms by chance. Randomization is intended to prevent any systematic difference between patients assigned to the treatments being compared and is a critical assumption for valid statistical comparisons. It is also intended to produce groups that are comparable (statistically balanced) with respect to both known and unknown factors. 

Randomization Schedule (also called a randomization scheme) is a list of randomization numbers and the corresponding treatment assignments in a data set (or in a printout in the early days). Randomization Schedule can be generated using SAS Proc Plan. A SUGI paper"Generating Randomization Schedules Using SAS Programming" I wrote 20 years ago is still applicable. 

Three steps for generating the randomization schedule for use in clinical trials: 

• Create randomization specifications according to the study protocol requirements
• Create and validate dummy randomization schedule for review and approval
• Create and validate the final randomization schedule - the final randomization schedule for implementation

The dummy randomization schedule and the final randomization schedule have the same display but are generated with different random seeds (therefore different treatment assignments). The dummy randomization schedule can be reviewed by the study team and the final randomization schedule can only be distributed to the designated recipients who are unblinded to the treatment assignments. 

Here is an example randomization specification: 

Here are the elements for the randomization specifications: 

Study Design: clinical trial design dictates how the subjects are assigned to receive different study treatments. In clinical trials with parallel design, subjects are randomized to receive the treatments; in clinical trials with cross-over design, subjects are randomized to different treatment sequences. 

The study design will also include a randomization strategy: 

Fixed randomization: 

• fixed-randomization scheme (rarely used)
• block randomization
• stratified randomization, 

Dynamic randomization: 

       Adaptive randomization. 

See FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications for definitions of these different types of randomizations. 

Blind and blindness: concealing treatment assignments and treatment allocations. 

Block: Block randomization works by randomizing subjects within blocks such that within each block, the # of subjects is balanced between treatment groups or according to the randomization ratio. 

Block Size: The size of each block. 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 sizes 2, 4, 6 etc. For 1:1:1 randomization of 3 groups or 2:1 randomization of 2 groups, blocks can be sizes 3, 6, 9 etc. 

If the randomization is by site, to prevent the potential unblinding/guessing, the block size can be set up as variable for different blocks or is not revealed to the investigators and study team. With central randomization, potential unblinding is less of a concern and the block size can be the smallest multiples (for 1:1 randomization of 2 groups, the block size can be 2). 

Number of Blocks

Total Number of Randomizations: Total number of randomization numbers to be generated. Total number of randomizations = Number of blocks x Block size. Usually, randomization numbers more than the protocol-specified sample size are generated to make sure that there is a sufficient number of randomizations in the situation that the sample size may be increased or randomization errors that results in some randomization numbers not being used. If the study protocol specifies 300 subjects to be randomized, it may be good to generate 600 randomizations. 

Strata and Stratification Factors: Stratification factors are those known factors that may have an impact on treatment responses. Stratification factors are the known confounders. The most common stratification factor is the baseline disease severity which usually has an impact on the treatment responses. When stratification factors are specified, stratified randomization is employed to prevent imbalance between treatment groups for known factors that influence prognosis or treatment responsiveness. The randomization schedule is essentially generated for each stratum. 

See previous posts "Restricted randomization, stratified randomization, and forced randomization"; "Minimization Algorithm to Achieve Treatment Balance across Strata in Stratified Randomization", and "Handling Randomization Errors in Clinical Trials with Stratified Randomization"

Randomization Ratio (or allocation ratio): The ratio for treatment groups. The typical randomization ratio is balanced: 1:1 ratio for two treatment groups (if the block size is 2, for every 2 subjects randomized, there will be one assigned to group A and one assigned to group B); 1;1:1 ratio for three treatment groups, ... The randomization ratio can also be unbalanced such as 2:1 (if the block size is 3 (minimal), for every three subjects randomized, there will be two assigned to group A and one assigned to group B) and 3:1,...  FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications described the randomization ratio (allocation ratio) as the following: 

Allocation of patients to treatment and control arms can be uniform or nonuniform. Uniform allocation (i.e., equal numbers allocated to each arm) is the usual practice and provides the most statistical power for a given total sample size. Nonuniform allocation  may lower costs (if one arm is substantially more expensive) and improve recruitment (if one arm is generally preferred) and may increase the size of the exposed patient safety database. In general, the loss of statistical power in seeking to detect a difference between treatments going from uniform allocation to 2:1, or even 3:1, is fairly small; however, as more imbalanced allocation occurs, power drops off more rapidly. A special case is where a trial seeks both to show effectiveness versus placebo and to compare the test drug with an active control. In that case, it usually is necessary for the active treatment groups to be substantially larger to examine the smaller differences between the active treatments. 

Randomization Number: a series of sequential numbers corresponding to treatment assignments. 'randomization number' is not random, the associated treatment assignments are random. 

Randomization can be recorded in the database and serve as the subject identifier (same as the subject number). Seeing the randomization number will not unblind the subject's treatment assignment.  

Treatment Code: short description or abbreviation for long treatment descriptions. Treatment code can be just the letters (such as A = Active; P = Placebo). 

Treatment Description: the detailed description of the treatment groups. It can be just 'Active', 'Placebo' or more descriptive as "Inhaled drug X BID', 'Inhaled Placebo BID'.

Dummy Randomization Schedule: also called surrogate randomization schedule - the randomization schedule for review and approval purposes. The dummy randomization schedule should have exactly the same features as the final randomization schedule except that a different random seed is used (therefore, the treatment assignments are different). 

Random Seed: A number (integer) used to initiate a pseudorandom number generator. Random Seed is a number used in SAS Proc Plan to generate the randomization schedule. Random Seed needs to be specified in the program in order to reproduce the same randomization schedule. 

After dummy randomization schedule is reviewed and approved, a final randomization schedule can be generated for implementation by changing the random seed. 

Randomization Envelopes: Envelopes that contain the treatment assignment information. The outside of the envelope contains the randomization number, and the inside of the envelope contains the randomization number and the corresponding treatment assignments and treatment descriptions. Randomization envelopes were used in the randomization process in the early days. The randomization process using randomization envelopes is now replaced with the Interactive Response Technology (IRT) including the Interactive Web Response System (IWRS) or Interactive Voice Response System (IVRS). 

Central Randomization is the opposite of randomization by the site. When a subject is eligible to be randomized, the site will contact a centralized contact (usually the computer system, IRT) to obtain the next available randomization number in the corresponding stratum regardless of the individual sites.

References: SAS/STAT User's Guide The PLAN Procedure