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Practical Issues in Trial Design


Part 8: Methods of Randomization in Clinical Trials
Randomization is the unpredictable allocation of a patient to a particular treatment strategy in a clinical trial. When a large number of patients are involved, simple randomization will balance the groups in a trial for patient characteristics and other factors that might bias outcomes. The remaining differences in efficacy or safety outcomes between the groups can then be assumed to be due to the effects of the different treatment strategies. Randomization is therefore the cornerstone of a well-conducted clinical trial.
Why should patients in a clinical trial be randomized?
The randomized controlled trial (RCT) is considered the gold standard for testing the efficacy of medical treatments. A fundamental assumption that forms the basis of the RCT is that patients in different groups are similar for characteristics such as age, gender, social class, time of year of presentation, country of presentation and type of hospital. In a large trial involving more than 1000 patients, these characteristics should be balanced across each group so that any difference seen between the groups at the end of the trial is then due to the different treatment strategies, i.e. if patients do better in one group we can assume that this is due to the treatment effect. This assumption is the basis of all comparative statistical tests performed in the trial. To achieve this balance we randomly assign the patients (hence the term randomized in an RCT) to each treatment strategy so that, for example, men have an equal chance of being given treatment A or B, people aged over 60 have an equal chance of being given treatment A or B, and so on. Simple randomization is one way of performing this balancing function, but other methods are needed when the number of patients is small.

Minimizing bias
A further requirement of randomization is that it must not be predictable by the person assigning patients to the treatment strategies, otherwise there is a chance that the groups will contain bias. To prevent this, certain methods of blinding or masking are used so that patients and staff (with the exception of the data and safety monitoring committee) are not aware whether treatment A or B is the new treatment, or even which group patients are in (active or placebo/ standard treatment), until the end of the trial. Physicians and study coordinators providing the treatments to the patients use a randomization code to find out which treatment pack has been assigned to each patient (A or B), but the code provides no information about which treatment is which (active or placebo/standard treatment). Randomization must be protected by masking (methods of which will be discussed next month) so that it remains unpredictable.

Duolao Wang and Ameet Bakhai*, London School of Hygiene and Tropical Medicine
and *Royal Brompton Hospital, London, UK Dr Duolao Wang is a lecturer at the Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK, and a statistical consultant to the Clinical Trials and Evaluation Unit (CTEU) at the Royal Brompton Hospital in London, UK. He has been a trial statistician for 20 clinical trials and has published extensively in other peerreviewed journals. He is currently involved in the Wellcome-funded project Developing methodology to take account of treatment changes in the analysis of randomized clinical trials. Dr Ameet Bakhai is a cardiology specialist registrar and senior research fellow in the CTEU at the Royal Brompton Hospital in London, UK. He is currently evaluating the clinical and economic impact of acute coronary syndromes and is director of an interventional study looking at the use of specially coated stents in small coronary arteries of subjects with coronary artery disease. His main interests lie in well-designed and carefully conducted registries and trials that improve the standards of care for all subjects.

How should the randomization code be determined?


A randomization code is a list of which treatment a subject should receive. It is usually determined by a statistician using

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computer-generated random numbers or a random-number table. Some trials use methods for assigning subjects according to date of birth (odd or even years), hospital record number or date of screening for the study (odd or even days), but these randomization methods have a level of predictability so strictly are not acceptable methods of randomization.

While simple randomization is unpredictable and easy to implement, it can often produce small inequalities between treatment groups
unpredictable. However, as it is somewhat inconsiderate to previous allocations, it can often produce small inequalities between treatment groups, e.g. if 200 women were assigned to treatment A and 205 women to treatment B. In a large trial this makes only a small difference, but in smaller trials at an early clinical stage that involve only a few dozen subjects, these inequalities could have a substantial impact. Example Consider an example trial with 12 patients. While there is an equal chance of being allocated treatment A or treatment B, the number of subjects randomly assigned to each treatment ends up being 5 and 7, respectively (Table 1). This imbalance in the initial allocation results in significant difficulties in the statistics and possibly a lower power for detecting differences between the treatments. Therefore, in cases where there are few patients, there is a need for other methods of randomization.

Which are the common randomization methods?


The generation of a randomization code can be achieved using one of a variety of procedures. Once a code and method of allocation are decided on, their rules must be adhered to throughout the study. Common types of randomization methods are: Simple randomization Permuted-block randomization Stratified randomization Minimization or adaptive randomization A combination of these methods can also be used, and other special methods do exist. Let us now discuss the more common randomization methods listed above.

Example Consider a clinical trial comparing treatments A and B in 24 patients. Here, we should choose a block size of 4 because the sequence would become predictable with blocks of 2, and block sizes of 6 or above are too large for this small sample size. Using this size we must ensure that, after every fourth randomized subject, the number of subjects in each arm is equal. Therefore, each block must contain two patients on treatment A and two on treatment B. Step 1: Given a sample size of 24 and using a block size of 4, we need six blocks Step 2: There are six possible permutations that allow 2 As and 2 Bs in each box: AABB, ABAB, ABBA, BAAB, BABA and BBAA Step 3: The randomization code for blocks can be generated by producing a random-number list for permutations 16 Table 2 provides a listing of random permutations of A and B for each subject using this method. Note that after every four patients there is a balance of subjects
Table 2. Example of block randomization using a block size of 4. Block 1 Permutation 6 Subject 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Treatment B B A A B A A B A B B A A A B B A B A B B A B A

Simple randomization
The most common form of randomization, referred to as simple or complete randomization, is a procedure that makes each new treatment allocation without regard to those already made. The principle of this method for a trial with two treatments can be demonstrated by deciding treatment assignment by tossing an unbiased coin, e.g. heads for treatment A and tails for treatment B. When the next subject is to be assigned, previous allocations are not considered. This method is easy to implement and
Table 1. Example of simple randomization.

Block randomization
The block randomization method, also known as permuted-block randomization, is a popular method in clinical trials. A block randomization method can be used to periodically enforce a balance in the number of patients assigned to each treatment. The size of each block of allocations must be an integer multiple of the number of treatment groups, so with two treatment strategies the block size can be either 2, 4, 6, and so on. A block randomization can be implemented in three steps: Step 1: Choose the block size and the number of blocks needed to cover the number of patients in the study Step 2: List all possible permutations of treatments in a block Step 3: Generate a randomization code for the order in which to select each block
2 4

Subject
1 2 3 4 5 6 7 8 9 10 11 12

Treatment
A B A A B B B B A A B B

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between treatments A and B. If we need more than six blocks (or have >24 patients), we can continue sampling more of the six possible block permutations shown above. The procedure is repeated until all patients are randomized. The balance forced by blocking is especially important in long-term trials if: Recruitment is slow The type of patients recruited in the trial changes during enrollment period The trial should be stopped early for safety or efficacy reasons Routine practice changes for patients in both groups during the trial The only disadvantage of blocking is that every fourth patient, and occasionally every third patient (when the sequence is AABB or BBAA), becomes predictable if the treatments are not masked and the previous allocations of that block are known.

Stratified randomization
Stratified randomization takes the balance correction suggested by blocking one step further. Not only are the numbers with treatments A and B balanced periodically, but a balance is also constantly maintained for a set of predetermined important factors that may impact on the prognosis of the patient, such as age, gender, diabetes, severity of illness or geography. If prognostic factors are not evenly distributed between treatment groups it can give the investigator cause for concern, although statistical methods, such as the Cox regression model, are available that allow for such a lack of comparability. Stratified randomization is implemented in three steps. We can illustrate the procedures using the CF-WISE (Withdrawal of Inhaled Steroids Evaluation Study in Patients with Cystic Fibrosis) trial currently being conducted at the Clinical Trials and Evaluation Unit of the Royal Brompton Hospital, London, UK. The CF-WISE study

is a randomized placebo-controlled trial designed to test the feasibility and safety of withdrawing inhaled corticosteroids (ICS) in 240 children and adults with cystic fibrosis who are already taking ICS. The two treatment strategies involve a return to either ICS treatment after withdrawal (A) or to placebo (B). The primary endpoint is the time to first respiratory exacerbation. Example Step 1: Choose the prognostic factors that could impact on the primary endpoint Experience of earlier trials and literature show that atopy, forced expiratory volume within 1 second (FEV1) and age are the most important determinants of time to first respiratory exacerbation. Step 2: Determine the number of strata for each factor When several prognostic factors are chosen, a stratum for randomization is formed by selecting one subgroup for each factor (continuous variables such as age are split into meaningful categorical ranges). The total number of strata is therefore the product of the number of subgroups in each factor. Table 3 describes the strata for stratified randomization in the CF-WISE study. In this example, the total number of strata is 2 (atopy) 3 (FEV1) 2 (age) = 12.
Table 3. Strata definitions for the CF-WISE study.
Stratum Atopy FEV1

Step 3: Generate randomization codes This is done by generating a randomization list for each stratum and then combining all the lists. Within each stratum, the randomization process itself could be simple randomization, but in practice most clinical trials use a blocked randomization method. In our example, three blocks of size 4 are shown for stratum 1. The key with this method is to choose the most important prognostic factors and keep the number of strata to a minimum so that randomization using blocks remains unpredictable.

Minimization
Minimizationalso called an adaptive randomization proceduretakes the approach of assigning subjects to treatments in order to minimize the differences between the treatment groups on selected prognostic factors. This method starts with a simple randomization method (the first of our examples) for the first several subjects, and then adjusts the chance of allocating a new patient to a particular treatment based on existing imbalances in those prognostic factors. Using minimization with the CF-WISE study as an example, if treatment A has more atopy-positive patients than atopynegative patients, then the allocation scheme is such that the next few atopy-

Age

Randomization

1 2 3 4 5 6 7 8 9 10 11 12

Positive Positive Positive Positive Positive Positive Negative Negative Negative Negative Negative Negative

4060% 4060% 6180% 6180% 81100% 81100% 4060% 4060% 6180% 6180% 81100% 81100%

<17 ! 17 <17 ! 17 <17 ! 17 <17 ! 17 <17 ! 17 <17 ! 17

ABAB, BABA, AABB...

Stratified randomization not only balances patient numbers but also maintains an even distribution of prognostic factors across the arms of a trial
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CF-WISE = Withdrawal of Inhaled Steroids Evaluation Study in Patients with Cystic Fibrosis

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Table 4. Treatment assignments based on three prognostic factors for 100 patients. Factor Atopy FEV1 Level Positive Negative 4060% 6180% 81100% <17 ! 17 Treatment A 22 28 19 20 11 25 25 Treatment B 21 29 18 21 11 26 24 Subtotal 43 57 37 41 22 51 49 Total

Concluding remarks
Several commonly used methods of randomization have been described here, but there are many others. Whichever method is used, the purpose of randomization remains the same: to validate the assumption that the differences seen in the outcomes are likely due to differences in the treatments. Acknowledgement We would like to thank Dr Belinda Lees (CTEU) and the CF-WISE team for material from the CF-WISE clinical study and for editorial suggestions.

100

100 100

Age

FEV1 = forced expiratory volume within 1 second

positive patients are more likely to be randomized to treatment B. This method is employed in situations involving many prognostic factors, and patient allocation is then based on the aim of balancing the subtotals for each level of each factor. Example Table 4 shows a hypothetical distribution of 100 patients according to treatment and three prognostic factors in the CF-WISE study. Consider that the next patient is atopy positive, has an FEV1 <60% and is aged 15 years old. To find the number of similar patients already assigned to each treatment arm, the patients in the corresponding three rows of Table 4 are added:

Sum for A = 22 + 19 + 25 = 66 Sum for B = 21 + 18 + 26 = 65 Minimization requires that the patient be given the treatment with the smallest marginal total, which in this case is treatment B. If the sums for A and B are equal, then simple randomization would be used to assign the treatment. Although this method is mathematically uncomplicated, it has not been widely used because of the practical difficulties associated with implementing it. However, with increasing use of computers and, more recently, interactive voice-response systems, this method is gaining popularity, particularly in large trials, thereby removing the need for pre-specified randomization lists.

Further reading
Pocock SJ. Clinical Trials: A Practical Approach. New York: John Wiley, 1983. Chow SC, Liu JP . Design and Analysis of Clinical Trials: Concepts and Methodologies. New York: John Wiley, 1998.

Next month:
Methods of masking

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