Design and Analysis of Clinical Trials...Treatment Allocation and Randomization.. Lesson 8

Lesson 8: Treatment Allocation and Randomization
Introduction

Treatment allocation in a clinical trial can be randomized or nonrandomized. Nonrandomized schemes, such as investigator-selected treatment assignments, are susceptible to large biases. Even nonrandomized schemes that are systematic, such as alternating treatments, are susceptible to discovery and could lead to bias. Obviously, to reduce biases, we prefer randomized schemes. Credibility requires that the allocation process be non-discoverable. The investigator should not know what the treatment will be assigned until the patient has been determined as eligible. Even using envelopes with the treatment assignment sealed inside are prone to discovery.

Randomized schemes for treatment allocation are preferable in most circumstances. When choosing an allocation scheme for a clinical trial, there are three technical considerations:

1. reducing bias;
2. producing a balanced comparison;
3. quantifying errors attributable to chance.

Randomization procedures provide the best opportunity for achieving these objectives.

Learning objectives & outcomes

Upon completion of this lesson, you should be able to do the following:

• Identify three benefits of randomization
• Distinguish simple randomization from constrained randomization.
• State the purpose of randomization in permuted blocks.
• State the objective of stratified randomization.
• Contrast the benefits of permuted blocks to those of adaptive randomization schemes.
• Use a SAS program to produce a permuted blocks randomization plan.
• Use an allocation ratio that will maximize statistical power in the situation where greater variability is expected in one treatment group than the other.
• Provide the rationale against randomizing prior to informed consent.

8.1 - Randomization

In some early clinical trials, randomization was performed by constructing two balanced groups of patients and then randomly assigning the two groups to the two treatment groups. This is not always practical as most trials do not have all the patients recruited on day one of the study. Most clinical trials today invoke a procedure in which individual patients, upon entering the study, are randomized to treatment.

• Randomization is effective in reducing bias because it guarantees that treatment assignment will not be based on patient's prognostic factors. Thus, investigators cannot favor one treatment group over another by assigning patients with better prognoses to it, either knowingly or unknowingly. Procedure selection bias has been documented to have a very strong effect on outcome variables.
  Another benefit of randomization which might not be as obvious is that it typically prevents confounding of the treatment effects with other prognostic variables. Some of these factors may or may not be known. The investigator usually does not have a complete picture of all the potential prognostic variables, but randomization tends to balance the treatment groups with respect to the prognostic variables.
  Some researchers argue against randomization because it is possible to conduct a statistical analysis, e.g., analysis of covariance (ANCOVA), that adjusts for the prognostic variables. It always is best, however, to prevent a problem rather than adjust for it later. In addition, ANCOVA does not necessarily resolve the problem satisfactorily because the investigator may be unaware of certain prognostic variables and because it assumes a specific statistical model that may not be correct.
  Although randomization provides great benefit in clinical trials, there are certain methodological problems and biases that it cannot prevent. One example where randomization has little, if any, impact is external validity in a trial that has imposed very restrictive eligibility criteria. Another example occurs with respect to assessment bias, which treatment masking and other design features can minimize. For instance, when a patient is asked "how do you feel?" or "how bad is your pain?" to describe their condition the measurement bias is introduced.

  Simple Randomization

  The most popular form of randomization is simple randomization. In this situation, a patient is assigned a treatment without any regard for previous assignments. This is similar to flipping a coin - the same chance regardless of what happened in the previous coin flip. Here is an animation of this process. Notice that each time, once treatment A or B is selected, the selection process begins again starting with the two treatment possibilities.

One problem with simple randomization is the small probability of assigning the same number of subjects to each treatment group. Severe imbalance in the numbers assigned to each treatment is a critical issue with small sample sizes.

Another disadvantage of simple randomization is that it can lead to imbalance among the treatment groups with respect to prognostic variables that affect the outcome variables.

For example, suppose disease severity in a trial is designated as mild, moderate, and severe. Suppose that simple randomization to treatment groups A and B is applied. The following table illustrates what possibly could occur.

Severity	Group A	Group B
Mild	17	28
Moderate	41	39
Severe	25	13

The moderate is fairly well balanced, the mild and severe groups are much more imbalanced. This results in Group A getting more of the severe cases and Group B more of the mild cases.