Clinical Trial Randomization
Clinical trial randomization is a study methodology that assigns participants to treatment groups by chance rather than by the choice of someone involved with the program (e.g., doctor, patient, study sponsor). Randomization in clinical trials is usually performed using computers to randomly allocate a sample of the population of interest. This ensures that each participant has the same opportunity to be assigned to any given group.
Also referred to as randomized controlled trials or randomization in clinical trials, this method is considered the most rigorous for hypothesis testing and the gold standard for effectively evaluating a treatment. It removes any element of human choice in the assignment of participants.
With randomization in clinical trials, apart from the interventions being compared, the groups are treated and observed in an identical manner. Because of this, differences in outcomes can be attributed to the intervention that is being studied.
Objectives of Randomization in Clinical Trials
Randomization in clinical trials aims to assess a treatment’s performance by making a fair comparison between:
- A new treatment and an existing treatment
- Two (or more) existing treatments
- A new treatment and no treatment, or a placebo
The outcomes of a randomized controlled trial can determine if:
- A treatment is better than another—superiority
- A treatment is no worse than an existing one—non-inferiority
- Two treatments are the same—equivalence
How Randomization in Clinical Trials Works
Multiple groups can be selected for a clinical trial, but the following is an example based on two groups. In this case, the two groups are the investigational group (receives the new treatment being studied) and the control group (receives the current standard treatment, which might be the best existing treatment, no treatment, or a placebo).
Throughout the study, the participants are closely monitored. Data about the safety, efficacy, effectiveness, and potential side effects are gathered and measured. Results from participants in the different groups are compared.
These results are reliable due to randomization; if a person chose which treatment a patient should receive as part of the trial, they might provide the preferable treatment to participants based on their age or degree of illness. This could influence the effects of the treatment, thereby making the study results unreliable.
Features of Randomization in Clinical Trials
- Uniform selection criteria for participants
- Random assignment of participants between intervention groups
- Identical treatment of all participants except for the treatment being used
- Similar size for each group
- Participants share similar attributes
- When feasible, neither researchers nor participants know which treatment was given (double-blind studies)
Participant Selection for Randomization in Clinical Trials
Choosing study participants should be based on specific criteria that ensure similarity between participants as related to the study’s focus. Randomization in clinical trials helps prevent selection bias by distributing the characteristics of patients that may influence the outcome randomly between the groups.
Randomization also balances differences between participants that might impact outcomes, such as age, sex, disease activity, and duration of disease. This helps researchers, because they can attribute differences in outcomes to the treatment and not differences in the participants.
The First Randomized Controlled Trial
The 1948 Medical Research Council Streptomycin Trial in England is thought to be the first recorded instance of randomization in clinical trials. A new drug was being considered as a treatment for tuberculosis. However, doses were limited, and resources to support a wide-scale treatment program were scarce due to the post-war depression.
There were ethical concerns about how to test the effectiveness of the drug. It was decided that the only fair way to distribute the drug was through randomization. This way, the data gathered would be of high quality, making it more valuable. If the drug performed well, it would be easier to make a case to support its use on a broader basis.
Not only did the drug prove to be effective, but the randomized clinical trial process also radically changed how medical treatments were evaluated. Randomization in clinical trials became standard practice.
Randomization and Bias in Clinical Trials
Randomization in clinical trials minimizes bias. Bias in clinical trials can negatively affect results by resulting in exaggerated or hidden effects of the treatment. Whether through conscious human choices or less direct factors, bias is inherent in human selections.
For example, the severity of symptoms or age would be difficult for a physician to completely ignore if they were assigning someone to a clinical trial group where they knew which subjects were receiving a placebo. Using randomization to assign participants to groups allows researchers to compare treatments or interventions more fairly and with higher quality data.
FDA on Randomization in Clinical Trials
“Assurance that subject populations are similar in test and control groups is best attained by randomly dividing a single sample population into groups that receive the test or control treatments. Randomization avoids systematic differences between groups with respect to known or unknown baseline variables that could affect outcome.”
FDA Guidance for Industry
E 10 Choice of Control Group and Related Issues in Clinical Trials
Considerations for Clinical Trial Randomization to Prevent Bias
- Use an interactive response technology (IRT) system
- Automates randomization using complex algorithms or trial-specific adaptive randomization
- Prevents unblinding
- Eliminates human error
- Provides an audit trail
- Ensures data integrity
- Allows for fast emergency unblinding
- Offers ability to assign permissions to access blinded data based on user credentials
- Assign an appropriate group size in the randomization
- Ensures well-balanced assignments
- Avoid the risk of unblinding
- Decrease treatment imbalance
- Maintain detailed audit trails
- Avoid approval delays
- Ensure regulatory compliance
- Maintain records of the group
- Limit stratification factors and associated levels to maintain statistical significance
Types of Randomization
Randomization in clinical trials can be conducted in several ways. Clinical trial randomization approaches are selected based on the study’s intent and desired features. Common types of randomization in clinical trials include the following.
With simple randomization in clinical trials, each participant has an equal chance of being assigned to one of the groups. Simple randomization in clinical trials is equivalent to tossing a coin for each participant. For example, Heads = Active, Tails = Placebo.
In reality, a random number generator ensures that treatment assignment is entirely unpredictable and random. Simple randomization is best used in larger studies, because there is a higher likelihood of groups being balanced—in terms of numbers in each group and characteristics.
With smaller studies, there is a greater chance of imbalanced groups, which reduces statistical power. For instance, a trial with 10 participants could be split 5-5 or 7-3, or have a disproportionate number of participants with certain criteria (e.g., gender, age).
Block randomization goes a step further than simple randomization. Participants are randomly separated into a number of “blocks” of equal size. Then, each block is assigned a different treatment protocol. With block randomization, there are more opportunities to compare and contrast the results from participants, because there are multiple smaller sample sizes instead of one large sample size (e.g., two groups—active and placebo).
For example, participants assigned to blocks of four for two treatment plans (A and B) will lead to six possible arrangements of two As and two Bs (blocks). It could look like this: AABB BBAA ABAB BABA ABBA BAAB. A random number sequence is used to assign participants to blocks and determine the order.
Participants are divided into groups based on specified criteria, such as age, race, gender, or diagnosis with the stratified randomization method. Then, the participants are assigned to subgroups based on the treatment plan by applying simple or block randomization. This process ensures that sample groups do not overlap and that the results are representative of the sample population’s response to treatment.
With stratified randomization, the number of groups should be relatively small to maintain balance in each group and have a statistically valid number of participants. Increasing the stratification variables or the levels within strata leads to fewer patients per group.
Although randomization in clinical trials mostly allocates equal numbers of patients in each group, there are scenarios when it makes sense to have more in one group or the other—unequal randomization. This method is often used when equal randomization is not feasible for economic or ethical reasons.
An example of unequal randomization in a clinical trial is giving fewer participants the expensive treatment and more the alternative. Using a randomization ratio of 2:1 could represent significant savings with minimal loss in statistical significance.
Another example is for trials where the treatment could save lives. In this case, a more extreme ratio would be used for the unequal randomization, such as 3:1. To offset the significant loss of statistical power, the sample size would be increased.
With adaptive randomization, the probability of treatment assignment changes as the clinical trial progresses. Adaptive randomization utilizes results accumulated in the trial to modify the trial’s course in accordance with pre-specified rules. As more effective treatments are identified, more participants are moved to those groups.
Allocation concealment is a technique that is used to help prevent selection bias by ensuring that no one can influence what group a participant is assigned to during the randomization process. The process for assignments is made totally opaque to prevent researchers, physicians, or patients from influencing assignments.
To prevent perceptions of the advantages of one treatment over another, blinding is used to hide details about the treatment options. There are several ways to perform blinding:
- Single-blind—only hide information from the participant
- Double-blind—withhold information from both the participant and the data collectors (e.g., healthcare professional, investigators)
- Triple-blind—information is withheld from everyone in the study—participants, data collectors, and data evaluators (e.g., statisticians)
Randomization and Ethics
Randomization in clinical trials is awash in ethical challenges that warrant careful consideration by clinical study teams. Generally, the problems stem from the issue of some participants potentially benefiting from a clinical trial, while others have the burden and potential risk of the trial.
In some cases, participants are exposed to adverse effects from a new treatment. In others, participants receive no treatment. From an ethical standpoint, the potential benefits to participants do not offset the risks, because the objective of the clinical trial is to produce data about the results of each scenario.
Blinding and randomization in clinical trials conflict with the inherent interests of the participants. One reason is that they are unable to make their treatment decisions, although they do explicitly consent to this as clinical trial participants.
Another ethical concern related to randomization in clinical trials is that participants have a chance of receiving an inferior treatment or one that could have adverse effects. In this case, randomization harms the participants by potentially denying them the best standard of care available.
However, the prevailing view is that genuine uncertainty regarding the comparative therapeutic merits of each arm of the trial (i.e., equipoise) relieves the trial investigators of some ethical burden. In this situation, randomization in clinical trials is not considered harmful, because it gives participants a fair chance at equally valuable treatments.
In addition, for studies where there is the chance that patients will be exposed to less effective treatments, unequal randomization or adaptive randomization methods are used. This minimizes the chance that participants are exposed to the less effective treatment, as they are randomly moved to the larger group when a treatment is proven more effective.
Navigating Research Objectives and Ethics
Any clinical trial must navigate a tight path between exploitation and ethical research. The research objective of clinical trials is to produce the highest quality data possible by safely testing and collecting information about participants’ responses to treatment protocols.
Clinical trials must also address ethical issues. Randomization in clinical trials eliminates potential contamination or degradation of the participant groups, which helps with data quality and with ethics by removing the risk of selection bias.
The importance of randomization in clinical trials cannot be overemphasized. It is widely agreed that randomization compromise (e.g., poor allocation concealment) of a clinical trial can be more damaging than an explicitly non-randomized study. Randomization in clinical trials is the most rigorous way of assessing whether a cause-effect relation exists between treatment and outcome.
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Last Updated: 18th December, 2021