Randomization: The forgotten component of the randomized clinical trial.

Area of Science:

• Biostatistics
• Clinical Trials Methodology
• Statistical Inference

Background:

• Randomization is a cornerstone of clinical trials, introduced by Sir Bradford Hill in 1946.
• Key rationales for randomization include unpredictability of assignments, balancing confounders, and enabling inference.
• The third rationale, randomization as a basis for inference, is often overlooked in contemporary practice.

Purpose of the Study:

• To review historical statistical literature on randomization methods.
• To highlight the often-forgotten inferential basis of randomization.
• To describe simple methods for applying randomization-based inference in clinical trials.

Main Methods:

• Review of historical biostatistics and statistics literature on randomization.
• Description of randomization-based inference techniques.
• Application of methods to various clinical trial outcomes and nonstandard situations.

Main Results:

• Identified three historical rationales for randomization in clinical trials.
• Demonstrated that randomization-based inference is applicable to virtually any trial outcome.
• Provided methods to rectify the oversight of randomization's inferential role.

Conclusions:

• Reemphasizing the inferential power of randomization is crucial for robust clinical trial design.
• Simple methods can integrate randomization-based inference into current trial practices.
• This approach enhances the validity of findings, particularly in complex trial designs.