The third in a series of papers on statistics for clinical trials, published Dec. 14 in the Journal of the American College of Cardiology, offers advice on the fundamentals of design for major randomized controlled trials. Topics covered include the choice of patients, choice of treatment and control groups, choice of primary and secondary endpoints, methods of randomization, appropriate use of blinding, and determination of trial size.

Stuart J. Pocock, PhD, et al., contend that when trial design pitfalls occur, they can have a negative impact on the reliability of the trial’s results. To avoid these hazards, the authors identify key fundamentals that determine whether a trial’s design is up to standard.

They explain that precise patient selection criteria – neither too broad nor too specific – are critical to ensuring successful recruitment while retaining the ability to identify a treatment effect in a specific population. The authors recommend performing large-scale, multicenter trials whenever possible, choosing appropriate geographic representation and using power calculations to determine required trial size.

The authors advise that precision also is necessary when choosing treatments and control groups. Depending on a number of circumstances, a trial may be best suited to a placebo control group, an active comparator or even a three-arm trial. Investigators must also consider whether or not a run-in period is necessary.

Pocock, et al., explain that defining a trial’s primary and secondary outcomes can present a number of challenges. They add that the events that should contribute to a composite primary endpoint depend on the disease and treatments being studied.

The paper also discusses the fundamental practices for randomization and blinding. Asserting that allocation concealment is crucial, the authors suggest three key elements to setting up and delivering random allocation of patients to treatments. In addition, they emphasize the importance of double-blinding, stating that it is “the optimal way to ensure that any potential influence that awareness of treatment might have on patient perceptions, patient management, and evaluation of endpoints is avoided.”

The authors provide detailed tables outlining the key issues regarding composite endpoints and randomization methods, as well as a central illustration of the fundamentals of design of major randomized controlled trials. The paper closes with a list of the essential elements of designing a worthwhile investigation. 

Keywords: Disease Management

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