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Practice Misalignments in Randomized Controlled Trials: Identification, Impact, and Potential Solutions

Katherine J. Deans, MD, MHSc^*, Peter C. Minneci, MD, MHSc^*,, Robert L. Danner, MD, Peter Q. Eichacker, MD, and Charles Natanson, MD

From the *Department of Surgery, The Children's Institute for Surgical Science, The Children's Hospital of Philadelphia; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland.

Address correspondence and reprint requests to Katherine J. Deans, MD, MHSc, Department of Surgery, The Children's Institute for Surgical Science, The Children's Hospital of Philadelphia, Abramson Research Center, Rm 1116, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Address e-mail to deansk{at}email.chop.edu.

Abstract

Appropriate control group selection in a randomized controlled trial (RCT) is a critical factor in generating results, which are both interpretable and generalizable. Control groups ideally encompass and realistically reflect prevailing medical practices. This goal can be challenging in investigations of standard therapies that are routinely titrated. To eliminate the heterogeneity in clinical practice from the trial design, recent investigations of titrated therapies have randomized patients to fixed-dose regimens. Although this approach may produce statistically significant differences, the results may not be interpretable or generalizable.

In this trial design, randomization disrupts the normal relationship between clinically important characteristics and therapy titration, thereby creating subgroups of patients within each study arm that receive levels of therapy inconsistent with current practices outside of the clinical study. These misaligned subgroups may have worse outcomes than usual care. Practice misalignments can occur in any clinical trial of a preexisting therapy that is typically adjusted based on severity of illness or other patient characteristics.

In this study, we review three recent RCTs to demonstrate how practice misalignments can affect the safety, results, and conclusions of RCTs. Furthermore, we discuss methods to prospectively identify potentially important relationships between therapy titration and patient- and disease-specific characteristics. Finally, we review trial design options that may minimize the occurrence and impact of practice misalignments. Because these designs may limit the feasibility of a clinical trial, a thorough characterization of usual care is necessary to determine whether one of these designs should be used to protect patient safety.