title: Assessing protocol adherence in a clinical trial with ordered treatment regimens: Quantifying the pragmatic, randomized optimal platelet and plasma ratios (PROPPR) trial experience.
abstract: BACKGROUND
  Medication dispensing errors are common in clinical trials, and have a significant impact on the quality and validity of a trial. Therefore, the definition, calculation and evaluation of such errors are important for supporting a trial's conclusions. A variety of medication dispensing errors can occur. In this paper, we focus on errors in trials where the intervention includes multiple therapies that must be given in a pre-specified order that varies across treatment arms and varies in duration.
  
  
  METHODS
  The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was a Phase III multi-site, randomized trial to compare the effectiveness and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with a 1:1:2 ratio. In this trial, these three types of blood products were to be transfused in a pre-defined order that differed by treatment arm. In this paper, we present approaches from the PROPPR trial that we used to define and calculate the occurrence of out of order blood transfusion errors. We applied the proposed method to calculate protocol adherence to the specified order of transfusion in each treatment arm.
  
  
  RESULTS
  Using our proposed method, protocol adherence was greater in the 1:1:1 group than in the 1:1:2 group (96% vs 93%) (p<0.0001), although out of order transfusion errors in both groups were low. Final transfusion ratios of plasma to platelets to red blood cells for the 1:1:1 ratio group was 0.93:1.32:1, while the transfusion ratio for the 1:1:2 ratio group was 0.48:0.48:1.
  
  
  CONCLUSIONS
  Overall, PROPPR adherence to blood transfusion order pre-specified in the protocol was high, and the required order of transfusions for the 1:1:2 group was more difficult to achieve. The approaches proposed in this manuscript were useful in evaluating the PROPPR adherence and are potentially useful for other trials where a specific treatment orders with varying durations must be maintained.
authors.affiliation: Department of Biostatistics, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA. Electronic address: hongjian.zhu@uth.tmc.edu.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Center for Translational Injury Research and Division of Acute Care Surgery, Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Fox
authors.affiliation: Department of Biostatistics, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Baraniuk
authors.affiliation: Center for Translational Injury Research and Division of Acute Care Surgery, Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Holcomb
authors.affiliation: Center for Translational Injury Research and Division of Acute Care Surgery, Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wade
authors.affiliation: Center for Translational Injury Research and Division of Acute Care Surgery, Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Del Junco
authors.affiliation: Department of Biostatistics, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Tilley
mesh_terms: D016913:Blood Component Transfusion / Q000009:adverse effects / Q000379:methods*; D001792:Blood Platelets / Q000166:cytology*; D002985:Clinical Protocols; D004906:Erythrocyte Count; D019983:Guideline Adherence; D006801:Humans; D010949:Plasma / Q000166:cytology*
keywords: Blood product transfusion; Medication dispensing error; Ordered treatment regimens; Protocol adherence