FORUM—EVIDENCE IN TRANSPLANTATION Expanding the Evidence Base in Transplantation: The Complementary Roles of Randomized Controlled Trials and Outcomes Research Steven K. Takemoto, 1,12 Wolfgang Arns, 2 Suphamai Bunnapradist, 3 Louis P. Garrison, 4 Lluis Guirado, 5 Zoltan Kalo, 6 Gabriel Oniscu, 7 Gerhard Opelz, 8 Maria Piera Scolari, 9 Sergio Stefoni, 9 Magdi Yaqoob, 10 and Daniel C. Brennan 11 Transplantation offers a unique opportunity to demonstrate the complementary roles of randomized controlled trials and outcome research. The surgery and collaboration necessary for the transplant procedure makes randomization and blinding difficult. Because essentially every recipient is included in a transplant registry, sampling bias is minimized. Regulatory agencies generally do not consider outcomes research when assessing efficacy of new drugs or medical interventions. This workgroup summary examines the suitability of outcomes research to complement results of randomized controlled trials and related issues: efficacy versus effectiveness, internal versus external validity, data types, limitations, and analysis methodologies. Many advances in outcomes research have been pioneered in transplantation. A case is made for regulatory and reimbursement authorities to use outcomes research when making efficacy, effec- tiveness, and coverage decisions in transplantation. (Transplantation 2008;86: 18–25) Keywords: Immunosuppression, Outcomes research, Randomized controlled trial, Registry analysis, Transplantation. I n December 2006, an international group of clinical and health outcomes researchers from seven countries con- vened in Munich, Germany, to discuss the importance of outcomes research as a complementary source of evidence to randomized controlled trials (RCTs) for guiding incor- poration of new medical interventions into clinical prac- tice. The goal of the meeting was to compare methodolo- gies and applications of RCTs and outcomes research in the field of transplantation. A recent evaluation of the ef- ficacy of newer immunosuppressive regimens in trans- plant therapy excluded studies that were not RCTs (1), thereby illustrating the need for this discussion and review. Such exclusion may not be practical or justified. Here, we summarize the main points of discussion, introduce basic concepts, compare the strengths and limitations of RCTs and outcomes research, and illustrate how many advances in outcomes research have been pioneered in the field of transplantation. Randomized Controlled Trial and Outcomes Research: Basic Concepts Randomized controlled trials provide an experimental framework for measuring the efficacy of new interventions under ideal controlled conditions. They can answer a simple but important question: Does the intervention work? This is performed by prospectively testing a hypothesis and mini- mizing confounding and reporting bias with blinding and random assignment to treatment groups so that the effect of a treatment can be accurately measured (2). Randomization provides an unpredictable allocation sequence and with con- cealment this assignment is unknown to patients and provid- ers before treatment. Double-blinded trials seek to eliminate ascertainment bias by shielding participants, care-givers, and outcomes evaluators from the sequence assignment until the final results are analyzed (3). This work was supported by Novartis Pharma AG, Basel, Switzerland. D.C.B. is supported in part by NIH K24-02886. 1 National Institute of Transplantation, S. Mark Taper Foundation Trans- plant Center, Los Angeles, CA. 2 Cologne General Hospital, Cologne, Germany. 3 Department of Medicine, University of California Los Angeles, Los Ange- les, CA. 4 Department of Pharmacy, University of Washington, Seattle, WA. 5 Fundacio ´ Puigvert, Barcelona, Spain. 6 Health Economics Research Centre, Eotvos Lorand University, Budapest, Hungary. 7 Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. 8 Institute of Immunology, University of Heidelberg, Heidelberg, Germany. 9 U. O. Nefrologia, Dialisi e Trapianto, Bologna, Italy. 10 The Royal London and St Bartholomew’s Hospitals, London, United Kingdom. 11 Department of Medicine, Washington University, Saint Louis, MO. 12 Address correspondence to: Steven K. Takemoto, Ph.D., National Institute of Transplantation, S. Mark Taper Foundation Transplant Center, 2200 West Third Street, Suite 100, Los Angeles, CA 90057. E-mail: sktakemoto@hotmail.com Received 18 September 2007. Revision requested 15 October 2007. Accepted 22 April 2008. Copyright © 2008 by Lippincott Williams & Wilkins ISSN 0041-1337/08/8601-18 DOI: 10.1097/TP.0b013e31817d4df5 18 Transplantation • Volume 86, Number 1, July 15, 2008