Jane Nikles · Geoff rey Mitchell Editors The Essential Guide to N-of-1 Trials in Health The Essential Guide to N-of-1 Trials in Health Jane Nikles (cid:129) Geoffrey Mitchell Editors The Essential Guide to N-of-1 Trials in Health Editors Jane Nikles Geoffrey Mitchell School of Medicine School of Medicine The University of Queensland The University of Queensland Ipswich , QLD , Australia Ipswich , QLD , Australia ISBN 978-94-017-7199-3 ISBN 978-94-017-7200-6 (eBook) DOI 10.1007/978-94-017-7200-6 Library of Congress Control Number: 2015952660 Springer Dordrecht Heidelberg New York London © Springer Science+Business Media Dordrecht 2015 T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer Science+Business Media B.V. Dordrecht is part of Springer Science+Business Media (www. springer.com) Pref ace T he fundamental problem facing the clinical research enterprise is this: what c linicians (and patients) want to know is not what clinical trials are equipped to say. Randomized controlled trials (RCTs) are all about the average patient; they yield average treatment effects. Doctors and patients want individual treatment effects: how a given patient will respond to Treatment A versus Treatment B. No amount of statistical subterfuge can make standard-issue, parallel group RCTs reveal precisely the results we want. There is one method, however, that under certain conditions can reliably identify the best treatment for an individual. That method is the N-of-1 trial. N-of-1 trials are crossover experiments conducted with a single patient. They are applicable principally to treatments used for symptomatic, chronic, nonfatal condi- tions. By systematically observing a patient’s response to two or more treatments, we can determine which of the treatments are likely to work best for that patient in the long run. N-of-1 trials were introduced to clinicians by Hogben and Sim as early as 1953, but it took 30 years before Gordon Guyatt brought them into the medical mainstream. Early pioneers established active N-of-1 trial units in academic cen- ters, only to abandon them once funding was exhausted. However, several units are still thriving, and over the past three decades, over 2,000 patients have participated in published N-of-1 trials. And yet, considering the signifi cant potential N-of-1 trials have for individual- izing care and supporting shared decision making, a compelling case could be made that they are woefully underused. One reason is that few clinical investigators and even fewer clinicians understand their rationale, methods, and applications. Now, here in one place is the information these individuals have been seeking. The Essential Guide to N-of-1 Trials in Health will be useful to two audiences: clinical researchers seeking a more direct approach to estimating individual treatment effects and clinicians aspiring to apply more rigor to their own therapeutic decision making. Written by many of the world’s most knowledgeable authorities on N-of-1 trials, the book provides a step-by-step approach to design and conduct of N-of-1 trials, from study conception and ethical approval to data collection, analysis, and interpretation. While some enthusiastic readers will read the guide cover to cover, each chapter can also stand alone. v vi Preface W hen clinicians and patients fi rst hear about N-of-1 trials, their initial incredulity frequently turns to intense interest. How, in an era when personalized medicine is all the rage, could such a powerful approach be so little known? As an accessible yet rigorous introduction to the method, the E ssential Guide to N-of-1 Trials in Health will help provide tools, answers, and inspiration. Sacramento, California, USA Richard Kravitz Acknowledgments W e are very appreciative of the time and skill contributed by Kylie O’Toole and Genevieve Clark in preparing this book for publication and for invaluable adminis- trative support. We thank our editor at Springer, Melania Ruiz, for her guidance and patience in the process of bringing this book to completion. vii Contents 1 Introduction ............................................................................................. 1 Jane Nikles and Geoffrey Mitchell 2 What are N-of-1 Trials? ......................................................................... 9 Jane Nikles 3 N-of-1 Trials in the Behavioral Sciences ............................................... 19 Robyn L. Tate and Michael Perdices 4 N-of-1 Trials in Medical Contexts .......................................................... 43 Geoffrey Mitchell 5 Aggregated N-of-1 Trials ........................................................................ 57 Geoffrey Mitchell 6 Methodological Considerations for N-of-1 Trials................................. 67 Keumhee C. Carriere , Yin Li , Geoffrey Mitchell , and Hugh Senior 7 Randomization, Allocation Concealment, and Blinding ..................... 81 Hugh Senior 8 Data Collection and Quality Control .................................................... 93 Hugh Senior 9 Individual Reporting of N-of-1 Trials to Patients and Clinicians ....... 105 Michael Yelland 10 Assessing and Reporting Adverse Events ............................................. 115 Hugh Senior 11 Research Ethics and N-of-1 Trials ......................................................... 125 Andrew Crowden , Gordon Guyatt , Nikola Stepanov , and Sunita Vohra 12 Statistical Analysis of N-of-1 Trials ....................................................... 135 Kerrie Mengersen , James M. McGree , and Christopher H. Schmid ix