Success in Academic Surgery_ Clinical Trials.pdf

Success in Academic SurgerySeries Editors:Herbert Chen Lillian KaoSuccess in Academic Surgery:Clinical TrialsTimothy M.PawlikJulie A.Sosa Editors Success in Academic SurgerySeries EditorsHerbert ChenLillian Kao For further volumes:http:/ Timothy M.Pawlik Julie A.Sosa Editors Success in Academic Surgery:Clinical Trials ISBN 978-1-4471-4678-0 ISBN 978-1-4471-4679-7(eBook)DOI 10.1007/978-1-4471-4679-7 Springer London Heidelberg New York Dordrecht Springer-Verlag London 2014 This 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.Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system,for exclusive use by the purchaser of the work.Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publishers location,in its current version,and permission for use must always be obtained from Springer.Permissions for use may be obtained through RightsLink at the Copyright Clearance Center.Violations are liable to prosecution under the respective Copyright Law.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.While the advice and information in this book are believed to be true and accurate at the date of publication,neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made.The publisher makes no warranty,express or implied,with respect to the material contained herein.Printed on acid-free paper Springer is part of Springer Science+Business Media()Editors Timothy M.Pawlik Department of Surgery Johns Hopkins Hospital Baltimore,MD USA Julie A.Sosa Department of Surgery Duke University School of Medicine Durham,NC USA We dedicate this book to our families and our colleagues,who consistently give us the inspiration to seek new knowledge.We also dedicate this book to patients everywhere who participate in clinical trials in their pursuit of hope,knowledge,and discovery.Foreword This book is long overdue as a reference source for surgeons conducting clinical trials and outcomes research.It has been some years since such a comprehensive and up-to-date treatise has been available for those in the arena of conducting clini-cal studies or those aspiring to do so.As a profession,surgical practice has evolved in the past few decades from an empirically based profession to one with a scientifi c underpinning based on pro-spective evidence that defi nes an increasing proportion of our surgical practice.Yet,so many facets of surgical practice are advancing so rapidly,such as in the fi elds of surgical oncology and transplantation,that it is becoming increasingly diffi cult for the practicing surgeons to know how to incorporate these new facts and technolo-gies into their surgical practice.This can only be accomplished with consistency across practices if we have a common factual basis for our treatment recommenda-tions through the scientifi c rigor of clinical trials.I like the way this book is organized,especially for the neophyte clinical investi-gator.Clinical research these days is much more complicated and regulated than ever before,so it takes a greater degree of understanding about the organizational structure,including team-building,as well as data management and ethics of patient research.Likewise,I like the emphasis on the transfer of new knowledge through a thoughtful and informative scientifi c publication,for I have witnessed as a journal editor,the tragedy of reviewing a manuscript with potentially important trial out-comes that had to be rejected because of poor composition.Paradoxically,the scientifi c and technical advances applicable to the surgical patient have expanded dramatically,at the same time that the environment and fund-ing for clinical research has become more arduous than ever before.Yet,the need for documenting systematically how to incorporate new devices,diagnostics,and drugs into surgical practice has never been greater.All of us in the surgical com-munity,whether in an academic or private practice setting,must commit to partici-pating in clinical trials as an integral component of our practice.The stakes are high and the urgency of conducting clinical trials as the scientifi c basis for our profession has never been greater!This valuable treatise is a practical and important manual on how to implement that commitment in our daily surgical practice.Dallas,TX,USA Charles M.Balch,MD,FACS Pref ace Clinical trials play a central role in the understanding of disease processes,as well as the identifi cation of new therapeutic interventions.They help the scientifi c com-munity fi nd better ways to care for patients whether it be through prevention,detection,or treatment of diseases.Unlike other types of scientifi c study,clinical trials are unique,in that the research specifi cally tests the given hypothesis in peo-ple.Participants in clinical trials represent a broad spectrum of individuals healthy controls,patients with advanced stage disease,as well as patients of different ages,ethnic groups,and genders.What unifi es study subjects,however,is the trust they place in the clinical investigator.As such,investigators involved in clinical trials have the professional responsibility to carry out their research not only with the highest ethical standards,but also with scientifi c and methodological expertise.Through ensuring rigorous clinical trial study design and implementation,investi-gators fulfi ll the contract they have with their study participants.This book aims to equip young investigators interested in performing clinical trials with the basic fund of knowledge and tools they will need to start their careers as academic surgeons focused on clinical research.It is a primer that covers a broad spectrum of topics important to the clinical trials investigator,including the history of clinical trials,statistical considerations,regulatory issues,data management,pre-sentation and publication of results,and ethics.While additional training and expe-rience is needed beyond the scope of this book for those academic surgeons who plan to make clinical trials a signifi cant part of their professional lives,the book provides important information to those seeking to know more about clinical research.It is our hope that the book will help to cultivate the next generation of clinical scientists who will continue to seek new knowledge to improve patient care.Baltimore,MD Timothy M.Pawlik,MD,MPH,PhD Durham,NC Julie Ann Sosa,MD,MA Acknowledgments We would like to acknowledge the Association for Academic Surgery for support-ing the Success in Academic Surgery series of books,as well as the efforts of all the young academic surgeons who have acted as our motivation to undertake this effort.Contents 1 Building Your Clinical Trial Research Team.1Jessica E.Gosnell 2 Clinical Trials:Ensuring Quality and Standardization.11Marquita Decker and Lee Gravatt Wilke 3 Statistics:Setting the Stage.27Sandra L.Wong 4 Clinical Trials:Handling the Data.39Christina E.Bailey and George J.Chang 5 Data Safety Monitoring Boards .53Kamran Idrees,Fei Ye,Yu Shyr,and Nipun Merchant 6 Planning for Data Monitoring and Audits.65Lisa Jacobs 7 The Budget .79Shuab Omer,Lorraine D.Cornwell,and Faisal G.Bakaeen 8 Regulatory Considerations in Human Subjects Research.95H.Richard Alexander Jr.,Edward Sausville,and Shannon Decker 9 Publishing a Clinical Trial.107Babak J.Orandi,Julie A.Freischlag,and Mahmoud Malas10 Device Versus Drug Clinical Trials:Similarities and Important Differences .119T.Clark Gamblin and William S.Ragalie11 Defi ning the Study Cohort:Inclusion and Exclusion Criteria.131Lisa M.McElroy and Daniela P.Ladnerxiv12 The History of Clinical Trials.141Sanziana Roman13 Ethics of Clinical Trials.153Jukes P.Namm and Peter Angelos14 Trial Design:Overview of Study Designs(Phase I,II,III,IV,Factorial Design).169Brigid K.Killelea and Anees B.Chagpar Index .179Contents Contributors H.Richard Alexander Jr.,MD Division of General and Oncologic Surgery,The Department of Surgery,Marlene and Stewart Greenebaum Cancer Center,University of Maryland School of Maryland ,Baltimore,MA,USA Division of General and Oncologic Surgery,Department of Surgery,University of Maryland School of Medicine ,Baltimore,MA,USA Peter Angelos Department of Surgery,University of Chicago,Chicago,IL,USA Christina E.Bailey ,MD,MSCI Department of Surgical Oncology,University of Texas,MD Anderson Cancer Center ,Houston,TX,USA Faisal G.Bakaeen ,MD Cardiothoracic Surgery,Baylor College of Medicine,Michael E DeBakey Veterans Affairs Medical Center ,Houston,TX,USA Anees B.Chagpar Department of Surgery,Yale University School of Medicine ,New Haven,CT,USA George J.Chang ,MD,MS Department of Surgical Oncology,University of Texas,MD Anderson Cancer Center ,Houston,TX,USA Lorraine D.Cornwell ,MD Cardiothoracic Surgery,Baylor College of Medicine,Michael E DeBakey Veterans Affairs Medical Center ,Houston,TX,USA Marquita Decker ,MD,MPH Department of Surgery,University of Wisconsin ,Madison,WI,USA Shannon Decker ,MPH,JD Division of Medical Oncology,The Department of Medicine,Marlene and Stewart Greenebaum Cancer Center,University of Maryland School of Maryland ,Baltimore,MA,USA Julie A.Freischlag ,MD Department of Surgery,Johns Hopkins Hospital ,Baltimore,MD,USA T.Clark Gamblin ,MD,MS Department of Surgery,Medical College of Wisconsin ,Milwaukee,WI,USA xvi Jessica E.Gosnell ,MD Department of General Surgery,UCSF Mt Zion Medical Center ,San Francisco,CA,USA University of California ,San Francisco,CA,USA Kamran Idrees ,MD Division of Surgical Oncology and Endocrine Surgery,Department of Surgery,Vanderbilt University ,Nashville,TN,USA Lisa Jacobs ,MD Department of Surgery,Johns Hopkins University ,Baltimore,MA,USA Brigid K.Killelea Department of Surgery,Yale University School of Medicine ,New Haven,CT,USA Daniela P.Ladner ,MD,MPH Division of Transplantation,Department of Surgery,Northwestern University Transplant Outcomes Research Collaborative(NUTORC),Chicago,IL,USA Department of Surgery,Feinberg School of Medicine,Northwestern University ,Chicago,IL,USA Mahmoud Malas ,MD,MHS Department of Vascular and Endovascular Surgery,Johns Hopkins Bayview Medical Center ,Baltimore,MD,USA Lisa M.McElroy ,MD Division of Transplantation,Department of Surgery,Northwestern University Transplant Outcomes Research Collaborative(NUTORC),Chicago,IL,USA Department of Surgery,Feinberg School of Medicine,Northwestern University ,Chicago,IL,USA Nipun Merchant ,MD Division of Surgical Oncology and Endocrine Surgery,Department of Surgery,Vanderbilt University ,Nashville,TN,USA Jukes P.Namm Department of Surgery,University of Chicago,Chicago,IL,USA Shuab Omer ,MD Cardiothoracic Surgery,Baylor College of Medicine,Michael E DeBakey Veterans Affairs Medical Center ,Houston,TX,USA Babak J.Orandi ,MD,MSc Department of Surgery,Johns Hopkins Hospital ,Baltimore,MD,USA William S.Ragalie ,MD Department of Surgery,Medical College of Wisconsin ,Milwaukee,WI,USA Sanziana Roman ,MD,FACS Department of Surgery,Duke University School of Medicine ,Durham,NC,USA Edward Sausville ,MD,PhD Division of Medical Oncology,The Department of Medicine,Marlene and Stewart Greenebaum Cancer Center,University of Maryland School of Maryland ,Baltimore,MA,USA Contributorsxvii Yu Shyr ,PhD Department of Biostatistics,Vanderbilt Center for Quantitative Sciences ,Nashville,TN,USA Lee Gravatt Wilke ,MD,FACS Department of Surgery,University of Wisconsin ,Madison,WI,USA Sandra L.Wong ,MD,MS Department of Surgery,University of Michigan ,Ann Arbor,MI,USA Fei Ye ,PhD Division of Cancer Biostatistics,Department of Biostatistics,Vanderbilt Center for Quantitative Sciences ,Nashville,TN,USA Contributors CFR Code of Federal Regulations CONSORT Consolidated Standards of Reporting Trials DHHS Department of Health and Human Services DSMB Data and Safety Monitoring Board FDA Food and Drug Administration GCP Good Clinical Practice ICMJE International Committee of Medical Journal Editors IRB Institutional Review Board IRB Institutional Review Board NAACP National Association for the Advancement of Colored People RCT Randomized Controlled Trial Abbreviations 1T.M.Pawlik,J.A.Sosa(eds.),Success in Academic Surgery:Clinical Trials,Success in Academic Surgery,DOI 10.1007/978-1-4471-4679-7_1,Springer-Verlag London 20141.1 Building Your Clinical Trial Research Team On the 20th of May 1947,I took 12 patients in the scurvy,on board the Salisbury at sea.Their cases were as similar as I could have them.They all in general had putrid gums,the spots and lassitude,with weakness of their kneesTwo of these were ordered each a quart of cyder a-day.Two otheres took two spoon-fuls of vinegar three times a-day.Two otheres took 25 gutts of elixer vitriol three times a-day.Two of the worse were put under a course of sea-waterTwo otheres had each two oranges and one lemon given them every day.These they ate with great greedinessThe two remaining patients took the bigness of nut-meg three times a-day.The consequence was,that the most sudden and visible good effects were perceived from the use of the oranges and lemons;one of these who had taken them,being at the end of 6 days,fi t for duty.James Lind 9 One of the earliest reported clinical trials involved the treatment of scurvy 9.In this streamlined clinical trial,one study doctor,at sea,developed a protocol with 12 patients and 6 interventions and published fi ndings that eventually led to the cure of this previously fatal disease.Clinical trials are of course much more complex today,with detailed protocols,highly regimented record keeping and data reporting,independently hired vendors and study monitors,high ethical stan-dards,potential confl icts of interest,and a web of federal state and institutional regulating bodies.Recent changes in the health care environment in the United States have added to the challenges 13.Certainly,more than one study doctor is Chapter 1 Building Your Clinical Trial Research Team Jessica E.Gosnell J.E.Gosnell,MD Department of General Surgery,UCSF Mt Zion Medical Center,1600 Divisadero Street,1674,San Francisco,CA 94143,USA University of California,San Francisco,CA,USA e-mail:jessica.gosnellucsfmedctr.org 2usually needed.In fact,many people