Stephen P. Glasser Editor Essentials of Clinical Research Second Edition Essentials of Clinical Research Stephen P. Glasser Editor Essentials of Clinical Research Second Edition Editor Stephen P. Glasser Division of Preventive Medicine University of Alabama at Birmingham Birmingham, AL , USA ISBN 978-3-319-05469-8 ISBN 978-3-319-05470-4 (eBook) DOI 10.1007/978-3-319-05470-4 Springer Cham Heidelberg New York Dordrecht London Library of Congress Control Number: 2014940938 1st edition: © Springer Science+Business Media Dordrecht 2008 2nd edition: © Springer International Publishing Switzerland 2014 T his work is subject to copyright. 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Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Contents 1 The Beginning – Historical Aspects of Clinical Research, Clinical Research: Defi nitions, “Anatomy and Physiology,” and the Quest for “Universal Truth” ..................................................... 1 Stephen P. Glasser 2 Introduction to Clinical Research Concepts, Essential Characteristics of Clinical Research, Overview of Clinical Research Study Designs ....................................................... 11 Stephen P. Glasser 3 A Focus on Clinical Trials ....................................................................... 33 Stephen P. Glasser 4 Alternative Interventional Study Designs ............................................. 75 Stephen P. Glasser 5 Phase 4 (Postmarketing) Research ........................................................ 91 Stephen P. Glasser , Elizabeth Delzell, and Maribel Salas 6 The Role of the USA Food and Drug Administration in Clinical Research ................................................................................ 117 Stephen P. Glasser , Carol M. Ashton, and Nelda P. Wray 7 The Placebo and Nocebo Effect ............................................................. 145 Stephen P. Glasser and William Frishman 8 Recruitment and Retention in Clinical Research................................. 177 Stephen P. Glasser 9 Data Safety and Monitoring Boards (DSMBs) ..................................... 193 Stephen P. Glasser and O. Dale Williams 10 Meta-analysis, Evidence-Based Medicine, and Clinical Guidelines........................................................................... 203 Stephen P. Glasser and Sue Duval v vi Contents 11 Research Methods for Genetic Studies ................................................. 233 Sadeep Shrestha and Donna K. Arnett 12 Research Methods for Pharmacoepidemiology Studies ...................... 257 Maribel Salas and Bruno Stricker 13 Implementation Research: Beyond the Traditional Randomized Controlled Trial ................................................................ 275 Amanda S. Mixon , Lauren Powell , and Carlos A. Estrada 14 Research Methodology for Studies of Diagnostic Tests ....................... 313 Stephen P. Glasser 15 Statistical Power and Sample Size: Some Fundamentals for Clinician Researchers ....................................................................... 327 J. Michael Oakes 16 Association, Cause, and Correlation ..................................................... 345 Stephen P. Glasser and Gary Cutter 17 Bias, Confounding, and Effect Modifi cation (Interaction) .................. 363 Stephen P. Glasser 18 It’s All About Uncertainty ...................................................................... 373 Stephen P. Glasser and George Howard 19 Grant and Manuscript Writing ............................................................. 391 Donna K. Arnett and Stephen P. Glasser 20 The Media and Clinical Research .......................................................... 419 Stephen P. Glasser 21 Mentoring and Advising ......................................................................... 427 Stephen P. Glasser and Edward W. Hook III 22 Presentation Skills: How to Present Research Results ........................ 437 Stephen P. Glasser Index ................................................................................................................. 449 Chapter 1 The Beginning – Historical Aspects of Clinical Research, Clinical Research: Defi nitions, “Anatomy and Physiology,” and the Quest for “Universal Truth” Stephen P. Glasser Scientifi c inquiry is seeing what everyone else is seeing, but thinking of what no one else has thought A. Szentgyorgyi. 1873 (he won the Nobel Prize for isolating Vitamin C) [1 ]. Abstract T o answer many of their clinical questions, health care practitioners need access to reports of original research. This requires the reader to critically appraise the design, conduct, and analysis of each study and subsequently interpret the results. This fi rst chapter reviews some of the key historical developments that have led to the current paradigms used in clinical research, such as the concept of randomization, blinding (masking) and, placebo-controls. Keywords Clinical research defi nition • Clinical research history Introduction A s a former director of a National Institutes of Health (NIH)-funded K30 program it was my responsibility to provide a foundation for young researchers to become independent principal investigators. A part of our curriculum was a Course entitled Hulley S, Cummings S, Browner WS. Designing clinical research. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000. S. P. Glasser , M.D. (*) Division of Preventive Medicine , University of Alabama at Birmingham , 1717 11th Ave S MT638 , Birmingham , AL 35205 , USA e-mail: [email protected] S.P. Glasser (ed.), Essentials of Clinical Research, DOI 10.1007/978-3-319-05470-4_1, 1 © Springer International Publishing Switzerland 2014 2 S.P. Glasser ‘The Fundamentals of Clinical Research.’ This course, in addition to guiding students, towards becoming research investigators, was also designed to aid ‘students’ who wanted to read the medical literature more critically. The importance of this latter point is exemplifi ed by the study of Windish et al., who note “ physicians must keep current with the clinical information to practice evidence-based medicine…. to answer many of their clinical questions, physicians need access to reports of original research. This requires the reader to critically appraise the design, conduct, and analysis of each study and subsequently interpret the results ” [2 ]. Although aimed at physicians, this observation can and should be applied to all health scientists who must read the literature in order to place the results in context. The Windish study surveyed 277 completed questionnaires that assessed knowledge about biostatistics, and study design. The overall mean percent correct on statistical knowledge and interpretation of results was 41.4 %. It is my belief that the textbooks currently available are epidemiologically “slanted”. There is nothing inherently wrong with that slant, but I have written this book to be more specifi cally geared to the clinical researcher interested in conducting Patient Oriented Research (POR). In this fi rst chapter I will provide a brief overview of the history of clinical research. The chapter will also address the question of why we do clinical research; defi ne ‘clinical research’; discuss our quest for ‘universal truth’ as the reason for doing clinical research; outline the approach taken to answer clinical questions; and describe (as Hulley and colleagues so aptly put it) ‘the anatomy and physiology of clinical research’ [3 ]. F uture chapters will examine such issues as causality (i.e., causal inference or cause and effect relationships); the strengths and weaknesses of the most popular clinical research designs; regression to the mean; clinical decision making; meta- analysis; and the role of the Food and Drug Administration (FDA) in the clinical trial process. We will also focus on issues related to randomized clinical trials, such as the intention-to-treat analysis, the use and ethics of placebo-controlled trials, and surrogate and composite endpoints. Defi nition of Clinical Research The defi nition of clinical research might appear to be self-evident; however, some researchers have narrowly defi ned clinical research to refer to clinical trials (i.e., intervention studies in human patients), while others have broadly defi ned it as any research design that studies humans (patients or subjects) or any materials taken from humans. This latter defi nition may even include animal studies, the results of which more or less directly apply to humans. For example, in 1991, Ahrens included the following in the defi nition of clinical research: studies on the mechanisms of human disease; studies on the management of disease; in vitro studies on materials of human origin; animal models of human health and disease; the development of new technologies; the assessment of health care delivery; and fi eld surveys [4 ]. In an attempt to simplify the defi nition, some wits have opined that clinical research occurs when the individual performing the research is required to have malpractice 1 The Beginning – Historical Aspects of Clinical Research, Clinical Research… 3 insurance, or when the investigator and the human subject are, at some point in the study, in the same room, and both are alive and warm. So, there is a wide range of defi nitions of clinical research, some valid, some not. I have chosen to adopt a ‘middle of the road’ defi nition that encompasses the term ‘patient-oriented-research,’ which is defi ned as research conducted with human subjects (or on material of human origin) for which the investigator directly interacts with the human subjects at some point during the study. It is worth noting that this defi nition excludes in vitro studies that use human tissue that may or may not be linked to a living individual unless the investigator during the conduct of the trial has signifi cant interaction with a living breathing human. History of Clinical Research Perhaps the fi rst clinical trial results were those of Galen (circa 250 BC) who concluded that ‘some patients that have taken this herbivore have recovered, while some have died; thus, it is obvious that this herbivore fails only in incurable diseases.’ Galen’s observations underline the fact that even if we have carefully and appropriately gathered data, there are still subjective components to its interpretation, indicating our quest for ‘universal truth’ may be bedeviled more by the interpretation of data than by its accumulation (more about this in Chap. 3 ). J ames Lind is generally given credit for performing and reporting the fi rst ‘placebo-c ontrolled’ interventional trial in the treatment and prevention of scurvy. In the 1700s, scurvy was a particularly vexing problem on the long voyages across the Atlantic Ocean. The research question that presented itself to Lind was how to prevent the condition. To arrive at an answer, Lind did what every good researcher should do as the fi rst step in converting a research question into a testable hypothesis— he reviewed the existent literature of the time. In so doing, he found a report from 1600 that stated ‘1 of 4 ships that sailed on February 13th, 1600, was fortuitously supplied with lemon juice, and almost all of the sailors aboard the one ship were free of scurvy, while most of the sailors of the other ships developed the disease .’ This was not a planned experiment, however. The fi rst planned experiment was perhaps one that involved smallpox, performed in 1721, in which six inmates of Newgate Prison were offered to have their sentence commuted if they volunteered for inoculation. All remained free of smallpox. However, in this experiment there was no concurrent control group. Returning to Lind’s review of the literature, on the one hand, Lind’s job was easy; there was not a great deal of prior published works. On the other hand, Lind did not have computerized searches via Med Line, Pub Med etc available. As a result of the above, in 1747, Lind set up the following trial. He took 12 patients ‘in the scurvy’ on board the HMS S alisbury . ‘ These cases were as similar as I could have them…. They lay together in one place…and had one diet common to all. The consequence was that the most sudden and visible good effects were per- ceived from the use of oranges and lemons .’ Indeed, Lind evaluated six treatment groups: