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LyndaH.Powell

KennethE.Freedland

PeterG.Kaufmann

Behavioral

Clinical Trials

forChronic

Diseases

Scientific Foundations

Behavioral Clinical Trials for Chronic Diseases

LyndaH.Powell • KennethE.Freedland •

PeterG.Kaufmann

Behavioral Clinical Trials

for Chronic Diseases

Scientic Foundations

ISBN 978-3-030-39328-1 ISBN 978-3-030-39330-4 (eBook)

https://doi.org/10.1007/978-3-030-39330-4

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of

the material is concerned, specically the rights of translation, reprinting, reuse of illustrations, recitation,

broadcasting, reproduction on micro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 speci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, expressed or implied, with respect to the material contained herein or for any

errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional

claims in published maps and institutional afliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG

The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

LyndaH.Powell

Department of Preventive Medicine

Rush University Medical Center

Chicago, IL, USA

PeterG.Kaufmann

College of Nursing

Villanova University

Villanova, PA, USA

KennethE.Freedland

Department of Psychiatry

Washington University in St. Louis

St. Louis, MO, USA

This book is dedicated to

Thomas A.Deutsch, MD,

former Dean of Rush Medical College.

In taking a leap of faith,

he inspired a pursuit of excellence.

https://t.me/medicina_free

vii

Acknowledgments

The inspiration for this book came from the Fellows of the US National Institutes of

Health Summer Institute on Behavioral Randomized Clinical Trials. Over its rst

19years, the Institute trained over 800 Fellows in behavioral clinical trial methodol-

ogy. These Fellows contributed to the evolving methodology in behavioral trials

with their questions. Although the diseases and treatments varied from Fellow to

Fellow, and from year to year, their questions were much the same. They were less

interested in how to do something than they were in why they should do it. These

questions informed the choice of topics for each of the chapters as well as the style

of presenting them. I want to acknowledge the leadership of Peter Kaufmann who

conceived, founded, and led the Summer Institute from its beginning in 2000, and

Kate Stoney who later assumed leadership and pulled it off with equal success. I

also want to acknowledge the support provided by the US National Institutes of

Health Ofce of Behavioral and Social Sciences Research, which was initiated by

Peter Kaufmann and continued by Raynard Kington, David Abrams, Bob Kaplan,

Bill Riley, and Christine Bachrach.

This book’s focus on the integration of good science and good methods came from

my inspirational sabbatical year at the Center for Advanced Study in the Behavioral

Sciences at Stanford University. During that year, scientists from diverse areas of

behavioral sciences, including philosophy, political science, law, psychology, soci-

ology, evolutionary biology, anthropology, linguistics, economics, geography, his-

tory, public affairs, public health, and literature, presented their work. These diverse

disciplines pursue behavioral problems from different perspectives, contribute a

piece of a puzzle, and together progress knowledge. The Center encouraged us to

look beyond the science of any single discipline in pursuit of excellence within our

own. I would like to extend my sincerest admiration and gratitude to Margaret Levi,

the charismatic Director of the Center, for her vision and for the many ways she

encouraged discovery through cross-fertilization.

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viii

All chapters have been reviewed by at least two junior or senior investigators with

interests and expertise in behavioral clinical trials. These reviews were not always

easy, as is clear from such comments as– “I have no idea what you are trying to

say!” “You have completely missed the point.” But they helped us to see weak-

nesses and enhance strength. A special shout-out goes to Rachel Wu who reviewed

and commented on every single chapter. Her basic science studies led her to make a

creative leap to interventions. To do so, she needed to “learn about this stuff.” All of

these reviewers are listed in the Appendix. We thank them sincerely for their help.

On a more personal level, I would like to thank Bob Kaplan for his ongoing encour-

agement. He has written 21 books; this was my rst. He never stopped asking for

progress reports, providing tips, and normalizing the challenges. He expected suc-

cess, and it was infectious. I would also like to thank Rick Reiss for his emotional

support. After long hours at the computer on a beautiful summer day, he would

describe what his day had been like on the outside, helping me to experience vicari-

ously a post-book life. I am hoping that my family and friends, particularly Celeste

Fraser, will now give me a second chance after several years of declining their many

invitations.

And nally to Joyce Mack, my faithful Assistant, I give my heartfelt thanks. Joyce

worked on every reference, gure, table, and formatting problem, obtained all the

permissions, and served as a liaison between me and many moving parts of this

book. She did this with a commitment to excellence, and a sense of ownership, that

was equal to mine.

Lynda H. Powell

(On behalf of my coauthors, Ken Freedland and Peter Kaufmann)

October 2019

Acknowledgments

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Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

WINDOW OF OPPORTUNITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

THE EVIDENCE: OBSERVATIONAL STUDIES . . . . . . . . . . . . . . . . 3

THE EVIDENCE: INTERVENTION STUDIES . . . . . . . . . . . . . . . . . . 4

WHY WE WROTE THIS BOOK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

ORGANIZING PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

“Why Should You?” Rather Than “How To” . . . . . . . . . . . . . . . . . . . 6

Progressive Translational Science Model . . . . . . . . . . . . . . . . . . . . . . 7

Cross-Disciplinary Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

THE AUDIENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2 Quality of a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

SCIENTIFIC PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

High-Quality Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

High-Quality Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

CHALLENGES FOR BEHAVIORAL TRIALS . . . . . . . . . . . . . . . . . . 15

Not Enough Phase III Behavioral Efcacy Trials . . . . . . . . . . . . . . . 16

Evidence for an “Evidence-Based” Behavioral Treatment . . . . . . . . . 17

Need for Progressive Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

OVERCOMING THESE CHALLENGES IN A BEHAVIORAL

TRIAL. Overview of the Book . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Progression of Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Strong Behavioral Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Protection of Internal Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

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3 Behavioral Treatment Development . . . . . . . . . . . . . . . . . . . . . . 27

SCIENTIFIC PRINCIPLE. The Drug Development Model . . . . . . . . . . 28

Regulations Protect Consumers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

The Process of Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

General Features of the Drug Development Process . . . . . . . . . . . . . 31

CHALLENGES FOR BEHAVIORAL TRIALS . . . . . . . . . . . . . . . . . . 32

Multiple Perspectives on Behavioral Treatment Development . . . . . . 32

Consequences of Not Being Guided by a Model

for Treatment Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

OVERCOMING THESE CHALLENGES IN A BEHAVIORAL

TRIAL. The ORBIT Model for Developing Behavioral

Treatments for Chronic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

The Design Phase: Phase I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Preliminary Testing: Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

SELECTED EXPERIENCE FROM A BEHAVIORAL TRIAL . . . . . . 54

Scientic Progression in the Diabetes Prevention Program . . . . . . . . 54

RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Funding Agencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Publication Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Investigators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

APPENDIX: Obesity-Related Behavioral Treatment Intervention

Trials (ORBIT) Consortium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

4 Hypothesized Pathway and Bias. . . . . . . . . . . . . . . . . . . . . . . . . 69

SCIENTIFIC PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

The Logic of Scientic Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Application of the Logic of Scientic Hypotheses . . . . . . . . . . . . . . . 73

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

CHALLENGES FOR BEHAVIORAL TRIALS . . . . . . . . . . . . . . . . . . 76

Exploratory Aims in Conrmatory Trials . . . . . . . . . . . . . . . . . . . . . . 76

Discipline-Specic Approach to Bias . . . . . . . . . . . . . . . . . . . . . . . . . 79

OVERCOMING THESE CHALLENGES IN A BEHAVIORAL

TRIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Guide Trial Design with a Hypothesized Pathway . . . . . . . . . . . . . . . 79

Interpret Trial Results with a Hypothesized Pathway . . . . . . . . . . . . . 81

Develop Cross-Disciplinary Sophistication in Common

Trial Biases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

SELECTED EXPERIENCE FROM BEHAVIORAL TRIALS . . . . . . . 88

The Hypothesized Pathway in a Successful Behavioral Trial . . . . . . . 88

The Hypothesized Pathway Explains a Null Trial . . . . . . . . . . . . . . . 89

Contents

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Consequences of Mistaking a Failed Treatment for a Failed

Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Stick Your Neck Out . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Advance Academically as a Behavioral Trialist . . . . . . . . . . . . . . . . . 93

Become an Expert in Behavioral Clinical Trial Biases . . . . . . . . . . . . 94

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

5 Clinical Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

SCIENTIFIC PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Inferential Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Limitations of Inferential Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

CHALLENGES FOR BEHAVIORAL TRIALS . . . . . . . . . . . . . . . . . . 103

“One-Size-Fits-All” Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Signicance Tests Are the Status Quo . . . . . . . . . . . . . . . . . . . . . . . . 104

OVERCOMING THESE CHALLENGES IN A BEHAVIORAL

TRIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Clinically Signicant Treatment Target . . . . . . . . . . . . . . . . . . . . . . . 106

Clinically Signicant Treatment Effect. . . . . . . . . . . . . . . . . . . . . . . . 108

Clinical Signicance in Sample Size Calculations . . . . . . . . . . . . . . . 110

SELECTED EXPERIENCE FROM BEHAVIORAL TRIALS . . . . . . . 113

Clinically Signicant Treatment Target from Epidemiology . . . . . . . 113

Clinically Signicant Sample Size Calculation for a Phase II

Efcacy Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Clinical Versus Statistical Signicance in Phase III

Efcacy Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Does the Treatment Achieve a Clinically Signicant Benet? . . . . . . 119

Does the Treatment Achieve a Better Response than

a Comparator? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

What Is the Scientic Conclusion from This Trial? . . . . . . . . . . . . . . 120

How Conclusive Is the Evidence That This Treatment

Improves Health? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

6 The Choice of a Comparator . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

SCIENTIFIC PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Decision-Making Frameworks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

CHALLENGES FOR BEHAVIORAL TRIALS . . . . . . . . . . . . . . . . . . 131

Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

The Status Quo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

OVERCOMING THESE CHALLENGES IN A BEHAVIORAL

TRIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

The Pragmatic Model for Comparator Selection

in Health- Related Behavioral Trials . . . . . . . . . . . . . . . . . . . . . . . . 133

Contents

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