Analyzing Longitudinal Clinical Trial Data: A Practical Guide

330 Pages·2017·4.619 MB·English

by  Craig H. Mallinckrodt, Ilya Lipkovich

Analyzing
Longitudinal
Clinical Trial Data
A Practical Guide
Published Titles
Benefit-Risk Assessment Methods in Design and Analysis of Animal Studies
Editor-in-Chief
Medical Product Development: Bridging in Pharmaceutical Development
Shein-Chung Chow, Ph.D., Professor, Department of Biostatistics and Bioinformatics, Qualitative and Quantitative Assessments Shein-Chung Chow and Jen-pei Liu
Duke University School of Medicine, Durham, North Carolina
Qi Jiang and Weili He
Design and Analysis of Bioavailability
Series Editors Bioequivalence and Statistics in Clinical and Bioequivalence Studies, Third Edition
Byron Jones, Biometrical Fellow, Statistical Methodology, Integrated Information Sciences, Pharmacology, Second Edition Shein-Chung Chow and Jen-pei Liu
Scott Patterson and Byron Jones
Novartis Pharma AG, Basel, Switzerland Design and Analysis of Bridging Studies
Jen-pei Liu, Professor, Division of Biometry, Department of Agronomy, Biosimilars: Design and Analysis of Jen-pei Liu, Shein-Chung Chow,
National Taiwan University, Taipei, Taiwan Follow-on Biologics and Chin-Fu Hsiao
Shein-Chung Chow
Karl E. Peace, Georgia Cancer Coalition, Distinguished Cancer Scholar, Senior Research Scientist Design & Analysis of Clinical Trials for
and Professor of Biostatistics, Jiann-Ping Hsu College of Public Health, Biostatistics: A Computing Approach Economic Evaluation & Reimbursement:
Georgia Southern University, Statesboro, Georgia
Stewart J. Anderson An Applied Approach Using SAS & STATA
Bruce W. Turnbull, Professor, School of Operations Research and Industrial Engineering, Iftekhar Khan
Cancer Clinical Trials: Current and
Cornell University, Ithaca, New York
Controversial Issues in Design and Design and Analysis of Clinical Trials
Published Titles Analysis for Predictive Medicine
Stephen L. George, Xiaofei Wang, Shigeyuki Matsui, Marc Buyse,
Adaptive Design Methods in Clinical Bayesian Analysis Made Simple:
and Herbert Pang and Richard Simon
Trials, Second Edition An Excel GUI for WinBUGS
Causal Analysis in Biomedicine and Design and Analysis of Clinical Trials with
Shein-Chung Chow and Mark Chang Phil Woodward
Epidemiology: Based on Minimal Time-to-Event Endpoints
Adaptive Designs for Sequential Bayesian Designs for Phase I–II
Sufficient Causation Karl E. Peace
Treatment Allocation Clinical Trials
Mikel Aickin
Design and Analysis of Non-Inferiority Trials
Alessandro Baldi Antognini Ying Yuan, Hoang Q. Nguyen,
Clinical and Statistical Considerations in Mark D. Rothmann, Brian L. Wiens,
and Alessandra Giovagnoli and Peter F. Thall
Personalized Medicine and Ivan S. F. Chan
Adaptive Design Theory and Bayesian Methods for Measures
Claudio Carini, Sandeep Menon, and Mark Chang
Difference Equations with Public Health
Implementation Using SAS and R, of Agreement
Clinical Trial Data Analysis using R Applications
Second Edition Lyle D. Broemeling
Ding-Geng (Din) Chen and Karl E. Peace Lemuel A. Moyé and Asha Seth Kapadia
Mark Chang
Bayesian Methods for Repeated Measures
Clinical Trial Methodology DNA Methylation Microarrays:
Advanced Bayesian Methods for Lyle D. Broemeling
Karl E. Peace and Ding-Geng (Din) Chen Experimental Design and Statistical
Medical Test Accuracy
Bayesian Methods in Epidemiology
Analysis
Lyle D. Broemeling Computational Methods in Biomedical
Lyle D. Broemeling
Sun-Chong Wang and Arturas Petronis
Research
Analyzing Longitudinal Clinical Trial Data:
Bayesian Methods in Health Economics
Ravindra Khattree and Dayanand N. Naik DNA Microarrays and Related Genomics
A Practical Guide
Gianluca Baio
Techniques: Design, Analysis, and
Craig Mallinckrodt and Ilya Lipkovich Computational Pharmacokinetics
Bayesian Missing Data Problems: EM, Interpretation of Experiments
Anders Källén
Applied Biclustering Methods for Big
Data Augmentation and Noniterative David B. Allison, Grier P. Page,
and High-Dimensional Data Using R Confidence Intervals for Proportions
Computation T. Mark Beasley, and Jode W. Edwards
Adetayo Kasim, Ziv Shkedy, and Related Measures of Effect Size
Ming T. Tan, Guo-Liang Tian,
Dose Finding by the Continual
Sebastian Kaiser, Sepp Hochreiter, Robert G. Newcombe
and Kai Wang Ng
Reassessment Method
and Willem Talloen Controversial Statistical Issues in
Bayesian Modeling in Bioinformatics Ying Kuen Cheung
Applied Meta-Analysis with R Clinical Trials
Dipak K. Dey, Samiran Ghosh,
Dynamical Biostatistical Models
Ding-Geng (Din) Chen and Karl E. Peace Shein-Chung Chow
and Bani K. Mallick
Daniel Commenges and
Basic Statistics and Pharmaceutical Data Analysis with Competing Risks
Benefit-Risk Assessment in Hélène Jacqmin-Gadda
Statistical Applications, Second Edition and Intermediate States
Pharmaceutical Research and
Elementary Bayesian Biostatistics
James E. De Muth Ronald B. Geskus
Development
Lemuel A. Moyé
Bayesian Adaptive Methods for Andreas Sashegyi, James Felli, Data and Safety Monitoring Committees
Empirical Likelihood Method in
Clinical Trials and Rebecca Noel in Clinical Trials
Survival Analysis
Scott M. Berry, Bradley P. Carlin, Jay Herson
Mai Zhou
J. Jack Lee, and Peter Muller
Published Titles
Benefit-Risk Assessment Methods in Design and Analysis of Animal Studies
Medical Product Development: Bridging in Pharmaceutical Development
Qualitative and Quantitative Assessments Shein-Chung Chow and Jen-pei Liu
Qi Jiang and Weili He
Design and Analysis of Bioavailability
Bioequivalence and Statistics in Clinical and Bioequivalence Studies, Third Edition
Pharmacology, Second Edition Shein-Chung Chow and Jen-pei Liu
Scott Patterson and Byron Jones
Design and Analysis of Bridging Studies
Biosimilars: Design and Analysis of Jen-pei Liu, Shein-Chung Chow,
Follow-on Biologics and Chin-Fu Hsiao
Shein-Chung Chow
Design & Analysis of Clinical Trials for
Biostatistics: A Computing Approach Economic Evaluation & Reimbursement:
Stewart J. Anderson An Applied Approach Using SAS & STATA
Iftekhar Khan
Cancer Clinical Trials: Current and
Controversial Issues in Design and Design and Analysis of Clinical Trials
Analysis for Predictive Medicine
Stephen L. George, Xiaofei Wang, Shigeyuki Matsui, Marc Buyse,
and Herbert Pang and Richard Simon
Causal Analysis in Biomedicine and Design and Analysis of Clinical Trials with
Epidemiology: Based on Minimal Time-to-Event Endpoints
Sufficient Causation Karl E. Peace
Mikel Aickin
Design and Analysis of Non-Inferiority Trials
Clinical and Statistical Considerations in Mark D. Rothmann, Brian L. Wiens,
Personalized Medicine and Ivan S. F. Chan
Claudio Carini, Sandeep Menon, and Mark Chang
Difference Equations with Public Health
Clinical Trial Data Analysis using R Applications
Ding-Geng (Din) Chen and Karl E. Peace Lemuel A. Moyé and Asha Seth Kapadia
Clinical Trial Methodology DNA Methylation Microarrays:
Karl E. Peace and Ding-Geng (Din) Chen Experimental Design and Statistical
Analysis
Computational Methods in Biomedical
Sun-Chong Wang and Arturas Petronis
Research
Ravindra Khattree and Dayanand N. Naik DNA Microarrays and Related Genomics
Techniques: Design, Analysis, and
Computational Pharmacokinetics
Interpretation of Experiments
Anders Källén
David B. Allison, Grier P. Page,
Confidence Intervals for Proportions
T. Mark Beasley, and Jode W. Edwards
and Related Measures of Effect Size
Dose Finding by the Continual
Robert G. Newcombe
Reassessment Method
Controversial Statistical Issues in
Ying Kuen Cheung
Clinical Trials
Dynamical Biostatistical Models
Shein-Chung Chow
Daniel Commenges and
Data Analysis with Competing Risks
Hélène Jacqmin-Gadda
and Intermediate States
Elementary Bayesian Biostatistics
Ronald B. Geskus
Lemuel A. Moyé
Data and Safety Monitoring Committees
Empirical Likelihood Method in
in Clinical Trials
Survival Analysis
Jay Herson
Mai Zhou
Published Titles Published Titles
Essentials of a Successful Biostatistical Modern Adaptive Randomized Clinical Sample Size Calculations in Clinical Statistical Methods in Drug Combination
Collaboration Trials: Statistical and Practical Aspects Research, Second Edition Studies
Arul Earnest Oleksandr Sverdlov Shein-Chung Chow, Jun Shao, Wei Zhao and Harry Yang
and Hansheng Wang
Exposure–Response Modeling: Methods Monte Carlo Simulation for the Statistical Testing Strategies in the
and Practical Implementation Pharmaceutical Industry: Concepts, Statistical Analysis of Human Growth Health Sciences
Jixian Wang Algorithms, and Case Studies and Development Albert Vexler, Alan D. Hutson,
Mark Chang Yin Bun Cheung and Xiwei Chen
Frailty Models in Survival Analysis
Andreas Wienke Multiregional Clinical Trials for Statistical Design and Analysis of Clinical Statistics in Drug Research:
Fundamental Concepts for New Clinical Simultaneous Global New Drug Trials: Principles and Methods Methodologies and Recent
Trialists Development Weichung Joe Shih and Joseph Aisner Developments
Scott Evans and Naitee Ting Joshua Chen and Hui Quan Statistical Design and Analysis of Shein-Chung Chow and Jun Shao
Generalized Linear Models: A Bayesian Multiple Testing Problems in Stability Studies Statistics in the Pharmaceutical Industry,
Perspective Pharmaceutical Statistics Shein-Chung Chow Third Edition
Dipak K. Dey, Sujit K. Ghosh, and Alex Dmitrienko, Ajit C. Tamhane, Statistical Evaluation of Diagnostic Ralph Buncher and Jia-Yeong Tsay
Bani K. Mallick and Frank Bretz Performance: Topics in ROC Analysis Survival Analysis in Medicine and
Handbook of Regression and Modeling: Noninferiority Testing in Clinical Trials: Kelly H. Zou, Aiyi Liu, Andriy Bandos, Genetics
Applications for the Clinical and Issues and Challenges Lucila Ohno-Machado, and Howard Rockette Jialiang Li and Shuangge Ma
Pharmaceutical Industries Tie-Hua Ng Statistical Methods for Clinical Trials Theory of Drug Development
Daryl S. Paulson Optimal Design for Nonlinear Response Mark X. Norleans Eric B. Holmgren
Inference Principles for Biostatisticians Models Statistical Methods for Drug Safety Translational Medicine: Strategies and
Ian C. Marschner Valerii V. Fedorov and Sergei L. Leonov Robert D. Gibbons and Anup K. Amatya Statistical Methods
Interval-Censored Time-to-Event Data: Patient-Reported Outcomes: Statistical Methods for Healthcare Dennis Cosmatos and Shein-Chung Chow
Methods and Applications Measurement, Implementation and Performance Monitoring
Ding-Geng (Din) Chen, Jianguo Sun, Interpretation Alex Bottle and Paul Aylin
and Karl E. Peace Joseph C. Cappelleri, Kelly H. Zou, Statistical Methods for Immunogenicity
Andrew G. Bushmakin, Jose Ma. J. Alvir,
Introductory Adaptive Trial Designs: Assessment
Demissie Alemayehu, and Tara Symonds
A Practical Guide with R Harry Yang, Jianchun Zhang, Binbing Yu,
Mark Chang Quantitative Evaluation of Safety in Drug and Wei Zhao
Development: Design, Analysis and
Joint Models for Longitudinal and Time-
Reporting
to-Event Data: With Applications in R
Qi Jiang and H. Amy Xia
Dimitris Rizopoulos
Quantitative Methods for Traditional
Measures of Interobserver Agreement
Chinese Medicine Development
and Reliability, Second Edition
Shein-Chung Chow
Mohamed M. Shoukri
Randomized Clinical Trials of
Medical Biostatistics, Third Edition
Nonpharmacological Treatments
A. Indrayan
Isabelle Boutron, Philippe Ravaud,
Meta-Analysis in Medicine and
and David Moher
Health Policy
Randomized Phase II Cancer
Dalene Stangl and Donald A. Berry
Clinical Trials
Mixed Effects Models for the Population
Sin-Ho Jung
Approach: Models, Tasks, Methods
Sample Size Calculations for Clustered
and Tools
and Longitudinal Outcomes in Clinical
Marc Lavielle
Research
Modeling to Inform Infectious Disease
Chul Ahn, Moonseong Heo,
Control
and Song Zhang
Niels G. Becker
Published Titles
Sample Size Calculations in Clinical Statistical Methods in Drug Combination
Research, Second Edition Studies
Shein-Chung Chow, Jun Shao, Wei Zhao and Harry Yang
and Hansheng Wang
Statistical Testing Strategies in the
Statistical Analysis of Human Growth Health Sciences
and Development Albert Vexler, Alan D. Hutson,
Yin Bun Cheung and Xiwei Chen
Statistical Design and Analysis of Clinical Statistics in Drug Research:
Trials: Principles and Methods Methodologies and Recent
Weichung Joe Shih and Joseph Aisner Developments
Shein-Chung Chow and Jun Shao
Statistical Design and Analysis of
Stability Studies Statistics in the Pharmaceutical Industry,
Shein-Chung Chow Third Edition
Ralph Buncher and Jia-Yeong Tsay
Statistical Evaluation of Diagnostic
Performance: Topics in ROC Analysis Survival Analysis in Medicine and
Kelly H. Zou, Aiyi Liu, Andriy Bandos, Genetics
Lucila Ohno-Machado, and Howard Rockette Jialiang Li and Shuangge Ma
Statistical Methods for Clinical Trials Theory of Drug Development
Mark X. Norleans Eric B. Holmgren
Statistical Methods for Drug Safety Translational Medicine: Strategies and
Robert D. Gibbons and Anup K. Amatya Statistical Methods
Dennis Cosmatos and Shein-Chung Chow
Statistical Methods for Healthcare
Performance Monitoring
Alex Bottle and Paul Aylin
Statistical Methods for Immunogenicity
Assessment
Harry Yang, Jianchun Zhang, Binbing Yu,
and Wei Zhao
Analyzing
Longitudinal
Clinical Trial Data
A Practical Guide
Craig Mallinckrodt
Eli Lilly Research Laboratories
Indianapolis, Indiana, USA
Ilya Lipkovich
Quintiles
Durham, North Carolina, USA
Analyzing
Longitudinal
Clinical Trial Data
A Practical Guide
Craig Mallinckrodt
Eli Lilly Research Laboratories
Indianapolis, Indiana, USA
Ilya Lipkovich
Quintiles
Durham, North Carolina, USA
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2017 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed on acid-free paper
Version Date: 20161025
International Standard Book Number-13: 978-1-4987-6531-2 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts
have been made to publish reliable data and information, but the author and publisher cannot assume
responsibility for the validity of all materials or the consequences of their use. The authors and publishers
have attempted to trace the copyright holders of all material reproduced in this publication and apologize to
copyright holders if permission to publish in this form has not been obtained. If any copyright material has
not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmit-
ted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented,
including photocopying, microfilming, and recording, or in any information storage or retrieval system,
without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.
com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood
Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and
registration for a variety of users. For organizations that have been granted a photocopy license by the CCC,
a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used
only for identification and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Mallinckrodt, Craig H., 1958- | Lipkovich, Ilya.
Title: Analyzing longitudinal clinical trial data / Craig Mallinckrodt and 
Ilya Lipkovich.
Description: Boca Raton : CRC Press, 2017. | Includes bibliographical 
references.
Identifiers: LCCN 2016032392 | ISBN 9781498765312 (hardback)
Subjects: LCSH: Clinical trials--Longitudinal studies.
Classification: LCC R853.C55 M33738 2017 | DDC 615.5072/4--dc23
LC record available at https://lccn.loc.gov/2016032392
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
Contents
Preface .................................................................................................................xvii
Acknowledgments .............................................................................................xix
List of Tables ........................................................................................................xxi
List of Figures ...................................................................................................xxvii
List of Code Fragments ....................................................................................xxxi
Section I Background and Setting
1. Introduction .....................................................................................................3
2. Objectives and Estimands—Determining What to Estimate ...............5
2.1 Introduction ...........................................................................................5
2.2 Fundamental Considerations in Choosing Estimands....................8
2.3 Design Considerations in Choosing Estimands ...............................9
2.3.1 Missing Data Considerations .................................................9
2.3.2 Rescue Medication Considerations ......................................9
2.4 Analysis Considerations ....................................................................12
2.5 Multiple Estimands in the Same Study ...........................................14
2.6 Choosing the Primary Estimand ......................................................15
2.7 Summary ..............................................................................................16
3. Study Design—Collecting the Intended Data ........................................17
3.1 Introduction .........................................................................................17
3.2 Trial Design .........................................................................................18
3.3 Trial Conduct ......................................................................................21
3.4 Summary ..............................................................................................23
4. Example Data .................................................................................................25
4.1 Introduction .........................................................................................25
4.2 Large Data Sets ....................................................................................25
4.3 Small Data Sets ....................................................................................26
5. Mixed-Effects Models Review ...................................................................35
5.1 Introduction .........................................................................................35
5.2 Notation and Definitions ...................................................................36
5.3 Building and Solving Mixed Model Equations ..............................37
5.3.1 Ordinary Least Squares ........................................................37
5.3.2 Generalized Least Squares ...................................................44
5.3.3 Mixed-Effects Models ............................................................45
5.3.4 Inference Tests ........................................................................48
ix