Table Of ContentQuantitative Drug Safety and
Benefit-Risk Evaluation
Practical and Cross-Disciplinary
Approaches
Chapman & Hall/CRC Biostatistics Series
Series Editors
Shein-Chung Chow, Duke University School of Medicine, USA
Byron Jones, Novartis Pharma AG, Switzerland
Jen-pei Liu, National Taiwan University, Taiwan
Karl E. Peace, Georgia Southern University, USA
Bruce W. Turnbull, Cornell University, USA
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Edited by William Wang, Melvin Munsaka, James Buchanan and Judy X. Li
For more information about this series, please visit: https://www.routledge.
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Quantitative Drug
Safety and Benefit-
Risk Evaluation
Practical and Cross-
Disciplinary Approaches
Edited by
William Wang, Melvin Munsaka,
James Buchanan and Judy X. Li
First edition published 2022
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Contents
Editors ....................................................................................................................vii
List of Contributors .............................................................................................viii
Introduction Chapter ..........................................................................................xiii
Part A Regulatory Landscape and Interdisciplinary
Collaboration in Safety Evaluation
1. The Emergence of Aggregate Safety Assessment across the
Regulatory Landscape ....................................................................................3
James Buchanan and William Wang
2. Monitoring of Aggregate Safety Data in Clinical Development:
A Proactive Approach ..................................................................................15
Lothar Tremmel and Barbara Hendrickson
3. Safety Signaling and Causal Evaluation ..................................................45
James Buchanan and Mengchun Li
4. Safety Monitoring through External Committees ..................................77
Amit Bhattacharyya, William Wang and James Buchanan
Part B Statistical Methodologies for Safety Monitoring
5. An Overview of Statistical Methodologies for Safety
Monitoring and Benefit-Risk Assessment .............................................101
William Wang, Ed Whalen, Melvin Munsaka and Judy X. Li
6. Quantitative Methods for Blinded Safety Monitoring .......................119
Melvin Munsaka and Kefei Zhou
7. Bayesian Safety Methodology ..................................................................133
Michael Fries, Matilde Kam, Judy X. Li, Satrajit Roychoudhury,
Mat Soukup and Brian Waterhouse
8. Likelihood-Based Methods for Safety Monitoring ..............................167
Ed Whalen, Krishan Singh, Li-An Lin, Melvin Munsaka and
William Wang
v
vi Contents
9. Meta-Analysis of Drug Safety Assessment ...........................................187
Rositsa B. Dimova, Sourav Santra and Melvin Munsaka
Part C Design and Analysis Considerations
in Randomized Controlled Trials and Real-World
Evidence for Safety Decision-Making
10. Pragmatic Trials with Design Considerations for
Cardiovascular Outcome Trials ................................................................215
Li-An Lin, Ed Whalen, Melvin Munsaka and William Wang
11. Post-Market Safety Assessment Using Observational Studies
and the Food and Drug Administration Sentinel System ..................233
Yong Ma, Rima Izem, Ellen Snyder and Wei Liu
12. Analysis Considerations for Real-World Evidence and
Clinical Trials Related to Safety ...............................................................253
Richard C. Zink, Melvin Munsaka, Birol Emir, Yong Ma,
Judy X. Li, William Wang and Dimitri Bennett
Part D Safety/Benefit-Risk Evaluation and
Visualization
13. Trends and Recent Progress in Benefit-Risk Assessment
Planning for Medical Products and Devices .........................................285
Lisa R. Rodriguez, Cheryl Renz, Brian Edwards and William Wang
14. Estimands in Safety and Benefit-Risk Evaluation ................................317
Shuai S. Yuan, Yodit Seifu, William Wang and Michael Colopy
15. Visual Analytics of Safety and Benefit-Risk from
Clinical Trial Data .......................................................................................351
Melvin Munsaka, Kefei Zhou, Krishan Singh, Michael Colopy,
Chen Chen and Meng Liu
Index .....................................................................................................................375
Editors
William Wang, PhD, is currently Executive Director in Clinical Safety
Statistics and Late Develop Statistics (Asia Pacific region), Biostatistics and
Research Decision Sciences (BARDS), Merck Research Laboratories. He has
over 25 years of global clinical development experiences. He has co-c haired
the ASA Safety Working Group and served as the deputy topics leader for
the ICH E17 Multi- Regional Clinical Trial Working Group. He is an elected
ASA Fellow.
Melvin Munsaka, PhD, is currently Senior Director and Head of Safety
Statistics at AbbVie. He has more 25 years of industry experience working in
various capacities including strategic leadership roles. He has participated in
multiple global submissions covering a wide range of therapeutic areas and
is a member of the ASA Biopharmaceutical Safety Scientific Working Group
(WG), DIA Bayesian Scientific WG, the PHUSE Safety Analytics and the Data
Visualization and Open- Source Technology WGs.
James Buchanan, PharmD, is President of Covilance LLC, a drug safety con-
sulting firm. He teaches the Advanced Signal Detection course for DIA, is
a co- lead of the American Statistical Association Biopharmaceutical Safety
Working Group and also co-l ead on the Interactive Safety Graphics task force
that is developing novel, open- source interactive graphical tools to identify
and evaluate safety issues during drug development.
Judy X. Li, PhD, is currently Senior Director and Biostatistics Lead for San
Diego site at Bristol Myers Squibb. Before joining the industry, she worked at
the US Food and Drug Administration (FDA) as a master statistical reviewer
and supervisory mathematical statistician in multiple centers. She is an
active member of the ASA Biopharmaceutical Section Executive Committee,
as the co-chair of 2019 ASA Biopharmaceutical Section Regulatory Industry
Statistics Workshop, and the founding co-c hair of the ASA Safety Working
Group.
vii
Contributors
Dimitri Bennett, MD, MPH, is the Director Pharmacoepidemiology at
Takeda Pharmaceuticals, where his key responsibility includes leader-
ship for the development of global safety pharmacoepidemiology pro-
grams for Gastroenterology and Cardiovascular products. He has 20
years of experience in epidemiology and is a Fellow of the International
Society of Pharmacoepidemiology and the American College of
Epidemiology.
Amit Bhattacharyya, PhD, is currently the Senior Director of Biostatistics at
Alexion, where he leads statistical support for the Amyloidosis program. He
has more than 25 years of experience in various statistical leadership roles
globally in drug discovery and development in R&D. He is an elected Fellow
of the American Statistical Association.
Chen Chen, PhD, is a Senior Biostatistician at UCB. She previously worked
for AbbVie in clinical development and in regulatory submissions. She is
involved in research on visual analytics of safety data. Since joining UCB,
she has been engaged in the development of Bayesian methods for blinded
safety signal detection and visualization tools for benefit- risk assessment.
Michael Colopy, PhD, is a Safety Statistics and Decision Scientist at UCB
with over 25 years of industry experience. His areas of expertise include sta-
tistical methods in clinical trials and epidemiology, signal detection, benefit-
risk analysis and Monte Carlo simulation, Patient Preference and Structured
Benefit-R isk Network, predictive analytics, visualization and Bayesian deci-
sion science. He is an active collaborator on the ASA Safety Monitoring Work
Stream and EFSPI Benefit-R isk Special Interest Group.
Rositsa B. Dimova, PhD, is affiliated with the Center for Biologics Evaluation
and Research at the U.S. Food and Drug Administration. She has more than
13 years of experience in the biopharmaceutical research area. Dr. Dimova
received her PhD degree in Biostatistics from Columbia University and is a
member of the ASA Safety Working Group.
Brian Edwards, MD, spent 14 years in hospital medicine and clinical research
before joining the UK Medicines Control Agency for 5 years. Over the last 20
years, he has held senior roles in pharmacovigilance in Parexel, Johnson &
Johnson and latterly NDA group. Currently he consults for his own com-
pany, Husoteria Ltd.
viii
Contributors ix
Birol Emir, PhD, is Senior Director and RWE Statistics Group Lead in the
Statistical Research and Data Science Center at Pfizer. He is also Adjunct
Professor of Statistics at Columbia University in New York and External PhD
Committee Member in the Graduate School of Arts and Sciences at Rutgers,
The State University of New Jersey. He is co- author of the book Interface
Between Regulation and Statistics in Drug Development.
Michael Fries, PhD, is Head, Biostatistics at CSL Behring which provides sta-
tistical support for clinical trials, statistical innovation, and product develop-
ment. He has over 20 years of experience in Pharmaceuticals and academics.
Mike has research interests in safety biostatistics, quantitative decision making
including go/no go criteria and assurance, and Biomarkers in clinical trials.
Barbara Hendrickson, MD, is Immunology Therapeutic Area Head in
Pharmacovigilance and Patient Safety, AbbVie. She is a subspecialist in
Pediatric Infectious Diseases with over 15 years in academic medicine and 17
years of pharmaceutical industry experience. She has been involved in mul-
tiple safety statistics initiatives and co-l eads the DIA-A SA Aggregate Safety
Assessment Planning Task Force.
Rima Izem, PhD, is an Associate Director at Novartis where she supports devel-
opment and implementation of novel statistical methods using RWD or hybrid
designs in clinical development across therapeutic areas. Her experience includes
pioneering work in causal inference, signal detection, and survey research at
FDA, comparative effectiveness in rare diseases at Children’s National Research
Institute, and dimension reduction methods at Harvard University.
Maria Matilde Kam, PhD, is Associate Director for Analytics and Informatics
for the Office of Biostatistics (OB) at FDA/CDER. She has strategic and over-
sight responsibility for data standards, data integrity, data science, scientific
computing and statistical programming activities in OB. She has over 25
years of industry and regulatory experience.
Mengchun Li, MD, MPA, is the Director of Pharmacovigilance at TB
Alliance, where she chairs the multidisciplinary safety management team
and takes the leading role on clinical safety. She has more than 13 years of
drug development experience in the pharmaceutical industry. She co- leads
the DIA-A SA Interdisciplinary Safety Evaluation workstream under the ASA
Biopharmaceutical Safety Working Group.
Li- An Lin, PhD, is the Associate Principal Biostatistician at Merck, where
he leads the statistical support for early oncology safety. He has more than
6 years of experience in safety statistics with research interest in the areas
of adaptive trial design, blinded safety monitoring, meta-a nalysis, Bayesian
methods, and causal inference methods.
