Podcast Episode
54: Making Sense of Hierarchical Composites
Subscribe to In the Interim...
Scott Berry, Ph.D.
President & Senior Statistical Scientist
In this episode of "In the Interim…", Dr. Scott Berry is joined by statisticians Dr. Amy Crawford, Dr. Cora Allen-Savietta, and Dr. Jessica Overbey for a technical deep dive into hierarchical composite endpoints and the win ratio in clinical trial design.
In this episode of "In the Interim…", Dr. Scott Berry is joined by statisticians Dr. Amy Crawford, Dr. Cora Allen-Savietta, and Dr. Jessica Overbey for a technical deep dive into hierarchical composite endpoints and the win ratio in clinical trial design. The group addresses clinical and statistical justifications for layered endpoint structures, demonstrates the mechanics of pairwise win ratio analysis, and explores operational and interpretive consequences in both conventional and adaptive trials. The panel scrutinizes analytic limitations, regulatory concerns, and emerging modeling strategies—all grounded in real-world trial examples.
Key Highlights
Precise definition and use case for hierarchical composite endpoints in cardiovascular and related trials.
Stepwise breakdown of win ratio mechanics, tie-handling, and the distinction between effect estimation (win ratio) and hypothesis testing (FS-test).
Discussion of endpoint prevalence and dominance, risk of clinical interpretation being tied to lower-order outcomes, the role of patient exposure, and methods to parse component contributions.
Overview of statistical power, role of simulation, and comparative advantages over other composite approaches.
Identification of core limitations: interpretive complexity, opaque weighting, and mutable meaning of wins with maturing data.
Review of predictive probability for adaptive interim analysis and modeling using ordinal regression.
Opinions of US and European regulatory perspectives including support, reservations, and expectations for transparency with graphics and complementary analyses.
Download PDF
View
54: Making Sense of Hierarchical Composites
In this episode of "In the Interim…", Dr. Scott Berry is joined by statisticians Dr. Amy Crawford, Dr. Cora Allen-Savietta, and Dr. Jessica Overbey for a technical deep dive into hierarchical composite endpoints and the win ratio in clinical trial design.
53: The SNAP Trial with Professors Tong and Davis
In this episode of "In the Interim…", Dr. Scott Berry interviews Professors Steven Tong and Josh Davis about the SNAP platform trial for Staphylococcus aureus bacteremia.
52: Bayesian Borrowing in Phase 3 Trials
In this episode of "In the Interim…", Dr. Scott Berry and Dr. Kert Viele examine Bayesian borrowing in Phase 3 clinical trials, focusing on statistical handling of prior information and real-world FDA interactions.
51: The Art of Storytelling with Shaun Cassidy
In Episode 51 of "In the Interim…", Dr. Scott Berry interviews writer, producer, and performer Shaun Cassidy to examine the practical elements of storytelling that matter in scientific and statistical communication.
50: The Fallacy of Ordinal Endpoints
In this episode of "In the Interim…", Dr. Scott Berry and Dr. Lindsay Berry investigate the statistical foundations and clinical implications of analyzing ordinal endpoints, drawing on experience from major stroke and COVID-19 trials.
49: Mr. Berry Goes to Washington
In this episode of "In the Interim…", Dr. Scott Berry marks the podcast’s one-year anniversary, sharing listener metrics, watch data, and regional engagement. He then delivers a step-by-step analysis of the FDA meeting process, detailing the progression from initial sponsor meeting requests and question submission to briefing book preparation, feedback cycles, and in-person logistics.
48: Platform Trial in Orthopaedic Surgery
Dr. Nathan O’Hara (University of Maryland), Dr. Gerard Slobogean (UC Irvine), and Dr. Sheila Sprague (McMaster University) describe the launch and design of the Musculoskeletal Adaptive Platform Trial (MAPT)—the first major adaptive platform trial in orthopaedic surgery.
47: A Visit with Michael Harhay
In this episode of "In the Interim…", Dr. Scott Berry speaks with Dr. Michael Harhay, Associate Professor at the University of Pennsylvania and Director of the Center for Clinical Trials Innovation.
46: The FDA Bayesian Guidance
In this episode of "In the Interim…", Dr. Scott Berry and Dr. Kert Viele deliver a quick reaction to the FDA’s draft guidance on Bayesian statistics for clinical trials of drugs and biologics.
45: Path 2 Parkinson's Prevention with Drs. Simuni and Wendelberger
In this episode of "In the Interim…", Dr. Scott Berry is joined by Dr. Tanya Simuni, Arthur C. Nielsen Jr. Professor of Neurology and Director of the Parkinson’s Disease and Movement Disorders Center at Northwestern University, and Dr. Barbara Wendelberger, Senior Statistical Scientist at Berry Consultants.
44: Statistical Communication
In this episode of “In the Interim…,” host Dr. Scott Berry examines the challenge of communicating complex statistical concepts to non-statistical audiences.
43: The Rumor of One Trial for Substantial Evidence
In this episode of "In the Interim…", host Dr. Scott Berry and frequent co-host Dr. Kert Viele, Senior Statistical Scientist at Berry Consultants, analyze the potential shift in FDA regulatory policy from requiring two independent trials to accepting a single trial as sufficient for “substantial evidence” in drug approvals.
42: Communication for Scientists: A Discussion with Jenny Devenport
In this episode of "In the Interim…", Dr. Jenny Devenport, Global Head of Methods, Collaboration, and Outreach at Roche, joins Dr. Scott Berry for a detailed discussion on career evolution, statistical culture, and communication in the pharmaceutical industry.
41: Navigating the Arena: Platform Trials
In this episode of "In the Interim…", Dr. Scott Berry delivers a metaphoric critique of single-question trial infrastructure through the sports arena analogy, illustrating the cost, patient burden, and data inefficiency of conventional clinical trials.
40: Jumping Hurdles: Interim Analyses for Funding Decisions
In episode 40 of "In the Interim…", Dr. Scott Berry examines the statistical, operational, and behavioral challenges of using interim analyses as triggers for funding in adaptive and seamless Phase II/III clinical trials.
39: Discussion with Kaspar Rufibach
In this episode of "In the Interim...", Dr. Scott Berry interviews Dr. Kaspar Rufibach, Co-Head of Advanced Biostatistical Sciences at Merck.
38: Bayesian Statistics in Clinical trials: The Past, Present, and Future
In this episode of "In the Interim…" guest host Cooper Berry moderates a detailed discussion on the evolution and practice of Bayesian methodology in clinical trials with fellow family members Dr. Don Berry, Dr. Scott Berry, Dr. Lindsay Berry, and Dr. Nick Berry.
37: A Visit with Stroke Neurologist Dr. Jeff Saver
In episode 37 of "In the Interim…", Dr. Jeff Saver, Director of the UCLA Comprehensive Stroke and Vascular Neurology Program, details his shift from behavioral neurology to clinical stroke research after early engagement with multicenter trials like TOAST.
36: The Saga of the Lecanemab Adaptive Phase II Trial
In Episode 36 of "In the Interim…", Dr. Scott Berry and Dr. Don Berry analyze the Phase II trial of Lecanemab (BAN2401) in Alzheimer’s disease, focusing on the application of adaptive Bayesian methods following persistent failures in Alzheimer’s drug development.
35: Teaching Statistics and Data Science through Sports
On this episode of “In the Interim…”, which is co-sponsored by the Journal of Statistics and Data Science Education, Dr. Scott Berry talks with Dr. Jim Albert, Professor Emeritus at Bowling Green State University, whose extensive work encompasses Bayesian statistics and computation, sports analytics, and decades of exemplary teaching.
34: Digital Googols
In this episode of "In the Interim…", Dr. Scott Berry examines the concept of “digital twins” in clinical trials. He details how simulation of clinical trials is a direct analog of digital twin methodology, allowing for the in-silico modeling of the physical trial conduct, enrollment, dropouts, and patient outcomes under varied assumptions.
33: A Visit with Andrew Thomson
In this episode of "In the Interim…", Dr. Scott Berry interviews Dr. Andrew Thomson, owner and lead consultant of Regnitio.
32: Moving Clinical Trial Goalposts
In this episode of "In the Interim…", Dr. Scott Berry and Dr. Kert Viele analyze how regulatory, editorial, and science community standards often impose additional, inconsistent requirements for novel methods in clinical trial design, rarely applied to standard approaches.
31: The Not So Promising Zone Design
In this episode of "In the Interim…", Dr. Scott Berry examines the mathematical foundations and efficiency claims of the promising zone design for adaptive sample size in clinical trials.
30: A Visit with Dr. Janet Wittes
Episode 30 of “In the Interim…” features Dr. Janet Wittes, Fellow of the American Statistical Association, past president of the Society of Clinical Trials, and founder of Statistics Collaborative, in discussion with Dr. Scott Berry.
29: Bayesian Clinical Trials with Frank Harrell
In this episode of "In the Interim…", Dr. Scott Berry chats with Frank Harrell, a professor of Biostatistics at Vanderbilt University and W.J. Dixon Award winner. Harrell describes his transition from frequentist to Bayesian clinical trial design, prompted by a decisive meeting with Dr. Don Berry, informed by David Spiegelhalter’s published work.
28: A Visit with Dr. Derek Angus
In this episode of "In the Interim…", Dr. Scott Berry interviews Dr. Derek Angus, Distinguished Professor and Chair of Critical Care Medicine at the University of Pittsburgh and senior editor at JAMA.
27: The Mystery of Clinical Trial Simulation
Dr. Scott Berry hosts this episode of "In the Interim…", opening with statistical analysis of elite athletes before focusing on the misunderstood role of clinical trial simulation.
26: Discussions on the ICH E20 Draft Guidance
In this episode of "In the Interim…", Dr. Scott Berry and Dr. Kert Viele review the ICH E20 draft guidance on adaptive clinical trial designs, offering a technical yet accessible breakdown for trial sponsors, practitioners, and those interested in clinical development.
25: A Discussion with Michael Proschan on Response-Adaptive Randomization
In this episode of "In the Interim…", Dr. Scott Berry and NIH’s Dr. Michael Proschan conduct a detailed discussion from opposing viewpoints on response-adaptive randomization (RAR) in clinical trials.
24: STEP Statistical Modeling
In this episode of "In the Interim…", Dr. Scott Berry, Dr. Elizabeth Lorenzi, and Dr. Amy Crawford discuss the STEP platform trial’s statistical methodology for evaluating which acute stroke patients benefit and which do not from endovascular therapy (EVT).
23: Bayesian Approach in Clinical Trials
This episode of "In the Interim…" features Dr. Scott Berry, Dr. Kert Viele, and Dr. Melanie Quintana of Berry Consultants dissecting the technical and operational landscape of Bayesian statistics in clinical trial design.
22: The Time Machine
Dr. Scott Berry and Dr. Kert Viele discuss the origins and implementation of the “time machine” modeling approach, beginning with sports analytics and progressing to adaptive platform clinical trials.
21: The Legend of I-SPY 2 - Part B
In this episode, Dr. Don Berry and Dr. Scott Berry provide an in-depth account of I-SPY 2, focusing on the trial’s use of the “time machine” methodology—an Bayesian solution allowing bridging across arms to inform ongoing analyses.
20: The Legend of I-SPY 2 - Part A
In Episode 20 of Berry’s "In the Interim..." Podcast, The Legend of I-SPY 2 - Part A, Dr. Don Berry and Dr. Scott Berry discuss the origins and design of the I-SPY trials.
19: The STEP Platform with Dr. Eva Mistry and Dr. Jordan Elm
This episode of "In the Interim..." features an in-depth discussion of the StrokeNet Thrombectomy Endovascular Platform (STEP), a multi-domain, adaptive platform trial for acute stroke, anchored in the NIH StrokeNet network.
18: A Statistician Reads JAMA
Dr. Scott Berry applies a statistician’s review of a random trial result published in JAMA – the FAIR-HF2 clinical trial. Interrogating the frequentist paradigm and the focus on the binary outcome of the primary hypothesis test.
17: Seamless 2/3 Trial Designs
Scott Berry convenes co-authors Kert Viele, Joe Marion, and Lindsay Berry to discuss the statistical and developmental nuances of inferentially seamless phase 2/3 clinical trial designs.
16: Spending Alpha
In this solo episode of "In the Interim...", Scott Berry, President and Senior Statistical Scientist at Berry Consultants, addresses deep-rooted confusion in the field of adaptive clinical trial design surrounding the concept of “spending alpha.”
15: Prof Craig Ritchie: Looking Back at EPAD, Moving Forward in Alzheimer's Disease
Scott Berry, Founder of Berry Consultants, interviews Professor Craig Ritchie—specialist in brain health and neurodegenerative diseases, Chief Investigator of EPAD (European Prevention of Alzheimer Dementia), and CEO of Scottish Brain Sciences—for a precise analysis of platform trial methodology in Alzheimer’s research.
14: Drug Developers' Lessons from Sports: Regression-to-the-Mean
In this engaging episode of "In the Interim...", host Dr. Scott Berry is joined by Dr. Nick Berry to explore the intriguing parallels between sports and drug development, focusing on the concept of "regression-to-the-mean."
13: DSMBs in Adaptive Trials with Roger Lewis
In this episode of "In the Interim…", host Dr. Scott Berry is true to the name of the podcast, as he discusses the unblinded world of adaptive clinical trials alongside Dr. Roger Lewis, a renowned expert in both statistical science and clinical medicine.
12: Platform Trial in Psychiatry with Dr. Husseini Manji
In the latest episode of "In the Interim...", Dr. Scott Berry and Dr. Mike Krams sit down with Dr. Husseini Manji, to explore the potential of platform trials in advancing precision medicine within psychiatry, particularly in tackling complex mental illnesses.
11: Implementing Adaptive Trials
In Episode 11 of "In the Interim...", host Scott Berry discusses the nuances of implementing adaptive clinical trials with Dr. Anna McGlothlin and Dr. Michelle Detry from Berry Consultants.
10: Revisiting Seamless 2/3 Trial for GLP-1 Agonist
In this episode of "In the Interim..." we revisit the ground-breaking seamless phase 2/3 clinical trial for the GLP-1 agonist, dulaglutide—better known as Trulicity.
9: I-SPY 2 to GBM AGILE and Beyond
In this episode of "In the Interim...," we sit down with Dr. Meredith Buxton to explore the evolution of platform trials from I-SPY 2 to GBM AGILE and Beyond.
8: External Data in Clinical Trials
In this episode of "In the Interim...," Scott Berry and Kert Viele navigate the nuanced debate surrounding the integration of external data in clinical trials.
7: Remembering Jimmie Savage
In this episode of "In the Interim," Don Berry shares the life and work of Jimmie Savage, his advisor and a legendary figure in Bayesian statistics.
6: The Art and Slog of Innovating
In this compelling episode of "In the Interim," Dr. Mike Krams, a seasoned expert in clinical trials and drug development, joins us to discuss the art and slog of innovation in pharmaceutical companies.
5: Religion, Politics, and Ordinal Outcomes
In this episode of "In the Interim," Scott Berry discusses the vital topic of ordinal outcomes in clinical trials—a subject as controversial as politics and religion at the dinner table.
4: HEALEY ALS Platform Trial with Dr. Merit Cudkowicz and Dr. Melanie Quintana
In this episode of the podcast, we sit down with Dr. Merit Cudkowicz and Dr. Melanie Quintana to discuss the inception and execution of the Healy ALS Platform Trial, a revolutionary approach designed for efficiency and impactful data collection.
3: FACTS 7.1 Release with Tom Parke
In this episode of In the Interim, Berry's Director of Software, Tom Parke, discusses the intricacies and updates surrounding FACTS, a sophisticated clinical trial simulation software.
2: When should you use adaptive design clinical trials?
In this episode of "In the Interim," we consider the nuances of adaptive design clinical trials with distinguished guests Dr. Scott Berry and Dr. Kert Viele from Berry Consultants. The conversation centers around the vital question: when should these adaptive designs be implemented?
1: The story of Berry Consultants
Discover the transformative journey of Berry Consultants, pioneers in adaptive clinical trials, and their impact on the future of medical research.