In the Interim...

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. Scott discusses model-based patient prediction and highlights scenarios where prediction of counterfactual outcomes can increase efficiency, particularly in rare disease or limited-data settings. He provides a systematic comparison of Unlearn’s PROCOVA neural network approach with traditional covariate adjustment, noting that proprietary models must demonstrate clear improvement over sta...

Duration: 00:38:14

In this episode of "In the Interim…", Dr. Scott Berry interviews Dr. Andrew Thomson, owner and lead consultant of Regnitio. Thomson discusses his academic progression from mathematics at Cambridge to a Master’s at Southampton and advanced study with Prof. Sylvia Richardson at Imperial College, followed by doctoral work in cluster randomized trials at the London School of Hygiene and Tropical Medicine. He recounts the realities of regulatory roles, including contemplative study of data, working within multidisciplinary teams, and delivering regulatory assessments to senior committees. The episode contrasts EMA’s collaborative cross-country structure against the more centralized FDA process and ex...

Duration: 00:43:37

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. Examples from oncology, enrichment trials, platform studies, and endpoint analysis illustrate how adaptive and Bayesian designs are frequently subject to higher scrutiny, shifting metrics, or distinct evidentiary demands. The episode covers technical and regulatory issues, such as the selective application of Type 1 error controls, evolving multiplicity guidance, and challenges in ethical reasoning with adaptive allocation. Scott and Kert frame the di...

Duration: 00:37:13

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. Scott unpacks the conditional power thresholds that trigger sample size increases without the need to adjust alpha, as originally presented by Mehta & Pocock. He systematically demonstrates, via simulation, that the promising zone rarely provides meaningful efficiency gains over fixed designs and is consistently outperformed by group sequential designs that allocate alpha across multiple analyses. Using a driving-route analogy, Scott highlights the practical flaw in making pivotal trial decisions earlier than ne...

Duration: 00:39:39

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. Dr. Wittes details her progression from Radcliffe biochemistry to Harvard statistics, shaped by targeted mentorship and her family’s insistence on advanced scientific training. She describes teaching at Hunter College, her NIH/NHLBI tenure overseeing extensive DSMB work, and the launch of Statistics Collaborative 32 years ago, building the business with her children and their peers. The episode explores her consulting on clinical trial design for orphan a...

Duration: 00:40:50

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. The dialogue addresses persistent academic opposition to Bayesian methods, operational constraints in trial implementation, regulatory work at FDA, and technical Bayesian modeling details.

Key Highlights

Harrell credits Don Berry’s direct influence for converting him to Bayesian methods during his early career at Duk...

Duration: 00:47:20

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. The discussion addresses the decades-long controversy surrounding steroid use in community-acquired pneumonia (CAP) and sepsis. The episode delivers a chronological assessment of the evidence base—summarizing trial results from pivotal studies, including CAPE COD, REMAP-CAP, ADRENAL, and multiple French trials led by Dr. Djillali Annane. Dr. Angus analyzes why discrepancies persist in outcomes, clinical recommendations, and international guidelines, and underscores the challenge of heterogeneous treatment effects. The episode...

Duration: 00:41:58

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. He distinguishes simulation as a predictive tool from its use as an in-silico process that enables trial design exploration, iteration, and optimization. Clinical trial simulation provides a mechanism for iterative comparison of multiple designs, driven by ongoing team feedback and evolving trial objectives. Scott stresses that rigid simulation plans are “not productive,” since the most effective designs typically emerge when stakeholders view real trial examples and suggest new design options in real time...

Duration: 00:41:38

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. Drawing on their practical experience in creating and presenting adaptive trial designs to regulators, they discuss the document’s strengths, areas of consensus, and where cautionary or restrictive language appears. Listeners are guided through the evolving regulatory landscape, distinctions between Bayesian and frequentist approaches, and what new harmonization efforts mean for planning adaptive confirmatory trials. The episode conveys hand...

Duration: 00:38:17

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. The discussion focuses on where they agree – on the positives and negatives of RAR, and where they disagree on its scientific use.

Key Highlights

Potential issues of using RAR: Potential temporal trends, unblinding, reduction in statistical efficiency in 2-arm trialsPotential benefits include improved statistical efficiency in multi-arm trials  depending on the goals (e.g. dose-finding trials).Potential unblinding of results in non-blinded trials and the need for ope...

Duration: 00:44:45

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). The discussion critiques the inadequacy of traditional clinical trials powered for a single population to show benefit, as the goal of the trial is to identify who benefits, not if the entire population has a net benefit. The team walks through the development and simulation of a Bayesian change point model, addressing heterogeneous treatment responses across the NIH Stroke Scal...

Duration: 00:33:43

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. The episode discussed what is Bayesian statistics, the impact of informative and non-informative priors, and clarifies when and why Bayesian approaches surpass frequentist analyses—especially in adaptive, platform, and rare disease trial settings. The discussion directly challenges the misconception that Bayesian methods “lower the bar," presenting evidence that they often require broader data synthesis and can raise evidentiary standards.

Key regulatory developments at FDA and EM...

Duration: 00:43:43

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. The episode focuses on how techniques for comparing athletes across eras translate into methodology for platform trials.

Key Highlights

Sports analytics as foundation: Early work of modelling athlete comparisons across eras using bridging methodologies.Platform trial application: The time machine model in I-SPY 2 enabled efficient control allocation through overlapping arms over extended trial periods.Core modeling principles: Additive treatment effect assumptions and the necessity of sufficient temporal over...

Duration: 00:39:08

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—a Bayesian solution allowing bridging across arms to inform ongoing analyses. The discussion details how predictive probabilities and adaptive randomization shaped pivotal decisions, including the handling of Pertuzumab’s approval and Neratinib’s subtype-specific performance. This episode also documents the technical and operational contributions of Laura Esserman, Anna Barker, Janet Woodcock, Meredith Buxton, and Ashish Sanil, clarifying the roles that enabled the platform’s success and broader impact on subsequent adaptive trials.

Key Highl...

Duration: 00:25:45

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. Their conversation explains the inefficiency of traditional adjuvant breast cancer trials and details the shift to the neoadjuvant approach, where tumor response can be observed prior to surgery. 

I-SPY 1 served as a proof-of-concept using MRI for probabilistic prediction of pathologic complete response (pCR). I-SPY 2 represents a major advancement in clinical trial science, introducing a multi-arm bandit methodology, integration of biomarker-driven subtypes and signatures, and a str...

Duration: 00:40:09

This episode of "In the Interim..." features an in-depth discussion of the StrokeNet Thrombectomy Endovascular Platform (STEP), a multi-domain, multi-factorial, adaptive platform trial for acute stroke, anchored in the NIH StrokeNet network. Guests Dr. Eva Mistry (University of Cincinnati) and Dr. Jordan Elm (Medical University of South Carolina) join us to explain how STEP enables simultaneous investigation of multiple treatment strategies in patients with acute ischemic stroke. The conversation details the use of a master protocol, the integration of industry partners through the Other Transactional Authority (OTA) NIH mechanism, and innovative statistical designs to efficiently identify improved treatment strategies.<...

Duration: 00:40:39

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. He scrutinizes the Hochberg multiplicity adjustment, challenges the prevailing disregard for accumulated scientific evidence, and contrasts the limitations of black/white view of clinical trial of over 1000 patients and 6 years of enrollment. A contrast is made to what a potential Bayesian approach, grounded in practical trial interpretation and evidence integration would look like. The episode argues how current norms, created by dogmatic statistical views...

Duration: 00:39:03

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. The group dissects the simple method for distributing alpha when including stage 1 data, whether it is a good idea to distribute alpha, and the optimal allocation of sample size when Stage 1 data are carried forward, all referencing their recently published work in Pharmaceutical Statistics.

Key Highlights:

Systematic definition of seamless phase 2/3 trial designs, contrasting fixed, separate-phase models with integrated, inferentially seamless approaches.Detailed explanation of the required alpha adjustment when selecting...

Duration: 00:45:48

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.” Drawing on practical experience and rigorous statistical foundations, Berry addresses the prevailing language and myths that conflate interim analysis with loss of type I error. He clarifies that, with planned and transparent allocation of alpha, interim analyses enable more power with more efficient design, and robust clinical trials—without sacrificing statistical validity. This is a precise and fact-driven examination for those demanding technical clarity, not ma...

Duration: 00:37:59

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 broad discussion of platform trial methodology in Alzheimer’s Disease research as well as looking towards the future of drug development. The conversation dissects the origins and ambitions of the EPAD initiative, the conception and scientific function of the readiness cohort, and the pragmatic obstacles to deploying innovative trial models within rigid institutional frameworks. Professor Ritchie details why the EPAD platform trial failed to initiate any th...

Duration: 00:37:17

In this engaging episode of "In the Interim...", host Dr. Scott Berry is joined by Dr. Nick Berry to explore the intriguing statistical parallels between sports and drug development, focusing on the concept of "regression-to-the-mean." Presenting examples that seem clear in sports, they discuss how these insights can illuminate the challenges faced in clinical trials and scientific inferences in medical decision making. Whether you're a statistician, drug developer, or sports enthusiast, this episode offers valuable perspectives on data interpretation and statistical phenomena.

Key Highlights:
• Discussion on how lessons from sports can benefit drug developers, emphasizing the co...

Duration: 00:41:09

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. Together, they explore the critical role of Data Safety Monitoring Boards (DSMBs) in safeguarding trial integrity and participant safety specifically for adaptive trials. The discussion navigates the complexities and challenges faced by DSMBs, particularly in adaptive trial contexts, offering valuable insights for anyone involved in clinical trial science.

Key Highlights
• Overview of the fund...

Duration: 00:37:36

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. Listen as we discuss how an adaptive platform trial could transform drug development, paving the way for breakthroughs in understanding and treating psychiatric disorders.

Key Highlights:

Overview of the burden of serious mental illness and the pressing need for innovative treatment approaches.Discussion on precision psychiatry and the potential of a platform trial to address the heterogeneity of psychiatric disorders.Insights into th...

Duration: 00:39:12

In Episode 11 of "In the Interim…", we discuss the nuances of implementing adaptive clinical trials with Dr. Anna McGlothlin and Dr. Michelle Detry from Berry Consultants. Both Anna and Michelle, seasoned Directors and Senior Statistical Scientists, shed light on the critical role their team plays in innovative adaptive clinical trials. They describe the frequent challenges and highlight the importance of high-quality trial implementation to ensure accurate and reliable outcomes, making this episode a must-listen for anyone involved in clinical trials.

Key Highlights:

Insight into the statistical implementation of adaptive clinical trials.Logistics of data handling, to ru...

Duration: 00:41:25

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. We discuss the intricacies of the adaptive trial design, and the unique features that helped expedite development by 12-18 months. Listeners will gain insight into how Bayesian algorithms and innovative statistical methods were pivotal in navigating a complex trial design, benefiting Eli Lilly's pipeline and changing the landscape of diabetes treatment.

Key Highlights:

Outline of the trial design and the barriers faced during its inception in 2007-2008.Explanation of the Clinical Utility In...

Duration: 00:42:37

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. With a rich history in innovative trial design, Meredith shares the journey from pioneering adaptive clinical trials in breast cancer with I-SPY 2 to her current role at the Global Coalition for Adaptive Research (GCAR). This conversation offers insights into accelerating clinical trial timelines, innovative operational frameworks, and their applications across multiple medical domains, making it a must-listen for anyone involved in clinical development and platform trials.

Key Highlights:

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Duration: 00:33:26

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. Discover the implications and potential benefits and pitfalls of leveraging historical and real-world evidence in the analysis of clinical trials.

Key Highlights:

• Exploration of how external data can influence clinical trial analyses and the inherent risks versus rewards.
• Examination of the frequentist versus Bayesian perspectives on data integration.
• Discussion of real-world cases where external data has been used.
• Debate on the conservative nature of current scientific approaches and how...

Duration: 00:28:35

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. Hosted by Scott Berry, the discussion reveals the personal and professional experiences that shaped Savage's groundbreaking contributions. Discover the intricacies of Savage's influence on statistical thought and his profound legacy, from his tragic childhood to a profound effect on Bayesian statistics and scientific thought.

Key Highlights:

• Don Berry shares the personal story of Jimmie Savage's troubled childhood and how it influenced his work and personality.
• Insights into Savage's pion...

Duration: 00:38:59

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. With over 30 years in the field, Dr. Krams shares insights on leveraging Bayesian statistics and innovative designs to transform development approaches. The conversation explores disruptive approaches to drug development, the importance of having champions for change, and the future of innovation in clinical trials. Mike highlights the necessity of integrating strategic decision-making with statistical expertise to enhance the efficiency and effectiveness of clinical trials.

...

Duration: 00:27:55

In this episode of "In the Interim," Dr. Scott Berry discusses the vital topic of ordinal outcomes in clinical trials—a subject as controversial as politics and religion at the dinner table. Using historical examples like James Lind's 1747 scurvy trial and Austin Bradford Hill’s pioneering randomized trial, the episode explores the complexities and ongoing debates about analyzing ordinal endpoints. Berry challenges conventional analysis methods and advocates for more refined, explicit approaches, delivering valuable insights for statisticians, clinicians, and anyone involved in clinical trial designs.

Key Highlights

• Examination of the historical context of ordinal outcomes, starti...

Duration: 00:30:18

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. With insights from both medical and statistical perspectives, this episode offers a comprehensive understanding of the trial's structure and outcomes, shedding light on its potential to reshape neuro-therapeutics research.

Key Highlights

Dr. Merit Cudkowicz discusses the motivation behind adopting master platform trials for ALS and the collaboration that brought it to life.Dr. Melanie Quintana explains the...

Duration: 00:27:47

In this episode of "In the Interim," Berry's Director of Software, Tom Parke, takes us into the fascinating realm of clinical trial simulation. With Tom joining from the UK, we discuss the intricacies and updates surrounding FACTS, a sophisticated clinical trial simulation software. Learn about its significance in designing adaptive trial designs and its latest enhancements with the release of FACTS 7.1. Discover the balance between expanding features and maintaining user simplicity, ensuring that both Berry Consultants and external users can innovate effectively.

Key Highlights:
• Introduction of FACTS 7.1, emphasizing enhancements in code quality and simulation capabilities.
• Disc...

Duration: 00:27:33

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? Listeners will gain invaluable insights into the mechanics of adaptive trials, the Bayesian approach, and scenarios where these designs prove most effective. Whether you're involved in clinical research or simply intrigued by the evolution of clinical trials, this episode enriches your understanding with expert perspectives and practical examples.

Key Highlights:

Dr. Scott Berry...

Duration: 00:30:59

In the inaugural episode of Berry's "In the Interim...," we sit down with the founders of Berry Consultants, Dr. Don Berry and Dr. Scott Berry. Celebrating their 25th anniversary as a company, they explore the pioneering journey of their firm, known for transforming the landscape of clinical trials with their adaptive and Bayesian methodologies. With stories from their early days to innovative projects on the horizon, this episode provides a fascinating look into how Berry Consultants is redefining clinical research and impacting global health.

Key Highlights

The founding story of Berry Consultants and the inspiration behind...

Duration: 00:36:26