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 marketing gloss.

Key Highlights

• Explains the basics of hypothesis testing in superiority trials, highlighting why a one-sided 2.5% alpha is the operational standard despite persistent use of two-sided 5% language in clinical protocols.
• Refutes the widespread belief that reviewing interim data costs available alpha, making clear that statistical error is not “penalized”—it is allocated, with potential efficiencies in average sample size and, in thoughtfully extended designs, gains in operating characteristics such as power.
• Describes real-world examples, including the SEPSIS-ACT (selepressin) trial sponsored by Ferring Pharmaceuticals, which incorporated more than 20 interim analyses while maintaining a pre-specified final alpha of 0.025; underscores the necessity of transparent, prospective design and explicit documentation for regulatory acceptance.
• Distinguishes between interim actions—such as futility analyses or response-adaptive randomization, which require no alpha adjustment, and early efficacy analyses, which must be precisely modeled to preserve type I error.
• Challenges terminology like “penalty” and “spending alpha,” asserting that imprecise language fosters misunderstanding and leads to missed opportunities in adaptive trial efficiency.
• Emphasizes the crucial role of prospective, simulation-based planning and clear protocol definition at every interim, anchoring statistical practice in measured evidence, not historical convention.

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 therapies, explores the fallout and industry shifts following COVID-19, and maps how Scottish Brain Sciences is directly applying these lessons—establishing the IONA readiness cohort to drive integration between clinical research and clinical practice.

Key Highlights
• Systematic review of EPAD’s objectives, specifically the platform trial and the development of a readiness cohort to streamline patient recruitment
• Detailed account of practical barriers that prevented EPAD from launching interventional arms, including pharmaceutical sponsor reluctance, inflexible IMI funding mechanisms, and the inherent risk aversion surrounding novel platform structures
• Discussion of participant contribution to research design and delivery—an early demonstration of patient involvement models now broadly recognized as best practice
• Analysis of COVID-19's dual impact—derailing EPAD's momentum while catalyzing a change in industry and regulatory acceptance of platform trials in drug development
• Tracing the origins and operationalization of the IONA readiness cohort at Scottish Brain Sciences, including direct integration of recruitment, biobanking, and engagement systems to address the translational gap in dementia medicine
• Evidence-based critique of persistent use of conventional clinical trial formats in Alzheimer’s disease, dissecting operational, financial, and data limitations that stall progress

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 concept of regression-to-the-mean.
• Personal anecdotes from Scott and Nick's experiences, illustrating statistical learning through sports.
• Examination of the regression-to-the-mean phenomenon through examples from baseball and golf.
• Exploration of how misunderstanding the regression-to-the-mean can lead to poor decision-making in clinical trials.
• Insights into placebo effects and how they are often confused with natural statistical phenomena.
• How regression-to-the-mean impacts expectations in financial markets and personal finance decision-making.

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 fundamental role and responsibilities of DSMBs in clinical trials.
• Discussion on how DSMBs ensure scientific integrity and participant safety in adaptive trials.
• Differences in DSMB involvement between traditional and adaptive trial designs.
• The evolving skillset required for DSMB members in the context of complex, adaptive trials.
• Exploration of the critical collaboration between DSMBs and Statistical Analysis Committees.

Quotes
• "The DSMB is tasked with balancing efficacy and safety at a very fundamental level." — Roger Lewis
• "Adaptive trials expand the role of the DSMB to ensure trials are conducted as intended." — Roger Lewis
• "The DSMB needs to review efficacy and safety to appropriately balance them." — Roger Lewis

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 the advantages of biomarker-based adaptive trials in improving drug development success rates.
• Examination of potential sponsorship models for platform trials, emphasizing patient and industry collaboration.

Quotes:

• "Mental illnesses represent a significant global challenge with a staggering unmet need." – Husseini Manji
• "There's a real excitement about precision psychiatry—moving away from a one-size-fits-all approach." – Husseini Manji
• "The patient perspective is crucial for driving significant advances in psychiatric treatment." – Mike Krams
• "We believe that precision medicine biomarker-based adaptive trials could be game-changing in this space." – Husseini Manji

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 running the statistical model, to interactions with Data and Safety Monitoring Boards (DSMBs).
• Preparatory steps required before an adaptive analysis, ensuring the pre-specified design is adhered to and carried out as planned.
• The importance of understanding data in real-time and dealing with interim data idiosyncrasies.

Quotes:

• "We want the adaptive part of the trial to be invisible to sites—analyses might happen in the background without interference." – Scott Berry
• "Our goal is five business days from when we receive the data to when we send the result to the DSMB." – Michelle Detry
• "We always want to make sure that we have time, not just to hit a button and run an analysis and spit out a table, but to think and make sure that the results we’re producing make sense." – Anna McGlothlin

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 Index and its role in adaptive randomization.
• The DSMB's role and interaction with Bayesian decision-making models.
• Simulation-based design to optimize development efficiencies.
• Insights into the predictive power of the trial on weight loss outcomes in subsequent trials.

Quotes:

• "The trial was run entirely by Bayesian algorithms." – Scott Berry
• "They believed this utility function was absolutely the right way to go forward." – Scott Berry

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:

• Meredith Buxton discusses the origins and groundbreaking operations of the I-SPY platform in breast cancer.
• Exploration of how the I-SPY 2 model inspired subsequent platform trials in diverse areas such as glioblastoma and COVID-19.
• GCAR's role as a non-profit entity to foster adaptive trial designs and Meredith’s influential contributions to its formation and success.
• Discover the operational complexities and regulatory considerations essential for modern platform trials.
• Insights into Meredith’s vision for the future of drug development and the ongoing necessity for innovation in trial design.

Quotes:

• “The ideas of this are groundbreaking in many ways.” – Scott Berry
• "The I-SPY2 model could be replicated in other spaces." – Meredith Buxton