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

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 they may hinder progress.
• Insight into the future of clinical trials harnessing external data – a step towards better medical science.

Quotes:

• "If prior data isn't generally leading us in the right direction, we ought to reconsider the basis of scientific inquiry." – Kert Viele
• "The industry's hesitance to use existing data slows innovation and limits our ability to bring effective treatments to market." – Scott Berry

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 pioneering role as the father of modern Bayesian statistics.
• Discussion on Savage's varied interests and collaborations with figures like Milton Friedman and John von Neumann.
• Don Berry recounts his academic experiences alongside Savage and his own journey into clinical trial design.
• Exploration of Savage's legacy through his students and his axiomatic approach to subjective probability.

Quotes:

• "I think he's the father of modern Bayesian statistics. How can you argue about that?" – Don Berry
• "The world around you when you're with Savage is tingling with intellect." – Don Berry
• " We probably wouldn't exist... if it were not for him." – Don Berry

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.

Key Highlights:

• Discussion on the ASTIN Stroke Trial, a groundbreaking experience with Bayesian methodology in drug trials.
• Examination of how adaptive designs can lead to more efficient learning processes in clinical research.
• Exploration of the cultural and strategic challenges of bringing innovative trial designs to conservative pharmaceutical environments.
• Insight into the vital role of having internal champions to advocate for change and innovation.
• The importance of integrating strategic thinking with statistical expertise to drive innovation forward.

Quotes:

• "Respect is earned, but very good communication skills are a necessary condition for implementing innovation." – Mike Krams
• "Innovation for innovation's sake is not the goal; it's about making better decisions for future patients." – Mike Krams

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, starting with James Lind's 1747 scurvy trial.
• Discussion of the first randomized human clinical trial by Austin Bradford Hill and its implications for ordinal endpoint analysis.
• Exploration of the Modified Rankin Score as a current example of ordinal outcomes in stroke trials.
• Critique of conventional methods like dichotomization and proportional odds models for analyzing ordinal data.
• Argument for adopting utility-based approaches in clinical trial analysis for meaningful outcomes.

Quotes

• "Almost every endpoint is ordinal. So you can't escape this." – Scott Berry
• "My claim is nobody has that weight. But yet, it's very commonly done." – Scott Berry
• "Hiding behind ad hoc ways to do this, I think just leads us to bad places." – Scott Berry

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 statistical design of the trial, emphasizing the sharing of control groups and Bayesian methods for efficiency.
• Insights into the FDA's enthusiastic support and the iterative process to align on innovative statistical approaches.
• The dual roles of the trial: significant patient engagement and industry collaboration as facilitating factors for successful trial implementation.
• Discussion on the future adaptation of trial designs based on collected data and emerging biomarkers.

Quotes

• "There was such an energy about your group... everybody had really done their homework." – Dr. Melanie Quintana
• "ALS is a very complex disorder, and we actually did learn a lot." – Dr. Merit Cudkowicz
• "We're adapting with learnings." – Dr. Merit Cudkowicz

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.
• Discussion on the history and evolution of clinical trial simulators at Berry Consultants.
• Exploration of FACTS' new features, such as Bayesian predictive probabilities and phase one dose escalation improvements.
• Insight into the challenges of creating user-friendly software with extensive features for trial simulation.
• Plans for future developments, including wizards and enhanced design comparison tools.

Quotes:
• "FACTS turns trial design and statistics into a game—where you can explore and try different options." – Tom Parke
• "You're creating software that allows exploring designs you can't calculate an answer to." – Tom Parke
• "It's all about making sure the designers have the right tools to efficiently explore different trial designs." – Scott Berry