In the Interim...

On the latest episode of "In the Interim…", Dr. Scott Berry provides an empirical examination of two recent JAMA trials: TRACK (low-dose rivaroxaban in advanced kidney disease) and VICTORY (IV vitamin C in severe burn injury). The TRACK trial lacked any pre-specified futility criteria, with a DSMB-initiated stop based on conditional power calculations. Scott argues that conditional power, especially in this interim context, is a poor, misleading tool—contrasting it against a Bayesian predictive probability calculation that produced a much lower and more realistic estimate of success. In VICTORY, a pre-specified risk ratio threshold for futility was incorporated, with simulation confirming minimal effect on bias and statistical power. Scott underscores the practical and ethical importance of rigorously pre-specified, simulation-based futility rules and operationalizes the case for Bayesian predictive probability as a decision metric in interim monitoring. He reiterates that responsibility for defining futility belongs to trial designers, not left to ad hoc DSMB judgment, and calls for precise statistical planning in adaptive trial protocols.
Key Highlights
TRACK: No pre-specified futility rule; DSMB stopped for futility using conditional power post hoc.
Technical critique of conditional power as misguided at interim, supporting Bayesian predictive probability instead.
VICTORY: Pre-specified futility threshold, with simulation confirming minimal operational bias and power reduction.
Emphasizes pre-specified, simulation-based futility planning and predictive probability monitoring as standards for all trials.
For more, visit us at https://www.berryconsultants.com/

In this episode of "In the Interim…", Dr. Scott Berry and Dr. Kert Viele examine response-adaptive randomization (RAR) in clinical trials, dissecting its statistical rationale, common criticisms, and implementation challenges. Drawing on extensive experience with trials such as BAN2401 (lecanemab), ICECAP, dulaglutide seamless Phase 2/3, I-SPY2, REMAP-CAP, PROSPECT, and the historical ECMO trial, they discuss the scientific advantages and disadvantages and ethical impact. RAR reallocates patient assignments during interim analyses to direct more patients to better-performing arms, but this can reduce power in two-arm trials, introduce complexity from temporal trends, and create operational complexity. The ECMO trial and "play-the-winner" approaches are discussed as cautionary examples emphasizing the need for thorough simulation before deployment. The hosts highlight RAR’s strengths for dose-finding, multi-arm, and some platform designs, but underscore its limitations in confirmatory two-arm settings. Operational demands, data reliability, simulation across scenarios, and resistance to overgeneralization are recurrent themes. The episode concludes by situating RAR within the broader context of adaptive platform trials and learning healthcare systems.
Key Highlights
Definition and mechanics of RAR, with interim analysis guiding allocation updates
Multi-arm adaptive and platform trial experiences (BAN2401, ICECAP, dulaglutide, I-SPY2, REMAP-CAP, PROSPECT)
Critique of RAR in two-arm trials (power loss), temporal trends, unblinding, and overgeneralized literature
ECMO/play-the-winner: risks of poorly simulated RAR
Necessity for rigorous pre-trial simulation and robust data flows
Contextualization of RAR’s role in both traditional and learning healthcare environments
For more, visit us at https://www.berryconsultants.com/

In this episode of "In the Interim…", Dr. Scott Berry explores the origins of REMAP-CAP with Prof. Steve Webb, former chair of the REMAP-CAP International Trial Steering Committee. This episode examines how pandemic preparedness efforts after 2009 H1N1 shaped the design of an international, adaptive platform trial to be able to respond rapidly to new infectious threats. Steve and Scott explain the sequence of strategy meetings, the role of the PREPARE consortium in securing EU funding and subsequent federation across Australia and Canada. The discussion details REMAP-CAP’s technical foundations: a modular master protocol, domain architecture, Bayesian adaptive methods, and frequent interim analyses. When COVID-19 emerged, these core elements permitted immediate platform activation to combat the pandemic infection with assessment of treatments across multiple domains—including steroids, immune modulation, and anticoagulation—generating actionable evidence in weeks. The episode also addresses international data harmonization, multi-platform trial collaboration, and the capacity to adapt trial structure as infectious disease threats evolve.
Key Highlights
Response to H1N1 and feckless pandemic trials
International strategy meetings—origins of platform concept
PREPARE consortium and cross-continental funding
Modular master protocol, factorial allocation, and domain-specific appendices
Bayesian triggers and response adaptive randomization
Pivot to COVID-19 and rapid data generation
Multi-platform international collaboration
For more, visit us at https://www.berryconsultants.com/

In this episode of "In the Interim…", Dr. Scott Berry explores the challenge of protracted endpoint timelines in adaptive clinical trials and the statistical strategies used to increase the rate of actionable information gain. Drawing on detailed case studies from breast cancer (I-SPY 2), Alzheimer’s disease (BAN 2401), diabetes (AWARD-5/Trulicity), and cardiac arrest, Scott addresses the technical demands of longitudinal modeling and interim data imputation for accelerating learning. The discussion prioritizes a critical, empirical perspective of demonstrating how carefully constructed statistical models, simulation, and Bayesian methods can convert interim patient data into more robust estimates of delayed outcomes and support key design adaptations. The episode is a direct account of the methods, uncertainties, and real-world impact of fighting time in adaptive trials.
Key Highlights
Analyzes how delayed primary endpoints challenge adaptive trial efficiency, and how adaptive trial designs use accumulating in-trial data to inform adaptive allocation, arm graduation, and early trial conclusions.
Dissects the use of longitudinal models in I-SPY 2, in which interim MRI measurements at one and three months are mapped to predicted six-month pathologic complete response, through an ordinal stratified, pre-specified modeling approach—illustrating both the strengths and limits of interim forecasting.
Reviews the BAN 2401 adaptive Alzheimer’s trial, where early cognitive assessments were modeled to forecast 12-month outcomes enabling response adaptive randomization and sample size adaptation based on projections from interim data.
Details the AWARD-5 seamless trial for dulaglutide (Trulicity), where strategic enrollment pacing, predictive modeling of early HbA1c and weight loss, and a utility function across four endpoints supported both dose selection and seamless transition to phase 3 without requiring full cohort maturation.
Summarizes recent cardiac arrest trial (ICECAP), using 30-day ordinal scales and multiple imputation to predict 90-day outcomes and improve interim decision-making.
Unpacks the importance of prior-data-driven modeling, simulation, and strict robustness checks in the construction of all predictive models used for interim adaptation.
For more, visit us at https://www.berryconsultants.com/

In this episode of "In the Interim…", Dr. Scott Berry is joined by Dr. Will Meurer, professor of Emergency Medicine and Neurology at the University of Michigan, for an in-depth discussion of the ICECAP trial’s adaptive Bayesian design. The discussion breaks down the scientific rationale for hypothermia after cardiac arrest, critiques legacy studies, and explores the justification for including both shockable and non-shockable rhythm types. The episode provides a detailed account of ICECAP’s methodological strategies: a weighted mRS primary endpoint, Bayesian adaptive trial structure, response-adaptive randomization (governed by strict allocation guardrails), a unique Bayesian model for duration-response, and futility rules. The trial’s development is described in the context of the ADAPT-IT initiative, an FDA/NIH partnership, and the operational leadership of the MUSC Data Coordinating Center. Results are pending publication which will be highlighted in a future episode of “In the interim…”.
Key Highlights
Rationale for exploring duration of hypothermia after cardiac arrest with review of prior evidence.
Enrollment of shockable and non-shockable populations to address clinical uncertainty.
Primary endpoint: weighted mRS, independently developed for ICECAP.
Bayesian adaptive design with response-adaptive randomization, interim analyses, and allocation guardrails.
Management of missing data with multiple imputation from 30-day outcomes.
For more, visit us at https://www.berryconsultants.com/