In the Interim...

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. Reflecting on the statutory and regulatory definitions originating with the 1962 Federal Food, Drug, and Cosmetic Act and 21 CFR 314.126, they dissect current and emerging interpretations, referencing recent statements by Dr. Martin Makary and coverage described in a STAT article. The conversation focuses on the scientific and statistical foundations of the two-trial threshold, challenges with dichotomous results, and how pooled evidence might increase efficiency and rigor. They discuss statistical implications including alpha thresholds, sample size effects, program power, and the consequences for clinical labeling. The episode also introduces Bayesian approaches as a method for integrating totality of evidence. Attention is given to both population breadth and the possible risks of a narrowed evidentiary base under a single-trial standard.Key HighlightsRegulatory and historical context of “substantial evidence” since 1962 and current FDA directives.Industry practice: simultaneous Phase III trials, statistical power, and evidentiary replication.Criticism of binary, trial-level significance thresholds; merits of pooling or meta-analysis.Potential efficiency gains and tradeoffs with a more stringent alpha requirement for single trials.Strategic and operational effects on trial design, sample size, and label indications.Bayesian statistical approaches for full evidence integration, discussed as an analytical viewpoint.

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. Dr. Devenport describes her transition from psychology in New Mexico to statistical leadership in Basel, emphasizing the formative role of early academic mentors and her experience working across the US and Europe. She outlines her current functions in methods development, internal collaboration, and industry outreach, highlighting active engagement with academic and regulatory communities. The episode scrutinizes differences in workplace culture, such as the emphasis on debate and long-term collaboration in Europe, and differences in educational backgrounds among statisticians. The conversation covers practical barriers and slow adoption of Bayesian methods and the importance of communication in the acceptance of futility analyses in pharma, the importance of scale in problem-solving, and the emergence of AI as a tool for statisticians. Dr. Devenport provides pragmatic strategies for statisticians to improve their influence through tailored, audience-specific communication.Key HighlightsDr. Devenport’s academic and geographic move from the US to EuropeResponsibilities in methods development, collaboration, and outreach at RocheContrasts in US and European pharmaceutical statistics culturesMeasured perspective on AI’s effect on statisticians’ responsibilitiesPractical guidance for statisticians on communication and influence

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. He provides a methodical comparison of traditional trial models and the platform trial approach, clarifying distinctions between platform, basket, and master protocol structures. Through examples from HEALEY ALS, I-SPY 2, PALM (Ebola), REMAP-CAP, RECOVERY, EPAD, GBM AGILE, and Precision Promise, Scott outlines the measurable efficiencies of platform trials: shared control arms, flexible arm addition and removal, reduced placebo exposure, accelerated timelines, and improved statistical inferences. The episode further examines platform trial performance during the COVID-19 pandemic, highlighting  trial adaptability, and the rapid generation of actionable evidence. Scott also addresses failure scenarios, focusing on EPAD Alzheimer’s as a cautionary case in platform sustainability, cost allocation, and initial funding barriers. Listeners will gain a perspective on the operational and statistical design choices governing today’s most innovative clinical studies.Key HighlightsArena analogy applied to delineate clinical research inefficiency.Operational, statistical, and patient-focused efficiencies in platform versus single-question trials.Precision in terminology: platform, basket, and master protocol definitions.Effects of platform trials on speed and scientific rigor.Factors underlying both platform trial successes and failures.For more, visit us at https://www.berryconsultants.com/

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. The episode presents a typical hypothetical scenario for rare disease drug development, contrasting conventional two-stage development with a seamless design and highlighting efficiency gains in sample size, patient allocation, and trial duration. Scott details the construction of administrative (financial) interim analyses, underscoring their distinction from futility analyses and their role in funding decisions when complete funding is not secured upfront. He addresses FDA operational bias concerns, emphasizing blinding and limiting information sharing to protect trial integrity. Finally, the episode focuses on developing objective interim funding criteria—using Bayesian predictive probability and assurance—and on leveraging illustrative simulation outputs and sample datasets to bridge the “I’ll know it when I see it” divide between scientists and funders. Practical, empirical, and tailored to real funding barriers in clinical research.Key HighlightsStatistical structure and efficiency of seamless Phase II/III trial designsAdministrative (financial) interim analysis setup as funding decision triggers, distinct from futility analysesFDA operational bias guidance and requirements for trial blindingPredictive probability and assurance as objective interim criteriaSample data and simulation outputs to facilitate stakeholder alignmentFor more, visit us at https://www.berryconsultants.com/

In this episode of "In the Interim...", Dr. Scott Berry interviews Dr. Kaspar Rufibach, Co-Head of Advanced Biostatistical Sciences at Merck. The conversation tracks Rufibach’s evolution from academic training in actuarial and mathematical statistics through cancer research collaborations, postdoctoral work, and academic consulting, leading to applied roles in Roche and Merck. Discussion centers on methodological rigor, pragmatic approaches to assurance and predictive probability, and real-world experience in drug development. Rufibach examines the organizational integration of quantitative disciplines at Merck—incorporating pharmacology, real-world data, statistics, programming, and data science—while remaining candid on the role and boundaries of AI in current pharmaceutical practice.Key HighlightsStatistical education in Switzerland, bridging theory and early applied cancer trial experienceMove from academic consulting to a trial statistician role at Roche, emphasizing structured problem-solving in drug developmentApproach to predictive probability and assurance, balancing Bayesian and frequentist tools with strict emphasis on practicalityFormation of professional special interest groups with EFSPI and PSI, stepping in to address unmet community needs rather than seeking formal leadershipPerspective on Merck’s unified quantitative department, designed to remove silos and leverage interdisciplinary expertiseCautious view of AI as a complement to specific tasks, but not yet a replacement for nuanced clinical trial design or regulatory-facing strategiesCurrent focus on expanding causal inference methods and multi-state modeling for improved trial efficiency and evidence synthesisFor more, visit us at https://www.berryconsultants.com/