In this episode of "In the Interim...", Dr. Scott Berry dissects prevailing concepts of “clinically meaningful difference” in clinical trials focusing on progressive diseases. Through detailed examples from pancreatic cancer (Ben Sasse, Revolution Medicines), emphysema (Elevair), Alzheimer’s disease (lecanemab), and IVF, Scott challenges the adequacy of the population-mean of a continuous outcome in reflecting true patient benefit. The episode discusses inconsistent usage and interpretation of acronyms such as MCID, CSD, and Target Product Profile (TPP). Dr. Berry advises trialists to resist interpreting the mean difference using patient-level minimal effects, and adopt responder analyses and cumulative probability approaches to enhance patient-level relevance. Guidance is offered for analyzing the effect of time-saved instead of a mean differences in a clinical endpoint at a single time for progressive diseases – measuring “sweet time.”

Key Highlights

• Focus on added time not the change from baseline as the most meaningful outcome for a progressive disease.
• In-depth evaluation of MCID, CSD, TPP, and risk of misinterpretation.
• Critique of trying to interpret mean-based endpoints for clinical meaningfulness such as six-minute walk distance and CDR sum of boxes.
• FDA advisory panel guidance on MCID for IVF live birth endpoints and dichotomous versus continuous endpoints.
• Advocacy for responder analyses and cumulative probability of achieving thresholds in reporting the clinical effect of a treatment.

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In this episode of "In the Interim…", Dr. Don Berry provides a detailed account of co-chairing the 1997 NIH consensus development conference on mammography for women in their 40s. His conversation with Dr. Scott Berry covers the statistical and clinical complexities of breast cancer screening, addressing lead time and length bias, trial design limitations. Don discusses the panel’s finding, based on randomized trials and meta-analysis, that the average benefit of screening women in their 40s is modest (an estimated 1.4-day average life extension and 18% hazard reduction). The panel recommended individualized decision-making rather than universal screening. The episode follows the reaction: heated debate with radiologists, scrutiny from journalists and policymakers, Senate testimony, and personal threats. Don explains how these findings became distilled into soundbites, evidenced by coverage in The New York Times, Chicago Tribune, and a reference in James Patterson’s Murder Games. The conversation addresses overdiagnosis, false positives, and the consequence some called the “Berry effect”—an observed drop in mammogram rates after the panel’s recommendations.

Key Highlights

• Don Berry’s NIH consensus conference leadership and approach to breast cancer screening recommendations.
• Statistical bias and trial limitations inherent in mammography evidence.
• Meta-analysis findings: 18% hazard reduction; 1.4-day average life extension.
• Policy guidance supporting individualized patient decision-making over universal screening.
• Strong backlash from advocacy, media, radiology, and government—including Senate hearings and personal threats.
• Enduring debates, public misunderstandings, and continued citation of these events in scientific and popular sources.

For more, visit us at https://www.berryconsultants.com/

In this episode of "In the Interim…", Dr. Scott Berry speaks with Dr. Srinivas Murthy, Dr. Thomas Hills, and Dr. Lindsay Berry about the REMAP-CAP trial results on oseltamivir in critically ill influenza patients. The trial used a Bayesian covariate-adjusted platform design and found oseltamivir was not effective at reducing 90-day mortality with a “98% and 99% probability of harm in 90-day mortality” compared to control. Covariate adjustment addressed baseline and site variation. Subgroup analyses showed greater harm in patients with higher illness severity. Sensitivity analyses using alternative neutral, optimistic, and pessimistic priors produced important scientific exploration of the results. No evidence was found for benefit over control in any subgroup.

The discussion highlights the first randomized, controlled evidence in this patient group, contrasting prior observational studies and clinical guidelines. A mechanism of harm remains unclear. REMAP-CAP is continuing enrollment in moderate severity and pediatric cohorts to further examine population-specific effects. The episode also addresses the broader challenges of trial design and interpretation in acute care research, the limitations of nonrandomized evidence, and the importance of ongoing Bayesian analyses and transparent reporting.

Key Highlights

• Pre-print is available: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=7172531
• REMAP-CAP platform trial, Bayesian logistic regression, covariate adjustment
• Oseltamivir arms: statistical trigger for inferiority, “98 and 99% probability of harm”
• Greater harm in sicker subgroups, consistent results across sensitivity analyses
• Ongoing arms: moderate severity and pediatric cohorts, mechanistic questions unresolved
• Context: limitations of previous historical data studies, clinical practice impact, future research directions

For more, visit us at https://www.berryconsultants.com/