In this episode of "In the Interim…", Dr. Scott Berry and Dr. Kert Viele analyze how regulatory, editorial, and science community standards often impose additional, inconsistent requirements for novel methods in clinical trial design, rarely applied to standard approaches. Examples from oncology, enrichment trials, platform studies, and endpoint analysis illustrate how adaptive and Bayesian designs are frequently subject to higher scrutiny, shifting metrics, or distinct evidentiary demands. The episode covers technical and regulatory issues, such as the selective application of Type 1 error controls, evolving multiplicity guidance, and challenges in ethical reasoning with adaptive allocation. Scott and Kert frame the discussion with empirical comparisons and advocate for the use of clinical trial simulation to ensure fair, metric-driven evaluation of both novel and legacy designs.

Key Highlights:

• Oncology combination therapy trial with Bayesian borrowing facing heightened regulatory caution versus single-arm historical controls.
• Hierarchical versus pooled analysis in enrichment/basket trials, with focus on error definitions and subgroup effects that have always existed.
• ICH E20 guidance potentially discourages use of enrichment by imposing new subgroup comparison burdens absent from standard trials.
• Platform trial multiplicity rules contrasted with parallel single-arm trials; regulatory stance continues to evolve.
• Ethical debate on adaptive allocation: questioning rationale behind adaptive randomizing may be ethically challenging, but fixed allocation is okay despite same interim data.
• Critical review of explicit utility weighting in the DAWN trial, despite alternative methods having the same issues

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

In this episode of "In the Interim…", Dr. Scott Berry examines the mathematical foundations and efficiency claims of the promising zone design for adaptive sample size in clinical trials. Scott unpacks the conditional power thresholds that trigger sample size increases without the need to adjust alpha, as originally presented by Mehta & Pocock. He systematically demonstrates, via simulation, that the promising zone rarely provides meaningful efficiency gains over fixed designs and is consistently outperformed by group sequential designs that allocate alpha across multiple analyses. Using a driving-route analogy, Scott highlights the practical flaw in making pivotal trial decisions earlier than necessary due to arbitrary statistical rules rather than observing current data. He underlines that at Berry; simulation efforts have yet to reveal a scenario where the promising zone design is more efficient than a thoughtfully constructed group sequential or Goldilocks trial. The episode urges trialists to simulate, compare, and optimize—not to accept appealing mathematical tricks without rigorous evaluation.

Key Highlights

• Explanation of the promising zone’s conditional power mechanism and alpha control.
• Simulation-based comparison of power and average sample size across design types.
• Direct comparison of group sequential vs. promising zone designs.
• Discussion of futility rules and their impact on design choice.
• Commentary on Goldilocks designs for incomplete data.

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

Episode 30 of “In the Interim…” features Dr. Janet Wittes, Fellow of the American Statistical Association, past president of the Society of Clinical Trials, and founder of Statistics Collaborative, in discussion with Dr. Scott Berry. Dr. Wittes details her progression from Radcliffe biochemistry to Harvard statistics, shaped by targeted mentorship and her family’s insistence on advanced scientific training. She describes teaching at Hunter College, her NIH/NHLBI tenure overseeing extensive DSMB work, and the launch of Statistics Collaborative 32 years ago, building the business with her children and their peers. The episode explores her consulting on clinical trial design for orphan and neglected diseases—malaria, dengue, leishmania, ALS—and vaccine development, with technical commentary on adaptive trial methods, operational issues in low-resource contexts, and decision-making for small-sample trials. Dr. Wittes reflects on statistical leadership, ongoing DSMB involvement, and the importance of evidence-driven public health. She underscores the need for contextual and cultural awareness in trial design, illustrated by her Lilith magazine story on kosher certification and challenges in stakeholder understanding. Discussion covers career obstacles, the evolution of clinical science, vaccine advocacy, and the critical role of diversity and practical on-site knowledge in advancing statistical research.

Key Highlights

• Early academic transition from biochemistry to statistics.
• Serendipitous transition from academic career at Hunter College to Branch Chief of biostatistics at NIH/NHLBI.
• Founding Statistics Collaborative, business growth with children, and specialization in orphan disease trials.
• Consulting expertise in adaptive design, small-sample challenges, tropical and vaccine studies.
• Continued advocacy for vaccines, scientific rigor, and ethical public health practice.
• Importance of representation and context in science, demonstrated by real-world consulting examples.