Theses Doctoral

Phase II/III Transitional Seamless Trial Designs with Different Objectives and Endpoint Types

Tumasian III, Robert A.

Accelerating regulatory science has become an urgent task due to the ongoing emergence of novel and highly complex diseases, such as coronaviruses and mpox, and the growing real-world evidence and precision medicine paradigms. In research and development, achieving this goal requires the formulation and implementation of innovative clinical trial designs and statistical approaches. Further efforts are needed to devise robust strategies toward expediting the evaluation of drugs and other medical products, which will help to quicken the delivery of safe and effective treatments to individuals in need.

One pioneering concept that has greatly contributed to speeding up product assessment is the application of pre-specified adaptations in clinical trials. Adaptive techniques (like early dose or treatment selection and sample size recalibration) are based on participant data collected during the trial, where investigators/sponsors are able to learn from the study population and adjust trial characteristics accordingly without diminishing the integrity of the study. However, adaptations must be employed cautiously; it is essential to ensure that they are both clinically reasonable and statistically sound (in the sense that they will not inflate the nominal type I error rate).

The evolution of seamless trial designs has also propelled drug/medical product evaluation. For instance, seamless trials that combine a phase II study (e.g., using a biomarker or short-term intermediate endpoint for early dose or treatment selection) and a phase III study (e.g., using a definitive endpoint for confirming efficacy) have become very popular in practice due to their flexibility and shorter duration compared to running separate studies. In phase II/III seamless trials, a correlation is usually pre-specified between the intermediate and definitive endpoints in order to bridge the phase II and phase III studies and accomplish the overall aims of the intended trial. However, this can be difficult to quantify, especially when the endpoints are non-continuous. An inappropriate or unsubstantiated enumeration of this correlation can yield flawed results and thus misguide approval and labeling decisions, leading to potentially serious consequences.

To avert this issue, a three-stage phase II/III transitional seamless trial design was constructed that does not demand prior knowledge of the correlation between the intermediate and definitive endpoints. The design also allows for interim sample size re-estimation according to the accrued intermediate endpoint data. The utility and validity of the design, with and without sample size adaptation, were considered for different types of endpoints. For each, theoretical proofs establish that the design can control the nominal type I error rate while still reaching the targeted power, and simulations reinforce these findings. Therefore, the design exhibits promise in precipitating the assessment of experimental interventions in a wide range of therapeutic areas.

This dissertation is organized as follows. First, Chapter 1 presents (1) an introduction to the drug/medical product evaluation process, (2) an overview of adaptive techniques used in clinical trials, (3) a description of seamless trial designs, including a real-world example to demonstrate how they can be applied in different data situations, (4) the research goals, and (5) a display of the proposed three-stage phase II/III transitional seamless trial design and its workflow. Chapters 2-5 lay out the models and procedures for the proposed design when using a continuous intermediate endpoint and a continuous definitive endpoint, a binary intermediate endpoint and a continuous definitive endpoint, and a binary intermediate endpoint and a time-to-event definitive endpoint in the presence and absence of censored observations. This is proceeded by statistical justification and supporting simulations for each procedure. As some authors remain skeptical toward the use of adaptations in clinical trials, Chapter 6 counters an argument posed in the literature. In closing, Chapter 7 summarizes the work and its limitations and provides several additional considerations toward enhancing the proposed design and its generalizability.


This item is currently under embargo. It will be available starting 2025-04-17.

More About This Work

Academic Units
Thesis Advisors
Cheng, Bin
Ph.D., Columbia University
Published Here
May 3, 2023