Evaluating Challenges in Designing External Control Arm (ECA) Studies to Contextualize Effectiveness in Single-Arm Clinical Trials: A Case in Hematologic Malignancies

Background: Regulatory agencies, pharmaceutical companies, and payors are increasingly interested in appropriately leveraging real-world data (RWD) to provide evidence of drug effectiveness. Companies have increasingly included ECAs in submissions, particularly in oncology and rare diseases, where randomized trials can be infeasible. However, patterns of care and data capture in the real-world often differ from trials in aspects such as method and frequency of outcome assessment, capture and timing of assessment of key covariates and intercurrent events. In addition, sample size may be of concern when conducting ECAs in rare disease areas. Various design and analytical approaches can be used to optimize fit-for-purpose ECAs; however, such choices may introduce their own challenges. Generation of robust evidence requires understanding of data limitations and rigorous methods to appropriately contextualize externally controlled trials (ECTs).

Objectives: To discuss common challenges and approaches to designing and executing ECAs to contextualize effectiveness of ECTs, drawing from case examples in hematologic malignancies.

Description: 1) Wenzhen Ge will set the stage by discussing the common challenges when constructing ECAs using RWD to contextualize ECTs in hematological malignancies (5min)
2) Bingcao Wu will discuss specific considerations in selecting appropriate RWD for ECAs, including generalizability, sample size, feasibility of implementing the trial eligibility criteria in RWD, and opportunities to curate RWD to address data barriers (12min)
3) Christian Hampp will discuss the issue of outcome assessment. Trials assess progression at set timepoints using uniform outcome ascertainment which may not be routinely conducted or use the same imaging techniques in clinical practice as reflected in RWD. He will discuss the challenges this poses to the design and execution of ECAs with imaging-based outcomes (12 min).
4) Paul Spin will discuss approaches to selecting lines of therapy (LOT) when multiple LOTs per patient are available for building an ECA (12 min)
5) K. Arnold Chan will discuss methodology considerations in utilizing ECA to study drug effects (12 min)
6) Donna Rivera will discuss the regulatory perspective on ECTs, including fit-for-purpose data and comparability of external controls focusing on oncology as well as regulatory considerations on the conduct and design of ECTs through the newly published FDA draft guidance (12min)
7) Wenzhen Ge will moderate a panel discussion and a Q&A session (25min)