Greater Alignment Needed for External Control Arms: Stakeholders
A panel involving FDA, industry leaders, and policy experts said broader adoption of external control arms (ECAs) in oncology drug development will depend on improved data quality, closer collaboration with regulators, and clearer expectations around evidentiary standards.
Speaking last week at a Friends of Cancer Research policy-focused session (see video beginning at 2:23:00 mark), participants agreed that while there is growing consensus on the potential role of ECAs — particularly in settings where randomized controlled trials are impractical — significant challenges remain in translating that agreement into routine regulatory use.
“There is a shared understanding of the role ECAs should play,” said Biotechnology Innovation Organization’s Joe Franklin. “The real question is how we get there.” Panelists repeatedly emphasized that ECAs introduce complexities not typically encountered in traditional clinical trials. These include challenges related to study design, data sourcing, and methodological rigor.
Donna Rivera of Canal Road Advisors outlined multiple factors complicating ECA implementation, including data completeness, population comparability, bias, and endpoint selection. She stressed that no single issue is responsible, but rather a combination of interrelated challenges tied to what she described broadly as “regulatory alignment.” Unlike randomized trials, ECAs lack standardized frameworks, making it difficult for sponsors and regulators to reach consensus on what constitutes acceptable evidence.
CDER Associate Director for Rare Disease Strategy Amy Comstock Rick noted that in some ultra-rare conditions, traditional trial designs are simply not viable. “For very small populations, you may only have one shot on goal for a trial,” she said. “Saying something is infeasible cannot be the end of the conversation.” However, she added that regulatory standards for demonstrating effectiveness remain unchanged, even as flexibility is applied in how evidence is generated.
A central theme throughout the discussion was the need for high-quality, “fit-for-purpose” data. Panelists stressed that ECAs depend heavily on the availability of robust datasets with consistent endpoints, complete covariates, and minimal bias. Mark Lee of PenPower Medicine said the field has learned extensively from past shortcomings — particularly around missing data and poorly defined endpoints — but still lacks clarity on what level of evidence is sufficient for regulatory decision-making. “There’s still uncertainty about what ‘good enough’ looks like,” he said.
Panelists also pointed to the growing importance of prospective data collection, rather than relying solely on retrospective real-world data. Building datasets intentionally, with regulatory use in mind, could significantly improve the reliability of ECAs.
Participants underscored the importance of early and frequent interaction with the FDA to improve study design and reduce uncertainty. Franklin noted that more intensive communication — similar to efforts seen during Covid-19 data initiatives — could help bridge gaps between sponsors and regulators. “The type of back-and-forth interaction that builds confidence is critical,” he said.
Rick cautioned sponsors against assuming they understand FDA expectations based on past experience. “FDA is evolving,” she said, “and an answer given five years ago doesn't necessarily mean it'll be the answer now, and so please don't assume that you know the answer to a question you haven't just asked.”
Looking ahead, panelists said wider adoption of ECAs over the next three to five years will likely depend on:
- More validated case studies demonstrating regulatory success
- Greater use of prospective and hybrid trial designs
- Improved data standardization and sharing
- Continued collaboration across stakeholders
While some described routine use of ECAs as a “lofty goal,” there was broad agreement that the approach holds significant promise for accelerating drug development and expanding patient access to therapies. “This is an incredible opportunity,” a panelist said. “If we get it right, it could shorten development timelines by years.”
The panel concluded with a common message: progress will require sustained collaboration across regulators, industry, researchers, and patient communities to generate high-quality evidence and build confidence in new approaches to clinical research.