A Friends of Cancer Research working group believes “seamless” trial designs could be used more frequently for rare cancer drug development, but advanced planning is key.
Key Takeaways
- A Friends of Cancer Research working group argued “seamless” clinical trials could be used more often in rare cancer treatment development.
- Lola Fashoyin-Aje said the design requires upfront planning, rather than real-time reaction to data as it is gathered.
- An FOCR white paper on the design is not breaking new ground, but hopefully will spur more use of it, she said.
“Seamless” clinical trial designs should be used more often to develop potential rare cancer treatments, a Friends of Cancer Research working group argued.
“Seamless trial designs remain underutilized in rare cancer drug development,” according to a white paper released in conjunction with the FOCR annual meeting.
The trials are an adaptive design that compresses two or more traditional development phases into a single, continuous study. They can reduce downtime between phases, maximize the information gathered from each patient and allow modifications as information emerges.
Seamless trial designs were the topic of one of the three Friends of Cancer Research white papers released ahead of the annual meeting. The US Food and Drug Administration has not released guidance on seamless trials, but the designs are mentioned briefly in a 2019 final guidance on adaptive clinical trials. FDA officials participated in the FOCR working group that developed the white paper, but could not attend the meeting due to the government shutdown, which was ongoing at the time.
The authors said that while challenges with typical, phased drug development are not unique to oncology or rare diseases, they often are “magnified” with small patient populations, as well as time-consuming.
The “pauses” after each phase “may introduce delays that hinder patient access, risk losing the momentum of site engagement and patient recruitment, and limit efficient use of trial data across stages,” they wrote.
By using seamless trials, sponsors can combine trial stages (Phase I/II, II/III or even I/II/III) into a single, continuous protocol, which could be “integrating multiple, sequential stages of drug development, such as dose escalation, dosage optimization, cohort expansion, and efficacy assessment, within a single framework.”
But while early-phase oncology studies often employ dose-finding and cohort expansion, “more deliberate integration of additional seamless elements, such as adaptive cohort transitions or combined efficacy and safety assessments, remain limited in rare cancer development,” the white paper states. “Shared experience and best-practice frameworks for implementing these approaches are still sparse.”
Seamless trials require careful upfront planning, Lola Fashoyin-Aje, former director of the FDA Office of Therapeutic Products’ Office of Clinical Evaluation, said during a panel discussion of the white paper. Sponsors must plan ahead to address issues like dose optimization, patient size and endpoints, rather than “reacting in real time to the data,” she said.
Fashoyin-Aje left OTP in March and now is senior VP-regulatory strategy at Parexel, where she heads oncology and cell/gene therapy activities.
When using seamless trials in rare cancers, “it’s really important to determine a priori where the key decision points are and the critical scientific questions that are intended to be answered during the course of the clinical development program,” she said.
The risk with seamless designs is when sponsors “react in almost real time” to the data being collected without pre-specifying changes, Fashoyin-Aje said.
“When you’re doing that without a plan, you obviously risk introducing a lot of multiplicity issues,” she said. ”And what you end up with is a case series where you’re describing data, but you’re not able to really quantify benefit, or reach some definitive conclusion.”
Fashoyin-Aje said the working group is not breaking new ground, but is raising the issue to provide guidance and hopefully increase use of the design.
“We didn’t invent anything, and I don’t think anyone here would suggest that we learned something where there was no precedent,” she said. “What could move things forward would be more collaboration and sharing of real cases, and more transparency about what worked and what didn’t work, what was acceptable and what wasn’t acceptable and why.”
The panel added that seamless trials are not appropriate for all development programs.
“The approach to the clinical development program, including specific trials, should be based upon the questions that are being asked,” Fashoyin-Aje said. “A seamless approach may not be appropriate in every setting, because there’s a lot of reliance on assumptions.”