For someone who has worked in the industry for years, one thing I miss about school is the Socratic method of teaching used by some professors. It involves asking and answering questions to encourage critical thinking. By engaging in thoughtful Q&A sessions, I often find myself understanding the core elements of complex topics better compared to reading textbooks or papers alone.
To me, adaptive clinical trial design is one of these complex topics. Adaptive design offers increased flexibility, allows modifications to the trial procedures based on interim results, and can potentially make the trial more efficient. Although sometimes, I’m a bit overwhelmed by the literature. It seems people often ask different questions under varying contexts, providing unique solutions. Not every adaptation strategy fits every situation. It becomes clear to me that having a perspective, understanding the context, and asking the right question is critical.
To the rescue, my colleagues Keaven, Sabrina, and Hongtao published an article about practical considerations for adaptive design (page 11–15) in the summer 2023 issue of the Biopharmaceutical Report. I enjoy how they approached this topic using a Q&A format and offering perspectives, just like teaching with the Socratic tradition. I highly recommend everyone interested in this topic to read the full article. Below is a brief summary of the 9 key questions on adaptive design discussed in the article.
Does adaptation slow planning?
It could because this is complicated. To minimize potential delays, one should get familiar with the designs, standardize the design methods/software/templates, and get stakeholders on board early.
Does adaptation slow execution?
Adaptive design demands efficient trial operations due to the extra steps in the feedback loop.
How do adaptations impact cost considerations beyond patient enrollment?
Opening too many sites before a decision, especially in a Phase 2/3 trial, can increase costs. It’s important to strike a balance between enrollment continuation and data cleaning during decision-making phases.
Is interim decision-making appropriately executed?
Interim data can be limited, making decisions challenging. Ensuring the integrity of these decisions is important, especially when operations teams need to stay blinded.
Operationally seamless or inferentially seamless adaptation?
One should weigh the benefits of combined analysis against distinct phase evaluations. While inferentially seamless trials can potentially reduce sample size and accelerate trial completion, they may introduce complexities. It is noteworthy that an inferentially seamless trial with narrow review and adaptation can be converted to an operationally seamless trial where adaptation can account for complete review of interim data.
Data homogeneity issues before and after adaptation?
Unblinded sample size estimation assumes consistent treatment effects before and after adaptation. This homogeneity is essential for the success of adaptive designs and can be challenging to meet in practice.
Can simpler methods be more effective?
Sometimes, traditional methods like group sequential design can offer clarity and quick planning, avoiding the complexities of adaptation.
Can doses or treatments realistically be adapted mid-trial?
Considering the nuances of various treatments and the minor differences in their effectiveness can impact interim analysis outcomes.
Is futility analysis beneficial?
Introducing futility analysis can save investments for more effective alternatives, but also needs careful consideration about delayed effects, conditional power, and timing of analyses.
In the end, I think the article underscores that while adaptive designs are valuable tools, their successful implementation requires rigorous planning, meticulous consideration, and efficient execution. I hope you find the practical considerations in the article helpful, too.