Design risks and benefits for innovative vs. traditional 3+3 trials
Regulators recognize that innovative trial designs offer attractive benefits but also carry risks and challenges. Adaptive trial design guidance helps clarify regulatory positioning and concerns.1,2
Potential benefits of innovative trial designs are that fewer patients receive ineffective treatments while development costs and timelines are improved. Potential risks include the introduction of operational and statistical biases, such as a heightened Type 1 (false positive) error rate. Challenges include extensive preparations, complex statistical analyses, and the logistics of executing and monitoring more complex studies.
For instance, in umbrella trials, care must be taken to avoid difficulties in attributing adverse events or efficacy to multiple experimental agents. A common control for the multiple experimental arms is often helpful.
Basket trials, on the other hand, permit efficacy and safety data to be shared among the various groups, but this requires innovative statistical design with extensive evaluation of the operating characteristics and assumptions.3 Appropriate candidates for basket study consideration include targeted therapies, biotech, and innovative drugs — or any study for which there is a pressing need to expedite clinical drug development.
Basket Trial (as an example) vs. Traditional Phase I Trial Design
Key takeaways
While basket trials offer a rapid-to-market strategy, faster development of new drugs, and possibly reduced patient burden, they also come with higher operational complexity, increased risks for drug delivery, and lack of expertise and acceptance into healthcare systems. On the other hand, traditional phase I trials using the 3+3 design offer standardized and well-known drug management basics, medium operational complexity, and require fewer communication pathways.
Ultimately, the choice of trial design depends on the specific objectives, patient population, and resources available. It is important to work closely with your CRO partner to weigh the risks and benefits of each approach and select the most appropriate design to ensure the safety and efficacy of the investigational medicinal product.
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References
- EMA. Adaptive Pathways. European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory/research-development/adaptive-pathways. Published October 26, 2022. Accessed November 11, 2022.
- Center for Drug Evaluation and Research. Adaptive designs for clinical trials of drugs and Biologics guidance. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adaptive-design-clinical-trials-drugs-and-biologics-guidance-industry. Published December 2019. Accessed November 11, 2022.
- Lu C, Li X, Broglio K, et al. Practical considerations and recommendations for master protocol framework: Basket, umbrella and platform trials. Therapeutic Innovation & Regulatory Science. 2021;55(6):1145-1154. doi:10.1007/s43441-021-00315-7
