FDA issues guidance on developing cancer drugs in combination with other treatments
The US Food and Drug Administration (FDA) has issued draft guidance on developing cancer drugs intended for use in combination with other therapies. The guidance focuses on demonstrating each drug's contribution to the overall treatment.“Combination therapy in oncology is an important treatment modality. Scientific advances have increased our understanding of the pathophysiological processes that underlie many cancers,” according to the draft guidance. “This increased understanding has provided further impetus to develop new therapeutic approaches using combinations of drugs directed at multiple therapeutic targets to improve treatment response, minimize adverse events, or both.”
According to the Federal Register announcement, “A critical aspect of codevelopment of novel combinations of oncology drugs is the characterization of the safety and effectiveness of the individual drugs in the combination because the benefit of using the individual drugs in combination is weighed against the added toxicity when they are used together.”
The guidance addresses the use of clinical data for the following types of novel combinations in oncology: two or more investigational drugs that have not been previously approved by the FDA, an investigational drug combined with a drug approved for a different indication, and two or more drugs that are approved for different indications.
The guidance notes that sponsors can use a factorial design to demonstrate the contribution of each drug's effect. “This factorial trial design allows for characterization of the safety and effectiveness of each individual drug and the combination compared with standard of care while also demonstrating the contribution of the individual drugs to the efficacy demonstrated by the combination.”
The use of an adaptive factorial trial design can also enhance the efficiency of developing new treatment combinations. In this design, all participants are initially randomized into the treatment groups defined by the factorial method. It also allows sponsors to eliminate study arms that appear to be ineffective, among other adjustments. This approach reduces the total number of participants required for the trial while minimizing the exposure of participants to potentially less effective therapies.
When assessing fitness for purpose and deciding whether to utilize external data to support the drug combination, sponsors should consider where there is a “strong biological plausibility” to support the combination regimen, the natural history of the diseases is predictable, and the magnitude of the treatment effect of the combination is expected to be large.
The guidance states that “due to the potential limitations of the external data source – e.g., lack of comparable participant populations for the indication under consideration, variances in study conduct, and variability in endpoint assessment – comparisons between different data sources may or may not be appropriate.”
The guidance aims to elaborate on the 2013 guidance regarding the "Codevelopment of Two or More New Investigational Drugs for Use in Combination."
The deadline for submitting comments is 15 September via www.regulations.gov; reference docket number FDA-2025-D-1071.
Draft guidance
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