Stakeholders seek clarity from FDA on cancer drug combo guidance

Drugmakers and research advocacy groups want the US Food and Drug Administration (FDA) to clarify and expand its proposed guidance regarding developing cancer drugs in combination with other novel treatments. Several stakeholders asked the agency to provide more details on how it will assess the contribution of each treatment in the combination therapy and expand on the data sources that can be used to evaluate the drugs.

FDA issued its draft guidance in July and received more than a dozen comments from stakeholders by the close of the comment period. (RELATED: FDA issues guidance on developing cancer drugs in combination with other treatments, Regulatory Focus 16 July 2025)

In its comments, Friends of Cancer Research (FoCR) agreed with FDA that recognizing the contribution of effect (COE) in combination therapies is important and appreciates its flexibility but asked the agency to be clearer about its expectations.

"In particular, we appreciate the openness to real-world data/evidence (RWD/E) as a potential source of evidence," said FoCR. "More explicit reference to RWD sources—such as electronic health records (EHRs), claims data, and registries—and cross-references to and alignment with FDA’s existing guidance documents on RWD/E would strengthen this section and provide sponsors with clearer direction."

While the guidance states a preference for trial designs that use full factorial arms, FoCR asked FDA to provide more examples where such trials may not be appropriate. More specifically, the group asked the agency to acknowledge that such trials may not be feasible when considering contexts of synthetic lethality or strong biologic co-dependency, investigational drugs with limited monotherapy activity but with compelling biomarker-driven rationale, and in trials where use of a monotherapy already failed to show efficacy.

"Explicit recognition of these situations would help guide sponsors in focusing resources on informative designs and ensuring patients are not unnecessarily exposed to less effective therapies," said FoCR. "In addition, operational feasibility should be considered.

"In rare biomarker-defined populations or small patient pools, factorial designs may not be practical, and alternative approaches should be recognized as appropriate," the group added.

The American Association for Cancer Research (AACR) echoed similar sentiments and asked for clarity on when it was acceptable to deviate from factorial designs. The group said such trials are often limited by large sample size requirements, especially when developing drugs for rare cancers.

"While factorial trials remain the preferred approach, their feasibility is often limited by large sample size requirements, particularly in rare cancers or biomarker-defined subpopulations, and by limited monotherapy activity.

“We urge FDA to specify quantitative or qualitative thresholds for effect size that would justify alternative designs (e.g., adaptive, hybrid, or external control–based approaches); to clarify, for three- or four-arm trials, which pairwise comparisons are primary and must be powered (e.g., A+B vs SOC/placebo) to guide efficient trial planning; and to address the acceptability of unequal randomization schemes (e.g., 3:1:1:1) to reduce patient exposure to potentially less effective monotherapies," said AACR.

FoCR asked for more clarity in several other key parts of the guidance, including FDA's recommendations on using external data to show CoE. The group asked the agency to explicitly state that biomarker data and other clinically relevant characteristics should be considered in the inclusion/exclusion criteria and comparability assessments, include patient-level RWD when considering trial participant data, and more.

AACR asked FDA to incorporate toxicity and therapeutic index into its CoE evaluation and said that efficacy gains in clinical practice may come at the cost of significant added toxicity and undermine care, especially in cancers that may have multiple treatment options.

“We recommend that the COE framework explicitly integrate therapeutic index considerations, balancing incremental efficacy against the severity, reversibility, and manageability of adverse events," the group said. "This would align COE assessment with the clinical decision-making process oncologists navigate daily, in which treatment selection frequently depends on tolerability and its impact on patients’ quality of life."

FoCR also asked FDA to clarify the acceptability of endpoints beyond overall survival (OS) or progression-free survival (PFS) in clinical trials, regulatory expectations for handling crossover in combination trials, and acceptable approaches for demonstrating CoE in situations where prior exposure or progression on one component has occurred.

"By explicitly incorporating patient-level RWD, biomarker and covariate assessments, and clear examples of acceptable external data sources, FDA can further strengthen the guidance and support the generation of high-quality, interpretable evidence," the group added.

AACR also recommended several areas for clarification, including emphasizing that the guidance’s objective is to evaluate individual drugs against a combination therapy to understand their efficacy and outlining pragmatic, fit-for-purpose pathways for developing drugs for rare cancers. The group asked for explicit guidance on when the omission of monotherapy arms is justified.

Several drugmakers also commented on the guidance, including Novartis, which asked FDA to expand its expectations for combination treatments used to treat blood cancers with complex treatment regimens that include multiple phases. It also wanted more details on the agency’s expectations for safety information for a drug when there is already substantial safety data for the drug for another indication.

EMD Serono asked FDA to include using Model-Informed Drug Development (MIDD) to assess how different components of the combination therapy. The drugmaker proposed that the agency consider feasible translational pharmacokinetic and pharmacodynamic modeling and simulation when evaluating a drug.

The guidance lists four factors when considering external data to demonstrate CoE, but EMD Serono again emphasized the need to allow the use of data from other sources.

"With reference to our General Comment, we believe it is important to utilize all available knowledge to build evidence of the contribution of effect of components," said EMD Serono. "This includes MIDD principles (e.g., Quantitative Systems Pharmacology, translational PK/PD and pharmacometric exposure-response models), external data in another histology (same biomarker/driver mutation), extrapolation of information to a different treatment line in the same tumor type, and information on disease similarity (e.g., same mutation).

"Depending on the level of evidence and the situation, it should be possible to waive the necessity to assess the individual drugs’ effects," the company added.

Like other commentators, Pfizer also asked for more clarity and examples on when external data can be used to develop drugs used in combination with other treatments. The drugmaker also asked for examples of acceptable clinically relevant covariates when comparing data sources and using descriptive comparisons instead of a pre-specified statistical analysis plan.

Pfizer also asked FDA to clarify its expectations when the drug is being developed in combination with a drug of the same class and mechanism of action.

“Please clarify the agency’s recommendations for the development of innovative therapies belonging to the same class of molecules previously approved in a combination treatment regimen,” said Pfizer. “For example, if an innovative compound belongs to the same class of chemical compound (i.e., it follows the same mechanism of action and has demonstrated comparable or superior efficacy) as one that has previously demonstrated its contribution of effect within a combination therapy, would the agency continue to recommend a randomized clinical trial for the innovative compound of the same class within the combination therapy?”

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Stakeholders seek clarity from FDA on cancer drug combo guidance

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