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Regulatory Focus – FOCR offers path for validating ctDNA as an early endpoint for drug approval

Regulatory Focus – FOCR offers path for validating ctDNA as an early endpoint for drug approval

Friends of Cancer Research (FOCR) has issued an evidentiary roadmap for validating circulatory tumor DNA (ctDNA) as an early endpoint for accelerated drug approval in solid tumors, spelling out a strategy for generating the data needed to support the use of ctDNA levels as a drug development tool in regulatory decision making.

The roadmap builds on earlier work on ctDNA from FOCR, including a white paper outlining opportunities to use ctDNA in early-stage cancer and the ctMoniTR Project, in which researchers demonstrated that reductions in ctDNA were strongly linked to better clinical outcomes in lung cancer patients receiving immunotherapy. (RELATED: White paper bolsters ctDNA as potential ‘early endpoint’ in cancer approvals, Regulatory Focus 09 November 2021; Friends of Cancer Research project tracks early cancer therapy response, Regulatory Focus 09 June 2021)

The US Food and Drug Administration (FDA) recently offered insights into how ctDNA could be used in early-stage solid tumor drug development in draft guidance for industry. (RELATED: Drugmakers seek details on use of ctDNA as a biomarker or early endpoint, Regulatory Focus 07 July 2022)

At a meeting hosted by FOCR to discuss the roadmap, Patrizia Cavazzoni, MD, director of FDA’s Center for Drug Evaluation and Research, said the agency is open to studying and understanding new early endpoints for cancer treatments, but that more data are needed to support the use of ctDNA as an early endpoint.

“We recommend that trials collect appropriate data on ctDNA before and after drug treatment, as well as the long-term outcome, so that we can include these trials into our growing body of evidence about this promising endpoint,” Cavazzoni said. “We also encourage companies to come to us and discuss and provide details of any proposed meta-analysis plan to validate the use of ctDNA in a particular context.”

Currently, the FDA most commonly sees ctDNA being used a selection marker for clinical trials, mainly in the metastatic setting, and multiple ctDNA companion diagnostics have been approved in that context, explained Julia Beaver, MD, chief of medical oncology at FDA’s Oncology Center of Excellence. There are also multiple potential regulatory uses of ctDNA in the early-stage cancer setting, including using ctDNA to detect a certain targetable alteration, enriching a high- or low-risk population for study in a trial, and reflecting a patient’s response to treatment. “We’re already seeing and encouraging the use of ctDNA as an enrichment marker for determining molecular residual disease,” Beaver said.

In terms of validating ctDNA as an early endpoint, Beaver said there needs to be a standardized approach to the use of ctDNA and clinical trials will need to be powered for the long-term outcome. Public-private partnership efforts, the FDA’s guidance, and industry collaboration will all be key in moving that forward, she said. “While the evidence still needs to be generated, we can really put these steps in place now to do this in a manner that sets us up for success in the future.”


The FOCR roadmap calls for collaboration to align methodologies so that clinical trial data on ctDNA levels can be compared. Currently, comparing individual trials can be challenging because of differences in therapeutic modalities, inconsistencies in how ctDNA is collected and measured, and variability in the performance of assays.

FOCR identified several sources of variability in ctDNA clinical studies, including:

  • Tumor type, histology, and stage of disease
  • Sample collection timepoints
  • Timing of radiographic surveillance
  • Assay performance parameters
  • Assay sequencing platform
  • Algorithm design for ctDNA quantification

The FOCR roadmap also outlines gaps in the current evidence around the use of ctDNA, such as the need to establish evidence on baseline ctDNA levels for cancer type and stage across assays. This type of effort would involve collaboration among multiple diagnostic developers, FOCR noted. There is also a need for evidence about whether the same type of association between ctDNA and treatment response that have been seen in the metastatic setting are also true in the early-stage disease setting.

FOCR also suggests using a meta-analytical approach to evaluating ctDNA across trials and assays, as was used in the ongoing ctMoniTR project. This could help identify approaches to analyze data across different assay technologies and ways to increase alignment in assay quantification and determination of ctDNA “positivity.”

“Comparing associations between ctDNA and other established endpoints, such as RECIST, will help evaluate differences in timing and duration of response and inform what constitutes ‘meaningful change.’ Once established, this could serve as a performance benchmark for determining whether an assay is optimal for detecting clinically meaningful changes in ctDNA levels,” according to the FOCR roadmap.

Evidentiary Roadmap