The U.S. Food and Drug Administration (FDA) released draft guidance on May 3, 2022, to assist drug developers in utilizing circulating tumor DNA (ctDNA) as a biomarker in early-stage solid tumor clinical trials. This guidance aims to support the development of novel therapies and in vitro diagnostic assays by providing a framework for the use of ctDNA in regulatory submissions.
Understanding ctDNA and its Applications
Circulating tumor DNA is fragmented DNA derived from tumors that circulates freely in a patient's bloodstream. It originates directly from the tumor or circulating tumor cells and can reflect the tumor's genome. The quantity of ctDNA depends on factors such as tumor type, location, stage, tumor burden, and response to therapy. Due to these characteristics, ctDNA is used in liquid biopsies to detect tumors, monitor tumor progression, and identify minimal residual disease (MRD), which indicates the presence of tumor cells remaining after treatment and is a major cause of cancer relapse. Therefore, ctDNA serves as a valuable biomarker in clinical trials for early-stage solid tumor drugs.
However, variations in ctDNA assessment approaches and technologies among clinical laboratories can lead to inconsistent results, affecting the reliability of ctDNA's regulatory applications.
Regulatory Uses of ctDNA as a Biomarker
The FDA's draft guidance outlines four primary uses for ctDNA as a biomarker in early-stage solid tumor clinical trials:
- Patient Selection: ctDNA can be used to establish eligibility criteria for clinical trials, targeting specific genetic or epigenetic alterations in patients. It can also serve as a stratification factor to define patient subgroups. The FDA recommends evaluating the sensitivity of ctDNA assays for detecting all variants of clinical interest within tumor tissue and suggests confirmatory tumor testing if no variants are detected.
- Patient Enrichment: As a marker of MRD, ctDNA can enrich trials with patients at higher risk of disease recurrence or death after treatment. For such trials, the primary endpoint should be disease-free survival (if only adjuvant therapy is given), event-free survival (if neoadjuvant therapy is given), or overall survival. The FDA advises against early interim analyses of the primary endpoint due to limited events.
- Measure of Response: ctDNA can be used in early-phase clinical trials to indicate drug activity. The FDA encourages sponsors to develop evidence regarding the usefulness of ctDNA response after neoadjuvant therapy.
- Early Endpoint: The FDA acknowledges the potential of changes in ctDNA in response to a drug as an early endpoint to support drug approval. The agency provides specific guidelines on the evidence needed to validate this use and requests that sponsors discuss their validation plans with the FDA. Trials should collect ctDNA before and after drug treatment, along with long-term data.
Assay and Investigational Device Considerations
For assays, the FDA provides considerations for MRD panel types, sampling, and assay analytical validation for marketing applications. The draft guidance lists the strengths and limitations of MRD panels utilizing tumor-informed methods, tumor-naive methods, and smaller panels of candidate genes. It encourages sponsors to discuss the timing of ctDNA testing with the FDA, supported by performance characteristics of the test, disease characteristics, and tumor biology. Detailed instructions for conducting analytical validation to establish the performance characteristics of ctDNA assays are also included.
Sponsors using ctDNA technology for in vitro diagnostic devices in oncology therapeutic clinical trials can utilize the FDA's streamlined submission process for investigational devices. This process allows sponsors to submit information about the investigational device in an Investigational New Drug (IND) submission. As part of the IND review, CBER or CDER will consult with CDRH or CBER, as appropriate, to determine the investigational device's risk level and the corresponding requirements applicable under the FDA's investigational device exemption regulations.
