Final FDA Guidance Lays Path for Drugmakers to Establish Circulating Tumor DNA as Trial Endpoint

Original from: genomeweb

The US Food and Drug Administration has issued its anticipated guidance for drug and device makers on the use of circulating tumor DNA tests in clinical trials of drugs for early-stage cancer, embracing the increasingly widespread use of these tests to genotype patients as well as their emerging value to enrich trials by identifying patients more likely to benefit from adjuvant or neoadjuvant treatment.

The FDA's guidance documents are not meant to define legally enforceable responsibilities, but rather to make clear the agency's thinking on certain topics.

For trial enrichment, the agency recommended that study sponsors make sure the ctDNA tests they use — variably referred to as molecular residual disease or minimal residual disease tests — have high sensitivity and negative predictive value if they are used to inform de-escalation of treatment, and high specificity and positive predictive value if they are used to support escalation of treatment.

According to the FDA, a trial's primary endpoint in this setting should be disease-free survival if only adjuvant therapy is given, event-free survival if neoadjuvant therapy is given, or overall survival.

The guidance also laid out the kind of considerations it wants industry to keep in mind, and the depth of data the FDA expects to see, for changes in ctDNA to be recognized as a true trial endpoint.

With some early data emerging, the agency views this application as having the potential to accelerate trials of drugs for early-stage, non-metastatic cancers. In this setting, studies are relatively large and more cumbersome than in advanced cancer and require multiple years of follow-up with "time-to-event" endpoints.

"Better approaches are needed to determine which patients may benefit from (neo)adjuvant and escalated therapy, and which patients are unlikely to benefit and may be spared from unnecessary toxicity," the FDA wrote in the guidance.

Liquid biopsy tests, if proven to reliably identify patients who have cleared their disease, could deliver an early, surrogate measure of whether a treatment has worked or not, similar to the analysis of pathologic complete response in surgical samples.

The guidance encourages industry to design trials that collect ctDNA data before and after drug treatment, and to track long-term outcome data to characterize the association between ctDNA clearance and overall survival. The agency also stressed that quantitative testing and the use of tests at multiple time points would be ideal.

Further, the FDA noted that a meta-analysis seeking to validate the use of ctDNA as an endpoint should include only randomized trials. Sponsors should discuss proposals for such a meta-analysis with the FDA, including details of trial designs, inclusion and exclusion criteria, ctDNA assessment methods, and disease setting, the agency said. It also stressed various other best practices, including making sure the trial patient population reflects the drug and test's intended population and analyzing data at both an overall trial-level and an individual level for each subject.

The guidance cites many of the same advantages and caveats to tumor-informed and tumor-naive ctDNA technologies that have been the subject of growing debate and industry competition. The FDA did not endorse any specific approach, but the agency did outline various best practices for analytical validation of minimal residual disease tests, such as using a predefined assay cutoff and appropriate reference materials.

Source: Final FDA Guidance Lays Path for Drugmakers to Establish Circulating Tumor DNA as Trial Endpoint