Experts from industry and academia welcomed new draft guidelines from the FDA on how best to use minimal residual disease (MRD) testing as a surrogate endpoint in blood cancer trials. However, they called for more guidance on the technological aspects of MRD testing.

The FDA issued a road map in October for drug companies looking to use highly sensitive measures of low-level disease in trials of patients with hematologic malignancies.

In a draft guidance, available at, the agency highlights many potential applications of minimal residual disease (MRD) testing in investigational studies, including patient diagnosis, participant selection, and the assessment of treatment responses. The document also describes the FDA's willingness to consider MRD as a surrogate endpoint to support accelerated drug approvals—although additional validation studies are still needed to prove that this biomarker offers a suitable stand-in for clinical measures of long-term survival.

“It is a clear signal that the FDA is cognizant of the potential and challenges associated with measurable residual disease in blood cancers, not only for patient care, but also as a potential surrogate endpoint in drug approvals,” says Christopher Hourigan, MD, DPhil, head of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, MD.

Three months ago, the European Medicines Agency drafted similar policy recommendations, available at, for MRD testing in multiple myeloma studies. The FDA document goes much further, detailing specific considerations for five other blood cancers: acute lymphoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia, chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia.

Charles Sang, senior vice president of diagnostics at Adaptive Biotechnologies in Seattle, WA—the company behind clonoSEQ, the only MRD assay to have received marketing authorization from the FDA—describes the FDA's draft guidance as a “solid framework” with “all the right metrics” for incorporating MRD data in regulatory submissions. However, “it would be useful for the agency to clarify or qualify the language that they provided regarding the ability to interpret results across assays,” he says.

The draft guidance discusses the use of next-generation sequencing, flow cytometry, and PCR-based assays. Although it says the FDA is “agnostic to which technology platform is used in clinical trials assessing MRD,” sponsors must “analytically validate the platform for its context of use.”

Davy Chiodin, PharmD, vice president of regulatory science and quality assurance at Acerta Pharma, says that after the agency revises and finalizes the guidance to address community feedback, it will have an opportunity to “continue to help define some of the more ambiguous questions on the methods, such as cut-off choice and justification.”

The public can submit comments to the FDA at until December 17. –Elie Dolgin

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