Hematologic Malignancies: FDA Offers Draft Guidance on Use of MRD
The US Food and Drug Administration (FDA) on Monday released new draft guidance to help sponsors planning to use minimal residual disease (MRD) as a biomarker in clinical trials or to support marketing approval of drugs and biologics treating specific hematologic malignancies.The 18-page guidance features sections on developing MRD as a biomarker for regulatory use, including meta-analyses for validation of MRD as a surrogate endpoint, technology considerations and disease-specific considerations, with a focus on acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and multiple myeloma.
“FDA views MRD as a biomarker that is a reliable quantitation of tumor burden, independent of assay,” the draft guidance notes. It also points to five different potential biomarkers that sponsors can use MRD status to support, including diagnostic biomarker, prognostic biomarker, predictive biomarker, efficacy-response biomarker and monitoring biomarker.
Last April, FDA for the first time used MRD as a biomarker for a regulatory decision.
Background
Despite the development of treatments that eliminate morphologically detectable malignant cells, some patients with hematologic malignancies who have achieved complete remission or complete response (CR), will experience relapses.
“Conventional morphologic detection for hematologic malignancies has a threshold limit of 1 tumor cell in 100 cells. Technology exists that can detect the persistence of malignancy at orders of magnitude below the limit of conventional morphologic detection, a level of disease burden known as MRD,” the draft notes.
MRD as a measure of tumor burden has multiple potential regulatory and clinical uses as a biomarker and “may reflect a patient’s response to treatment or it may be used as a prognostic tool to assess the patient’s risk of future relapse,” the draft notes. MRD can also be used to enrich clinical trial populations or to guide allocation into specific treatment arms in trials.
“There are challenges within each context of use that need to be addressed, such as underlying disease, patient heterogeneity, therapeutic context, target of therapy, or a combination of disease parameters, to allow effective use of MRD in regulatory decision-making,” the agency notes.
Other challenges include the fact that MRD assessments can vary among laboratories and technologies, which can have different performance characteristics, the draft says.
Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment: Draft Guidance for Industry