Regulatory Focus™ > News Articles > 2020 > 1 > FDA Finalizes 2018 Guidance on Use of Minimal Residual Disease

FDA Finalizes 2018 Guidance on Use of Minimal Residual Disease

Posted 24 January 2020 | By Zachary Brennan 

FDA Finalizes 2018 Guidance on Use of Minimal Residual Disease

The US Food and Drug Administration (FDA) on Friday finalized guidance to help sponsors planning to use minimal residual disease (MRD) as a biomarker in clinical trials for treating specific hematologic malignancies.

The 18-page guidance discusses technology that can detect the persistence of malignancy at, what FDA says are, "orders of magnitude below the limit of conventional morphologic detection," which has a threshold limit of one tumor cell in 100 cells. This level of disease burden is known as MRD, the guidance says.

"These technologies measure cell characteristics such as genetic mutations, cell surface markers, or specific DNA gene rearrangements. MRD as a general measure of tumor burden has multiple potential regulatory and clinical uses as a biomarker. Depending upon the clinical setting, MRD may be used to reflect a patient’s response to treatment or as a prognostic tool to assess a patient’s risk of future relapse. As such, MRD can be used to enrich clinical trial populations or guide allocation into specific treatment arms in clinical trials."

FDA says that changes from the 2018 draft to the final guidance include editorial changes and clarifications throughout, as well as the addition of definitions for "individual-level association," which is the “strength of the association between the surrogate and the true clinical endpoint,” as well as "trial-level association," which is the “strength of the association between the effects of treatment on the surrogate and the true endpoint.”

The guidance further notes that although single-arm trial data may be used to demonstrate individual-level association and assess efficacy outcomes of interest in subgroups by MRD level for the purposes of hypothesis generation, “the meta-analysis to validate MRD at the trial level should include only randomized trials.”

On the topic of using MRD for patient selection, the final guidance also adds the recommendation that sponsors consult with FDA about incorporating any MRD assay into a trial before submitting the protocol for trials that include MRD for patient selection or as an endpoint (primary or key secondary).

So where can MRD be potentially used in clinical trials?

Dario Campana, a professor at the National University Cancer Institute in Singapore and scientific founder at Unum Therapeutics, previously explained to Focus: “MRD is the most powerful prognostic parameter in both ALL [acute lymphoblastic leukemia] and acute myeloid leukemia (AML). Data suggest that it may also be important in other hematologic malignancies, such as multiple myeloma.” (Two Amgen authors discussed FDA and EMA guidance on using MRD as a surrogate endpoint for developing products in multiple myeloma).

The expanded FDA approval of Amgen’s Blincyto (blinatumomab) in March 2018 to treat adults and children with B-cell precursor ALL who are in remission, but still have MRD, was the first time FDA has used MRD as a biomarker for a regulatory decision.

“With the increasing availability of new agents, other uses of MRD are emerging, e.g., MRD as eligibility and response criteria. In the case of immune-oncology agents, such as Blincyto or CAR-T cells, treating patients with low leukemic burden might be advantageous, as it could maximize the likelihood of disease eradication while minimizing potential toxicities due to excessive T cell activation. The approval of Blincyto for this specific indication seems to validate this concept,” Campana added.

Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment


© 2021 Regulatory Affairs Professionals Society.

Regulatory Focus newsletters

All the biggest regulatory news and happenings.