Keywords: MRD; Minimal Residual Disease; Regulatory guidance; surrogate; endpoint; study design
Minimal residual disease (MRD) negative status indicates that the number of remaining malignant cells is so low that it is below the detection limit of the assessment method. MRD negativity has become an acceptable intermediate endpoint for clinical benefit in certain hematologic therapeutic areas (e.g., chronic lymphocytic lymphoma) but not in others.
Clinical publications have shown association between MRD negativity and PFS/OS, however no surrogacy of MRD for long term endpoints has been established. In the statistics world, topics of surrogate endpoints have been studied quite extensively, however no specific methodology or analysis of MRD as an surrogate endpoint has been published or presented. There is a need to close this gap and to bring statistical rigor to this potentially meaningful endpoint.
There have been efforts among industry, academia, and regulators (both FDA and EMA) to better understand, define, and utilize MRD negativity, either as a surrogate clinical endpoint or as an intermediate endpoint supported by a longer-term clinical endpoint such as PFS or OS, esp. in patient populations where a long timeframe is anticipated in order to achieve meaningful statistical and clinical results from registration trials.
In this roundtable discussion, definition of MRD negativity as an endpoint and its complexity, current efforts to establish the surrogacy of MRD negativity, statistical methods to assess the prognostic vs. surrogate value of this endpoint, available clinical data or analysis on MRD, current Regulatory position (e.g., draft EMA guidance on MRD that was released in July 2018; effort by FDA on this topic), and implication for study designs of future clinical trials, will be explored.