Qualification of Composite Quantitative Imaging Biomarkers for Diagnostic Enrichment in Nonalcoholic Steatohepatitis (NASH) Clinical Trials (DDTBMQ000112) - SUMMARY The long-term goals of this U01 grant proposal are to reduce the number of liver biopsies required to achieve target enrollment in nonalcoholic steatohepatitis (NASH) drug development trials by rigorously qualifying composite quantitative imaging biomarkers through the FDA CDER Biomarker Qualification Program; repeat this process for other contexts of use related to NASH drug development trials; and monitor and assess the use of FDA-qualified quantitative imaging biomarkers in NASH drug development trials to help further refine the process by which these biomarkers are qualified. Our immediate goal is to prepare, submit, and obtain approval for the Qualification Plan being proposed here for the composite quantitative imaging biomarkers proposed in our Letter of Intent. This work is leveraged by ongoing development of metrics of conformance from the Quantitative Imaging Biomarkers Alliance (QIBA), pending results from the $15M NIMBLE Study being conducted by the Foundation of the NIH and funded by numerous pharmaceutical industry partners, and FDA guidance on contexts of use in medical research. The central hypothesis of this proposal is that prior research and pending NIMBLE Study results on the quantitative imaging biomarkers described in our Letter of Intent are sufficiently mature for purposes of diagnostic enrichment to merit preparation of a Qualification Plan. We are encouraged in PAR-21-178 to focus our grant proposal on filling gaps for the Qualification Plan submission. Hence, we chose four Primary Aims to address the fourteen questions provided to us by FDA concerning biomarker descriptions, and context-of-use-related analytical, clinical, and statistical considerations. Our milestone of success for each of our four Primary Aims is acceptance by FDA of our responses to their questions. Potential impact of this project is high because it addresses a critical barrier to progress in NASH drug development. Successful completion of this project will help change the current paradigm of diagnostic enrichment in NASH drug development trials, and will accelerate the development of safe and effective medical products for the patients who need them the most. If the aims of this grant proposal are met, preparation of a Full Qualification Package will be justified. If that package is also accepted, our methodology to secure biomarker approval may expedite qualification of other biomarkers for other contexts of use including early detection, diagnosis, staging, monitoring, and treatment response for NASH, thereby facilitating screening, enrollment, and execution of clinical trials to accelerate drug discovery.
