DDT-BMQ-000161 Analytic Validation ofNon-Calcified Plaque Volume (NCPV) for Regulatory Qualification as an Enrichment Biomarkerin Coronary Artery Disease Trials

Coronary CT angiography (CCTA) imaging is a well-developed, non-invasive tool which
visualizes atherosclerosis, satisfying conditions be based on early assessment of the actual
disease process of atherosclerosis, or plaque and has been shown to accurately risk stratify
individuals for early progression of atherosclerosis as well as late adverse events. Here we
propose several studies to streamline drug development and encourage innovation by detecting
early, beneficial drug responses on atherosclerosis; and identify atherosclerosis biomarker(s) to
serve as surrogate endpoints for clinical trials. The overarching significance of the current grant
is to address the unmet need for non-invasive measurement of coronary atherosclerosis, by
supporting investigations that will advance the Qualification Plan application for qualification of
CCTA-derived NCPV as an FDA prognostic biomarker. The intended use of NCPV is as an
accurate, validated and widely available enrichment biomarker that can optimize risk
assessment of clinical trial participants prior to enrollment in ASCVD studies. As part of the
larger effort to develop CCTA NCPV assessment as an enrichment biomarker, we will perform a
series of studies to comprehensively assess analytic validity. Specifically, we are proposing
three Aims comprising 5 five measurement quality studies to provide analytic validity for NCPV
by standardizing the minimal acceptable precision, short and long interval repeatability, and
accuracy of CCTA NCPV measurement. Further we will compare the results obtained with the
two most well-established and widely used software packages, to demonstrate the impact of
different tools on measurements. These studies are essential for submission of an FDA
Qualification Plan for NCPV as a prognostic marker. Finally, we will work to establish consensus
standards for measurement quality that is acceptable to academic, corporate and regulatory
stakeholders.
The ultimate goal of the proposed work is to establish measurement validity for NCPV
biomarkers based upon well-defined validation techniques using a data driven
consensus regarding minimal acceptable quality thresholds. Application of the NCPV as a
biomarker has the potential to de-risk clinical endpoint-based trials by enriching trial populations
with participants at higher likelihood of MACE, including in primary prevention individuals who
have not yet had a myocardial infarction. Importantly, this work is an integral part of an
international consortium of academics, pharma, device manufacturers, software vendors, and
regulators, (the A2D2 Consortium) to advance the use of CCTA as a drug development tool
(DDT). This Consortium provides this work with robust, critical support including access to
appropriate images (Step a), development of consensus standards (Step e) and dissemination
and implementation (Step f) to ensure the acceptability of these studies by all stakeholders.
With completion of the proposed investigations, we will have performed a comprehensive set
of image assessments and analyses using well established techniques which will firmly
establish the measurement quality and validity of CCTA quantitation of NCPV. Importantly,
this is a component of the in-progress qualification process of NCPV as a prognostic biomarker
to enrich study populations for trials of investigation atherosclerosis therapies (context of use)

Grant Number: 1U01FD008652-01
NIH Institute/Center: FDA
Principal Investigator: MATTHEW BUDOFF