Psychometric Analyses and Quantitative Study Report for Qualification of the Chronic Heart Failure Symptom Scale (CHF-SS) (DDT COA #000112)

ABSTRACT Heart failure is a major worldwide health problem, with a prevalence of over 6.2 million in the United States (US), and over 26 million worldwide. Heart failure is associated with signs and symptoms such as breathlessness with exertion, shortness of breath, fatigue, tiredness or weakness, difficulty breathing when lying down, sleeping

problems, swollen legs or ankles, and weight gain, which can negatively impact health-related quality of life and physical function. Although multiple clinical outcome assessments (COAs), specifically patient-reported outcome (PRO) measures, have been developed to assess heart failure symptoms, tested against the scientific

processes of their time, and widely used in evaluating heart failure interventions, they each present their own limitations with respect to recent US Food and Drug Administration (FDA) COA-related guidances. A new measure of CHF symptom severity was accepted into the Center for Drug Evaluation and Research’s

(CDER’s) COA Qualification Program under DDT #000112 on May 3, 2019. As requested by FDA in the Letter of Intent response, a Qualification Plan (QP) was prepared and submitted to FDA on March 24, 2023, that documents the development of and content validity evidence supporting the CHF-SS, along with the CHF

Working Group’s research plan for obtaining the quantitative evidence necessary to support qualification of the measure for a limited context of use in CHF drug development. A reviewability assessment memo was subsequently received, indicating that the QP was determined to be reviewable by FDA on October 2, 2023. An

amended statistical analysis plan (SAP) was submitted to FDA on March 20, 2024, to reflect the evolution in our approach to these analyses in light of recent FDA feedback on other qualification submissions and current thinking regarding the best practices in our field. Once FDA feedback on the QP is received, additional

modifications to the SAP may be necessary. Our application includes 3 aims. For Aim 1, we will finalize the SAP for cross-sectional analyses in response to FDA feedback. For Aim 2, we will analyze the available cross-sectional dataset containing CHF-SS data, in accordance with the QP and the final SAP incorporating FDA feedback. For Aim 3, we will prepare a quantitative

study report for the CHF-SS for future submission with the CHF-SS Full Qualification Package. The long-term result of this project will be to qualify the CHF-SS for the assessment of symptom severity in CHF treatment trials according to the most recent, rigorous standards and best practices to develop fit-for-purpose COAs for

regulatory decision making.