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.
