PSI Scientific Committee Webinar: Heart Failure Trials: Novel Estimands and Methodologies to Evaluate Therapies based on the Totality of Evidence
Heart failure (HF) is a common and global health problem affecting approx. 2% of adults in developed countries. Good news is that with new treatments on the market, HF has been converted from a short-term and quickly fatal condition to a chronic disease, which is characterized by recurrent non-fatal events (HF hospitalizations) and relatively low disease-related mortality. Classical heart failure trials have used a composite primary endpoint of cardiovascular (CV) death and HF hospitalization. This endpoint was then analyzed using a ‘time to first composite event’ analysis.
Various limitations of this endpoint have been raised in recent years. Among others, the ‘time to first composite event’ endpoint is thought to not fully capture the disease burden as it ignores all events that occur after the first event. Given that a number of recent large HF
outcome trials have failed to show a clinical benefit for patients using the traditional endpoint, clinical teams are reviewing novel endpoints that better capture clinical benefit and which
adapt to the changing disease profile.
In this session, we will discuss some of the recently proposed estimands and their associated analysis methods, ranging from composite endpoints of recurrent HF hospitalizations (HFH) and death to joint frailty models for recurrent HFH and death. We will illustrate these approaches based on various case-studies and discuss benefits as well as limitations from an academic, regulatory and industry perspective.
Application of Recurrent Events Methodology in Cardiovascular Trials
Dr. Brian Claggett (Harvard Medical School)
We describe a range of alternative models for recurrent events data collected in cardiovascular trials. We consider their applicability and interpretation from a medical context and illustrate them using data from a particular trial.
The Totality of Evidence: Is More the Same as Better?
Dr. Bruce Binkowitz (Merck)
Analysis of time to first event is a long held tradition for trials in the cardiovascular area, including heart failure. Yet subjects in these studies can experience more than 1 event. Recent literature has focused on utilizing all events experienced by each subject as a way of increasing efficiency through having to enroll less subjects, use less investigator sites, and save money. Consideration for examining all events further extends to measuring total patient burden, cost effectiveness, and most importantly, capturing the best picture of a subject's condition and therefore the best potential therapy. This presentation will discuss how analyzing total events isn't as simple as designing a traditional time to first event study and, for example, running an Anderson-Gill extension to a Cox PH model on all events. Examples will be taken from actual trials including a trial examining subjects with acute decompensated heart failure.
Recurrent or Multiple Event Analyses in Cardiovascular Trials
Dr. H.M. James Hung, US FDA
In cardiovascular or renal trials that we have seen in regulatory applications, major adverse clinical events are almost always assessed using analysis of time to first occurrence of the events. As some component events occur much more frequently, such as hospitalizations, during the trial, the analysis that includes all the events may improve statistical efficiency and capture disease burden of patients more properly. In this talk, I shall share a number of regulatory experiences with recurrent or multiple event analyses to give my insights into the possible values of such analysis and to stipulate the issues that need more attention.
Registration fee: None
This webinar is free of charge. However, attendees must register on the PSI website in order to obtain the dial-in details and the webinar link.
We do encourage your participation. If you have questions relating to this webinar, or any of the listed talks, ahead of the webinar, please email them to Mouna.Akacha@novartis.com
We will do our best to discuss them at the webinar.
Joint PSI, EFSPI & ASA BIOP Webinar: Estimands
PSI, the European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) and the Biopharmaceutical Section of the American Statistical Association (ASA) are jointly organising a webinar on Estimands in Practice. Speakers from regulatory authorities (FDA and EMA) and industry will present on their experience on this topic to date.
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