Clinical Development & Statistical Methodology for Cardiovascular Risk Assessment

Posted by Cytel

Feb 3, 2015 2:00:00 PM

A new publication co-authored by Cytel Co-Founder and President Cyrus Mehta considers a range of clinical development methods for cardiovascular outcome trials. Cardiovascular outcome trials, (often referred to as CVOTs), reflect safety standards implemented by the FDA and EMA to determine whether or not new drugs impose undue cardiovascular risk on patients. CVOTs typically occur after Phase 3 trials, and often make up for the slow rate of observed events by enrolling thousands of patients. This adds substantial delay in getting a drug to market.

In this paper, Cyrus and his co-authors explore how adaptive and group sequential methods might shorten this process without compromising the quality of the trial. In particular they consider increases in sample size and early stopping boundaries. They consider the possible benefits of unblinded sample size re-estimation (also known as the Promising Zone Design) in CVOT trials. 

They take the ongoing EXAMINE trial as a case study. 


Title: Clinical Development Approaches and Statistical Methodologies to Prospectively Assess the Cadiovascular Risk of New Antidiabetic Therapies for Type 2 Diabetes

Abstract: In December 2008, the US Food and Drug Administrat

ion (FDA) issued a guidance for industry requiring sponsors to demonstrate that a new antidiabetic therapy being developed to treat type 2 diabetes does not increase cardiovascular (CV) risk to an unacceptable extent. CV events reported during phase 2 and phase 3 trials should be prospectively and independently adjudicated. Before submission of a new drug application or biologics license application, sponsors should compare the incidence of major CV events occurring with the investigational agent versus the control group to show that the upper bound of the 2-sided 95% confidence interval (CI) for the estimated risk ratio is less than 1.8. If the CI includes 1.3, a postmarketing trial will be necessary to definitively show that the upper bound of the 95% CI for the estimated risk ratio is then less than 1.3. In 2012, the European Medicines Agency (EMA) issued an updated guideline on the clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus that detailed its CV safety assessment requirements. Although similar to the FDA guidance, the EMA guideline does not prospectively define any preor postapproval risk margins. This expert perspective, prepared by members of the Cardiac Safety Research Consortium, discusses clinical development strategies, operational issues, and statistical methodological issues to satisfy the FDA’s CV safety requirements, and, where appropriate, the EMA guideline. Actual case examples, where applicable, are presented. 

Related Items of Interest 

Geiger, Mary Jane, et al. "Clinical development approaches and statistical methodologies to prospectively assess the cardiovascular risk of new antidiabetic therapies for type 2 diabetes." Therapeutic Innovation & Regulatory Science 49.1 (2015): 50-64.(Please note you will need subscription to journal in order to access the paper.)

FDA-Industry Session on Cardiovascular Outcome Trials: Mehta on EXAMINE Trial’s Promising Zone Design




Topics: Cardiovascular, Group Sequential, Adaptive Clinical Trials

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