The FDA requires sponsors of new antidiabetic drugs to conduct cardiovascular outcome trials (CVOTs). CVOTs demonstrate that new therapies do not place unacceptable cardiovascular risk on patients suffering from Type 2 diabetes. The average CVOT requires about 5000 patients and takes an average of 5 years to complete. However, a recent white paper by the Cardiac Safety Research Consortium outlines a variety of methods to decrease sample size and study duration, by employing group sequential and adaptive CVOT designs.
During an FDA and Industry Workshop on September 23, 2014, Cytel President Cyrus Mehta will join a panel sponsored by the FDA Division of Biometrics and Eli Lilly & Company, to discuss adaptive and group sequential approaches for CVOTs. Cyrus's presentation will draw on his work with the EXAMINE trial, which used a promising zone that was designed to give sponsors a chance to demonstrate superiority only if an interim look established non-inferiority. Cyrus will contrast this design with the costly design of the SAVOR-TIMI Trial which powered for superiority at the outset.
Paper Abstract: Adaptive Designs to Demonstrate Risk Reduction in CV Outcome Trials (Slides of Cyrus's Talk)
It is now mandatory to demonstrate that new antihyperglycemic drugs do not elevate cardiovascular risk. The current approach to demonstrate CV safety is through an event-driven trial with adequate power for the upper confidence bound of the 95% confidence interval of the hazard ratio to be below 1.3. It would be desirable, however, to prolong a trial that has satisfied the 1.3 threshold in the expectation of concluding, eventually, that the hazard ratio is below 1. We shall show how this can be achieved in a statistically valid manner, with minimal risk of unnecessary trial prolongation, through an adaptive "promising zone" design. As no antihyperglycemic agent has so far shown actual risk reduction, the first agent to do so would enjoy tremendous competitive advantage besides benefiting the large population with type-2 diabetes. We will illustrate our approach with the help of the recently completed EXAMINE trial (NEJM, September 2014) a group sequential trial of patients with acute coronary syndrome treated with alogliptin.
Co-Sponsors: Aloka Chakravarty, Ph.D. Division of Biometrics VII, FDA and Brenda Gaydos, Ph.D. Eli Lilly & Company
Session Chair: Mary-Jane Geiger, M.D., Ph.D. Regeneron Pharmaceuticals, Inc.
To ensure that a new therapy does not increase cardiovascular risk to an unacceptable extent, the FDA issued a Guidance to Industry in 2008 subtitled "Diabetes Mellitus -- Evaluating Cardiovascular Safety in New Antidiabetic Therapies to Treat type 2 diabetes". Under this guidance sponsors are required to rule out an excess amount of cardiovascular risk: an 80% relative increase in risk pre-marketing and a 30% relative increase in risk post-marketing, in terms of time to major adverse cardiac event (MACE). A number of strategies have emerged for designing studies that comply with the FDA Guidance. These include meta-analysis of the CV events obtained from ongoing phase 2 and 3 trials, possibly combined with events from a separate CV outcome trial (CVOT), events gathered exclusively from a CVOT, and events from two CVOTs in series. Due to relatively low event rates, CVOTs typically require very large sample sizes (on the order of 5000 patients) and long study durations (at least 5 years). Efficiency gains are, however, possible through the implementation of group sequential boundaries for early stopping. Additionally, adaptive methodologies can be incorporated into the design of a CVOT. For example, if an interim analysis shows promise, the targeted number of CV events may be increased, and the objective of the trial may be switched from ruling out a 30% relative increase in CV risk to actually demonstrating CV benefit. This approach reduces the risk associated with making an up-front commitment to a large (10,000+ patient) superiority trial, given that no CVOT has demonstrated CV benefit to date. The Cardiac Safety Research Consortium (CRSC) (www.cardiac-safety.org), a public-private partnership developed to advance scientific knowledge on cardiac safety based on the principles of the FDA's Critical Path Initiative, has prepared a White Paper to discuss the above approaches and evaluate the merits and drawbacks of each. This session presents key concepts from this white paper through three presentation and a discussion.
Presentation 1: Meta-analysis Approach to Establish Cardiovascular Safety. Stefan Hantel, Ph.D. Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
Presentation 2: The EXAMINE trial - Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. Cyrus Mehta, Ph.D. Cytel Inc. (Member of EXAMINE steering committee)
Presentation 3: An Adaptive CV Outcomes Design to Efficiently Evaluate Superiority and Non-Inferiority in Diabetes. William Prucka, Ph.D. Eli Lilly & Company.
Discussant: Mat Soukup, Ph.D. Team Leader, Division of Biometrics VII, FDA.