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How to Shorten a Cardiovascular Outcome Trial By Two Years

Cardiovascular outcome trials (CVOTs) have earned the reputation of being the untamable behemoths of the clinical world. Needless to say these trials are long and require extremely large sample-sizes. The Contrave LIGHT study required 8900 patients. The SAVOR TIMI trial enrolled 16,492 patients. Even the EXAMINE trial, which benefited from a promising zone design, required 650 patients. 

However, since the explosive controversy over the FDA’s conditional approval of anti-obesity drug Contrave four years ago, there is much we have learned about how to make these trials shorter while also diminishing the financial risks of investing in them. For example, one of our clients managed to shorten the expected study length of an a CVOT by two years using a four point MACE Assessment (see below). 

In this post, we explore some of the lessons we have learned when designing these large-scale clinical trials.  

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Then and Now

In January 2011, the FDA asked Orexegin Therapeutics to perform a CVOT for its drug Contrave, despite the fact that an FDA Advisory Committee had given the drug a positive recommendation [1] [2]. Such a study was meant to ensure that cardiovascular side-effects of the drug would not ultimately diminish its risk-benefit profile. According to the FDA’s complete response letter to drug sponsors, "[B]efore your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug's benefit-risk profile."

Many worried at the time that such a strict safety measure would alter the financial risk profile, to the point where few pharmaceuticals would be willing to invest in anti-diabetic treatments [3]. However, Orexegin resubmitted Contrave in December 2013 and gained approval in September 2014 [4] [5].  In the meantime, several other anti-diabetic drugs have undertaken large CVOTs. While none of the studies have been short, per se, many trial design strategies emerged to make the studies much more feasible.

Shortening a Cardiovascular Outcome Trial:

What makes CVOTs so large-scale is the fact that major adverse cardiac events (MACE) are relatively infrequent. In order to obtain the number of events necessary to complete a trial, CVOTs naturally require large sample sizes.

However, our clients have successfully implemented a few other strategies to diminish the length and scale of such a trial:

  • Adaptive Designs: The Contrave LIGHT study obtained permission for an adaptive CVOT trial and successfully demonstrated safety after interim analysis [5].  According to a recent article in Therapeutic Innovation & Regulatory Science co-authored by Cytel President and Co-Founder Cyrus Mehta, many CVOTs are positioned to benefit from adaptive and group sequential designs [6].    

  • Promising Zone: The promising zone is an adaptive design which allows for sample size re-estimation based on the results of an interim analysis. When conducting a CVOT, the risk of powering a trial up front to demonstrate superiortiy can be catastrophic. The SAVOR-TIMI trial, for example, enrolled 16,492 patients and demonstrated 1222 MACE events, only to fail to show superiority. A promising zone design allows a non-inferiority trial to become a superiortiy trial based on interim results [7]. 

  • Four Point MACE Assessments: According to the FDA and EMA, MACE include death, non-fatal myocardial infarcation and stroke. However, other events such as myocardial ischaemia can also count as MACE events in some cases [8]. As a result, one of our clients got permission from the FDA to include angina when measuring MACE assessments. This permission helped to shorten the expected study length by two years, and subsequently led to FDA approval of their drug.

Related Items of Interest 

[1] FDA Issues Complete Response to New Drug Application for Contrave for the Management of Obesity - February 1, 2011

[2] Orexigen Therapeutics' Investigational Drug Contrave Receives Positive Recommendation from FDA Advisory Committee for Treatment of Obesity - December 8, 2010

[3] Pollack A. (2011, February 1)  FDA Fails to Approve Diet DrugNew York Times

[4] FDA Approves Contrave (bupropion/naltrexone) for Weight Management - September 10, 2014

[5] Orexigen Resubmits Contrave New Drug Application - December 11, 2013

[6] 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.)

[7] Adaptive Designs to Demonstrate Risk Reduction in Cardiovascular Outcome Trials: A Case Study of the EXAMINE Trial (Slides) by Cyrus Mehta (Cytel) 

[8]  European Medicines Agency Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus

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

[10] Clinical Development & Statistical Methodology for Cardiovascular Risk Assessment

[11] Planning and Implementing Large Cardiovascular Trials (Slides) by Zoran Antonijevic (Cytel) and Paul Strumph (Lexicon) 

[12] Diabetes Mellitus — Evaluating Cardiovascular Risk in New  Antidiabetic Therapies to Treat Type 2 Diabetes (FDA Guidance

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