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

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Abstract

In December 2008, the US Food and Drug Administration (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 pre- or 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.

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Authors and Affiliations

  1. Cardiovascular and Metabolism Therapeutics, Regeneron Pharmaceuticals Inc, Tarrytown, NY, 10591, USA

    Mary Jane Geiger MD, PhD, FACP

  2. Cytel Inc and Harvard School of Public Health, Cambridge, MA, USA

    Cyrus Mehta PhD

  3. Quintiles Inc, Durham, NC, USA

    J. Rick Turner PhD

  4. Boerhringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA

    Christophe Arbet-Engels MD, PhD, MBA

  5. Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany

    Stefan Hantel PhD

  6. AstraZeneca, Wilmington, DE, USA

    Boaz Hirshberg MD

  7. Merck Research Laboratories, Whitehouse Station, NJ, USA

    Joerg Koglin MD, PhD & Deborah Shapiro DrPH

  8. BioClinica Inc, London, UK

    Boaz Mendzelevski MD

  9. Stanford University School of Medicine, Palo Alto, CA, USA

    Philip T. Sager MD, FACC, FAHA

  10. GlaxoSmithKline, King of Prussia, PA, USA

    Murray Stewart DM, FRCP

  11. Medpace, Cincinnati, OH, USA

    Thomas G. Todaro MD, JD, FACC

  12. Eli Lilly and Company, Indianapolis, IN, USA

    Brenda Gaydos PhD

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  1. Mary Jane Geiger MD, PhD, FACP
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  2. Cyrus Mehta PhD
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Correspondence to Mary Jane Geiger MD, PhD, FACP.

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Geiger, M.J., Mehta, C., Turner, J.R. et al. Clinical Development Approaches and Statistical Methodologies to Prospectively Assess the Cardiovascular Risk of New Antidiabetic Therapies for Type 2 Diabetes. Ther Innov Regul Sci 49, 50–64 (2015). https://doi.org/10.1177/2168479014549860

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