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Abstract
This article is a result of the efforts of the American Statistical Association Biopharmaceutical Section Working Group on Safety. With representatives from different institutions, this group reviewed the drugs approved by the United States Food and Drug Administration (FDA) to treat Type 2 diabetes mellitus during 2002–2014 with a focus on the cardiovascular (CV) risk assessment. The main objective of this article is to understand the impact of FDA guidance of 2008 on assessment of CV risk in antidiabetes development programs, which are summarized and displayed in chronological order. Compared to New Drug Applications (NDAs) submitted prior to the FDA 2008 guidance, the number of patient-years significantly increased for NDAs approved in the post-guidance era. To meet guidance requirements on CV risk assessment, meta-analyses and large cardiovascular outcome trials (CVOTs) have been conducted. These CVOTs provide an opportunity to assess safety signals beyond CV risk and assess the benefit/risk ratio better in diabetic patients with a high risk for CV events, but they also present challenges. The advantages and disadvantages of different CV assessment strategies are summarized in this manuscript. Finally, we raise some emerging questions and discuss future opportunities for CV risk assessment research. Supplementary materials for this article are available online.
Acknowledgements
Authors acknowledge Drs. Lisa LaVange, Mat Soukup, Eugenio Andraca-Carrera, Janelle Charles, and Bo Li for their regulatory insight and leadership in review of cardiovascular safety of T2DM products. The authors also thank Xan Gregg for sharing his graphical expertise.
Additional information
Notes on contributors
Olga Marchenko
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Qi Jiang
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Aloka Chakravarty
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Chunlei Ke
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Haijun Ma
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Jeff Maca
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Estelle Russek-Cohen
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Matilde Sanchez-Kam
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Richard C. Zink
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).
Christy Chuang-Stein
Olga Marchenko (E-mail: [email protected]), and Jeff Maca (E-mail: [email protected]), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Aloka Chakravarty (E-mail: [email protected]), and Estelle Russek-Cohen (E-mail: [email protected]), Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biometrics VII, Office of Biostatistics, Silver Spring, MD 20993. Qi Jiang (E-mail: [email protected]), Chunlei Ke (E-mail: [email protected]), and Haijun Ma (E-mail: [email protected]), Amgen, Global Biostatistical Science, One Amgen Center Drive, 24-2-C, Thousand Oaks, CA 91320. Matilde Sanchez-Kam, Arena Pharmaceuticals, Biostatistics and Data Management, 6331 River Downs Rd, Alexandria, VA 22312 (E-mail: [email protected]). Richard C. Zink, JMP Life Sciences, SAS Institute, Cary, NC 27513, and Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599 (E-mail: [email protected]). Christy Chuang-Stein, Pfizer, Kalamazoo, MI 49009 (E-mail: [email protected]).