CERSI Collaborators: Nihar Desai, MD, MPH (Yale), Harlan Krumholz, MD (Yale), Rozalina McCoy, MS (Mayo Clinic), Joseph Ross, MD, MHS (Yale) (PI), Nilay Shah, PhD (previously at Mayo Clinic, now at Delta Airlines) (PI), Joshua Wallach, PhD (Yale), Xiaoxi Yao, PhD (Mayo Clinic)

FDA Collaborators: Robert Busch, MD, MMSC, Jacqueline Corrigan-Curay, JD, MD, Khair El-Zarrad, PhD, MPH, Charu Gandotra, MD, Mark Levenson, PhD, Nahleen Lopez, PharmD, Yong Ma, PhD, MS, Dianne Paraoan, MPH, Kenneth Quinto, MD, MPH, Robert Temple, MD, Rongmei Zhang, PhD, MS

CERSI Subcontractors: Flying Buttress Associates- Jeph Herrin, PhD

CERSI In-Kind Collaborators: OptumLabs - William Crown, PhD; University of San Francisco - Sanket Dhruva, MD

Project Start and End Date: September 2019 - October 2022

Regulatory Science Challenge

Clinical trials are considered the gold standard for understanding the safety and efficacy for clinical or health system interventions, and results from clinical trials most often form the basis of FDA regulatory evaluations. Similarly, clinical trial data has traditionally been prioritized when making clinical practice guidelines and treatment decisions. In recent years, however, the potential to use observational research for medical product evaluation has improved due to greater availability of clinical data, and the increasing detail provided in clinical data. In addition, advances in computing and the development of statistical methods are making it more feasible to use large-scale, real-world data to inform our understanding of the safety and effectiveness of medical products. This project’s goal was to better understand the potential advantages and limitations of applying observational research methods to real-world data for medical product evaluation.

Project Description and Findings

This project used OptumLabs claims data to predict the results of ongoing clinical trials used for regulatory evaluations of drugs used for cardiovascular disease or diabetes management.

The first part of this study aimed to use electronic health record and administrative claims data to emulate the PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease), a clinical trial of men with cardiovascular disease undergoing treatment for prostate cancer. The PRONOUNCE trial found that degarelix was not associated with a lower risk of cardiovascular events than leuprolide, and this project also found that degarelix was not associated with a lower risk of cardiovascular events than leuprolide.1

The second part of this study aimed to emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A1c (HbA1c). The GRADE trial found that glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining glycemic control compared to sitagliptin or glimepiride while on metformin; this study found that liraglutide was more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy.2


  1. PMID: 34677594; Citation: Wallach JD, Deng Y, McCoy RG, Dhruva SS, Herrin J, Berkowitz A, Polley EC, Quinto K, Gandotra C, Crown W, Noseworthy P, Yao X, Shah ND, Ross JS, Lyon TD. Real-world Cardiovascular Outcomes Associated With Degarelix vs Leuprolide for Prostate Cancer Treatment. JAMA Netw Open. 2021;4(10):e2130587. doi:10.1001/jamanetworkopen.2021.30587.

  2. PMID: 36191949; Citation: Deng Y, Polley EC, Wallach JD, Dhruva SS, Herrin J, Quinto K, Gandotra C, Crown W, Noseworthy P, Yao X, Lyon TD, Shah ND, Ross JS, McCoy RG. Emulating the GRADE trial using real world data: retrospective comparative effectiveness study. BMJ. 2022 Oct 3;379:e070717. doi: 10.1136/bmj-2022-070717.