Focus Area: Current Project
Focus Area: Global Regulatory Engagement
Derived from data sources such as electronic health recourse, claims data, registries, and mobile devices, real world evidence (RWE) has the potential to bring innovative products to patients more quickly. Unlike randomized controlled trials (RCTs), which may not be representative of a general population due to strict inclusion and exclusion criteria, RWE may more closely identify how an investigational product will perform in a general population. To address the absence of widely accepted best practices for utilizing RWE, the MRCT Center collaborated with Duke-Margolis Center for Health Policy to define a framework to establish best practices for utilizing RWE for regulatory decision-making.
The Observational Patient Evidence for Regulatory Approval and uNderstanding Disease (OPERAND) Project was conceptualized by the MRCT Center and OptumLabs. OPERAND aims to understand the sources of variation in design, approach, methodologies, statistical analyses, and decision-making using real world evidence (RWE, specifically claims and EHR data) to emulate phase 3 clinical trials. First, RWE is used to replicate published clinical trials, using and analyzing data limited explicitly to the eligibility criteria of the trial. Later, the aperture of inclusion is broadened to determine any change in effect size by the broader population.
The OPERAND project convened a technical expert panel (TEP) comprising key stakeholders from industry, academia, and regulators, to consider the principles behind, the methodology to draw upon, and the appropriate utilization of, observational data in regulatory review and approval and comparative effectiveness research.
After securing funding, two separate institutions, Brown University and Harvard Pilgrim Health Institute, were selected to replicate two trials:
ROCKET trial for atrial fibrillation (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and EmbolismTrial in Atrial Fibrillation (ROCKET AF), a multicenter, randomized, double-blind, double-dummy, event-driven trial that was conducted at 1178 participating sites in 45 countries) and
Lead-2 trial for Type 2 Diabetes control (Liraglutide Effect and Action in Diabetes (LEAD-2): Effect on Glycemic Control After Once Daily Administration of Liraglutide in Combination With Metformin Versus Metformin Monotherapy Versus Metformin and Glimepiride Combination Therapy in Subjects With Type 2 Diabetes, a multi-center, randomized, double-blind, parallel assignment of 1091 participants conducted at 190 study sites across 4 continents).
Current Status: Active Project
Anticipated Impact:
Validate the use of observational data to complement evidence from RCTs
Innovate observational clinical research design, while developing empirical data to understand methodologies and sources of variability
Inform policy on the use of real-world evidence to support regulatory approvals of new drug indications and to satisfy post-approval safety surveillance requirements
To determine whether observational studies using RWE replicate RCTs submitted for regulatory decision-making
To develop empirical data to understand data quality – and the limitations of RWD – from various data sources (e.g. Claims, EHR) and the assumptions necessary to use such data for replication
To determine whether and how the addition of EHR to Claims data improves sensitivity and utility of data, and thus RWE utility
To determine the sensitivities and variability of various statistical approaches given a common dataset and a common goal
Following replication, to determine how RWE informs understanding of effectiveness for on-label indications in approved populations
Key Milestones:
March 2017: Started collaborating with Duke-Margolis Center for Health Policy to develop a framework for real world evidence for regulatory decision-making
August 2017: Launched Project OPERAND and held first conference call with the Technical Expert Panel (TEP)
October 2017: First face-to-face TEP meeting to finalize study design and methods for Phase II approach
November 2017- June 2018: Additional TEP teleconferences to finalize study design and methods for Phase II approach. Request for Proposal (RFP) initiated and reviewed by TEP
February 2019: Research partners selected to replicate two trials
June 2019: Grants announced for two academic institutions to replicate two clinical trials using real world data
September 2019: Duke-Margolis released Determining Real-World Data's Fitness for Use and The Role of Reliability
October 2019 – December 2019: Research partners complete trial replication
November 2019: Duke Margolis released Understanding the Need for Non-Interventional Studies Using Secondary Data to Generate Real-World Evidence for Regulatory Decision Making, and Demonstrating Their Credibility
December 2019: Meetings held with the Operational Committee (OC) & TEP reviewed trial results and decided to proceed with next phase of study
December 2019: Duke-Margolis released Adding Real-World Evidence to a Totality of Evidence Approach for Evaluating Marketed Product Effectiveness
January 2020- May 2020: Research partners conduct next phase of study.
June 2020 – Present: Publications in draft.
Project Leadership:
Barbara Bierer, MD. Faculty Director, MRCT Center
William Crown, PhD. Chief Scientific Officer, Brandeis University (formerly Optum Labs)
Project Manager:
Hayat Ahmed, MSc.
See all Project Resources
Observational Patient Evidence for Regulatory Approval and uNderstanding Disease (OPERAND) (Presentation)
Issues in the registration of database studies (Publication)
Determining Real-World Data's Fitness for Use and The Role of Reliability (Publication)
06/25/2019 : OptumLabs and MRCT Center Award Grants for Replication of Drug Clinical Trials Using Real-World Data