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  1. Advancing Regulatory Science

Utilizing the UNC Clinical Data Warehouse for Assessing Efficacy, Toxicity, and Dose-Response Relationships of Molecularly Targeted Therapies in Real-World Patients

CERSI Collaborators: Triangle CERSI, UNC-Chapel Hill: Yanguang Cao, PhD; Benyam Muluneh, PharmD

FDA Collaborators: Mirat Shah, MD; Elizabeth Duke, MD; Jonathon Vellejo, PhD; Kun Wang, PhD; Lori Ehrlich, MD, PhD; Donna Rivera PharmD, MS

CERSI In-Kind Collaborators: Joshua Zeidner, MD; Rushabh Shah, PharmD, MBA

Project Start Date: September 1, 2023

Regulatory Science Framework:

Modernize Development & Evaluation of FDA-Regulated Products, Methods to Assess Real-World Data to serve as Real-World Evidence; Strengthen Post-market Surveillance & Labeling of FDA-Regulated Products, Methods to Assess Real-World Data to Support Regulatory Decision Making

Regulatory Science Challenge

The doses and schedules for molecularly targeted therapies are often not well-characterized prior to initiating trials with registrational intent for marketing approval. This can lead to the selection of dosages that have increased toxicity without additional efficacy. Therapies may be poorly tolerated at approved dosages, leading patients or providers to prematurely modify the dosage or discontinue an otherwise efficacious treatment. FDA launched Project Optimus to emphasize the need for dosage optimization prior to drug approval. An understanding of how the toxicities and dosage modifications for approved targeted therapies affect outcomes for patients in the real world setting will enhance Project Optimus efforts, in collaboration with the Oncology Real World Evidence program, to advance potential patient-centric uses of real-world data. To bridge this knowledge gap, researchers will investigate the prevalence of dosage modifications in patients and the resulting safety and effectiveness profiles of targeted therapies commonly prescribed for patients with Chronic Lymphocytic Leukemia (CLL) and Chronic Myeloid Leukemia (CML). They will primarily use real-world data (RWD) sourced from the Clinical Data Warehouse at the University of North Carolina at Chapel Hill to address these questions.

Project Description and Goals

In this project, researchers will address three key questions. Firstly, they will assess the frequency of dosage modifications in patients in the real-world setting using pharmacy refill records and electronic medical record information. Secondly, they will aim to determine whether modifications in treatment doses, made in response to tolerability, have any negative impact on clinical outcomes including survival. Lastly, they will explore whether the toxicity associated with treatment directly affects clinical outcomes including survival among patients in the real-world setting. The clinical data warehouse at UNC Health Care System will be primarily utilized for this project, and Triangle CERSI is also considering other sources of real-world data, such as medical claims data and randomized clinical trials, where appropriate to support the analyses. Recognizing the potential challenges and biases that can be associated with RWD studies, the capabilities of statistical modeling and advanced data mining and causal inference approaches will be harnessed to explore methodological approaches for providing valid answers to these questions.

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