Decoding the Past, Crafting the Future: Unraveling the Role of Confounding in Exposure-Response Relationships for Small and Large Molecules

Recorded On: 11/13/2024

Session Description

Description: Dose selection is driven by exposure-response (E-R), combined with dose-response and dose-exposure analyses. However, confounding factors may yield artificially flat or over-exaggerated E-R relationships. This problem has been on full display in recent years for monoclonal antibody therapeutics (mAbs), especially in oncology, where clearance-response relationships have been mis-interpreted as E-R relationships within a single dose level in phase 2 development and beyond. The problem is exacerbated with time-varying clearance, which is observed for many mAbs and is coupled to improvement in disease status. It is important to recognize that E-R confounding is not limited to mAbs in oncology and may occur broadly with other diseases and therapeutic modalities. Despite a growing recognition of this problem, underlying mechanisms leading to E-R confounding are poorly understood, as are the markers that may help to detangle the role of exposure in driving the response. In addition, the guidance for exposure metrics/pharmacometric approaches that yield confidence in dosing decisions remains to be developed. Awareness of these issues is important during study design and data analysis to avoid misinterpretation of spurious E-R relationships and ultimately improve dosing recommendations. This symposium will highlight pitfalls encountered in E-R analyses, provide insight into current understanding of confounding mechanisms for both small and large molecules, provide industry, academia, and regulatory perspectives, share case studies, as well as current strategies to identify and minimize the confounding. During the panel discussion, a path forward to address the gaps and enhance the value of E-R analyses for dosing decisions will be explored.

Conference Date

November 10-13, 2024

Conference Location

Phoenix, Arizona, USA

DOI

10.70534/YVSB2491

Yulia Vugmeyster, PhD

Executive Director, Clinical Pharmacology

Mural Oncology

Dr. Yulia Vugmeyster, PhD, is currently an Executive Director of Clinical Pharmacology at Mural Oncology. She earned her PhD from the Massachusetts Institute of Technology. She has over 20‐year pharmaceutical/biotech industry experience, advancing biologics and small molecule drugs from preclinical to clinical phases and to NDA/BLA approvals in multiple therapeutic areas. She has published both original research and review papers and has presented her research at multiple meetings.

David Turner, PhD

Distinguished Scientist, Clinical Pharmacology

Genentech

David Turner is currently a Distinguished Scientist in the Department of Clinical Pharmacology at Genentech, since September 2021. With over a decade of experience in Clinical Pharmacology (CP) and Modeling and Simulation (M&S), David has played a pivotal role in various global regulatory submissions and health authority interactions. During his time with Merck, his work on the anti-PD1 treatment pembrolizumab in NSCLC has been particularly influential, helping to establish it as a new standard of care in metastatic NSCLC. Prior to joining Genentech, David worked at GSK, where he served as a clinical pharmacology lead for oncology programs and led an MBMA capability build for benchmarking internal oncology assets against external standard-of-care agents. Since joining Genentech, David has led CP efforts for the mosunetuzumab (bispecific anti-CD20/CD3) program, significantly impacting its global regulatory submissions and helping secure its first global approvals in relapsed/ refractory follicular lymphoma. Throughout his career, David has authored more than 40 publications, delivered 3 oral presentations, and presented more than 20 posters. His work in the area of exposure-response (E-R) confounding has been acknowledged as landmark and practice-changing. In the upcoming scientific conference session, David will underscore the importance of recognizing various potential sources of E-R confounding, using past examples from oncology biologics. The session will emphasize the importance of closely examining cause-and-effect relationships and advocate for continued research to address future E-R confounding issues that will challenge the field.

Mitch Phelps, PhD

Professor, College of Pharmacy

The Ohio State University

Mitch Phelps, PhD, is a Professor in the College of Pharmacy, Division of Pharmaceutics and Pharmacology, and is Director of the James Comprehensive Cancer Center Pharmacoanalytical Shared Resource. He also holds appointments as Professor in the Ohio State College of Medicine (Department of Biological Chemistry & Pharmacology and Department of Obstetrics & Gynecology). Dr. Phelps’ research focuses on the development of small-molecule, oligonucleotide and biologic anti-cancer agents and understanding mechanisms of resistance in patients receiving experimental agents and marketed therapies. He has collaborated extensively with hematologists, medical oncologists, and other clinical researchers to study the clinical pharmacology of novel agents, novel drug formulations, and drug combinations in early-phase clinical trials, as well as medicinal chemists, formulation/drug delivery scientists, and disease biologists to guide early drug-like property assessment of novel agents. Modeling and simulation represent a central theme and important tool for the research in Dr. Phelps’ group for identifying patient factors and underlying mechanisms associated with efficacy, toxicity and drug resistance. He serves as PI and Co-I on various funded research projects applying clinical and nonclinical pharmacometrics and PBPK modeling approaches to address questions related to drug disposition, efficacy and toxicity. Dr. Phelps’ research contributions are summarized in more than 160 co-authored publications and a similar number of abstracts presented at national and international meetings.

Youwei Bi, PhD

Team Lead

FDA, MD

Youwei Bi, Ph.D. Pharmacometrics Team Lead Dr. Youwei Bi is the Team Lead at the Division of Pharmacometrics, Office of Clinical Pharmacology, Center of Drug Evaluation and Research, FDA. He received his Ph.D. in Clinical Pharmaceutical Sciences and Master’s in Biostatistics from the University of Iowa. He has been reviewing oncology, immunology, and dermatology drug products at FDA since 2016. His primary responsibilities include reviewing IND and NDA applications, assessing the drug dosing at the individual and population levels, and evaluating the application of quantitative methods to support regulatory review, labeling and policy development.