FDA-ISoP Public Workshop - November 9, 2023

FDA Office of Clinical Pharmacology and International Society of Pharmacometrics (ISoP) Public Workshop: Using Modeling and Simulation to Select Dosages for Combination Therapies and New Indications

Summary:

Project Optimus is an initiative to reform the dosage optimization and dosage selection paradigm in oncology drug development. New approaches to optimize dosages of oncology drugs are needed. FDA continues to strongly advocate for a paradigm shift that moves from identifying the maximum tolerated dose determined based on initial safety assessments to that of identifying dosage(s) based on relevant available information, including pharmacokinetic, pharmacodynamic, safety, tolerability, activity, and other factors. Quantitative methods can effectively leverage this information to support dosage selection for clinical trials and ultimately, labeling and clinical practice. 
 
In 2023, FDA Office of Clinical Pharmacology and ISoP co-sponsored the workshop discussing best practices and methods to incorporate quantitative methods to improve dosage optimization in the context of new disease and combination settings for oncology drug development. The purpose of this program is to educate about the importance of dosage optimization for oncology drugs during clinical development from which patients will benefit.  Previously, the Model Informed Drug Development (MIDD) for Oncology Products Workshop in 2018 focused on best practices of using model-informed approaches to integrate pharmacokinetics, pharmacodynamics, efficacy, and safety data to inform oncology drug development and this workshop initiated broader discussion regarding how to use model-based approaches to support dosage selection.

Goals

  • To discuss best practices and methods to incorporate quantitative methods into the clinical development of oncologic products as a means to support dosage optimization that has been strongly advocated for in recent engagements.
  • To describe the impact of dosage exploration on the benefit/risk assessment for oncologic drugs and highlight ongoing efforts from regulatory agencies, academic centers, and industry to shift current practices used to select dosages for investigation in clinical trials and identify the recommended dosage for marketing applications and labeling.
  • To discuss development of investigational and approved drugs in new combination or disease setting using model-based approaches to select, support and investigate dosing regimen(s). 

Optimizing Dosages for Oncology Drug Products: Using Modeling and Simulation to Select Dosages for Combination Therapies and New Indications

Section 1: Understanding Regulations and Impact of Response Variation on Dosage Selection

  • Nonclinical and Clinical Considerations for Combination Therapies and New Indications - A Regulatory Perspective  – Matthew Thompson, FDA and Mirat Shah, FDA  - Download PDF
  • Using Modeling and Simulation to Evaluate Response Variation and Optimal Dose in Clinical Development – Yanguang (Carter) Cao, University of North Carolina at Chapel
    Hill - Download PDF

Section 2: Understanding the Impact of Study Design and the Role of Model-Informed Development on Dosage Selection and Evaluation for Combination Therapies

  • Statistical Design Considerations for Clinical Trials Combination – Mark R Conaway, University of Virginia  - Download PDF
  • Modeling-Based Approaches for Dosage Optimization of Anticancer Drug Combinations – Dean Bottino, Takeda  - Download PDF
  • Oncology Novel/Novel Combination Dosage Optimization: General Considerations and a Case Study – Donghua Yin, Pfizer
  • Leveraging PK/PD Analyses to Optimize the Dosage of Isatuximab in Combination with Pomalidomide and Dexamethasone- Dorothée Semiond, Sanofi - Download PDF
  • Dosage Optimization for Combination of Decitabine and Cedazuridine-Aram Oganesian, Astex Pharmaceuticals -  Download PDF

Section 3: Understanding the Impact of Study Design and the Role of Model-Informed Development of Dosage Selection and Evaluation for New Indications

  • Design Considerations for Dosage Selection and Optimization for New Indications – Mark Ratain, University of Chicago - Download PDF
  • Model Informed Dosage Optimization for Antibody-Drug Conjugates (ADC's) and T-cell Dependent Bispecifics (TDBs) Across Indications – Chunze Li, Genentech - Download PDF
  • Model-Informed Dosage Optimization Strategies for Immune Checkpoint Inhibitors: Multiple Indications, Same Dosage Regimen? – Li Zhu, Bristol-Myers Squibb - Download PDF
  • Model-Informed Dosage Optimization Strategies for Targeted Oral Agents: Different Dosages, Different Indications – Ying C Ou, Beigene  - Download PDF