FDA Workshop

FDA/CDER Office of Clinical Pharmacology and International Society of Pharmacometrics (ISoP) Public Workshop: Using Modeling and Simulation to Evaluate the Effects of Intrinsic and Extrinsic Factors

October 16th, 2023 | 10:00 AM - 4:30 PM ET

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 two workshops discussing best practices and methods to incorporate quantitative methods to improve dosage optimization in the context of intrinsic and extrinsic factors as well as 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.

The Oncology Center of Excellence (OCE) Project Optimus is an initiative to reform the dose optimization and dose selection paradigm in oncology drug development. New approaches to optimize doses of targeted anticancer agents 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 2018, the FDA and ISoP conducted a public workshop focusing 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. In the 2023 workshops, the FDA and ISoP discussed best practices and methods to incorporate quantitative methods to improve dose optimization in the context of intrinsic and extrinsic factors as well as in the context of new disease and combination settings for oncology drug development.

  • 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). 

October 16th, 2023 Session

Optimizing Dosages for Oncology Drug Products:  Using Modeling and Simulation to Evaluate Effects of Intrinsic and Extrinsic Factors

Session 1: Using Model-Informed Approaches to Develop Oncology Drugs for Pediatric Patients and Older Adults  

  • Understanding the Regulations and Recommendations for Drug Development in Pediatrics and Older Adults with Cancer – Youwei Bi, FDA - Download PDF
  • Understanding the Effects of Chronological and Functional Age on Dosage Selection in Older Adults– Ginah Nightingale, Abbvie - Download PDF
  • Model-informed Approaches to Support Dosage Selection in Pediatric Patients – Tomoyuki Mizuno, University of Cincinnati - Download PDF

Session 2:  Evaluating How Race, Ethnicity, Geography & Ancestry Influence Dosage Optimization for Oncology Drug Development 

  • Expanding Clinical Trial Eligibility to Include Relevant Populations – Olanrewaju Okusanya, FDA - Download PDF
  • Clinical Pharmacology Considerations for Evaluation of Race, Ethnicity, Geography, and Ancestry During Drug Development and Regulatory Review – Anuradha Ramamoorthy, FDA  - Download PDF
  • The Role of Clinical Pharmacology in Dosage Selection and Design of Multi-Regional Clinical Trials– Karthik Venkatakrishnan, EMD Serono - Download PDF
  • PMDA Experience with Dosage Selection - Shinichi Kijima, Pharmaceuticals and Medical Devices Agency - Download PDF

Session 3: Understanding the Effects of Food and Drug-Drug Interactions on Dosage Optimization 

  • Impossible Recommendations Regarding Administration with Food and Use of Concomitant Medications – Brian Booth, FDA - Download PDF
  • Leveraging Modeling to Understand the Effects of Food on Dosage Selection– Xinyuan (Susie) Zhang, Daiichi Sankyo - Download PDF
  • DDI Management in Oncology Drug Development - Ping Zhao - Download PDF

November 9th, 2023 Session

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

  • Optimizing Dosages for Oncology Drug Products - Watch Recording
  • 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 - MISSING IF THERE ARE SLIDES

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

  • Understanding the Impact of Study Design and the Role of Model-Informed Development on Dosage Selection and Evaluation for Combination Therapies - Watch Recording
  • Statistical Design Considerations for Clinical Trials Combination – Mark R Conaway, University of Virginia  - MISSING IF THERE ARE SLIDES
  • Modeling-Based Approaches for Dosage Optimization of Anticancer Drug Combinations – Dean Bottino, Takeda  - MISSING IF THERE ARE SLIDES
  • Oncology Novel/Novel Combination Dosage Optimization: General Considerations and a Case Study – Donghua Yin, Pfizer– Donghua Yin, Pfizer  MISSING IF THERE ARE SLIDES
  • A Case Study: Leveraging PK/PD Analyses to Optimize the Dosage of Isatuximab in Combination with Pomalidomide and Dexamethasone- Dorothée Semiond, Sanofi - MISSING IF THERE ARE SLIDES
  • A Case Study: Dosage Optimization for Combination of Decitabine and Cedazuridine – Aram Oganesian, Astex Pharmaceuticals - MISSING IF THERE ARE SLIDES

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

  • Understanding the Impact of Study Design and the Role of Model-Informed Development on Dosage Selection and Evaluation for New Indications - Watch Recording
  • Design Considerations for Dosage Selection and Optimization for New Indications – Mark Ratain, University of Chicago - MISSING IF THERE ARE SLIDES
  • Model Informed Dosage Optimization for Antibody-Drug Conjugates (ADC's) and T-cell Dependent Bispecifics (TDBs) Across Indications – Li Zhu, Bristol-Myers Squibb  - 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  - MISSING IF THERE ARE SLIDES

Meeting Information:

  • NOT ON EITHER AGENDA!!!! Clinical Development of ASTX727 (Oral Decitabine with Cedazuridine) for MDS/CMML and AML - Download PDF

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