First Phase-O/Microdosing Stakeholder Meeting

State of the Art and Future Directions

A 1-day meeting prior to the 2019 ASCPT Annual Meeting, Washington D.C. (March 12, 2019)

Organized by the Phase-0/Microdosing Network (Phase-0Microdosing.org)
Courtyard Washington, DC/U.S. Capitol, located at 1325 2nd Street NE, Washington, DC 20002, (202) 898-4000

Contact:  talburtmd@gmail.com

Chair
Tal Burt, MD, Burt Consultancy, LLC, New York, NY, USA
Co-Chair
Graeme Young, Ph.D., Director in Translational Medicine at GSK London, UK

Goals

1. To formulate guidelines for the application of Phase-O/Microdosing approaches in drug development, including a decision-tree
2. To establish recommendations for further research and development

Objectives

1. To provide an update on the validation, methodology, applications, and research of Phase-O/Microdosing approaches
2. To obtain input from major stakeholders (regulatory, academia, industry, patient advocacy, non-profit) on the value, prospects, and challenges facing the application of these approaches
3. To establish a consensus statement on future directions in research and applications

Meeting format
1-day, 8-hour meeting:
Registration/breakfast: 7 – 8 am
Meeting: 8 am – 5 pm
State-of-the-art presentations: 8 am – 12 noon
Small-group breakout sessions, topical discussions: 1 – 3 pm
Large-group consensus session: 3 – 5 pm

Abstract
Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities favor limited exposure clinical trials such as microdosing and other Phase-O approaches. Phase-O studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are a regulatory framework for First-in-Human (FIH) trials. Common to these approaches is the use and implied safety of limited exposure to the test article. With microdosing the dose is less than 100 µg or 1/100th of the anticipated therapeutic dose. Applications include study of drug pharmacokinetic (PK) and pharmacodynamic (PD) properties, target localization, drug-drug interactions (DDIs), effects in vulnerable populations (e.g., pediatric), and Intra-Target Microdosing (ITM). The use of sub-pharmacological doses in Phase-O/Microdose studies requires sensitive analytic tools such as Accelerator Mass Spectrometer (AMS), Positron Emission Tomography (PET) and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained. Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvement over traditional allometric approaches. Nevertheless, utilization of Phase-O/Microdosing by drug developers remains modest though growing in number and scope. The purpose of the meeting is to understand and address this under-utilization and formulate recommendations for future research, development, and applications of these approaches.

Morning Presentations 0800 - 1200

0800 – 0830: Introduction: Meeting goals, regulatory framework, current applications, and future directions - Tal Burt, M.D., Burt Consultancy, LLC., New York, NY, USA

0830 – 0855: Protein Drug Development Using AMS Microdosing - Wouter Vaes, Ph.D., Department of Kinetics Research, Netherlands Organisation for Applied Scientific Research (TNO)

0855 – 0920:  Microdosing in Pediatric Drug Development - Saskia de Wildt, M.D., Ph.D. Professor of Clinical Pharmacology, Pediatric intensivist; Radboud University, Nijmegen and Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands

0920 – 0945: PET-microdosing - Oliver Langer, Ph.D. Associate Professor, Department of Clinical Pharmacology, Medical University of Vienna, and Senior Scientist, AIT Austrian Institute of Technology

0945-1000: Break

1000 – 1025: Phase-0 in Oncology Drug Development - Jerry Collins, M.D. Associate Director of the DCTD Developmental Therapeutics Program of the NCI.

1025 – 1050: Microdose-induced drug-DNA adducts: pharmacodynamic markers of chemotherapy efficacy - Paul T. Henderson, Ph.D. Associate Adjunct Professor, UC Davis Cancer Center

1050 – 1115: Where Phase 0 works better for PET oncology imaging vs the traditional approach – Peter Choyke, Head of Imaging Intramural NCI

1115 – 1140: Drug development culture, incentives, and logistics: how to get buy-in and how to implement it – Graeme Young, Ph.D., Director in Translational Medicine at GSK

1140 – 1200: Q&A

1200 – 1245: Lunch

Breakout Sessions 1245 – 1445:

1. Recommendations for applications in drug development: identification of favorable scenarios, decision algorithms, and timelines, including recommendations for future research and development of the field (Moderators: Tal Burt, M.D., and Ilan Rabiner, MBBCh)
2. Stakeholder perspectives: motivations and challenges facing Phase-O/microdosing approaches (Moderators: Elizabeth Baker, Esq., Malek Okour, Ph.D.)
3. Development of drugs for vulnerable populations and special conditions (e.g., pediatric, pregnancy, frail elderly, renally/hepatically-impaired, orphan diseases), including the identification of specific risk/benefit considerations for inclusion of such populations in Phase-O/microdosing studies (Moderators: Saskia de Wildt, M.D., Ph.D., Marie Croft, Ph.D.)
4. Recommendations for drug development culture interventions, educational initiatives, management buy-in, and logistics (Moderators: Graeme Young, Ph.D., Kathleen Hillgren, Ph.D.)

1445 – 1500: Break

Consensus Session 1500 – 1700

 Presenters from each breakout session present their recommendations for the entire group to discuss and reach consensus

Moderators

1. Elizabeth Baker, Esq., Pharmaceutical Policy Program Director, Physicians Committee for Responsible Medicine, Washington, DC, USA
2. Graeme Young, Ph.D., Director in Translational Medicine at GSK London, UK
3. Tal Burt, M.D., clinical research and drug development consultant, New York, NY, USA
4. Ilan Rabiner, MBBCh, PET molecular imaging, EVP, Head of Translational Applications - Invicro, A Konica Minolta Company, Reader in Molecular NeuroImaging, Centre for Neuroimaging Sciences, IoPPN, King’s College, London, UK
5. Saskia de Wildt, M.D., Ph.D., Professor of Clinical Pharmacology, Pediatric intensivist; Radboud University, Nijmegen and Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands
6. Malek Okour, Ph.D., Manager, Clinical Pharmacology, Clinical Pharmacology Modeling and Simulation (CPMS), R&D Projects Clinical Platforms and Sciences, GSK
7. Marie Croft, Ph.D., Director, Scientific Operations, Xceleron / Pharmaron.
8. Kathleen Hillgren, Ph.D., Research Fellow, Investigational Drug Disposition, Elli Lilly.