Past Meetings

The Second International Phase-0 Microdosing Stakeholder Meeting: Enabling Human-Based Translation in Drug Development

A 1-day meeting: Friday, April 23, 2021
Organized by: Phase-0/Microdosing Network (phase-0microdosing.org) and Japanese Association for Promoting Drug Development (APDD; www.apdd-jp.org)

Tal Burt, MD - President, Phase-0/Microdosing Network and Burt Consultancy, LLC, New York, NY, USA

Hiroshi Yamazaki, PhD - President of APDD and Professor, Showa Pharmaceutical University

1.  Formulate guidelines for the application of Phase-O/Microdosing approaches

2.  Establish recommendations for further research and development 

1. Provide update on validation, methodology, applications, and research
2. Obtain input from stakeholders (regulatory, academia, industry, CROs) on the value, prospects, and
challenges of these approaches
3. Establish consensus statements on future directions in research and applications

State-of-the-art presentations: 9:30 am – 12:45 pm
Small-group breakout sessions, topical discussions: 13:45 – 15:30 pm
Large-group consensus session: 15:45 – 17:30 pm

Drug development is associated with exponential increase in costs and only modest productivity. In addition, there are concerns about the risks of exposing humans and animals to novel chemical entities. These challenges have led to efforts to improve the drug development process. Such efforts include limited exposure clinical trials
such as microdosing and other Phase-O approaches. These approaches are also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are an alternative regulatory framework for First-in-Human (FIH) trials. Common to these approaches is the use and implied safety of limited exposure to the drug. For example, with microdosing the dose is less than 100 μg or 1/100th of the anticipated therapeutic dose. 

The primary applications of Phase-0 approaches include study of drug pharmacokinetic (PK) and pharmacodynamic (PD) properties. Specific applications include use in target localization, drug-drug interactions (DDIs), effects in vulnerable populations (e.g., pediatric), and Intra-Target Microdosing (ITM). The sub-therapeutic doses in Phase-O/Microdose studies require the use of sensitive analytic tools such as Accelerator Mass Spectrometer (AMS), Positron Emission Tomography (PET) and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). These tools are used to study disposition, effects, and metabolites of the novel drug under study. Further, when these analytic techniques are used in combinations, they can increase the versatility of study design and the power of the data obtained. Validation studies over the past decade have demonstrated the reliability of extrapolation of data from sub-therapeutic exposures to therapeutic-level exposures in more than 80% of cases. This constitutes an improvement over traditional allometric approaches. Nevertheless, utilization of Phase-O/Microdosing by drug developers remains modest, although 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 09:30 - 12:45

Morning Presentations 09:30 - 12:45

09:30 – 09:55:
Introduction: Meeting scope, Phase-0/Microdosing definitions, and application criteria - Tal Burt

09:55 – 10:20:
Non-microdosing Phase-0 approaches: Applications in oncology and CNS drug development - Nader Sanai

10:20 – 10:45:
Prediction of drug clearance and DDI/PGx at therapeutic doses from microdosing clinical studies using PBPK modeling with in-vitro data on metabolism and transport - Yuichi Sugiyama

10:45 – 11:10:
Microdosing studies enabling a better look into target occupancy of small-molecule drugs: What are the key factors that make this possible? - Wooin Lee

11:10 – 11:20: Break

11:20 – 11:45:
Japanese industry experience with microdosing studies - Yoshiyuki Yamaura

11:45 – 12:10:
Micro-tracer mass balance study in healthy subjects in drug development stage - Yuuta Taniuchi

12:10 – 12:15:
Connecting microtracer studies with Phase-0 - Tal Burt

12:15 – 12:40:
The impact of industry’s drug development culture on Phase-0 approaches – Graeme Young 

12:15 – 12:40:
Review of morning presentations – Tal Burt 

12:00 – 12:45: Lunch

Breakout Sessions 13:45 – 15:30

Breakout Sessions 13:45 – 15:30

  1. Science and Methodology - Extrapolation from sub-therapeutic to therapeutic-level exposures, TMDD, PBPK modeling, simulations; Use in profiling drug PK, PD, and MOA (Moderators: Wooin Lee, Yuichi Sugiyama)
  2. Strategy and Feasibility - Applicability of Phase-0 approaches in drug development, identification of favorable scenarios, decision algorithms, timelines; ethical and economic considerations (Moderators: Tal Burt, Koji Chiba)
  3. Culture of Drug Development - Stakeholder perspectives: motivations and challenges facing Phase-O/microdosing approaches (Moderators: Graeme Young, Ichimaro Yamada)
  4. Future Directions - Recommendations for future research and development of the field, for drug development culture interventions, educational initiatives, management buy-in, and logistics (Moderators: Hiroshi Yamazaki, Tal Burt)

14:45 – 15:00: Break

Consensus Session 15:45 – 17:30

Consensus Session 15:45 – 17:30

Summary of breakout sessions, consensus statements, and action items (Chairs: Tal Burt & Hiroshi Yamazaki)

Organizing Committee

Organizing Committee:

  1. Ichimaro Yamada, PhD., Vice President APDD and General Manager for R&D, TNAX Biopharma Corporation
  2. Wooin Lee, PhD., Associate Professor, Laboratory of Molecular Pharmaceutics, College of Pharmacy, Seoul National University
  3. Graeme Young, PhD., Director and GSK Fellow, DMPK, David Jack Centre for R&D, GSK
  4. Koji Chiba, PhD., Professor, Laboratory of Clinical Pharmacology Yokohama University of Pharmacy

The First International Phase-0 Microdosing Stakeholder Meeting: State-of-the-Art and Future Directions

A 1-day meeting: Tuesday, March 12, 2019
The Phase-0 Microdosing Meeting is organized by the Phase-0/Microdosing Network (Phase-0Microdosing.org)
Courtyard Washington, DC/U.S. Capitol, 1325 2nd Street NE, Washington, DC. (202) 898-4000

Tal Burt, MD, Burt Consultancy, LLC, New York, NY, USA

Graeme Young, Ph.D., Director in Translational Medicine at GSK London, UK

  1. To formulate guidelines for the application of Phase-O including Microdosing approaches in drug development, including a decision-tree
  2. To establish recommendations for further research and development
  1. To provide an update on the validation, methodology, applications, and research of Phase-O including Microdosing approaches
  2. To obtain input from major stakeholders (regulatory, academia, industry, patient advocacy, non-profit) on the value, prospects, and challenges facing the applications of these approaches
  3. To establish consensus statements on future directions in research and applications

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

The Phase-0 Microdosing Stakeholder Meeting was conceptualized to address some of the challenges facing current drug development. 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 (ICH M3 guideline), 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 of Phase-0/Microdosing approaches 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 08:00 - 12:00

Morning Presentations 08:00 - 12:00

08:00 – 08:30:
Introduction: Meeting goals, regulatory framework, current applications, and future directions - Tal Burt, M.D., Burt Consultancy, LLC., New York, NY, USA

08:30 – 08:55:
Protein Drug Development Using AMS Microdosing - Wouter Vaes, Ph.D., Department of Kinetics Research, Netherlands Organisation for Applied Scientific Research (TNO)

08:55 – 09:20:
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

09:20 – 09:45:
PET-microdosing - Oliver Langer, Ph.D. Associate Professor, Department of Clinical Pharmacology, Medical University of Vienna, and Senior Scientist, AIT Austrian Institute of Technology

09:45 – 10:00: Break

10:00 – 10:25:
Phase-0 in Oncology Drug Development - Jerry Collins, M.D. Associate Director of the DCTD Developmental Therapeutics Program of the NCI.

10:25 – 10:50:
Microdose-induced drug-DNA adducts: pharmacodynamic markers of chemotherapy efficacy - Paul T. Henderson, Ph.D. Associate Adjunct Professor, UC Davis Cancer Center

10:50 – 11:15:
Where Phase 0 works better for PET oncology imaging vs the traditional approach – Peter Choyke, Head of Imaging Intramural NCI

11:15 – 11:40:
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

11:40 – 12:00: Q&A
12:00 – 12:45: Lunch

Breakout Sessions 12:45 – 14:45

Breakout Sessions 12:45 – 14:45

  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.)

14:45 – 15:00: Break

Consensus Session 15:00 – 17:00

Consensus Session 15:00 – 17:00

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

Moderators

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.

From Our Past Sponsors

Silver Sponsor

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Hammersmith Medicines Research (HMR) at www.hmrlondon.com

HMR is a CRO specializing in early clinical studies. It conducts about 25 studies each year. Since 1993 HMR has done more than 850 studies – almost all conceivable types, many of them First-in-Human (FIH). In particular, HMR has done over 50 PET studies and 5 microdose studies. HMR has purpose-built premises with 145 beds; 270 staff; MHRA GCP and GMP accreditation; and laboratory and pharmacy accreditation.

Bronze Sponsor

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National Electrostatics Corp. (NEC) at www.pelletron.com

NEC is a manufacturer of electrostatic ion beam accelerator systems. These systems produce ion beams of essentially all stable nuclei with energies ranging from a few keV to hundreds of MeV. NEC was formed in 1965 and, to date, over 230 Pelletron® systems have been sold or are in manufacture for laboratories in 33 countries throughout the world.

Silver Sponsor

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Novartis Institutes for BioMedical Research, Inc.  Major discovery efforts at the frontiers of science www.novartis.com.