Phase-0 Including Microdosing Approaches
Phase-0 drug development trials are clinical development approaches that include microdosing trials. These approaches are sometimes called ‘Exploratory Clinical Trials’ ‘Exploratory Investigational New Drug (eIND)’ applications. Phase-0 studies are aimed at providing human data to support selection of preclinical drug candidates prior to entering clinical development.
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Phase-0 approaches, also called 'Exploratory Clinical Trials', and 'exploratory Investigational New Drug' (eIND) applications:
Regulatory Framework
The International Conference on Harmonization (ICH) M3 Guidelines outline the regulatory position on Phase-0 including Microdosing approaches. In addition, examples of 5 Phase-0 approaches are provided.
Operational Factors
Phase-0 approaches offer many operational advantages over traditional Phase-1 approaches. These advantages enable arrival at meaningful developmental decisions in a safer, quicker, and cheaper manner than is possible with traditional Phase-1.
Application Criteria
The Phase-0 application criteria are developmental scenarios in which Phase-0 may provide advantages over traditional Phase-1. These criteria are the product of Phase-0/Microdosing Network discussions and stakeholder meetings.
Third International Phase-O/Microdosing Stakeholder Meeting: Safer, Accelerated, Targeted, and Human-Specific Translation in Drug Development
In-person / online meeting
Friday, April 22, 2022 (8:00 am - 5:00 pm Central European Standard Time)
Leiden, The Netherlands
Safer, Accelerate, Targeted, and Human-Specific Translation in Drug Development
In-person and online meeting
Friday, April 22, 2022
Organized by: Phase-0/Microdosing Network (phase-0microdosing.org)
Chair: Tal Burt, MD - President, Phase-0/Microdosing Network and Burt Consultancy, LLC
Co-Chair: Saskia de Wildt, MD, PhD - Professor of Clinical Pharmacology and pediatric intensivist at Radboud University Medical Center.
Organizing Committee:
Members:
Yuichi Sugiyama, PhD, - Special Professor Emeritus in Josai Interanational University.
Kirsten Anderson, - Vice President, Presage Bioscience.
Elizabeth Baker, Esq., - Pharmaceutical Policy Program Director for the Physicians Committee for Responsible Medicine (PCRM).
Oliver Langer, PhD, - Associate Professor at the Medical University of Vienna in Austria (Department of Clinical Pharmacology).
Esther van Duijn, PhD - Senior scientist at the Department of Metabolic Health Research within the Netherlands Organisation for Applied Scientific Research (TNO).
Safer, Accelerated, Targeted, and Human-Specific Translation in Drug Development
In-Person and Online Meeting
Friday, April 22, 2022, Leiden, The Netherlands
Organized by: Phase-0/Microdosing Network (phase-0microdosing.org)
Chair: Tal Burt, MD - President, Phase-0/Microdosing Network and Burt Consultancy, LLC.
Co-Chair: Saskia de Wildt, MD, PhD - Professor of Clinical Pharmacology and pediatric intensivist at Radboud University Medical Center.
Organizing Committee:
Chair: Tal Burt, MD - President, Phase-0/Microdosing Network and Burt Consultancy, LLC
Co-Chair: Saskia N. de Wildt, M.D., Ph.D. - Professor of Clinical Pharmacology, Pediatric intensivist; Radboud University, Nijmegen
Kirsten Anderson - Senior Vice President, Presage Biosciences
Esther van Duijn, Ph.D. - Senior Scientist/Study Director, TNO, The Netherlands
Elizabeth Baker, Esq. - Pharmaceutical Policy Program Director, Physicians Committee for Responsible Medicine
Oliver Langer, Ph.D. - Medical University of Vienna, Department of Clinical Pharmacology
Yuichi Sugiyama, Ph.D. - Special Professor Emeritus in Josai Interanational University, Yokohama, Japan
Goals:
- Formulate guidelines for the application of Phase-O/Microdosing approaches
- Establish recommendations for further research and development
Objectives:
- Provide update on validation, methodology, applications, and research
- Obtain input from stakeholders (regulatory, academia, industry, CROs) on the value, prospects, and challenges of these approaches
- Establish consensus statements on future directions in research and applications
AGENDA
9:30 - 12:45 : Plenary session:
TIME
SPEAKER
TITLE
8:00-8:20
Tal Burt
Overview of Phase-0 Approaches
8:20-8:45
Go van Dam
Hitting the R&D Sweet Spot with Phase 0/Microdosing Trials
8:45-9:05
Elizabeth Baker
Employing Phase 0 to Reduce Animal Use in Research
9:05-9:40
Yuichi Sugiyama & Yasunori Aoki
Intra-Target Microdosing {ITM) Modeling and Simulations
9:40-9:55
Break
9:55-10:20
Oliver Langer
PET-Microdosing
10:20-10:45
Saskia de Wildt
Microdosing in Pediatric and Pregnancy Drug Development
10:45-11:10
Jan Willem van der Laan
European Regulatory Perspective of Phase-0
11:10-11:35
11:35-12:00
Oliver Jonas
Joseph DiMasi
Use of ITM to Measure Multiple Drug Responses in Cancer Patients
Economics of Phase-0 Approaches
| Time | Speaker | Title |
|---|---|---|
| 8:00-8:20 | Tal Burt | Overview of Phase-0 Approaches |
| 8:20-8:45 | Go van Dam | Hitting the R&D Sweet Spot with Phase 0/Microdosing Trials |
| 8:45-9:05 | Elizabeth Baker | Employing Phase 0 to Reduce Animal Use in Research |
| 9:05-9:40 | Yuichi Sugiyama + Yasunori Aoki | Intra-Target Microdosing (ITM) Modeling and Simulations |
| 9:40-9:55 | Break | |
| 9:55-10:20 | Oliver Langer | PET-Microdosing |
| 10:20-10:45 | Saskia de Wildt | Microdosing in Pediatric and Pregnancy Drug Development |
| 10:45-11:10 | Jan Willem van der Laan | European Regulatory Perspective of Phase-0 |
| 11:10-11:35 | Oliver Jonas | Use of ITM to Measure Multiple Drug Responses in Cancer Patients |
| 11:35-12:00 | Joseph Dimasi | Economics of Phase-0 Approaches |
12:00 - 13:00 : Luncheon seminar (Lunch time talks by sponsors) and break
13:00 - 15:00 : Breakout Sessions:
TIME
Moderators
Group
Discussion item
13:00-15:00
Oliver Jonas
Yuichi Sugiyama
1
ITM
13:00-15:00
Saskia de Wildt
Bianca van Groen
2
Vulnerable populations
13:00-15:00
Ad Roffel
Kev Dhaliwal
3
Strategy and execution
13:00-15:00
Oliver Langer
Esther van Duijn
4
Regulatory environment and Phase-0
| Time | Moderators | Group | Discussion item |
|---|---|---|---|
| 13:00-15:00 | Oliver Jonas Yuichi Sugiyama | 1 | ITM |
| 13:00-15:00 | Saskia de Wildt Bianca van Groen | 2 | Vulnerable populations |
| 13:00-15:00 | Ad Roffel Kev Dhaliwal | 3 | Strategy and execution |
| 13:00-15:00 | Oliver Langer Esther van Duijn | 4 | Regulatory environment and Phase-0 |
15:00 - 15:15 : Break
Closeout session: 15:15 - 17:00 : Summary of breakout sessions, consensus statements, and action items (Chairs: Tal Burt & Saskia de Wildt)
Abstract
Drug development has been associated with increases in costs and duration and only modest increases in 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 by using limited exposure clinical trials such as microdosing and other Phase-O approaches that allow safer and earlier entry into human testing, and human-based selection from preclinical candidates. These approaches are also called Exploratory Investigational New Drug (eIND) applications and exploratory clinical trials and are regulated under the internationally harmonized ICH M3 guidance.
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.
Recent research has advanced the validity and applicability of Phase-0 approaches.
The approaches can accelerate drug development timelines and reduce developmental attrition by increasing the quality of candidates entering clinical development and by reducing the time to ‘go-no-go’ decisions. This can be done by adding human data to preclinical candidate selection, and by applying methodological and operational advantages that Phase 0 have over traditional approaches. The limited, sub-therapeutic exposure to the test article, means a reduced risk to research volunteers, and reduced regulatory requirements, timelines, and costs of first-in-human (FIH) testing. While many operational aspects of Phase 0 approaches are similar to those of other early-phase clinical development programs, they have some unique strategic, regulatory, ethical, feasibility, economic, and cultural aspects. The meeting will engage participants in discussion of the recent advances, implementation challenges, and future directions in research and applications of these approaches.
From Our Sponsors
Silver Sponsor
TNO (https://www.tno.nl/en/) is a non-profit research organization with a focus on innovation and applied science, and owns the only biomedical AMS facility in Europe. TNO’s microdosing and microtracer technology offers the opportunity to generate human data early in drug development.
Bronze Sponsor
The Physicians Committee for Responsible Medicine is a non-profit organization working for more effective, efficient, and ethical medical research, product testing, and training. (https://www.pcrm.org/).
Bronze Sponsor
Novartis Institutes for BioMedical Research, Inc. Major discovery efforts at the frontiers of science. (www.novartis.com)
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