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, Human-Based Trnslation in Drug Development
In-person / online meeting
Friday, April 22, 2022 (8:00 am - 5:00 pm Central European Standard Time)
Leiden, The Netherlands
Enabling Human-Based 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, 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: Hiroshi Yamazaki, PhD - President of APDD and Professor, Showa Pharmaceutical University
Ichimaro Yamada, PhD., Vice President APDD and General Manager for R&D, TNAX Biopharma Corporation
Wooin Lee, PhD., Associate Professor, Laboratory of Molecular Pharmaceutics, College of Pharmacy, Seoul National University
Graeme Young, PhD., Director and GSK Fellow, DMPK, David Jack Centre for R&D, GSK
Koji Chiba, PhD., Professor, Laboratory of Clinical Pharmacology Yokohama University of Pharmacy
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
8:00-8:25
Tal Burt
Overview of Phase-0 Approaches
8:25-8:50
Oliver Jonas
Intra-Target Microdosing (ITM)
8:50-9:15
Kirsten Anderson
Utility of Phase 0 Intratumoral Microdosing for Evaluation of MOA in Tumor Microenvironment (TME)
9:15-9:50
Yuichi Sugiyama & Yasunori Aoki
ITM Modeling and Simulations
9:50-10:05
Break
10:05-10:30
Elizabeth Baker
Phase-0 and Animal Research
10:30-10:55
Oliver Langer
PET-microdosing
10:55-11:20
Saskia de Wildt
Microdosing in Pediatric and Pregnancy Drug Development
11:20-11:45
Jan Willem van der Laan
EMA Regulatory Perspective of Phase-0
| Time | Speaker | Title |
|---|---|---|
| 8:00-8:25 | Tal Burt | Overview of Phase-0 Approaches |
| 8:25-8:50 | Oliver Jonas | Intra-Target Microdosing (ITM) |
| 8:50-9:15 | Kirsten Anderson | Utility of Phase 0 intratumoral microdosing for evaluation of MOA in tumor microenvironment (TME) |
| 9:15-9:50 | Yuichi Sugiyama + Yasunori Aoki | ITM Modeling and Simulations |
| 9:50-10:05 | Break | |
| 10:05-10:30 | Elizabeth Baker | Phase-0 and Animal Research |
| 10:30-10:55 | Saskia de Wildt | Microdosing in Pediatric and Pregnancy Drug Development |
| 10:55-11:20 | Oliver Langer | PET-microdosing |
| 11:20-11:45 | Jan Willem van der Laan | EMA Regulatory Perspective of Phase-0 |
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
Kirsten Anderson
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 Kirsten Anderson | 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 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.
When AMS, PET, and LC-MS/MS 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.
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.
Silver Sponsor
GSK is a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. www.gsk.com
Bronze Sponsor
The Physicians Committee for Responsible Medicine (PCRM) is dedicated to saving and improving human and animal lives through plant-based diets and ethical and effective scientific research (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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