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.
Second International Phase-O/Microdosing Stakeholder Meeting: Enabling Human-Based Trnslation in Drug Development
Online meeting
Friday, April 23, 2021 (9:30 am - 5:30 pm Japan time)
Enabling Human-Based Translation in Drug Development
Online meeting: Friday, April 23, 2021 (Japan time)
Organized by: Phase-0/Microdosing Network (phase-0microdosing.org) and Japanese Association for Promoting Drug Development (APDD; www.apdd-jp.org)
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
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
Enabling Human-Based Translation in Drug Development
Online Meeting: Friday, April 23, 2021 (Japan time)
Organized by: Phase-0/Microdosing Network (phase-0microdosing.org) and Japanese Association for Promoting Drug Development (APDD; www.apdd-jp.org)
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
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
CHAIR
SPEAKER
TITLE
9:30-9:55
Hiroshi Yamazaki
Tal Burt
Meeting scope, Phase-0/Microdosing definitions, and application criteria
9:55-10:20
Tal Burt
Nader Sanai
Non-microdosing Phase-0 approaches: Applications in oncology and CNS drug development
10:20-10:45
Tal Burt
Yuichi Sugiyama
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
10:45-11:10
Tal Burt
Wooin Lee
Microdosing studies enabling a better look into target occupancy of small-molecule drugs: What are the key factors that make this possible?
11:10-11:20
Break
11:20-11:45
Hiroshi Yamazaki
Yoshiyuki Yamaura
Japanese industry experience with microdosing studies
11:45-12:10
Hiroshi Yamazaki
Yuuta Taniuchi
Micro tracer mass balance study in healthy subjects in drug development stage
12:10-12:15
Hiroshi Yamazaki
Tal Burt
Connecting microtracer studies with Phase-0
12:15-12:40
Hiroshi Yamazaki
Graeme Young
The impact of industry’s drug development culture on Phase-0 approaches
12-40-12:45
Tal Burt
Review of morning presentations
| Time | Chair | Speaker | Title |
|---|---|---|---|
| 9:30-9:55 | Hiroshi Yamazaki | Tal Burt | Meeting scope, Phase-0/Microdosing definitions, and application criteria |
| 9:55-10:20 | Tal Burt | Nader Sanai | Non-microdosing Phase-0 approaches: Applications in oncology and CNS drug development |
| 10:20-10:45 | Tal Burt | Graeme Young | The impact of industry’s drug development culture on Phase-0 approaches |
| 10:45-11:10 | Tal Burt | Wooin Lee | Microdosing studies enabling a better look into target occupancy of small-molecule drugs: What are the key factors that make this possible? |
| 11:10-11:20 | Break | ||
| 11:20-11:45 | Hiroshi Yamazaki | Yuichi Sugiyama | 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 |
| 11:45-12:10 | Hiroshi Yamazaki | Yoshiyuki Yamaura | Japanese industry experience with microdosing studies |
| 12:10-12:35 | Hiroshi Yamazaki | Daisuke Miyatake | Micro tracer mass balance study in healthy subjects in drug development stage |
| 12:35-12:40 | Hiroshi Yamazaki | Tal Burt | Connecting microtracer studies with Phase-0 |
| 12-40-12:45 | Tal Burt | Review of morning presentations |
12:45 - 13:45 : Luncheon seminar (Lunch time talks by sponsors: Pharmaron and eurofins) and break
13:45 - 15:30 : Breakout Sessions:
TIME
Moderators
Group
Discussion item
13:45-14:10
Wooin Lee,
Yuichi Sugiyama
1
Science and Methodology
Extrapolation from sub-therapeutic to therapeutic-level exposures, TMDD, PBPK modeling, simulations; Use in profiling drug PK, PD, and MOA
14:10-14:35
Tal Burt,
Koji Chiba
2
Strategy and Feasibility
Applicability of Phase-0 approaches in drug development, identification of favorable scenarios, decision algorithms, timelines; ethical and economic considerations
14:35-15:00
Graeme Young,
Ichimaro Yamada
3
Culture of Drug Development
Stakeholder perspectives: motivations and challenges facing Phase-O/microdosing approaches
15:00-15:30
Hiroshi Yamazaki
Tal Burt
4
Future Directions
Recommendations for future research and development of the field, for drug development culture interventions, educational initiatives, management buy-in, and logistics
| Time | Moderators | Group | Discussion item |
|---|---|---|---|
| 13:45-15:30 | Tal Burt, Koji Chiba | 1 | Application Criteria Recommendations for applications in drug development: identification of favorable scenarios, decision algorithms, and timelines, and including recommendations for future research and development of the field |
| 13:45-15:30 | Graeme Young, Ichimaro Yamada | 2 | Adoption Challenges Stakeholder perspectives: motivations and challenges facing Phase-O/microdosing approaches |
| 13:45-15:30 | Wooin Lee, Yuichi Sugiyama | 3 | Vulnerable Populations 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 |
| 13:45-15:30 | Nader Sanai Hiroshi Yamazaki | 4 | Future Directions Recommendations for drug development culture interventions, educational initiatives, management buy-in, and logistics |
15:30 - 15:45 : Break
Closeout session: 15:45 - 17:30 : Summary of breakout sessions, consensus statements, and action items (Chairs: Tal Burt & Hiroshi Yamazaki)
Abstract
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.
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