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.
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Meetings
Phase-0 Microdosing Drug Development
Second International Phase-O/Microdosing Stakeholder Meeting
Enabling Human-Based Translation in Drug Development
Tentative: Friday, May 7, 2021
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:
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
9:30 - 12:45 pm: Plenary session:
State-of-the-art - Application Criteria - Adoption Challenges - Future Directions
| Time | Chair | Speaker | Title |
| 9:30-9:55 | Graeme Young | 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 | Graeme Young | The impact of industry’s drug development culture on Phase-0 approaches | |
| 10:45-11:10 | 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 | Yoshiyuki Yamaura | Japanese industry experience with microdosing studies | |
| 12:10-12:35 | Daisuke Miyatake | Micro tracer mass balance study in healthy subjects in drug development stage | |
| 12:35-12:40 | Tal Burt | Connecting microtracer studies with Phase-0 | |
| 12-40-12:45 | Tal Burt | Review of morning presentations | |
12:45 - 13:45 pm: Luncheon seminar (Lunch time talks with lunch boxes provided by sponsors) and break
13:45 -15:30 pm: Breakout Sessions:
Application Criteria - Adoption Challenges - Vulnerable Populations - Future Directions
| 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 |
| Graeme Young,
Ichimaro Yamada |
2 | Adoption Challenges
Stakeholder perspectives: motivations and challenges facing Phase-O/microdosing approaches |
|
| 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 |
|
| Nader Sanai
Hiroshi Yamazaki |
4 | Future Directions
Recommendations for drug development culture interventions, educational initiatives, management buy-in, and logistics |
15:30 - 15:45 pm: Break
Closeout session:
15:45 - 17:30 pm: Summary of breakout sessions, consensus statements, and action items
(Chairs: Tal Burt & Hiroshi Yamazaki)
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. 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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