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.

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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.

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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 Phase-O/Microdosing Stakeholder Meeting

Enabling Human-Based Translation in Drug Development

Monday, April 20, 2020, Tokyo, Japan 9:30 am - 5:30 pm

Organized by the Phase-0/Microdosing Network (Phase-0Microdosing.org) and Japanese Association for Promoting Drug Development (APDD www.apdd-jp.org/)

Contact:  tburt@phase-0microdosing.org

Chair
Tal Burt, MD, President, Phase-0/Microdosing Netwrok, Burt Consultancy, LLC, New York, NY, USA
Co-Chair
Hiroshi Yamazaki, Ph.D., President of Association for Promoting Drug Development (APDD), Professor, Showa Pharmaceutical University

Organizing Committee
Ichimaro Yamada, Ph.D., Vice President Association for Promoting Drug Development (APDD)
Wooin Lee, PhD., Associate Professor, Laboratory of Molecular Pharmaceutics, College of Pharmacy, Seoul National University
Graeme Young, Ph.D., Director and GSK Fellow, DMPK,  David Jack Centre for R&D, GSK
Koji Chiba, Ph.D., Professor, Laboratory of Clinical Pharmacology Yokohama University of Pharmacy

Goals
1. To formulate guidelines for the application of Phase-O/Microdosing approaches
2. To establish recommendations for further research and development

Objectives
1. To provide update on validation, methodology, applications, and research of these approaches
2. To obtain input from major stakeholders (regulatory, academia, industry, CROs) on the value, prospects, and challenges facing these approaches
3. To establish a consensus statement on future directions in research and applications

Meeting Format
Overall: 9:30 am - 5:30 pm
9:30 - 12:45 pm:  Presentations: state-of-the-art, application criteria, adoption challenges, future directions
12:45 - 1:45 pm: Lunch
1:45 - 3:30 pm: breakout sessions: state-of-the-art, application criteria, adoption challenges, future directions
3:30 - 3:45 pm:  Break
3:45 - 5:30 pm:  Closeout session: summary of breakout sessions, consensus statements, action items

Morning Presentations
Tal Burt, MD: Meeting scope, Phase-0/Microdosing Definitions, Application Criteria
Nader Sanai, MD: Non-microdosing Phase-0 Approaches: Applications in Oncology and CNS Drug Development
Graeme Young, PhD: AMS Microdosing, Industry Culture
Yuichi Sugiyama, PhD: 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
Wooin Lee, PhD: Target-Mediated Drug Disposition (TMDD) Phenomenon of Small-Molecule Drugs Analyzed by PBPK Modeling
Yoshiyuki Yamaura, PhD: Industry Microdosing Studies
Daisuke Miyatake, PhD: Industry 14C-labelled Microtracer Studies as Precursors to Phase-0/Microdosing Studies

Breakout Sessions
State-of-the-Art
Application Criteria
Adoption Challenges
Future Directions

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-pharmacological 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-pharmacological 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, developmen, and applications of these approaches.

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