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

State of the Art and Future Directions

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

Organized by the Phase-0/Microdosing Network and Japanese Association for Promoting Drug Development (APDD)

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

Goals
To formulate application guidelines and establish recommendations for further research and development

Objectives
1.  To provide update on validation, methodology, applications, and research
2.  To obtain input from major stakeholders on the value, prospects, and challenges
3.  To establish a consensus statement on future directions in research and applications

Meeting format
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, and action items

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 Phase-O including Microdosing 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, development, and applications of these approaches.

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