The First International Phase-0 Microdosing Stakeholder Meeting: State-of-the-Art and Future Directions

Tal Burt, MD, Burt Consultancy, LLC, New York, NY, USA

Graeme Young, Ph.D., Director in Translational Medicine at GSK London, UK

1. To formulate guidelines for the application of Phase-O including Microdosing approaches in drug development, including a decision-tree
2. To establish recommendations for further research and development

1. To provide an update on the validation, methodology, applications, and research of Phase-O including Microdosing approaches
2. To obtain input from major stakeholders (regulatory, academia, industry, patient advocacy, non-profit) on the value, prospects, and challenges facing the applications of these approaches
3. To establish consensus statements on future directions in research and applications

Registration/breakfast: 7 – 8 am
Meeting: 8 am – 5 pm
State-of-the-art presentations: 8 am – 12 noon
Small-group breakout sessions, topical discussions: 1 – 3 pm
Large-group consensus session: 3 – 5 pm

The Phase-0 Microdosing Stakeholder Meeting was conceptualized to address some of the challenges facing current drug development. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities favor limited exposure clinical trials such as microdosing and other Phase-O approaches. Phase-O studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials (ICH M3 guideline), are a regulatory framework for First-in-Human (FIH) trials. Common to these approaches is the use and implied safety of limited exposure to the test article. With microdosing the dose is less than 100 µg or 1/100th of the anticipated therapeutic dose.

Applications of Phase-0/Microdosing approaches include study of drug pharmacokinetic (PK) and pharmacodynamic (PD) properties, target localization, drug-drug interactions (DDIs), effects in vulnerable populations (e.g., pediatric), and Intra-Target Microdosing (ITM). The use of sub-pharmacological doses in Phase-O/Microdose studies requires sensitive analytic tools such as Accelerator Mass Spectrometer (AMS), Positron Emission Tomography (PET) and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained.

Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvement over traditional allometric approaches. Nevertheless, utilization of Phase-O/Microdosing by drug developers remains modest though 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.