Phase-O Including Microdosing Approaches: Enabling Human-Based Translation in Drug Development

Join our 2nd International Phase-0/Microdosing Stakeholder Meeting, Friday, April 23, 9:30 am - 5:30 pm Japan Standard Time (ONLINE MEETING) - see program below

Check our recent AAPS webinar:

Phase-0/Microdosing: Time for mainstream application in drug development

https://www.pathlms.com/aaps/events/2332/video_presentations/189322

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:

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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.

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 Standard Time)

Enabling Human-Based Translation in Drug Development

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:

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:

  1. Formulate guidelines for the application of Phase-O/Microdosing approaches
  2. Establish recommendations for further research and development

Objectives:

  1. Provide update on validation, methodology, applications, and research
  2. Obtain input from stakeholders (regulatory, academia, industry, CROs) on the value, prospects, and challenges of these approaches
  3. 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


TimeChairSpeakerTitle
9:30-9:55Hiroshi YamazakiTal BurtMeeting scope, Phase-0/Microdosing definitions, and application criteria
9:55-10:20Tal BurtNader SanaiNon-microdosing Phase-0 approaches: Applications in oncology and CNS drug development
10:20-10:45Tal BurtGraeme YoungThe impact of industry’s drug development culture on Phase-0 approaches
10:45-11:10Tal BurtWooin LeeMicrodosing studies enabling a better look into target occupancy of small-molecule drugs: What are the key factors that make this possible?
11:10-11:20Break
11:20-11:45Hiroshi YamazakiYuichi SugiyamaPrediction of drug clearance and DDI/PGx at therapeutic doses from microdosing clinical studies using PBPK modeling with in-vitro data on metabolism and transport
11:45-12:10Hiroshi YamazakiYoshiyuki YamauraJapanese industry experience with microdosing studies
12:10-12:35Hiroshi YamazakiDaisuke MiyatakeMicro tracer mass balance study in healthy subjects in drug development stage
12:35-12:40Hiroshi YamazakiTal BurtConnecting microtracer studies with Phase-0
12-40-12:45Tal BurtReview 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


TimeModeratorsGroupDiscussion item
13:45-15:30Tal Burt, Koji Chiba1Application 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
13:45-15:30Graeme Young, Ichimaro Yamada2Adoption Challenges
Stakeholder perspectives: motivations and challenges facing Phase-O/microdosing approaches
13:45-15:30Wooin Lee, Yuichi Sugiyama3Vulnerable 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
13:45-15:30Nader Sanai Hiroshi Yamazaki4Future 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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