Phase-0 Microdosing Network

Goals:
1. Enhance human-based translation and accelerate drug development by enabling safer, quicker, and more-cost effective transition between non-clinical and clinical stages of human drug development
2. Increase the application and utilization of Phase-0 approaches in human drug development
3. Advance research and knowledge dissemination pertaining to Phase-0
4. Reduce the use of animals in human drug development as a result of the application of Phase-0 approaches

The strategic plan of the Phase-0/Microdosing Network is consistent with its remit to use educational and research methods to advance the utilization of microdosing and other Phase-0 approaches in human drug development. The plan covers the period 2019 – 2024.

Objectives:
1. Enhance the familiarity of drug development stakeholders with Phase-0 approaches
2. Formulate guidelines for the application of Phase-O/Microdosing approaches
3. Establish recommendations for further research and development

Strategies:
1. Disseminate information about Phase-0 approaches and, specifically, provide update to drug development stakeholders on validation, methodology, applications, and research relevant to Phase-0 approaches
2. Obtain input from stakeholders (regulatory, academia, industry, CROs, patients, patient advocacy, and activists) on the value, prospects, and challenges facing these approaches
3. Establish consensus statements on future directions in education, research, and applications pertaining to Phase-0 approaches

Tactics:
1. Actual drug development (collaborations as sponsors, funders, CROs, and expert supporters of Phase-0 application)
2. Investigative Medicine (advancing the field of medicine, including ‘Blue Sky’ research with no immediate or tangible commercial goals)
3. Research advancing the science and methodology of Phase-0/Microdosing approaches. This line of research aims at expanding applicability and validity and therefore the utility of these approaches:
a) Novel applications (e.g., in hepatically- and renally-impaired, women of childbearing age, extreme environments)
b) Novel methodological approaches (e.g., adaptive Phase-0/Phase-1 designs, Intra-Target Microdosing [ITM])
c) Novel modeling and simulation approaches to increase the extrapolation validity of Phase-0/Microdosing study data (e.g., using PKPD modeling and in-vivo-in-vitro modeling and simulation, microdose vs. full dose in animal models)
d) Economic analyses – to determine what developmental scenarios favor the use of Phase-0/Microdosing approaches, what are the cutoff parameters for applicability and profitability

Our organization is composed of key global experts in the drug development field. They represent a wide range of stakeholders with interest in safe, effective, and productive drug development process. These stakeholders include industry, academia, regulatory, CROs, non-profit, patient advocacy, and the public at large. Through their connections, publications, research, education, and advocacy work, our organization and its members have the capability to improve global drug development. Specifically, by disseminating information on innovations and applications of microdosing and other Phase-0 approaches, our organization has the potential to enhance and improve the safety, speed, and cost-effectiveness of drug development.

The Phase-0/Microdosing Network has operated since 2012 to increase awareness about and impact of Phase-0 including microdosing approaches. It has disseminated information about this approaches to an increasing membership of global expert stakeholder, engaged in research on application and methodologies of Phase-0 approaches to increase their applicability and impact, and generated key publications of the topic such as those listed below. The Network holds quarterly teleconferences and annual meetings to update its members and the drug development community at large about progress in the field and engage these stakeholders in consensus-building discussion regarding the future of the field.

Recent Network member publications:
Burt, T., Roffel, A. F., Langer, O., Anderson, K., & DiMasi, J. (2022). Strategic, feasibility, economic, and cultural aspects of phase 0 approaches: Is it time to change the drug development process in order to increase productivity? Clin Transl Sci, 15(6), 1355-1379. doi:10.1111/cts.13269
Burt, T., Young, G., Lee, W., Kusuhara, H., Langer, O., Rowland, M., & Sugiyama, Y. (2020). Phase 0/microdosing approaches: time for mainstream application in drug development? Nat Rev Drug Discov. doi:10.1038/s41573-020-0080-x
Gundle, K. R., Deutsch, G. B., Goodman, H. J., Pollack, S. M., Thompson, M. J., Davis, J. L., . . . Maki, R. G. (2020). Multiplexed Evaluation of Microdosed Antineoplastic Agents In Situ in the Tumor Microenvironment of Patients with Soft Tissue Sarcoma. Clin Cancer Res. doi:10.1158/1078-0432.Ccr-20-0614
Kim, J., Ahn, S. W., Deans, K., Thompson, D., Ferland, B., Divakar, P., . . . Jonas, O. (2022). Intratarget Microdosing for Deep Phenotyping of Multiple Drug Effects in the Live Brain. Front Bioeng Biotechnol, 10, 855755. doi:10.3389/fbioe.2022.855755
Mooij, M. G., van Duijn, E., Knibbe, C. A., Allegaert, K., Windhorst, A. D., van Rosmalen, J., . . . de Wildt, S. N. (2017). Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism. Clin Pharmacokinet. doi:10.1007/s40262-017-0508-6
Okour, M., Derimanov, G., Barnett, R., Fernandez, E., Ferrer, S., Gresham, S., . . . Haselden, J. (2017). A Human Microdose Study of the Anti-Malarial GSK3191607 in Healthy Volunteers. Br J Clin Pharmacol. doi:10.1111/bcp.13476
Rowland, M. (2016). Microdosing of protein drugs. Clin Pharmacol Ther, 99(2), 150-152. doi:10.1002/cpt.275
van Groen, B. D., Vaes, W. H., Park, B. K., Krekels, E. H. J., van Duijn, E., Korgvee, L. T., . . . Turner, M. A. (2019). Dose-linearity of the pharmacokinetics of an intravenous [(14) C]midazolam microdose in children. Br J Clin Pharmacol. doi:10.1111/bcp.14047
Vlaming, M., van Duijn, E., Dillingh, M. R., Brands, R., Windhorst, A. D., Hendrikse, N. H., . . . Vaes, W. (2015). Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages. Clin Pharmacol Ther, 98(2), 196-204. doi:10.1002/cpt.131