Phase-0 Microdosing Studies Reported in the Literature
This section describes the properties of Phase-0 Microdosing in-vivo (humans and/or animals) studies reported in the literature. These studies expanded the methodology and/or applicability of Phase-0 approaches or were applied to actual novel drug development. There were 102 such studies as of November 2019. This is likely an underestimate since such studies are not mandated to be reported in the public domain. In addition, the list represents a likely underestimate since studies meeting the criteria of Phase-0 approaches are not always reported as such. The Phase-0 Microdosing studies list contains several studies with both microdose and therapeutic level exposures, normally not considered Phase-0 because of the therapeutic exposures, if they contributed to the the validation of the approaches, study of their methodologies, or enabled the expansion of their applicability. Although thought to start in 2003 with the seminal publication by Lappin and Garner there are a couple of studies that meet the criteria and antedate that publication. Please contact us if you are aware of studies not included in the list.
Of the 102 studies 96 are microdosing studies (consistent with ICH M3 [Table 3, p. 12] approaches 1 and 2) and 6 are non-microdosing Phase-0 studies (consistent with ICH M3 [Table 3, p. 12] approaches 3, 4, and 5). This probably reflects the greater appeal of microdosing studies in most developmental scenarios due to the minimal regulatory package required to initiate them. 5 studies are adaptive Phase-0/Phase-1 design, likely the most efficient approach in actual drug development. 47 reported on applications in actual drug development. 47 used LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry), 32 AMS (Accelerator Mass Spectrometry), 23 PET (Positron Emission Tomography), 4 NIRF (Near Infrared Fluorescence), and 3 IHC (Immunohistochemistry), with a few combinations. 60 of the Phase-0 Microdosing studies included healthy volunteers, 27 included patients, 18 included animals with 4 of these being non-human primates. The list excludes in-vitro studies except for 3 microdosing cell culture studies included because of their importance to the field.