The Phase-0 Microdosing Regulatory Framework: ICH M3 Guidelines
ICH M3 Guidelines govern the Phase-0 Microdosing regulatory framework. Table 3 below summarizes the guidelines. These guidelines have been internationally harmonized and adopted by USFDA, Europe's EMA, and Japan's PMDA. They specify the definitions and associated requirements of 5 sample approaches (Figure 1) on a range of exposures to the novel drug (See Table 3 in the guidelines). The exposures are defined by dosage and duration and range from a single microdose, to 14 days at the NOAEL (No Observed Adverse Effects Levels). The ICH M3 PHase-0 Microdosing regulatory guidelines use the term 'Exploratory Clinical Trials', which is synonymous with 'Phase-0', and also with 'Exploratory Investigational New Drug (eIND)'.
The Phase-0 Microdosing regulatory guidelines enable 4 important applications that are not possible with traditional Phase-1 approaches. These applications are: first-in-human (FIH) studies in patients, I.V. administration of oral drugs, cassette microdosing, and Intra-Target Microdosing (ITM). The ICH guidelines specify the possibility of using the Phase-0 Microdosing approaches in patients (see Section 7 in the guidelines): "The subjects included in these studies can be patients from selected populations or healthy individuals." The ICH M3 guidelines also allow the I.V. microdose use of oral drugs and waives the local tolerance preclinical requirements (see Section 8 of the guidelines): "For an i.v. microdose study that is supported by an oral toxicology package (see Section 7), evaluation of local tolerance of the drug substance is not warranted." The regulatory framework also allows the administration of multiple drugs simultaneously in microdose. This approach is called 'cassette microdosing'.
The regulators and other stakeholders are keen to emphasize the potential of the Phase-0 Microdosing regulatory framework to reduce the use of animals in human drug development. Such potential, consistent with the 3R's (Replacement, Reduction, Refinement), was specifically identified at the Phase-0 Microdosing Stakeholder Meeting and the Phase-0/Microdosing Network consensus discussions.
Figure 1. ICH M3 Guidelines. Their full name is: GUIDANCE ON NONCLINICAL SAFETY STUDIES FOR THE CONDUCT OF HUMAN CLINICAL TRIALS AND MARKETING AUTHORIZATION FOR PHARMACEUTICALS M3(R2). Current Step 4, version dated 11 June, 2009.
ICH M3 Table 3. Recommended Non-Clinical Studies to Support Exploratory Clinical Trials. The 5 examples of Phase-0 Microdosing regulatory approaches are on a range of dosages and duration of exposure. Approaches 1 and 2 are microdosing (#1 is single microdose; #2 is multiple microdoses). Approaches 3, 4, and 5 are non-microdosing Phase-0 approaches. Other approaches are possible as long as there are no exposures consisten with therapeutic intent or intent to study tolerance (e.g., maximum tolerated dose [MTD]).