Phase-0 Microdosing Definitions

It has been some time since our last discussion of Phase-0 including Microdosing definitions with many new members joining the Network since. This has impact, for example, on the kind of studies that are included in the list of studies shared recently, and of course on the scope of this Network. So here is a recap:

Phase-0 Microdosing Definitions

By Phase-0 we refer to first-in-human (or first in a population, such as pediatric patients) drug clinical studies with no therapeutic intent and no intent to study tolerance or safety effects directly (with ‘directly’ implying that no therapeutic or tolerance-related effects are observed in the research volunteers, though such effects can be inferred indirectly). These trials are called ’Phase-0’, ’Exploratory Clinical Trials’ (governed by the 2009 ICH M3 guideline), or ’Exploratory New Drug applications’ or ’eIND’ (these are the pre-ICH 2006 FDA guidelines, now superseded by the ICH guideline). These 3 terms are synonymous. Exposures to the tested drugs in such studies range from very low (i.e., microdose, consistent with approaches 1 and 2 in the ICH M3 guideline, Table 3, p. 12 in the attached) up through the low therapeutic-level exposures (but again, with no therapeutic intent) and up to 14 days (consistent with approaches 3, 4, and 5 in ICH M3 guideline Table 3, p.12 in the attached).

Microdose is defined as 100 micrograms, 1/100th of the minimal pharmacologic-level (to be interpreted as therapeutic-level), or 1/100th of the NOAEL (no observed adverse effect level) in the animal species tested (only one species is required to initiate microdosing studies, usually a rodent), whichever is the lower, but of course, lower doses may, and have, been given.

Microdosing is only one of several Phase-0 approaches.  Table 3 on page 12 in the ICH M3 guideline includes 5 approaches:
Approach #1 is the single-dose microdose that is done in most microdose studies (but the 100 microgram dose can actually be divided into multiple doses)
Approach #2 is multiple 100 microgram doses (up to 5) given at 6 half-lives separated from one another.

Approaches 3, 4, and 5 have increased exposure to the drug, up to the NOAEL for 14 days. This means therapeutic-level exposures but with no therapeutic intent and no intent to study safety or tolerance. So dose never reaches MTD (maximal tolerated dose). The more exposure there is to the drug, the more preclinical requirements there are. For example, approaches 3, 4, and 5 require testing in 2 animal species while approaches 1, and 2 require only one.

Non-microdose Phase-0 has been used mostly in oncology (but still very few, only about 10 are reported in the literature), maybe because first-in-human studies in oncology are done in patients and then Phase-0 allows testing for biomarkers at therapeutic-level exposures.  However, since all therapeutic areas can use patients in Phase-0 studies, this argument is not a good one.  In other words, all therapeutic areas should take advantage of the allowance to test the drug in patients in the first-in-human study.

It should be emphasized that the regulations include considerable flexibility, so the above should be considered as ‘guidance’.  Indeed, the regulators have been keen to emphasize this flexibility. For example, in the 2006 eIND document the FDA repeats the following 4 times in the 12-page document: “Existing regulations allow a great deal of flexibility in the amount of data that needs to be submitted with an IND application, depending on the goals of the proposed investigation, the specific human testing proposed, and the expected risks. The Agency believes that sponsors have not taken full advantage of that flexibility and often provide more supporting information in INDs than is required by regulations.”

Microdosing is different than microtracer studies. In the latter, a low dose (that could by itself meet the definition of a microdose) is given together with a therapeutic-level dose. The eagle-eyed among you might say: But Phase-0 approach 5 allows therapeutic level exposures; these could be given with a microdose and be technically a microtracer study.  And indeed, this flexibility is available in the regulations. Even further, the entire typical microtracer absolute bioavailability study where a therapeutic level dose is given orally together with an intravenous 14C-labelled microdose-level – this entire study can be done with microdose exposures.  For example: the oral dose is given at 99 micrograms and the IV 14C-labelled dose given at 1 microgram for a total of 100 micrograms. The relevance of the ‘tracer’ dose given IV at about 1/100th of the oral dose is that it does not interfere or contribute to the oral dose kinetics, yet, in parallel allows studying the kinetics of the IV administration reflecting the circulation compartment.  The difference between the two determines the bioavailability (i,e., how much of the drug given orally reached the general circulation).

What is important to clarify when talking about any specific microdosing or microtracer study is whether at that point in development it is allowed, or not, to give a drug with intent of studying therapeutic/tolerance intent or for longer than 14 days – because this radically changes your study design options and the regulatory package that needs to be submitted to initiate the study.

It is acknowledged that the literature, professional, and common, uses of the terms may differ from the above definitions. It is arguably in the best interest of the field that definitions, especially those fundamental ones, are used consistently and unambiguously. At the same time, of course, we encourage open discussion and debate about the nature of the definition and your thoughts are most welcome if they differ from the above.
With best regards,

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