Microdose studies are ultralow dose clinical studies that are gaining increasing acceptance from FDA and international regulators. They offer drug development companies a way to get a glimpse into how their candidate drugs will behave in humans. This can in turn help drug developers design a relatively fast and cost-effective path to IND submission. PBL can support the preclinical testing required for implementation of various “microdose studies”.
Microdose studies were the subject of a guidance document from the FDA:
The purpose of this regulatory documents was to encourage sponsors to take advantage of the considerable flexibility in regulatory requirements for preclinical data to support abbreviated Clinical Trials designs that address specific product development issues. The Exploratory IND approach outlined by the FDA was intended for a variety of study paradigms, and was not limited to just microdose studies. Examples of studies that were mentioned by the FDA include: microdose studies, limited repeat dose studies to determine pharmacologic or pharmacodynamic endpoints, and studies to establish a mechanism of action related to efficacy. The rationale for this guidance was the recognition that:
“Because exploratory IND studies involve administering either sub-pharmacologic doses of a product, or doses expected to produce a pharmacologic, but not a toxic, effect, the potential risk to human subjects is less than for a traditional phase 1 study that, for example, seeks to establish a maximally tolerated dose. Because exploratory IND studies present fewer potential risks than do traditional phase 1 studies that look for dose-limiting toxicities, such limited exploratory IND investigations in humans can be initiated with less, or different, preclinical support than is required for traditional IND studies”
Microdose clinical studies are typically designed to not induce pharmacologic effects. A microdose is defined as:
“less than 1/100th of the dose of a test substance calculated (based on animal data) to yield a pharmacologic effect of the test substance with a maximum dose of <100 micrograms (for imaging agents, the latter criterion applies). Due to differences in molecular weights as compared to synthetic drugs, the maximum dose for protein products is ≤ 30 nanomoles.” (FDA Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies, January 2006).
“less than 1/100th of the dose calculated to yield a pharmacological effect of the test substance based on primary pharmacodynamic data obtained in vitro and in vivo (typically doses in, or below, the low microgram range) and a maximum dose of ≤ 100 micrograms”. (Position Paper on Non-clinical Safety Studies to Support Clinical Trials with a Single Microdose. January 2003).
Because microdose clinical studies involve limited dose amounts (typically microgram quantities) and limited exposure times (single dose), the preclinical package required to support the regulatory submission can be abbreviated. Suggestions for the clinical information, the chemistry, manufacturing and controls (CMC) information, and the safety information required to support microdose studies can be found in the above referenced regulatory documents. Preclinical safety studies that are identified by the FDA guidance to support microdose clinical trials include:
- A single dose mammalian toxicology study in a single species. This can be justified if in vitro metabolism and in vitro pharmacology studies indicate the species of choice is representative of human.
- Both sexes should be tested.
- Exposure should be via the intended clinical route.
- Animals should be observed for 14 days post-dose.
- Necropsy should be performed at 2 days (24 hrs) and 14 days post-dose.
- Endpoints should include, at a minimum, body weights, clinical signs, clinical chemistries, hematology and histopathology.
- Doses should be selected to produce a minimal toxic effect, or a margin of safety.
- No genetic toxicology or safety pharmacology testing is required.
Because human exposures are so low in microdose studies, they depend on the availability of highly sensitive analytical methods. The development and application of the accelerator mass spectrometer (AMS) to the bioanalysis of new drug candidates has made microdose studies more accessible. A variety of contract research laboratories offer AMS services for support of preclinical and clinical microdosing studies, including: Accium Biosciences, and Xceleron.
The use of the term “microdose” can also be applied to instances where a small amount of a tracer (e.g., a radioactive label) is added to an otherwise pharmacologic dose of test compound. In this case, the microdose is the tracer that would normally require significant study before it could be administered to humans. Because the tracer is present in such low amounts, the normal requirements for qualification prior to human use may be abbreviated. The utility of this approach for a human radiolabel study with [14C]ixabepilone was evident in a recent publication [Beumer et al., Invest New Drugs (2007) 25:327-334]. In this instance, the typical radiolabel dose used in a human volunteer for a mass balance study (e.g., 100 µCi) was decreased to 80 nCi. The decrease in radiolabel dose was necessitated by a significant potential for autoradiolysis of the tracer, [14C]ixabepilone. The total intravenous dose of ixabepilone was maintained at 70 mg, and the [14C]radiotracer was measured in blood (plasma), urine, and feces by AMS.