While exploratory clinical trials have been proposed for years,1 interest has boomed since the publication of the ICH M3 R22 guidelines in 2008. These trials can be a tool for pharmaceutical and biotechnology companies to make faster, more cost-effective, and more informed clinical development decisions. In particular the studies have been proposed as a mechanism to allow earlier decision making in drug development to reduce investment risk and late phase attrition.
The utility of the data derived from these exploratory studies, and in particular Phase 0 microdose—a dose less than 0.01 of that calculated to yield phamacological effect and no greater than 100 µg—and intravenous microtracer studies, is now recognized by the U.S. Food and Drug Administration, European Medicines Agency, and Therapeutic Goods Administration, as well as other regulatory authorities around the world.
When properly used, microdose and microtracer studies can reduce both the time and the cost of drug development.
Phase 0 microdose study applications
While microdose studies have not become a routine part of drug development programs since their emergence in the early 2000s, pharmaceutical companies have identified valuable applications.
Microdosing has emerged as a fit-for-purpose, proactive application in early clinical pharmacology programs particularly for ranking molecules where human pharmacokinetics (PK) are a primary decision point to determine whether the drug will progress in development. Key applications include the selection of a back-up molecule from a range of candidates and the early identification of issues potentially impacting drug development, thereby influencing the construction of the subsequent clinical program.
Advances in analytical technology are helping to develop the approach. Traditionally, studies are performed with a carbon-14 radiolabeled drug and bioanalyzed using accelerator mass spectrometry (AMS). With the advances in analytical instrumentation, it is now possible to use conventional analytical methods such as LC-MS/MS. Examples demonstrate how LC-MS/MS has provided the primary analytical method and AMS has been used as a back-up technique.3,4 This reduces the time and cost of bioanalytical development and sample analysis, which makes the study type more accessible to pharmaceutical development teams. In addition, this advancement allows microdosing studies to be performed without the need for radiolabeled drug substance.
Microdose study utility is enhanced where there are multiple candidates to examine, or where the selection of a back-up molecule is required and the PK of a lead compound is understood. Typically, such a study would involve an intravenous/oral crossover microdose study designed to identify a lead and back-up molecule among a number of second generation compounds. The original lead candidate—which is already in Phase 1 after a conventional development program—would be used as a benchmark. All drug candidates, the second-generation candidates, and the original lead, would be studied in the intravenous and oral crossover design and the data compared. This design addresses many of the concerns about the extrapolation of data from micro to macro dose since human PK at macro levels is already understood from the Phase 1 program with the benchmark lead candidate molecule.
Microtracer study applications
Unlike microdosing, intravenous (IV) microtracer studies have become a well-established technique with multiple applications5,6 across different stages of clinical development. Primary benefits include the generation of IV PK data for drugs being developed for non-parenteral delivery, helping development teams to understand the drivers of poor or variable PK, as well as to characterize absolute bioavailability.
The IV microtracer approach provides significant cost and time savings over conventional approaches for generating these data, supporting decision-making early in clinical development and bolstering regulatory submissions later in the development process.
In early clinical development, an IV microtracer can be added to any standard Phase 1 study with limited impact on overall program budget. From a scientific perspective, this provides essential IV PK data to support clinical pharmacology understanding of drug performance and contributes information that supports formulation development. By adding the IV microtracer to an existing study in the development program, the incremental costs are limited to provision of carbon-14 labeled drug, the development and manufacture of a fit-for-purpose IV drug product, and the cost of differential sample analysis using AMS.
In later clinical development, IV microtracer studies can be used to establish the absolute bioavailability of the drug product intended for the marketplace. In one example, a standalone IV microtracer study design as described in Figure 1 was driven by a specific request from a regulatory authority. The oral dose reflected the intended marketed product formulation and an abbreviated fit-for-purpose IV formulation development was undertaken. The study was completed and data submitted to regulatory authority in 10 months. The abbreviated approach to IV formulation development realized significant time and cost savings for the development process, bringing the regulatory approval several months sooner than would have been possible with a conventional IV/oral absolute bioavailability study.
As regulatory authorities become more familiar with IV microtracer data, there is a greater expectation from those authorities that IV PK and absolute bioavailability data can and should be generated in this manner to support regulatory submissions.
Microdose and microtracer trials offer significant opportunities to enable drug development project teams. Although some applications have established a stronger foothold in the drug development paradigm than others, what is clear is that these approaches are successfully challenging the conventional approach to drug development. These methods can deliver valuable data and significant time and cost benefits where a study need is identified.
Overall, the position of microdose and microtracer studies is maturing in the pharmaceutical drug development arena with ever-increasing clarity on the potential applications. The data generated add value for the project team as they look to progress their drug molecule through development in a cost and resource efficient manner.
About the author
Iain Shaw focuses on the delivery of 14C clinical studies via Quotient’s Synthesis-to-Clinic platform. Lloyd Stevens uses his more than 35 years of experience to assist clients in addressing their drug development problems and issues.
1. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medicinal Products, FDA, 2004.
2. Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals, ICH M3 (R2), 11 June 2009.
3. Bessire AJ, et al. Metabolite profiling by accelerator mass spectrometry: a comparison with liquid scintillation –based radiometric analysis: advantages and limits. Poster AAPS 2010.
4. Harrison A, et al. Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms. Xenobiotica. 2012;42(1):57-74.
5. Wu A, et al. Absolute bioavailability of cc-11050, a low water soluble NCE, using an IV microdose of [14c]-cc-11050 solution concomitantly with an oral unlabelled dose, Poster ASCPT 2011.
6. Zann V, et al. The use of the IV microtracer technique to drive formulation optimisation, Poster AAPS 2011.