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Two steps forward, one back: Will Phase 0 or microdosing save drug discovery?
In early June, I had the pleasure of attending the annual meeting of the Canadian Society for Pharmaceutical Sciences (CSPS) in Toronto; an intimate meeting of a couple hundred mostly Canadian researchers and company administrators who spent three days discussing the technical and regulatory challenges of performing drug discovery science both in Canada and in general. While topics ranged from structural genomics and outsourcing to regulatory issues and processing, one subject continued to resonate throughout the meeting: microdosing.
Briefly stated, microdosing involves the nether region between pre-clinical and clinical testing—Phase 0—where many people believe the line between a successful drug and failure is drawn and in many respects, where the cost of drug discovery begins to skyrocket. Microdosing involves the administration of sub-pharmacological or sub-therapeutic doses (on the order of micrograms) of a drug candidate to humans.
Body samples are then analyzed with highly sensitive instruments to detect what happens to the compounds, generating a preliminary ADME (absorption, distribution, metabolism, and excretion) or pharmacokinetic profile of the compound. Phase 0 is only possible because of the technical advances in detection instrumentation—accelerated mass spec (AMS) and LC-MS/MS—that allows almost single-molecule detection.
It is hoped that by giving companies an earlier, safer heads-up on how the drug is processed in the body, it will dramatically accelerate the more expensive clinical testing phase. Proponents of Phase 0 argue that failing drug candidates aren't generally identified until they reach the human trials stage (or even worse, after they have been approved), after much money has been expended on R&D, and that this is the biggest challenge to the success of and costs associated with drug development.
The same people suggest that while animal models, in vitro testing, and in silico modeling are all valuable tools in the identification of new therapeutic compounds, the methods can still only offer an educated guess at how the human body will respond to these substances. Phase 0, in their eyes, affords companies and scientists the opportunity to see these effects first hand, in a safe and effective way.
Others are less convinced. They question the validity or use of Phase 0 data considering that typical microdosing experiments rely on 1% or less of the final therapeutic dose as identified in animal models or in vitro experimentation. They question whether scientists can be confident that the processes they measure—metabolism, bioavailability, elimination rates—for very small doses of a drug candidate are truly representative of the same processes at much higher doses.
To some extent, these concerns were addressed by the recent Consortium for Resourcing and Evaluating AMS Microdosing (CREAM) trial, which was sponsored by companies such as Eli Lilly, Schering AG, and Roche. The CREAM trial compared the microdose pharmacokinetic profiles of five compounds with similar data determined at pharmacological doses. The results of the study seemed to indicate that microdose data was largely predictive of therapeutic dose response.
So, where do regulatory agencies stand on microdosing? The Europeans have taken the lead on this, as the European Agency for the Evaluation of Medicinal Products (EMEA) put out a position paper on microdosing in early 2003, supporting its use as non-clinical safety studies in support of further clinical studies. As for the US FDA, the rhetoric about Phase 0 and microdosing seems to be increasing and there is talk of a potential position paper or statement to be released some time in 2005.