Failure during clinical development is an expensive burden to bear. According to information cited by the FDA, a novel compound entering Phase I trials has about an 8% chance of eventually reaching the market, with the success rate being even lower for those in the oncology field.2,4 The low success rate has been linked to the high number of new candidates exhibiting different mechanisms of action that need to be validated clinically, the lack of predictive preclinical models and problems relating to clinical trial design. Unfortunately, 75% of the costs of drug development are associated with compounds failing in the early stages of development.5
A better understanding of the characteristics of candidates emerging from discovery is desirable before they enter Phase I trials. If attrition rates in Phase I can be improved, this will save valuable time and resources and have a positive impact on the efficiency of latter clinical development stages. This is particularly important for smaller companies whose financial future is at stake when embarking on a clinical programme.
The interest in rethinking the way early clinical development is approached has led to the idea of exploratory or so-called Phase 0 trials. This concept has attracted the interest of pharmaceutical companies and regulatory bodies both in the US and Europe.
Phase 0 trials represent early clinical studies that focus on the traditional gap between preclinical and clinical testing phases.4 As first-in-man trials they should involve a very limited number of healthy volunteers or patients. The participants would be exposed to the drug at a reduced level in comparison with traditional Phase I studies and for a very short duration.2 Phase 0 trials are not intended to have a therapeutic effect, but examine whether the drug has appropriate pharmacokinetics and pharmacodynamics to warrant further clinical investigation.2 As such, they will not replace traditional dose escalation, safety and tolerance studies.
In 2004, the European Medicines Agency published a position paper examining the possibility of exploratory trials involving a single dose of a compound using microdose techniques.7 The agency defined a microdose as 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,2,7 and the FDA has also settled on this explanation of a microdose.2 Ultrasensitive analytical techniques, such as positron emission tomography and accelerated mass spectrometry will be required to guarantee that drug and/or metabolite concentrations can be determined at these extremely low doses.3 The European Medicines Agency also outlined that the total amount of test compound(s) were not to exceed 100 micrograms.7
The position paper stated that an extended single-dose toxicity study in only one appropriate mammalian study would be considered appropriate for the microdose human trial to proceed if justified by comparative in vitro data.2 Given the use of microdoses, the likelihood of clinically significant toxicity has been considered unlikely and this has led to the idea that the use of Phase 0 trials might mean reduced preclinical safety packages.2 The optimal scenario would be for such studies to reduce the preclinical work required and to reduce the time required to move to Phase I testing. Phase 0 trials would ideally make available data on the drug's characteristics in humans earlier than has typically been the case, thus providing senior managers with better information before making important decisions on a drug's future.