Dr. Mark Seymour
Xceleron Ltd, York Biocentre, Innovation Way, Heslington, York, YO10 5NY, UK.
The best model for humans is humans - how to accelerate early clinical development safely
Drug development is an expensive and risky business which whilst yielding drugs that can eradicate many human diseases has become more and more difficult over the past 10 years. The number of drugs being registed by the regulatory agencies has been falling whilst the costs of development have been escalating. Traditional drug development processes have changed little over the past twenty to thirty years. Once a candidate molecule has been identified prior to its administration to humans, a standard proscribed battery of preclinical tests is conducted the protocols for which are set out in an internationally recognised document ICH M3. Some animal alternatives have been built into the safety testing paradigm such as the Ames test and other tests for genetic toxicity. Changes in the way acute toxicity is measured have also been introduced. The US FDA, the body responsible for regulating marketing approval of drugs in the USA published in 2004 the 'Critical Path Document' which criticised the current drug development process for using the tools of the 20th century in the 21st. The FDA argued that new tools are needed if the efficiency of drug development was to be improved. New regulatory guidance documents have been published including the Exploratory IND which are designed to make it easier to develop drugs. One reason that drugs fail during development is through inappropriate metabolism properties. Study of the metabolism of a drug historically has focussed on using animal and in vitro models. These can sometimes be unreliable making human drug metabolism and pharmacokinetics difficult to predict. New approaches that enable human drug metabolism studies to be conducted earlier than currently practised include human Phase 0 microdosing studies, human ADME in Phase I and absolute bioavailability studies. Such studies can be facilitated using a number of analytical methods one of the most interesting which is a nuclear physics technique, accelerator mass spectrometry (AMS). Developed some 30 years ago for archaelogical dating, AMS is the most sensitive analytical instrument ever developed. Its use in biomedical research is just commencing but already shows considerable promise. With AMS,it is possible to take drugs into humans safely with very little preclinical data. In my presentation I will highlight the scientific, toxicology and regulatory aspects of using the AMS technique as well as providing some case studies.