Phase 0 trials in practice
The first specific feasibility study of the Phase 0 strategy, outlined by guidelines from the FDA, was conducted by the US
National Cancer Institute.4 The drug investigated was ABT-888, which preclinical studies had suggested inhibited Poly (ADP-ribose) polymerase (PARPs),
thereby inhibiting DNA repair and potentiating the cytotoxicity of DNA-damaging agents.4 The Phase 0 results for ABT-888 were considered to have been helpful when planning for Phase I and further clinical studies.
For example, the feasibility of twice daily oral dosing as well as proof of mechanism were shown and information was also
generated on a potential study biomarker.4
Since the ABT-888 Phase 0 trial, other companies have embarked on similar types of studies; however, the results of these
studies are not yet widely available. In addition, questions have been raised about the ethics of Phase 0 trials, since they
are not designed to offer clinical benefit.8 This is particularly the case when it comes to oncology, since patients may be seriously ill. There may also be confusion
from the subject about the goals of the trial since Phase 0 studies do not follow the traditional approach to clinical drug
development. Some authors have suggested that volunteers may be incentivised to participate if Phase 0 trials are shown to
reduce drug development time,4 but since few studies have been run it is not possible to verify this.
Although a number of Phase 0 trials are being conducted by the pharmaceutical industry, some supporters of exploratory studies
believe that many companies are still avoiding this approach out of fear. In 2007, Colin Garner, the CEO of the UK microdosing
service firm Xceleron, criticised companies for relying on gut feeling when rejecting the idea of Phase 0 trials, rather than
factual information.9 He explained that Xceleron had worked on 40 different molecules and generated Phase I data for 11 of them. Furthermore,
he concluded that there was very good correlation between microdose pharmacokinetic and pharmacologic pharmacokinetic properties.
According to the interview, Phase I trials typically cost between $5 million to $10 million whereas microdosing studies were
in the order of $500000.
Although Phase 0 is an additional cost on top of Phase 1, it can provide earlier information about a drug, which in turn will
give pharma companies more confidence in the project and help them to be better prepared for future studies.
There is a need for new approaches to evaluate promising new drug candidates in a manner that rules out failures as early
as possible in the drug development process. Both the European Medicines Agency and FDA have published position papers exploring
new ideas and technologies in the field of drug development, and the FDA also runs its Critical Path Initiative to deal with
the increasing difficulty and unpredictability of product development.10 Both agencies have recognised that Phase 0 trials offer a promising approach to better understanding a new drug before it
enters Phase I trials and beyond. However, many companies are awaiting formal recommendations from the agencies before using
Phase 0 trials as part of their drug development strategy.
Faiz Kermani is a freelance consultant and President of the Global Health Education Foundation, a 501 (c) (3), a non-profit charity that
supports medical education and research projects in developing countries. He is a member of Pharmaceutical Technology Europe's Editorial Advisory Board. firstname.lastname@example.org