Phase 0 studies, though not widely accepted, could effectively bridge the gap between preclinical and Phase I studies, and reduce the number of drug failures owing to differences in drug behaviour between animals and humans.
Bringing a new drug to market remains a costly and lengthy process, with current estimates suggesting that it takes approximately 15 years and as much as $1 billion to successfully develop a drug.1 Although huge amounts of money have been invested in drug development, particularly clinical trials, improvements in success rates have been inconsistent at best. A continuing problem is that clinical trials are unable to keep pace with the large number of new compounds emerging from discovery research and that the systems used for prioritising candidates remain unsatisfactory. Many investigational new drugs fail in clinical testing because they do not behave pharmacologically as predicted by preclinical studies.2 For example, efficacy failures may be caused by a low concentration of drug reaching the target for an inappropriate amount of time, whereas safety failures may be caused by an inappropriate concentration reaching the wrong target for too long a time period.3
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
Certain authors believe that improvements have been made in some areas of early clinical testing, particularly where drugs failed because of unanticipated differences in drug metabolism between laboratory animals and humans. For instance, in 1991 approximately 40% of the drugs entering Phase I trials failed because of such reasons,6 but by 2000 failure due to unexpected differences in drug metabolism had dropped to 10%. This was linked to the development of non-animal and computer modelling methods.6 Unfortunately, 40–60% of drug failures in Phase I are still associated with the inability of preclinical models to predict what happens when a drug enters humans.2,4,6
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.
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
1. Association of Clinical Research Organizations, "Drug Development Process" (2009). www.acrohealth.org
2. S. Marchetti and J.H.M. Schellens, Br. J. Cancer, 97, 577–581 (2007).
3. R.C. Garner and G. Lappin, Br. J. Clin. Pharmacol., 64(4), 367–370 (2006).
4. H. Eliopoulos et al., Clin. Cancer Res., 14(12), 3683–3688 (2008).
5. Boston Consulting Group, "Rising to the productivity challenge: a strategic framework for Biopharma" (2004). www.bcg.com
6. Fund for the Replacement of Animals in Medical Experiments, FRAME UK, "Testing novel drugs in animals" (2010). www.frame.org.uk
7. European Medicines Agency, "Position paper on non-clinical safety studies to support clinical trials with a single microdose" (2004). www.ema.europa.eu
8. E. Abdoler et al., Clin. Cancer Res., 14(12), 3692–3697 (2008).
9. Outsourcing Pharma, "More Phase 0 studies needed to sway 'conservative pharma'" (2007). www.outsourcing-pharma.com
10. FDA, "FDA's Critical Path Initiative" (2010). www.fda.gov