The ExpIND and the phase 0 clinical trial

I have a deep interest in cancer pharmacology and drug development. My dissertation project involves studying the mechanism of action of a novel analog of the spice curcumin which may be a potential chemotherapeutic in the future. Excitingly, this compound is entering phase 0 clinical trials for head & neck cancer to be lead by my PI and research physicians at the cancer institute. I had never heard of phase 0 clinical trials before this, and I was even asked about it in a recent oral research presentation, proving that this is a new and little known development in clinical trial design and execution. In my first couple of years in graduate school, we learned about the traditional phase I-III clinical trials, even the post-marketing phase IV trial for safety surveillance. This basic clinical testing structure has changed very little over the last 30 years. So what is a phase 0 trial?

It has been estimated that it takes between 15-20 years and an upwards of a billion dollars to take a drug from bench discovery through marketing stages. Most compounds, approximately 95% of oncology agents submitted to the FDA under an Investigational New Drug (IND) application, are dropped some time doing trials in human subjects. Almost half of the drug failures occur in phase I, the safety and tolerability stage, due to unfavorable bioavailability and clinical activity even though data from animal studies showed promising results. Lack of clinical success is especially high for molecularly-targeted agents, possibly due to the fact that most are not clinically effective as single agents though they are evaluate as such.

In order to address some of the problems that lie in transitioning a compound from pre-clinical to clinical testing, the FDA designed a model for Exploratory INDs which authorizes small clinical studies before extensive animal toxicology experiments are performed. Phase 0 are pre-phase I trials and are designated as first-in-human studies. These trials do not specifically address the safety or efficacy of the compound but examine the pharmacology of the potential drug. These trials are conducted in a smaller cohort of patients (<30) for a limited amount of time (usually only 7 days) and at smaller doses that would be used in standard phase I. This ultimately speeds up the testing in humans while not compromising safety in patients because of the low dosing. Proponents for phase 0 argue that these studies cut back on expenses for pre-clinical safety testing and huge scale-up drug production for larger trials. Reduced costs also opens the door for academic investigators and smaller biotechnology companies to participate the clinical development of novel molecules. It is important to note that phase 0 trials do not replace phase I but only serve to establish the clinical developmental path for the agent using data from human rather than animal studies. In terms of the molecularly-targeted agents that may be inactive as single agents, pharmacodynamic phase 0 trials can be designed to primarily examine target modulation as an endpoint rather than reduction of human malignancy, thus showing evidence that this compound potentially deserves full clinical development in combination with other anticancer agents. Therefore, the primary benefit for phase 0 trials would be to eliminated more agents that may be inactive in humans before they reach phase I and enrich for active agents in phase II clinical trials.

In terms of the ethical implications for phase 0 clinical testing, the risks to the patient are the same as in standard phase I and even has the opportunity to be less. The risks include harm from any invasive research-related intervention (i.e. biopsies) or administration of the drug itself and delay in participation in trials that may be of more therapeutic benefit. These are risks constant with those find in phase I. However, the limited compound exposure, as outlined in the design of phase 0 trials, decreases the potential toxicity from the agent. Nevertheless, great care should go into designing phase 0 trials to maximize the benefits without compromising the integrity of the clinical trial process and the health of the test subjects.

References:
Designing phase 0 cancer clinical trials
Oncologic phase 0 trials incorporating clinical pharmacodynamics: from concept to patient
Phase 0 trials: an industry perspective
The ethics of phase 0 oncology trials