Phase 0 Clinical Trials

Definition of phase 0 clinical trials

Phase 0 clinical trials are a relatively new type of clinical trial, introduced by the FDA in 2006 as a way to accelerate the preliminary evaluation of new drug candidates.[1] The main goal of these studies is to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug in humans.

Phase 0 trial: Exploratory investigational new drug (IND) study

Phase 0 clinical trials are also known as exploratory investigational new drug (IND) studies. Phase 0 trials usually involve administering sub-therapeutic doses of a drug (~1% of the intended clinical dose) to a small group of volunteers (i.e., 10 to 15), with the trial having a very short duration (generally about a week).[2] Phase zero trials represent an opportunity to conduct preliminary evaluations of an investigational new drug’s behavior in the body, on a smaller scale, requiring less investment and time than a phase I clinical trial. This unique design offers a few benefits and niche purposes, which we will explore in this article.

Purpose of phase 0 trials

Phase 0 trials are not always conducted; many drug candidates move straight to a phase I clinical trial after preclinical studies (more on phases of clinical trials). However, the unique design elements of phase 0 clinical trials do offer certain advantages, so they may be conducted for the following purposes:

1. To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug in humans for the first time, while minimizing the risk of exposure of participants to toxicity due to the use of sub-therapeutic doses
2. To assess the safety and tolerability of the drug on a preliminary/basic level - for example, to ensure that there are no unexpected toxic metabolites
3. To screen out drugs that are unlikely to be effective or safe before investing additional time and monetary resources into more-intensive phase 1 clinical trials

Is Phase 0 the same as preclinical?

No; preclinical studies refer exclusively to non-clinical research conducted before any human exposure has taken place. Such testing may include animal studies that examine toxicity or efficacy profiles. In contrast, Phase 0 trials involve administering an investigational new drug to humans, at very low doses for initial evaluation purposes. Thus, while preclinical and phase 0 studies both have important roles within the drug development pipeline, they are distinct from one another in terms of their objectives and scope of application. For a novel investigational new drug, either preclinical studies or a phase 0 trial (or both) are likely to be required before a phase I trial can be conducted.

Phase 0 vs phase I trials

Phase 0 trials are focused on assessing how a drug affects the body (pharmacodynamics; PD) and what the body does to the drug (pharmacokinetics; PK). Phase 0 trials do not have any therapeutic intent - they are purely investigational, and volunteers are not to expect any therapeutic benefit as subtherapeutic doses are tested.

On the other hand, phase I clinical trials utilize therapeutic doses of the drug to make preliminary evaluations of safety and determine the maximum tolerable dose (MTD). While therapeutic benefit is not an aim of phase I trials, it’s possible that certain participants experience a minor therapeutic response (these studies are typically not very long).

Both phase 0 and phase I clinical trials can enroll healthy volunteers or patients with a given condition being targeted by the study drug.

FDA guidance on Exploratory IND Studies (phase 0 clinical trials)

The FDA has released official guidance for investigators, industry stakeholders, and reviewers regarding the conduct of exploratory studies under an IND application. The official guidance document can be downloaded from the top of the FDA’s bulletin.

Conclusion

Phase 0 clinical trials represent an optional yet potentially time-saving step in the drug development process. They provide initial indications about the PK and PD of a new drug in humans, helping to eliminate infeasible drug candidates before time and money are spent on more intensive trials, and facilitating further investigation in phase I trials. Phase 0 trials are a relatively new introduction to the clinical research process, and are limited in scope and sample size, but they can offer unique benefits, particularly due to their simplicity and relatively high degree of safety, which can come in handy when drug developers wish to quickly obtain basic information about how the drug behaves in the human body in order to inform subsequent studies.