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Does a Phase 0 study influence your Phase 1 trial?

Maarten Brom, PhD

The most common misconception about Phase 0 trials is that it delays your overall clinical development plan. “I need to do a Phase 1 trial anyway, why should I also do a Phase 0 study?” Well, it actually has the opposite effect. A Phase 0 accelerates your path to market, including Phase 1, 2 and 3 trials. This all has to do with the unique characteristics of a Phase 0 study that positively impact the future and pace of your clinical development.

Skip large animal models with Phase 0 studies.

A Phase 0 study requires a proof-of-concept in a rodent model. After this you can immediately test your new drug in humans. Namely, you only need biodistribution and pharmacokinetics from your rodent study. This means you can often skip experiments in (large) animal models.

With positive in-human data from your Phase 0 trial, you also don’t need to perform large animal models to start Phase I. Your in-human data is more relevant and predictive than any studies in animal models.

Single dose extended toxicity study.

Before you can start a Phase 0 study you need to perform a toxicity study. As you only administer a very low dose to patients, a limited toxicity study is sufficient. This so-called single dose extended toxicity study is less costly and time consuming than regular toxicity studies for Phase I studies using therapeutic doses.

In general, a single dose extended toxicity study takes 3 months. To save time, you can run these tests during GMP manufacturing of your drug and writing your submission package for the ethical committee.

When moving to Phase I, you still need to perform additional toxicity studies. So, what do you gain from a Phase 0 study? The main benefit comes into play when you don’t have positive in-human data after your Phase 0 trial. This would most likely mean that you don’t want to take this compound into Phase I. As a result, the data from Phase 0 prevents you from performing expensive and time-consuming full toxicity studies for non-efficient compounds.

Your drug’s patient population.

The big advantage of Phase 0 trials is that you can test your new drug in the patient population you aim to treat. Where in classical Phase 1 trials (in healthy volunteers) you only obtain pharmacokinetic and safety data, you can also determine on- and off-target binding of your drug with Phase 0 studies. This is because the target is actually present in your patients. Based on this targeting data you can predict the efficacy of your drug.

After the phase 1 trail, you can use the molecular imaging tool from the Phase 0 trial. In Phase 2 and Phase 3 trials you can use molecular imaging to select patients that express the target of interest. When you see (high) uptake of your labeled drug in the tissue of interest, you expect a therapeutic effect. You don’t want to include patients that don’t express the target. Patients that don’t express the target will skew the therapeutic effect in your study population. When you use molecular imaging to select patients, you need less patients to show a therapeutic effect.

Does a Phase 0 study delay your clinical development?

Every new drug needs to go through all the phases of drug development, even if you conduct a Phase 0 study or not. However, Phase 0 studies allow you to enter the rest of your drug development much smarter and more efficient.

After a Phase 0 trial you have information about targeting, pharmacokinetics, and dosing. With this information you can plan your Phase 1 trials more efficient. For example, no large animal studies and understanding of your patient population. As such, you won’t lose time in the clinical development plan and might even speed up the process. At the same time, you can eliminate drug candidates with an unfavorable on- and off-target profile. This prevents you from investing in drugs that will fail in a later clinical stage. All the more reason why you should conduct a Phase 0 study.

Continue reading about the effect of molecular imaging on phase 2 or 3.

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