The importance of exploratory clinical trials

Exploratory trials provide drug developers with early in-patient studies and hold the promise to decrease the high failure rate of clinical trials.

Exploratory clinical trials are early-phase trials that bridge the gap between laboratory/animal studies (preclinical) and human studies (clinical trials). Regulatory agencies, such as the FDA, support exploratory trials to battle the high failure rate of Investigational New Drugs (INDs). For decades, the failure rate of INDs has been around 90%. This means on average that only 10% of INDs in clinical development get approval to be marketed. This article explains the importance of exploratory clinical trials.

Clinical phases of drug development

In clinical drug development, new medicines are being tested in humans. Conventionally, the main process is divided into 3 phases.

- Phase 1 assesses safety;

- Phase 2 assesses efficacy;

- Phase 3 compares the drug to existing therapies.

The process sounds logical: safety first, then efficacy, then comparison. However, in this process, many resources are spent on drugs that eventually fail. Where do exploratory trials fit into this process, and how can they decrease the number of failed INDs?

Phase 0 clinical trials

Exploratory clinical trials are also named Phase 0 clinical trial or Early Phase 1 since they are conducted before Phase 1. Phase 0 is designed to assess the compound in a small group of patients and provides proof of concept before moving to more extensive trials. Furthermore, the obtained data on biodistribution and pharmacokinetics can be used to design Phases 1 and 2 and to increase the efficiency and chances of success. Phase 0 can also be used to perform a lead compound selection in humans rather than in animal models.

How is safety ensured?

How will safety be ensured if phase 0 trials are taking place before phase 1? Phase 0 makes use of the microdosing approach. At least a 14-day extended single-dose toxicity study in rodents is mandatory. By using low dosing, the drug has no expected therapeutic effect and is below the evaluated safe dose in toxicity studies. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M3 provides guidance on this subject. For certain types of compounds and indications, the requirements can be higher.

How is it possible to examine an efficacy potential without a therapeutic effect?

The answer is imaging. Even a minimal dose is sufficient for the imaging to determine biodistribution and pharmacokinetics. There are not many Contract Research Organisations (CROs) specializing in innovative imaging techniques. Specialization is needed since it can be a challenge to label the IND for imaging without altering the drug’s distribution and mechanism of action in humans. TRACER CRO specializes in Phase 0 clinical trials and imaging and can provide drug developers with more specific information regarding their compound.

A small cohort and a fast study

Phase 0 is conducted in approximately 5-15 participants. This quantity is lower compared to Phase 1 and much lower compared to Phase 2. Phase 0 is often conducted directly in-patient, while for most compounds and indications, participants in Phase 1 are healthy volunteers. Phase 0 takes only around 16 months to be completed. During this period, Phase 1 can already be prepared, meaning little to no additional time is added to the drug development timeline.

Conclusion

A Phase 0 exploratory trial can be conducted before the conventional Phase 1-3, allowing drug developers to test their IND in-patient without extensive safety studies. Safety for Phase 0 is considered by using a low dose. For imaging, a small dose is sufficient to measure in-human biodistribution and pharmacokinetics. Drug developers should work with an experienced Phase 0 imaging CRO such as TRACER CRO to ensure that the data of the labeled drug is similar to the unlabeled drug. The aim of using Phase 0, is to increase the success rate of drugs in clinical trials.