Phase 0 Clinical Trials

Clinical Trial | Phase 0 Clinical Trial | Microdosing Trial 

What are Clinical Trials?

Clinical trials are a way of testing new methods of diagnosing, treating, or preventing health conditions. The goal of clinical trial is to determine whether the drug or device being tested is both safe and effective.

A range of things are assessed through clinical trials, including:

·         medications

·         medication combinations

·         new uses for existing medications

·         medical devices 

Before conducting a clinical trial, researchers perform preclinical research using animal models or human cell cultures. For example, they might experiment whether a new medicine is toxic to a small sample of human cells in a laboratory.

What are Phase 0 Clinical Trials

Phase 0 clinical trial is intermediate phase between preclinical and phase I clinical trial. Phase 0 trials help drug sponsors to improve their preclinical selection process. This involves a very small number of population, usually fewer than 15 and they are given a very small dose of a drug. To treat the condition to make sure it isn’t harmful to humans investigators use a very small dose of medication before they start using it in higher doses for later phases.  

Features of Phase 0 Clinical Trials

Objectives	·   Measure pharmacokinetics (PK) and toxicity in humans before Phase I Clinical Trials ·         Improve preclinical candidate selection
Therapy area	·         Any indication
Dosage	·         Subtherapeutic dosing (normally micro-dosing)
Trial length	·         Typically less than a week

 

If the medication acts differently than the expected aim of the study, the investigators will likely to do some additional research in animal before deciding whether to continue the clinical trial. Phase 0 studies have no therapeutic objective and are not likely to study drug safety or tolerance. 

Phase	Number of people taking part	Cancer type	Main aims of trial	Is it  randomised?
0	Small – often about 10 to 20 people	Often lots of cancer types	Testing a low dose of drug to check it isn’t harmful	No

Phase 0 Trials find out things such as:

• Whether the drug reaches the tumor cells
• How tumor cells respond to the drug in the body
• What occurs to the drug in the human body   

Goals of Phase ‘0’ Clinical Trials

The goals of phase ‘0’ clinical trials are as follows:

·         Define the Mode of Action (MOA) in animal models achieved in human

·         Define a biomarker test/assay by using human tumor tissue

·         Assesses PK and PD of drug candidate and its analogue for selecting most promising candidate

·         Make available PK and PD data for advance study i.e. Phase 1 and further.

Volunteers Recruitment in Phase ‘0’ Clinical Trials

Potential roadblocks to patient recruitment in phase ‘0’ clinical trials are:

·         No or very little therapeutic intent or chance of benefit

·         Tissue biopsies before and after treatment

·         Other clinical trials or therapies deletion and postponement study.

Plus points are:

·         Low risk

·         Avoid biopsies if possible

·     Washout period is shorter.

Advantages of Phase 0 Clinical Trials

·         Phase 0 method provides data that is not readily available with traditional approaches

·         Assessment of pharmacokinetics

·         Understanding of pharmacodynamics and mechanism of action of drugs

·         Phase 0 trials need fewer preclinical studies than are usually required for a Phase I trial

·         The time period can be reduced with earlier testing

·         Avoid and minimise needless exposure of the participants in the trial to the not so promising drug candidates

·         Small amount of the test drug is required

·         The not so promising drug candidates can be eliminated earlier, thereby cost saving.

·         Overall timeline of drug development is reduced.

·         Less risk of human toxicity with low dose and less time duration for exposure.

·         A very limited number of subjects are needed.

·         These trials mostly are a single dose administration as compared to a dose escalation study in the traditional phase 1 trials, there by further minimizing the risk.

·         Overall acceleration in the drug development by focusing only on the promising drug candidates. 

Disadvantages of Phase 0 Clinical Trials

Disadvantages of phase ‘0’ clinical trials are given below:

·         Lack of any therapeutic and diagnostic purpose.

·         Difficult to encourage the volunteers to be a part of the trial because no therapeutic intent.

·     Involvement in the phase ‘0’ trials may diminish the overall load of the subjects who become a part of the conventional phase 1 trials having therapeutic intention.

·         As the practice of micro-dosing is still in its early years, before applying this methodology caution needs to be taken to the drugs showing complex/non-linear kinetics.

·    Since certain drugs dissolve readily at low dose but demonstrate limited solubility at higher doses, it may be hard to predict the absorption characteristics at the micro-dose levels.

·  Phase 1 trial still necessitates to be done hence phase ‘0’ unnecessarily prolongs the development and inflates the expenditure.

Summary

A Phase 0 trial in human is also called a Pre-phase 1 clinical trial or a "proof-of-concept" clinical trial. Due to the unknown risk potential of the investigational new drug, volunteers selected for this phase is too small. Phase 0 trials may address fewer or more most challenging issues for new drug development in oncology. A Phase 0 trial is needed to increase the safety and accomplishment of new drug trials.

Phase ‘0’ clinical trials are beneficial for the sponsors and volunteers. Phase ‘0’ clinical trials enhanced the probability of investigational drug into the market and reduce the number of volunteers, unnecessary time, and cost in new drug development process by removing the unnecessary drug candidate prior to the phase.

Reference

1. Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are/phases-of-clinical-trials.

2.    Kummar S, Rubinstein L, Kinders R, et al. Phase 0 clinical trials: conceptions and misconceptions. Cancer J. 2008;14(3):133-7.

3.  Burt T, Young G, Lee W, et al. Phase 0/microdosing approaches: time for mainstream application in drug development? Nat Rev Drug Discov. 2020;19(11):801-818.