Difference Phases of Trials Article

In this stage. Dr Kristian Brock, previously a principal statistician at the Cancer Research UK Clinical Trials Unit at Birmingham explains the different phases of clinical trials.

You have already heard how randomised controlled trials tell us whether treatments are worth using, specifically, whether they are better than what we are already using in clinical practice.

These are typically large and costly trials and take a long time to run. When we conduct a trial like this, we usually already know quite a lot about the new treatment. For example, if our treatment is a drug, we would know which dose of the drug to give, and we would have some general expectation that the treatment could have beneficial effects.

So what do we do if we know very little about the new treatment? Well for new drugs, this is the role of early phase trials.

Drug trials are typically discussed in terms of their phase. The term early phase covers trials that are in phases I and II. With any subsequent large randomised controlled trial termed phase III. All of these phases refer to trials that recruit human participants. Any studies prior to this are known as pre-clinical.

The different phases of a drug trial laid as a timeline, from pre-clinical to phase IV.

The general purpose of a phase I trial is to investigate how a treatment can be given safely to patients. Phase I trials are generally quite small, with perhaps 10-40 patients. This reflects our relative ignorance about the new treatment. A phase I trial might give a drug to a human for the very first time, for instance. In this situation, you can imagine how carefully the doctors will want to proceed to minimise the risks of any unexpected side-effects.

Investigating how to give a treatment safely might involve dose escalation, where small groups of patients are treated at different doses. If a group of patients receives a low dose and do not experience unnecessary or excessive adverse reactions, the next group might receive a slightly higher dose.

The objective is to identify a dose that will be safe in the general population of patients. However, the dose must be high enough to do some good like fight disease or relieve symptoms. In this regard, dose-finding is a balancing act. We want to escalate the dose so that we see benefits, but not so high that we create new problems. For some drugs, this balancing act is insurmountable, and the treatment is abandoned for being too toxic. For some drugs, however, we get lucky, and the dose that looks promising is investigated further at phase II.

Phase II trials investigate whether a treatment does something beneficial. They do not try to prove that a new treatment is better than existing treatments, because that is the role of late phase (phase III) trials and generally requires a lot of resources. Instead, a typical phase II trial asks whether a new treatment looks promising enough to warrant further investigation. In this regard, a phase II trial can be thought of as the gate-keeper to phase III, helping us to avoid wasting our time and money pursuing inappropriate treatments. Whilst phase III trials are where we prove beyond reasonable doubt that treatments deserve to be the default approach by showing that they are better than the alternatives, the real “Eureka!” moments often come in early phase trials.

For the few drugs that make it as far as phase III trials and demonstrate effectiveness, licensing and approval will then be sought. After that, drugs often continue into phase IV (post licensing) trials which follow the drug’s implementation into clinical practice, monitoring its long-term effects and any rare side-effects.

For Canvas related technical support please see the 24/7. The 'Help' icon on the left-hand navigation