04.07 Phases of Clinical Trials

In drug development, it mandated that new drugs have to go through 4 Phases with each phase having different requirements. Each drug has to successful pass Phase I before moving onto Phase II, and so on (Figure 4.5). Clinical trialing usually starts with small numbers of participants and is mainly to test safety, and is often in health volunteers (Figure 4.5). Only when some safety has been established, does testing in larger numbers of participants occur, and efficacy starts to be considered (Figure 4.5).

Figure 4.5 The Phases of clinical trials (Copyright QUT, Sheila Doggrell)

Phase I clinical trials are often performed in University Hospitals using experts in clinical pharmacology. They are open with both subject and observer knowing what is happening. Phase I clinical trials use small numbers (20-80) of healthy volunteers. The exception to this is when testing toxic drugs for cancer and HIV. As these would be toxic to healthy volunteers, the Phase I testing of cancer and HIV drugs is in patients. The dose tested in Phase I will be a small fraction of that shown to cause toxicity in animals. The main reason for the trial is to establish safety, and the trial will measure toxicity and, possibly, efficacy. In Phase I, provided an assay is available to measure the drug, blood samples may be taken to measure the pharmacokinetics of the drug. If a drug shows unacceptable toxicity, the clinical trialling will stop after Phase I.

Phase II clinical trials are also often performed in University Hospitals using experts. They are single-blinded i.e. they use placebo/dummy tablets to prevent the subject knowing which is active drug, but the physician does know which is the active drug. Phase II trials may have a comparison with standard treatment. If there is a standard drug available for a certain conditions, it has to be established that the new drug is better than the standard drug before it can be registered. Phase II trials are in 10-200 patients with the disease the drug is indicated for. The Phase II trial is to establish the efficacy and toxicity of the drugs. This information is needed for more extensive Phase III trialling. If a drug does not show efficacy in Phase II trialling, it will not go forward to Phase III.

Phase III clinical trials are usually performed in the setting the drug will eventually be used in. Thus, if a drug is to be used in hospital, it will be tested in hospital, whereas if a drug is used in general practice, it will be tested in general practice. The investigators are usually specialists in the disease being treated. Phase III trials are double-blinded; neither the observer nor the subject knows which is active drug. A third person holds the code identifying the drug, which is not broken until the trial is completed. Phase III trials enrol large numbers of patients, and are expensive. Phase III clinical trials establish efficacy and toxicity.

Positive results in Phase III lead to applications for registration to market the drug to the Therapeutics Goods Administration (TGA).

Phase IV clinical trialling is also known as post-marketing surveillance. Even though Phase III trials enrol large numbers of patients, this may not be large enough to detect any rare or long-term adverse effects, and this is done in Phase IV. Phase IV is under the actual conditions the drug will be used. It is monitoring safety in large numbers of patients and over longer periods of time than previous Phase. Phase IV clinical trials, especially the monitoring of adverse effects, involves, all health professionals, not just investigators.