Phase III trials

The main objectives of early trials of chemopreventive agents that have been proven to be effective in laboratory tests, either in cell lines or in animal models, is to establish tolerance and side-effects. The major difference between the early trials of these agents, compared to cytotoxic agents, is that the duration of administration of the preventive agent will be much longer than a cytotoxic, so chronic side-effects are as important as acute side-effects. It is important to show proof of principle where possible, so if a particular drug is designed to show target-cell differentiation, then the endpoint would be a histological one. If the endpoint were to increase apoptosis where this had been defective, then measurement of apoptosis would be important.

A major side-effect would be either fatality or problems requiring intervention by a physician or long-term disability. Major side-effects would automatically rule out any further development of an agent. Dose and duration of administration of the new agent are essential endpoints, but escalation of dose would not necessarily be carried out to the level at which toxicity is produced. Rather a dose might be defined as ideal which achieves the biological effect as described.

An important part of Phase III trial evaluation is compliance and it is also important to get some sort of measure of this in the early clinical trials. Clearly this is frequently related to appearance of toxicity, but can also be influenced by the ease and route of administration. The target population will frequently be those at highest risk, for instance cancer patients who are cured but at high risk of a second malignancy.

A Phase II trial will frequently be of longer duration with more emphasis on compliances; it may well be randomized with a placebo control and may also, as in Phase I, evaluate further multiple-dose levels. Duration may be one to five years and the sample size could be anything from one hundred to many thousands of'patients' or potential patients.

Again the use of intermediate endpoints is extremely important for cost-efficient studies, though there is a paucity of good candidates for these biomarkers that are of proven value. Ease of recruitment is important because 'high risk' may be clear to a physician but not so clear to a normal individual.

These parameters are important for calculating the Phase III trial size and the statistical power, by which is measured.

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