Phase II – Selection of Doses for Proof of Concept (PoC) Studies

As a rule, PoC is tested at the maximum tolerated doses (MTD), or maximal administered dose if MTD was not defined. This is to minimise false negative results, and to provide best test of hypothesis, as well as to maximise pharmacodynamics (PD) effect(s).

The evaluation of several dose levels to assess dose response is preferred, but is not required. The assessment of dose response allows researchers to establish a minimum effective and optimal dose, to mitigate the risk of the MTD not being tolerated. Gathering these further data strengthens the weight of evidence, and guides dose selection for subsequent studies, however it increases the time required to complete phase II studies, and thus the cost.

Dose-response data is very important. In addition to formal dose-response studies, the sponsor of a clinical trial should look at the entire database of data for possible dose-response information (for example results from studies with fixed doses, blood concentration-response relationship from the variable concentrations attained in a fixed dose trial, etc.).

Dose-response studies are typically randomised parallel group studies which look at three or more dosage levels, one of which may be zero (placebo). It may also be useful to include one or more doses of an existing medicine as a control.

The information gained from dose-response studies:

• Identify a reasonable starting (minimum effective) dose, ideally with specific adjustments.
• Identify response-guided stepwise dose adjustment (titration) , and the intervals at which they should be taken.
• Identify a dose, or a response (desirable or undesirable), beyond which titration should not ordinarily be attempted because of lack of further benefit or an unacceptable increase in undesirable effect.
• Identify optimal dose