A cornerstone of a successful clinical trial is finding a correct dosage of a tested compound prior to Phase III.
In traditional clinical trials, two or three doses have usually been tested and the static design revealed the effects of the tested drugs only after the completion of a given trial. The limitations of such an approach are significant and are reflected by the high failure rate of traditional clinical trials. To improve the situation, adaptive designs have been developed where information from early periods of a trial is used to optimize the successive stages of the trial.
In adaptive design trials, finding the optimal dosage of a tested drug in an early phase is a key feature. Testing starts with a broad range of doses in a smaller number of participants per group. When the dose-response relationship is estimated, the doses on the optimal part of the dose-response curve can be selected and tested further in a larger number of participants. This allows avoiding drug concentrations close to low or high plateaus that place the trial at risk of using futile or toxic doses.
Employing a wider range of doses may raise concerns about higher trial costs. In this regard, the analysis of data obtained during the last decade shows that the studies focusing initially on a narrow dose range (on average four-fold) had to be repeated with a different set of doses. In studies employing a wider range of doses (on average eight-fold), only a single investigation of the dose-relationship was sufficient.
The pre-planned interim analyses of dose-response relationships allow researchers to determine which of the doses is effective. A wide range of tested drug doses can then be narrowed in the subsequent trial stage by dropping the suboptimal doses, and patients previously allocated to drop doses can be then randomized to efficacious doses.
In the end, this approach is more efficient, cost-effective, and safer for participants than static trial designs. The complexity of adaptive design raises some concerns, but the operations in these trials have been eased by new software tools that, for example, enable researchers to plan and simulate clinical trials prior to their start, or randomize the participants according to the observed effects of individual drug doses.
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Dr. Ivana Kawikova
Aptiv Solutions Blogging Team