“Selection of a dose (or doses) to carry into confirmatory Phase III trials is among the most difficult decisions that need to be made during drug development. Although the exact numbers are not known, it is thought that the high attrition rate which continues to plague the pharmaceutical industry in Phase III studies may, in part, be due to inadequate dose selection – doses that are too low to achieve adequate benefit, as well as doses that are too high and lead to dose-related adverse events in the population. There is also evidence that, even after registration, dose-adjustments in the label continue to be required with some frequency.”

Smarter clinical trial designs can draw on a number of techniques that can be used to help tackle this problem.

Modeling the dose response relationship allows more doses to be tested in a trail without requiring more subjects or losing power. Testing more doses usually allows the trial result to be more conclusive and makes it more likely that an ineffective dose is included. Without an ineffective dose regulators may require a dose finding study to be re-run as a minimum effective dose has nto been identified.
Monitoring the probabilities of a successful outcome to the trial often allows a failing trial to be identified early and (depending on the cause of the failure) either corrective action taken or the compound’s development stopped early – saving significant costs and allowing resources to be allocated elsewhere.

Adaptive allocation allows the number of subjects on ineffective doses or doses that are unnecessarily high to be minimized, and the number of subjects on the doses in the range likely to be used in phase 3 maximised.

Longitudinal or biomarker modeling allows early responses or early biomarker values to be used to predict subjects final outcomes, allowing earlier adaptation, stopping or study size decisions.

As new initiatives in drug discovery and pre-clinical yield more complex treatments that require drug-drug interactions or patient sub-populations to be catered for in the trial, so these can be tackled by new and extended smart trial techniques using models for disease progression, dose combinations, predictive biomarkers. It seems likely that the full benefits of current translational medicine initiatives can only be realised within smarter trial designs.