Dosing certainty

EMA backs model from Novartis to identify safest, most effective Phase III dose

Novartis AG has developed a new dosing model for Phase II trials that eliminates much of the guesswork around dose selection for Phase III. EMA has endorsed the model and the pharma is in discussions with FDA. And while it has its limitations, European regulators are hopeful that the model could increase the success of Phase III studies and reduce unwanted side effects.

One of the weaknesses of traditional dose-finding in Phase II is that the actual shape of the dose-response curve is usually unknown. As a result, companies are often just making a best guess about the one or two doses to take into Phase III.

These uncertainties have predictable knock-on effects in Phase III. Programs can fail because the dose was not high enough to produce the necessary effect size, or because the dose was too high and resulted in unacceptable side effects.

Moreover, sponsors may have to run larger trials to test multiple doses, or to see an effect from what ultimately turns out to be a suboptimal dose.

Novartis has developed a new tool called multiple comparison proceduremodeling (MCP-Mod) to help ensure that the dose selected for Phase III is optimal from both a safety and efficacy perspective.

Instead of the stepwise comparison that is traditionally used to compare lower and higher doses to placebo, which assumes a prespecified dose-response relationship, MCP-Mod compares different doses to one another as well as to placebo and fits the most likely curve to the data.

This approach gives a sponsor a better shot at finding the actual dose-response relationship based on the Phase II data, rather than relying on a hypothetical

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