European Medicines Agency Embraces MCP-Mod Approach To Dose Finding Studies
The European Medicines Agency (EMA) has embraced the use of multiple comparison procedure modeling (MCP-Mod) in the face of dose response testing and estimation models uncertainties.
Phase II studies often leave behind model uncertainties in dose response. Current analysis of dose finding studies are classified into either multiple comparison procedures or modeling techniques. The new approach integrates strengths from both strategies to represent a comprehensive approach.
MCP-Mod will allow researchers to design candidate models and then test doses through trend tests during the trial analysis stage. The best candidate model is selected once researchers determine a dose response signal. The approach allows for drawing of conclusions with control of false-positive error rate, mandated in the confirmatory developmental phase.
EMA said the current available version of MCP-Mod methodology is best used in trials which require satisfaction of specific criteria. This includes:
• Drug development stage: Phase II dose finding studies to support dose selection for phase III
• Response: Univariate (efficacy or safety/tolerability) variable. For efficacy, the response variable is ideally predictive to the clinical phase III efficacy outcome. Could be a binary, count, continuous or time-to-event endpoint. Observations could be cross-sectional (i.e. from a single time point) or longitudinal.
• Dose: Typically, the dose levels utilized in the actual trial are used for the design and analysis. However, more broadly, “dose” could be any univariate, continuous, quantitative measurement, as long as an ordering of the measurements is possible and the differences between measurements are interpretable.
• Number of doses: For the Mod step, a minimum of four distinct doses (including placebo) is required, ideally distributed over the effective range. For the MCP step (e.g. for dose response signal testing or identifying the type of plausible dose response shapes), at least three distinct doses (including placebo) are needed.
The EMA opinion on MCP-Mod approach adoption does not cover cellular/gene therapies, vaccines, or biologics.
Source:
http://www.fdanews.com/ext/resources/files/02/02-11-14-MCP-Mod.pdf