Aptiv Solutions announce that the European Medicines Agency (EMA) has issued a qualification opinion finding that the MCP-Mod1 methodology for dose finding provides the potential to “enable more informative Phase II study designs” and “provide a more solid basis for all subsequent dose selection strategies and decisions”. MCP-Mod is a core component of Aptiv Solutions ADDPLAN® DF software, currently the only validated commercial software available for this methodology.
Estimating dose-response and selecting the appropriate dose for Phase III trials is one of the most difficult challenges of the drug development process, according to the EMA. Currently half of Phase III trials fail, in part because of sub-optimal and inefficient practices for dose selection in Phase II. Current approaches for estimating the target dose are also prone to uncertainty, which can result in the use of an inappropriate statistical model that over- or under-estimates the true effective dose.
“Regulatory agencies and drug developers are concerned with safety and tolerability if the dose is too high and inadequate efficacy if the dose is too low. Accurately defining this risk/benefit ratio is critical to the clinical development process, both to ensure patient safety and the successful approval of groundbreaking medications,” says Professor Andy Grieve, Senior Vice President, Clinical Trial Methodology for Aptiv Solutions.
The MCP-Mod approach is unique in that it defines several plausible candidate dose-response models, tests them for significance, and then identifies the most appropriate statistical approach to model dose-response and estimate the target dose.
In the extensive simulations reviewed for the qualification opinion, the EMA found that the MCP-Mod methodology appears to be better than the common pairwise ANOVA-based approach in terms of bias and absolute error. “ANOVA approaches work well if the true dose response model is linear, but many drugs do not behave this way,” says Grieve. For other common dose-response relationships, such as a non-linear Emax scenario, the EMA found the ANOVA approach is always among the worst methods to estimate dose response. The EMA also identified that MCP-Mod controls the Type 1 error rate and is less likely than a pairwise ANOVA-based approach to identify a clinically relevant dose in the absence of true dose-response.
“This is a significant shift for the industry. The EMA opinion challenges the way most dose finding studies are performed, essentially saying that the number of doses and the dose range selected are sub-optimal. This leads to poor selection of the effective dose at Phase II, which causes significant problems in subsequent clinical trials,” says Grieve.
ADDPLAN® DF is a fully-validated design and analysis tool based on MCP-Mod and covers dose finding designs for establishing Proof of Concept and determining the optimum target dose to select for Phase III trials.
In July, ADDPLAN® DF was pre-released in beta version to a top 10 pharma company that served as the prime development partner for the software. The fully validated version launched in September. Two additional top 10 pharma customers are now using the software as founding members of the ADDPLAN® DF Consortium announced earlier this year.
This release of ADDPLAN® DF is the first in a series of novel methodologies from Aptiv Solutions for use in Phase II clinical trials.
The white paper titled ‘ADDPLAN® DF - An Advanced Tool for Optimizing Dose Selection in Exploratory Drug Development’ is available below: