The issue of picking the best drug dose in the exploratory stages of clinical development is no trivial matter. “If you get the dose selection right in phase 2, then you're reducing the chances of failure in phase 3,” says Andy Grieve, senior vice-president of clinical trials methodology at Aptiv Solutions, the Virginia-headquartered CRO anchoring the new ADDPLAN DF Consortium. Currently, around half of all pivotal phase 3 trials fail to meet their primary efficacy endpoints. “I would suggest that 70–80% of that is getting the dose selection wrong,” Grieve says.

The ADDPLAN DF Consortium is so named because it revolves around a software platform developed for the design, planning and analysis of dose-finding trials. ADDPLAN DF, released commercially by Aptiv last year, uses a method called multiple comparison procedure modeling, or MCP-Mod. Instead of comparing experimental doses head to head with placebo as most traditional statistical analyses do, MCP-Mod compares different doses to each other (as well as to placebo); it then fits the data to a handful of the most plausible dose-response relationships to help inform which doses should advance into phase 3 testing. The European Medicines Agency (EMA) endorsed the method earlier this year, and discussions are ongoing with the US Food and Drug Administration about validating the tool, as well.

MCP-Mod has the advantage that it allows investigators to include a wider range of drug doses without requiring larger sample sizes. But as written, MCP-Mod does not permit sponsors to use interim analyses to alter trial dynamics in progress. That should soon change: the new ADDPLAN DF Consortium is planning to produce an adaptive version of the software that can inform ongoing dose allotment and subject randomization by year's end. Because the basic statistical approach would be the same, this adaptive update would not need to be separately qualified or validated by drug regulators.

Christina Yap, a biostatistician and study methodologist at the University of Birmingham, UK, sees developments like the ADDPLAN DF Consortium as part of a larger trend in adaptive dose finding. “It's only in recent years that there's been great interest in the implementation of such novel designs,” says Yap, who helped develop the protocol behind a trial launched earlier this year in people with acute myeloid leukemia—the UK's first such adaptive dose-finding study in hematology to date. “People are realizing that early-stage trials are really important to do right.”