Aptiv Solutions, a global biopharmaceutical and medical device development services company, Novartis Pharma, Janssen Pharmaceuticals and Eli Lilly have joined in co-founding the ADDPLAN DF Consortium. The members of the consortium are collaboratively developing new statistical methodologies for the design of innovative dose-finding clinical trials, with an emphasis on adaptive designs. The ADDPLAN DF Consortium also will focus on enhancing the trial execution technologies required to handle the multiple adaptations integral to complex adaptive dose-finding trials. Aptiv Solutions will integrate and validate the methodologies that emerge from the ADDPLAN DF Consortium into its ADDPLAN DF software for the design, planning and analysis of dose finding trials, in addition to ensuring that these designs can be easily implemented through its proprietary execution platform.

Currently half of phase III trials fail, in part because of poor dose selection in phase II. Many designs focus on too few and too narrow a range of doses, often forcing sponsors to repeat studies in order to find the minimum effective dose, thereby increasing overall cost, duration and unnecessary patient risk. Furthermore, the most common statistical methods for estimating target dose are prone to uncertainty, which can result in the use of an inappropriate statistical model that over- or under-estimates the true effective dose.

“Innovative approaches such as adaptive dose finding, which allows inclusion of more doses, are gaining traction. These more sophisticated designs require a similarly-sophisticated approach to trial execution,” said Reinhard Eisebitt, executive vice president and head of the Innovation Center at Aptiv Solutions. “Novartis, Janssen and Eli Lilly are collaborating with us to build cutting-edge technologies that fundamentally improve the data that can be produced by clinical trials and, in turn, the decision-making that is essential to take a product from phase II to phase III. This ultimately leads to the approval of safer and more effective medicines for patients as well as cost savings for healthcare systems.”

The initial objective of the ADDPLAN DF Consortium is to further advance the MCP-Mod methodology, the subject of a qualification opinion by the EMA that described MCP-Mod as an efficient statistical methodology for model-based design and analysis of Phase II dose finding studies. According to the EMA, MCP-Mod has the potential to “enable more informative phase II study designs” and “provide a more solid basis for all subsequent dose selection strategies and decisions.” Aptiv Solutions ADDPLAN DF software, released in 2013, was the first commercial software to integrate MCP-Mod methodology.

“In addition to developing new, innovative trial design methodologies and technologies, the ADDPLAN DF Consortium also will consider the impact these sophisticated approaches have on the operational aspects of a clinical trial. Working closely with clinical experts, the Consortium will identify the technology and process enhancements required for efficient trial execution. The ultimate objective is to deliver a comprehensive platform and process map for integrated design and execution of innovative exploratory phase adaptive trials,” said Eisebitt.

Complex adaptive trials, particularly those in the exploratory phase of development, can involve several adaptations and multiple interim analysis steps. The benefit of a complex adaptive trial is that it substantially increases the value of data generated during the trial, which directly impacts subsequent development decisions. These trials require new technologies that enable efficient execution of the interim analysis step and maintain trial integrity including managing the logistics of dynamic changes to randomization and drug supply management.

The Aptiv Solutions AptivAdvantage technology platform handles the rapid logistical changes that occur during adaptive trials while maintaining appropriate blinding through the use of robust operational firewalls. The platform allows for real-time data capture and in-stream data cleaning so that interim analysis steps can be conducted effectively with minimal patient overrun and with the minimization of operational bias. It is the only technology platform designed specifically to address the complexities of adaptive trial execution, affording sponsor companies the opportunity to run complex designs, such as those available in ADDPLAN DF, efficiently and effectively.