FDA, EMA Extend Licenses for Aptiv Solutions ADDPLAN Software for Clinical Trials

Aptiv Solutions, a global biopharmaceutical and medical device development services company working for the adoption of innovative clinical trial approaches such as adaptive design, today announced the U.S. Food and Drug Administration (FDA) has purchased licenses to the company’s recently-released ADDPLAN DF software for the analysis of dose finding study results submitted as part of approval applications to the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH). Additionally, the FDA and the European Medicines Agency (EMA) have extended their licenses for the ADDPLAN platform used for the analysis of confirmatory adaptive clinical trials.

ADDPLAN DF, released in September 2013, is the first commercially-available design and analysis tool to employ the MCP-Mod methodology, which uniquely combines two key statistical approaches for better evaluation of target doses in Proof of Concept and Phase II dose selection trials. The MCP-Mod methodology has been described by the EMA, in a preliminary qualification opinion issued in October 2013, as having the potential to “enable more informative Phase II study designs” and “provide a more solid basis for all subsequent dose selection strategies and decisions.”

The EMA opinion stemmed from evidence that current statistical approaches for estimating the target dose are prone to user uncertainty, which can result in the selection of an inappropriate statistical model that over- or under-estimates the true effective dose. 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.

“This is a significant shift for the industry. The EMA opinion challenges the way mostdose finding studies are performed, essentially saying that the number of doses and the dose range selected are sub-optimal. This had led to poor selection of the effective dose at Phase II, which causes significant problems in subsequent clinical trials,” says Professor Andy Grieve, Senior Vice President, Clinical Trial Methodology for Aptiv Solutions. “Now, regulators can use ADDPLAN DF to evaluate dose-finding data in approval applications in a more robust manner.”

Additional data depicting how the MCP-Mod methodology and ADDPLAN DF enable more robust dose selection decisions will be presented by Aptiv Solutions adaptive trial experts during the opening session of the Phacilitate Washington BioLeaders’ meeting to be held on January 27-29, 2014 in Washington, D.C.

Deficits in Phase II Trials
Beyond EMA, other global regulators also acknowledge deficits in the ability of Phase II studies to reliably and accurately define dose and dosing regimens. These deficits stem from issues larger than the reliable selection of statistical methodology, explains Grieve.

“A majority of dose-finding trials conducted between 2002 and 2011 evaluated just two or three doses that covered, on average, a four-fold dose range. To focus on such a small region of the dose response curve means finding the minimum effectivedose often requires sponsors to repeat studies, which increases trial costs, duration, and unnecessary patient risk,” Grieve says, referring to a published analysis of ClinicalTrial.gov data.

Testing an increased number of doses and an expanded dose range to better elucidate complex dose–response relationships is not a simple switch of numbers, however. Current trial designs would require a substantial increase in the number ofpatients involved in the process, generating untenable costs for sponsors and exposing more patients to the risk of an investigational drug.

Reforming Clinical Trial Infrastructure
Resolving these deficits with improvements in clinical trial design and statistics has long been on regulators’ radar. For example, the FDA’s Critical Path Initiative, launched in 2004, has focused on transforming the way FDA-regulated products—including drugs, biologics, and devices—are developed, evaluated, and manufactured.

According to the Initiative's landmark report Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, “not enough applied scientific work has been done to create new tools to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, in faster time frames, with more certainty, and at lower costs.” To help counter this, the FDA added an incentive last year for utilizing adaptive trials by highlighting adaptive design as a criterion for Investigational New Drug applications to potentially receive priority review status.

“The infrastructure, the figurative ‘roads and bridges’ upon which medical hypotheses in clinical trials are tested, must improve as quickly as science advances,” says Pat Donnelly, Chairman and CEO of Aptiv Solutions, a company created to develop the necessary technologies and services to achieve long overdue deep reform for the drug and device industries.

One of the deep reforms that drug and device developers retain Aptiv Solutions to design and implement are adaptive design clinical trials.

Adaptive trials uniquely allow pre-planned adjustments in reaction to data acquired during the investigation, thereby increasing the utility of information thestudies produce for patients, physicians, regulators, and the sponsor. Traditional trial designs do not adjust to patient responses and can in certain cases become what Donnelly describes as a “one-shot educated gamble”. Various adaptive designs allow, for example, enrolling additional patients to ensure the necessary statistical power to prevent a trial from ending with inconclusive statistics, while other designs spare patients from exposure to ineffective treatments by terminating the study if interim efficacy or safety data is poor and indicates futility.

For dose selection in Phase II trials, adaptive designs utilize real-time trial data to dynamically allocate patients to a greater number of doses than currently tested in traditional trials, producing significantly higher quality information on complex dose–response relationships that can prevent selection of the incorrect dose. As errant dose selection is cited as a primary cause of failure in pivotal trials, Grieve says, applying adaptive modeling and analysis principles to dose-finding studies will dramatically increase success in this stage of development.

According to a recent Tufts Center for the Study of Drug Development report, adaptive designs represent approximately 20% of clinical trials and are expected to increase in number rapidly in the next few years.

Beyond regulatory support, a key driver of adaptive trial adoption in the next few years is the flexibility and risk-control that adaptive designs provide in the current, more restricted environment, helping biotech and medical device companies increase the valuation of early-stage assets and find development partners. Aptiv Solutions highlighted this concept in the keynote speech at a recent medical device investor event in Orange County, California, and will partake in further industry–investor discussions at the 7th Annual OneMed Forum on Investing in Healthcare 2014 (San Francisco, CA, January 13-15, 2014) and the Q1 CEO summit 4th Annual Life Science Chief Executive Officer Forum (Raleigh-Durham, NC, January 29-31, 2014).

Technology to Support Reform
Sophisticated adaptive trials, particularly those in the exploratory phase of development, require new technologies that enable the real-time data capture necessary to conduct efficient interim analyses and implement pre-planned adaptations, which can involve changes to drug supply management and patient randomization.

The Aptiv Solutions AptivAdvantageTM technology platform handles the rapidlogistical 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 analysissteps can be conducted effectively with minimal patient overrun and without the introduction 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 these studies efficiently and effectively.

The company’s ADDPLAN software platform, for which the FDA and EMA have extended their licenses, allows the design, simulation, and analysis of simple and complexadaptive trial designs, including adaptive dose-finding, early termination for futility, sample size reassessment and population enrichment.