Aptiv Solutions, a global biopharmaceutical and medical device development services company leading the adoption of innovative clinical trial approaches such as adaptive design, today announced the
ADDPLAN® DF, released in
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 most dose 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
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
• 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 effective dose 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 of patients 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
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
“The infrastructure, the figurative ‘roads and bridges’ upon which medical hypotheses in clinical trials are tested, must improve as quickly as science advances,” says
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 the studies 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
• Technology to Support Regulatory 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 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 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
About Aptiv Solutions
Aptiv Solutions is a global development services company focused on enhancing clinical trial decision-making, efficiency and productivity for pharmaceutical, biotech and medical device sponsors. It is the only CRO to offer design, simulation and execution of adaptive clinical trials and a novel statistical sampling approach to risk-based monitoring. These services span the entire product development cycle from first in human through regulatory approval to post-marketing. Aptiv Solutions has more than 850 professionals in
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