In early 2013, adaptive clinical trials represented 20 percent of all clinical trials, according to the Tufts CSDD seminal report, The Adoption and Impact of Adaptive Trial Designs. Though that number was expected to grow, lack of education and industry conservatism were named as some of the greatest barriers to widespread adoption of adaptive designs.
Nearly two years later, industry and regulatory support of adaptive designs has grown, as indicated by these five events.
1. FDA Grants Potential Priority Review Status
As an incentive for sponsors to use adaptive design, the U.S, Food and Drug Administration (FDA) announced that it may grant priority review status to drugs whose Investigational New Drug (IND) Applications plan for adaptive designs in Phase 2 and Phase 3 studies.
This FDA announcement is consistent with the agency’s acknowledgement and support of adaptive designs, including its draft guidance and a congressional testimony by Center for Drug Evaluation and Research (CDER) Director Janet Woodcock that greenlit adaptive designs, when appropriate, to improve clinical trial efficiency.
2. EMA Qualification of MCP-Mod
Inaccurate dose selection in Phase 2 is a major contributor to the Phase 3 failure rate, now around 40% when averaged over all indications. One reason for this is that models chosen to estimate dose are prone to uncertainty.
A newer method helps alleviate such uncertainty. An adaptive modeling approach called Multiple Comparison Procedure-Modeling (MCP-Mod) tests several different dose-response models for statistical significance, compares them, and then identifies the best for modeling dose-response and estimating the optimal Phase 3 dose.
The European Medicines Agency (EMA) qualified MCP-Mod as an “efficient statistical methodology for model-based design and analysis of Phase 2 dose-finding under model uncertainty.” This qualification opinion was the EMA’s first ever for a statistical methodology. Though MCP-Mod is not an adaptive design, per se, it can be designed with adaptive functionality to incorporate interim analyses to inform model selection. The EMA qualification indicates the agency’s support and desire for innovative trial designs to address common development issues.
3. Five Top Pharmas Form Adaptive Dose-Finding Consortium
In 2013, statisticians from Novartis, Eli Lilly, and Janssen joined Aptiv Solutions (now ICON) as founding members of the ADDPLAN DF Consortium, a group created to advance methodologies for improving dose-selection. Pfizer and Roche joined the ADDPLAN DF Consortium in 2014, further solidifying the industry support base for adaptive design.
The Consortium’s initial focus was to enhance the development of software, specifically ADDPLAN DF, to incorporate traditional MCP-Mod and adaptive MCP-Mod. The broader goal is to develop the technological infrastructure for the design and execution of exploratory phase adaptive trials.
4. Funding for Adaptive Trials
A number of organizations have appropriated funds for adaptive design-based projects. In 2013, the Innovative Medicines Initiative (IMI) announced €50 million in funding for adaptive proof of concept trials in Alzheimer’s disease. The European Platform for Proof of Concept for Prevention in Alzheimer’s Disease (EPOC-AD) will follow a multicenter platform format with rapid recruitment, a shared and rotating placebo population, and several treatment arms.
The NIH is accepting proposals for short-term interventional studies employing adaptive designs as part of its Exploratory Clinical Trials Grants Program. The flexibility of an adaptive design will allow for quick and efficient generation of initial data to support the launch of future clinical trials.
5. Adaptive Trials Make The News: I-SPY 2 and Ebola
The I-SPY 2 trial is a multi-center adaptive phase 2 trial for locally advanced breast cancer that uses biomarker analysis to predict therapeutic response. At the end of 2013, the first two candidates from the trial graduated to Phase 3: AbbVie’s veliparib and Puma Biotechnology’s neratinib.
Adaptive designs also made news as a potential solution to address ethical and operational issues associated with running a traditional randomized clinical trial for Ebola.
In its Potential Ebola Therapies and Vaccines report the World Health Organization stated that Ebola trial designs should allow real-time data analysis to “permit the adaptation of interventions as data becomes available.” These adaptive randomized clinical trial designs, it says, could be “useful to evaluate multiple arms of treatments and different subgroups.”
Adaptive designs offer significant promise to reduce clinical trial costs and accelerate timelines for bringing new treatments to market. Moreover, sophisticated adaptive designs deployed in exploratory development can dramatically improve decision-making. When applied across a portfolio or at the strategic alliance level these types of designs can save sponsors billions.
These examples demonstrate growing, albeit slow, acceptance of adaptive designs by regulators, funding organizations, and industry. As this trend continues, sponsors that fail to at least consider whether an adaptive design is appropriate for candidates in development are likely to fall behind.
Filed Under: Drug Discovery