By Dr. Phil Birch, VP of innovation strategy, alliance partnerships, ICON plc
The Phase 3 failure rate is hovering near 50 percent. One in five drugs requires a dose change within the first five years of marketing. The cause of these dismal statistics is rooted in the inaccuracy of the assumptions upon which trials are designed, particularly during dose selection in Phase 2.
Adaptive designs can significantly improve early-phase development decision making by allowing sponsors to correct assumptions made at the outset of the study. In the same way a football coach adapts his strategy at half-time if his team is losing, an adaptive design allows alteration of a trial’s “game plan” based on accumulating data at defined interim analysis steps.
In the case of adaptive dose-finding, this can mean economical testing of a wider range and number of doses and adapting the patient allocation by adding or dropping doses at the interim analysis point. The flexibility of adaptive designs allows for a more accurate estimation of the minimum effective dose and increases confidence that the right dose is moving into Phase 3.
Design assumptions are not flawed in every trial, and errant assumptions do not always lead to complete failures, but the only way to prevent these risks from draining resources is to institute a process that reduces the probability of error across an entire portfolio.
ADAPTIVE DESIGNS CONSERVE RESOURCES AND IMPROVE DECISION MAKING
Simple adaptive designs, which include re-estimating the sample size to prevent an underpowered trial from failing or stopping early for futility or efficacy, can provide substantial benefits. The Tufts CSDD (Center for the Study of Drug Development) estimates that simple designs could save $100 to $200 million annually when applied across a portfolio. Most of these cost savings are driven by futility stops, which means products are failing.
The real value of adaptive design lies not in accelerating failure, but driving success. Sophisticated designs deployed in exploratory development increase the probability of products completing pivotal trials — and the identification of the most favorable dosing and safety profiles for maximum commercial return. Sophisticated adaptive designs are central to the value proposition that “getting it right” at Phase 2 drives enterprise value.
ADAPTIVE DESIGNS ARE NOT NEW, AND REGULATORY AGENCIES UNDERSTAND THEIR VALUE
Adaptive designs are not new; Pfizer, for example, ran its first adaptive trial in 1984. While adaptive trial adoption grew at a rate of 38 percent from 2011 to 2013 to reach 20 percent of ongoing trials, further adoption is essential to realize benefits only possible at the portfolio level. Several top pharmaceutical companies are expanding the application of adaptive design as evidenced by widespread interest in Novartis’ adaptive dose-finding methodology and Janssen’s heavy investment in quantitative sciences for the design of adaptive trials. Furthermore, Novartis, Janssen, Eli Lilly, Pfizer, and Roche have recently partnered in the ADDPLAN DF Consortium to improve existing technologies for the design and execution of adaptive dose-finding trials.
Regulatory agencies understand the value of adaptive designs and encourage their use. The EMA (European Medicines Agency) recently qualified an adaptive analysis method called MCP-Mod as an improved procedure for dose-finding designs. The qualification indicates the organization’s desire to see more innovative trials. The FDA has issued several adaptive guidances and in 2013, began granting potential priority review status to IND (investigational new drug) applications that utilize adaptive design. In July 2014, CDER director Janet Woodcock testified to Congress that the FDA encourages adaptive designs, when appropriate, to increase trial efficiency.
INVEST IN RESOURCES UP FRONT TO IMPROVE RETURN LATER
Implementing an adaptive strategy across a portfolio requires input from experts in adaptive design, translational sciences, clinical development, and regulations in order to identify where, when, and how an adaptive design approach will add value for each indication and phase of development. For each asset selected, the choice of an adaptive design should be thoroughly reviewed on an ongoing basis during the life cycle of the asset.
Adaptive trials require additional upfront planning to simulate and select the optimal design before the trial begins. This has to become an integral part of the protocol development process. In an environment where the costs of drug development are still increasing and the Phase 3 failure rate remains high, optimal decision making has never been so critical. Taking time to set the stage for success instead of rushing to get to market will pay off.