Adapt or die

CAMBRIDGE, Mass.—Greater adoption of adaptive clinical trials may be around the corner now that Cytel Inc. and Wayland, Mass.-based Tourtellotte Solutions have integrated Cytel's DoseSim adaptive trial simulator and Tourtellotte's tcVisualize clinical trial supply chain simulator. Using Monte Carlo computational methods, they say, the joined products provide accurate simulation of the clinical supply and the randomization necessary to ensure more predictable, cost-effective adaptive trials.

This collaboration follows another one completed in April between the two companies, wherein tcVisualize was integrated with Cytel's FlexRandomizer to aid the design and implementation of innovative clinical trials, including adaptive trials. That product, however, deals with randomization alone and thus isn't a true simulator, notes Ed Tourtellotte, CEO of Tourtellotte Solutions.

"What we have done now is integrate our tcVisualize drug supply simulator with specially formed output from Cytel's DoseSim simulation package which is one of the very few—the only one as far as I know, at least—true dose ranging adaptive trial simulators on the market," Tourtellotte explains of the most recent deal. "I would expect that we will take this latter pairing forward fairly aggressively as both drug supply simulation and adaptive trials are rather hot topics these days individually and even more so together since drug supply is such a barrier to the spread of adaptive trials."

Adaptive trials can reduce development lead times and costs and boost clinical trial success rates, notes Ranganath Nayak, CEO of Cytel, in large part because they can examine several more dosing options than one would in a traditional trial (as many as eight instead of just two or three), and adjusting doses taken by trial participants as the trial progresses.

But if a company guesses wrong and has too much of a drug on hand, they waste money, and if they have too little of the drug on hand, they face problems of resupplying that drug and getting it out to all clinical sites in a timely fashion. "The necessary waste and overage levels can quickly become absurd," Tourtellotte points out.

"The uncertainties have caused some companies to abandon the idea of conducting response adaptive trials, or, at least, to drag their feet," Nayak adds.

The companies expect that their newly combined technologies will increase buy-in for flexible, adaptive trials, noting that the supply modeling and visualization capabilities of the integrated product make it significantly easier to plan complex, multi-site studies.

"Traditional trials have a fixed endpoint and, no matter what happens during the trial, you cannot change anything until millions of dollars and many years have been wasted," notes Michael Weitz, marketing programs director for Cytel. "Researchers and the FDA are beginning to recognize the value of adaptive trials and even though it's an evolving area where FDA still has to write final rules and guidelines, you see more adaptive trials approved with each passing month."

There is even an ethical imperative in getting adaptive trials out of the theoretical realm and into wider usage, Weitz says.

"Let's take an oncology trial, for example," he says. "You have looming life-determining implications there and with an adaptive model, you can have more patients on dosages that are meaningful sooner, as well as getting effective and safe medicines to the market quicker."

Cytel's DoseSim, the trial design and randomization component of the companies' newest integrated solution, offers planners the choice of either advanced Bayesian- or Frequentist-based statistical models to optimize the design of dose-finding and dose-selection trials. It maximizes the likelihood of choosing the right dose for confirmatory Phase III trials, thereby improving Phase III success rates, says Nayak, and he says it is a good way for sponsors to improve return on investment for clinical development of drugs and devices.

Tourtellotte's tcVisualize, the supply simulation component, is a desktop-based visual simulator and forecaster that allows a supply team to run and compare unlimited supply scenarios with varying parameters including Monte Carlo analysis and variable dosing capabilities.