As sponsors recognize the value of adaptive clinical trial designs and regulators come on board, CROs are beginning to shift their priorities to be more flexible.
Adaptive trial designs use data to allow sponsors or CROs (contract research organizations) to adjust parameters for ongoing clinical trials, including dosage, subject population or sample size. The adjustments typically come after the analysis of statistically significant safety or efficacy data can be seen to accelerate clinical development and improve efficiency.
Simple adaptive trial designs – such as early study terminations due to futility – are becoming widely adopted throughout the industry, especially in Phase II and III studies, according to a recent report from the Tufts Center for the Study of Drug Development.
Kenneth Getz, MBA, Director of the Tufts CSDD (Center for the Study of Drug Development) Sponsored Research Programs, told Outsourcing-Pharma.com that the report found a wide variation in the levels of adoption of adaptive trials.
“Industry as a whole is seeing an adoption rate of about 20 percent,” he said. In addition, companies are implementing simple adaptations more frequently but “the more sophisticated manifestations are more sporadic,” Getz said. Many companies’ regulatory affairs staff seem averse to what could potentially endanger an expensive development project.
“But in talking to regulators, they seem much more receptive to broader implementation” of adaptive designs “because they introduce certain behaviors” in sponsors and CROs, such as more up-front planning, that they “hope industry will support,” Getz said.
The understanding of adaptive trial design “goes back 20 years” and in recent years, “it’s become a hot topic,” though familiarity has increased over the last decade, Dr. Philip Doren, VP of biometrics at SynteractHCR told us.
Sample size re-estimation is another adaptive trial design that is viewed by some large pharmaceutical companies as relatively simple, though the reported adoption of this approach appears to be low when compared to futility, the report says.
As for more sophisticated designs, such as adaptive dose-finding and seamless Phase II/III studies, adoption has been slow, especially among CROs.
Many CROs “have the expertise” to conduct adaptive trials but they historically “haven’t been requested” to conduct such trials, Getz said. “But the interesting thing is that the current environment is favouring these partners to be more progressive and introduce more leading-edge ideas and improve their quality, speed and costs” of trials, he added.
Vlad Dragalin, PhD, senior vice president of software development and consulting at Aptiv Solutions, told Outsourcing-Pharma.com that because the current CRO business model relies on the ability to run large numbers of the same types of trials, adaptive trial designs have only begun to be recently adopted.
For instance, SynteractHCR recently completed validation and training on adaptive trial software to enhance its consulting services on adaptive trials for its clients.
“It enables us to simulate outcomes so we can test our assumptions on the sample sizes so we have a relatively good idea of what will impact a study,” Dr. Philip Doren, VP of biometrics at SynteractHCR told us.
Now that CROs are moving forward in this space, Dragalin said he believes the adoption of more simple adaptive designs will be similar to the trend of CROs implementing EDC (electronic data capture) systems, which are now widespread. He predicts that between the next five and 10 years, “the whole field will find that it can be streamlined” and the slow uptake of adaptive clinical trials “will be history.
“CROs are watching where the trends are going and they’re trying to adjust on the fly,” Draglin said, noting the since its inception, Aptiv has been able to run more customized trials.
Greatest Potential in Exploratory Phases
Draglin noted that the “greatest potential” in adaptive designs is in exploratory phases -- up to Phase II trials -- where companies can modify ongoing trials based on early data.
Tufts estimates in its report that early study terminations due to futility and sample size re-estimation could save sponsor organizations between $100 million and $200 million annually in aggregate costs.
But CROs are still slowly adopting more complex adaptive designs -- such as increasing the dose range for a study from two or three to between 10 and 15 doses, and shifting patients to “more promising doses,” he said.
“In confirmatory trials, there’s still an opportunity for adaptive designs, but the number of adaptations allowed is reduced,” he said. For Phase III trials, adaptive designs can mainly solve two drawbacks, Draglin continued – an insistence in companies to continue a trial even if there’s evidence the drug will not prove successful, and then the need to move resources to other compounds or use the same compound for other indications.
“From the point of view of building a business out of the current CRO business model, [adaptive clinical trials are] not something that can be done overnight,” Draglin said. “They need to have confidence there will be a lot of these types of trials so you can switch from one infrastructure to another.”