Industry anticipates FDA final guidelines prior to adopting adaptive design trials

With improved ethical treatment of patients, the pledge of adaptive design clinical trials continues to exist with a larger possibility of finding the optimal dose and shortened study duration. However, their extensive acceptance has been impeded by a range of sponsor-CRO barriers including lack of skilled, knowledgeable, and experienced personnel; misinterpreted trial benefits; and greater intricacy of trial design and execution.

Although adaptive design turned out to be crucial to clinical trials including FDA draft guidance to the industry; 5 years later, IRBs, CROs, and other industry professionals state that they are noticing only a relatively few protocols for flexible clinical trials.

For some, determining which adaptive designs are acceptable and which are not is just a matter of learning. Others continue to sustain designs that will transform the study drug supply chain, patient enrollment, randomization, and the data capturing process, but augment efficiency of trial design. Prior to conventional trials, for IRBs, these trials can decrease patient volunteer exposure to potentially injurious and ineffective experimental drug treatments.

Nonetheless, everyone is of the opinion that in order to streamline drug development, the final guidance on adaptive clinical trials by the FDA would formally encourage this type of flexible approach.

A member of the New England IRB and a former Harvard University assistant professor of neurology and neuroscience, Leonard F. Scinto, cautioned that “Adaptive designs are one of the tools to improve clinical development, but they are not a panacea. For IRBs they require more scrutiny in the trial design, dosing and making sure subject safety is protected. Still, we don’t see that many adaptive design trials.”
As a part of an open program to elucidate the IRB process and permit non-members to observe what happens at a closed IRB meeting, two conventional trial protocols were discussed by members at the latest NEIRB “mock trial” where his comments were followed.

Scinto noted that since 2008, Sponsors and CROs have been vigilant when there were major reviews of adaptive design clinical trials. Adaptive design employs information obtained from study progress in order to amend or potentially alter the study structure or other design features unlike traditional clinical trials where a protocol is formulated and executed without any modifications, except for amendments. Changes may comprise an interim analysis of patient sample size and a pilot study within the larger study.

Scinto added, “It’s all a matter of thinking through the process in adaptive design. You have to put the problem in clear English, articulate what it is and analyze what the solution could be.”
Because most adaptive design trials originate from larger drug sponsors and more knowledgeable CROs with particular consideration for a study conduct concerning adaptive design methods, other IRBs have had similar experiences.

Vice chair of Copernicus Group IRB and a former clinical assistant professor of pediatrics at East Carolina School of Medicine, Patience B. Stevens, M.D., MPH, CIP, said that “These trials do not require additional oversight on the part of the IRB when the adaptation is well-planned and well-described in the initial submission.”
Adaptive clinical trial designs are utilized cautiously even by pharmaceutical companies having the resources to conduct these trials.

Elsevier Business Intelligence recently surveyed 30 biostatisticians and product development executives in pharmaceutical and clinical research firms.

Although more than 75% of clinical trial practitioners had conducted or considered conducting an adaptive trial, 85% of those respondents had implemented or designed fewer than five adaptive trials. They said that they foresee a notably wider acceptance by regulatory authorities and anticipate a greater incidence of adaptive clinical trials in the future.

In a white paper entitled “Enhancing Success Rates with Adaptive Clinical Trials,” the Elsevier survey concluded that “Those (adaptive design) trials that represent a novel approach today will help determine the future landscape of clinical research.”

According to reports, 80% of those surveyed indicated that the expected utilization of adaptive design trials will be on the rise by 2015. As stated by the IRBs, the next major signal in their acceptance until then may be the final FDA guidelines on flexible trials.

Dr. Stevens said, “From the IRB’s perspective, it may be helpful if the final guidance included some discussion of the IRB’s role in the oversight of adaptive design clinical trials and some guidance on the timing and nature of communications between the sponsor, the principal investigators and the IRB.”