Despite seeing benefits, industry awaits FDA final guidelines before adopting adaptive design trials
The promise of adaptive design clinical trials exists, with increased ethical treatment of patients, greater likelihood of finding the optimal dose and shortened study duration. But a variety of sponsor and CRO barriers—lack of experienced personnel with the required skills and knowledge, misunderstood benefits and greater complexity of design and trial implementation—have slowed their widespread adoption.
Five years after adaptive design became a focal point of clinical trials that included FDA draft guidance to industry, IRBs, CROs and other industry professionals say they are seeing relatively few protocols for flexible clinical trials.
For some, it’s a matter of education as to which adaptive designs are acceptable and which are not. Others maintain designs will change the study drug supply chain, as well as patient enrollment, randomization and the data capturing process, but increase the efficiency of trial design. For IRBs, these trials can limit patient volunteer exposure to potentially harmful and ineffective experimental drug treatments earlier than traditional trials.
Yet all agree that the FDA’s final guidance on adaptive clinical trials would formally encourage the use of this type of flexible approach for streamlining drug development.
“Adaptive designs are one of the tools to improve clinical development, but they are not a panacea,” cautioned Leonard F. Scinto, a member of the New England IRB and a former Harvard University assistant professor of neurology and neuroscience. “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.”
His comments followed a recent NEIRB “mock trial,” at which members discussed two traditional trial protocols as part of an open program to explain the IRB process and allow non-members to observe what happens at a closed IRB meeting.
Scinto said since 2008, when there were major reviews of adaptive design clinical trials, sponsors and CROs have moved cautiously. Unlike traditional clinical trials for which a protocol is created and conducted without any modifications, except for amendments, adaptive design uses information obtained from the study as it progresses to modify or potentially alter the study’s structure or other design features. Those changes can include an interim analysis of the patient sample size and a pilot study within the larger study.
“It’s all a matter of thinking through the process in adaptive design,” said Scinto. “You have to put the problem in clear English, articulate what it is and analyze what the solution could be.”
Other IRBs have had similar experiences, as most adaptive design trials come from larger drug sponsors and CROs that often are more knowledgeable about the special considerations for the conduct of a study involving adaptive design methods.
“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,” said Patience B. Stevens, M.D., MPH, CIP, vice chair of Copernicus Group IRB and a former clinical assistant professor of pediatrics at East Carolina School of Medicine.
Pharmaceutical companies that have the resources to conduct these trials are also very cautious in the utilization of adaptive clinical trial designs.
A recent survey from Elsevier Business Intelligence of 30 biostatisticians and product development executives in pharmaceutical and clinical research firms found that more than 75% of clinical trial practitioners had performed or considered performing an adaptive trial.
However, 85% of those respondents had implemented or designed fewer than five adaptive trials. Most said they anticipated a greater presence of adaptive clinical trials in the future, notably wider acceptance by regulatory authorities.
“Those (adaptive design) trials that represent a novel approach today will help determine the future landscape of clinical research,” the Elsevier survey concluded in a white paper entitled “Enhancing Success Rates with Adaptive Clinical Trials.”
The reported said 80% of those surveyed indicated an increase in expected utilization of adaptive design trials by 2015.
Until then, IRBs say the final FDA guidelines on flexible trials may be the next major signal in their adoption.
“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,” said Dr. Stevens, “and some guidance on the timing and nature of communications between the sponsor, the principal investigators and the IRB.”