The Food and Drug Administration (FDA) has continued its release of new guidances, recently publishing “Adaptive Designs for Clinical Trials of Drugs and Biologics” and “Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics.”
The adaptive design draft guidance advises industry on the types of information FDA needs to evaluate the results from clinical trials with adaptive designs. This includes Bayesian adaptive designs and complex designs relying on computer simulations.
Karen Kesler, senior statistical scientist, Rho, said the FDA has learned a lot since first releases the 2010 draft guidances, calling the new release a tighter, more directive guidance that has been reorganized to reflect these lessons.
“In addition to reorganizing the content around the most commonly used adaptive study designs, there are more real world examples and less theorizing about what could happen,” she told us.
For example, one shift in language is the use of “non-comparative/comparative” studies instead of “unblinded/blinded studies.”
“It’s a more precise designation as the key issue is whether you’re looking at the treatment difference and open label studies can be adaptive, too,” said Kesler.
Language to address newer study concerns also is included, such as the use of surrogate or intermediate endpoints, which Kesler said weren’t as popular in 2010 as today.
“Overall, however, the message is the same—if you’re doing an exploratory adaptive study, you have a lot more room for experimentation than if you’re doing an adequate and well-controlled study for your submission,” said Kesler.
If a company wants the FDA to consider an adaptive design for an adequate and well-controlled effectiveness (A&WC) study, Kesler said it must prove that there is control of the Type I error, possible bias is adjusted for, and that operations keep the information limited to as few people as possible – all of which must be pre-specified.
Dr. William Aronstein, PhD, MD, FACP, VP of medical affairs, CTI Clinical Trial & Consulting Services said the company also is encouraged by the guidance. “Leading pharmaceutical innovators have already been using adaptive trial designs, in which the evolving interim results of a trial can be used to modify its design,” he noted.
Aronstein added, “It will be very helpful to understand clearly the FDA’s thinking about the results that can be achieved with these studies.”
The Association of Clinical Research Organizations (ACRO) also welcomes the FDA’s issuance of new guidance.
“These guidances address a number of important concepts, including flexibility and adaptability in regard to the engagement of patients, and providing a level of regulatory clarity for innovative approaches to the design and execution of clinical trials,” said Karen Noonan, ACRO’s VP of global regulatory policy.
“ACRO supports this benefit of adaptive design trials as a learning system, where clinical researchers can integrate new data and refine trials to be smarter and more efficient,” she told us, including concepts of adaptive enrichment, adaptive endpoint selection, and the use of single control arms.
The two guidances also address important ethical considerations, such as minimizing patient exposure to experimental products, to the extent of which it is possible, Noonan explained.
“Importantly, they also allow collaborative development across multiple sponsors, and facilitate improvement of subgroup identification,” she added.
Per the master protocol draft guidance, there has been increased interested in accelerating late-stage drug development through developing trial designs that test multiple drugs and/or multiple cancer subpopulations “in parallel under a single protocol, without a need to develop new protocols for every trial.”
Aronstein explained that master trials “enable a promising drug to be tested simultaneously in a number of different cancers, so that the most promising results can be more efficiently and more quickly followed up.”
The FDA also recently released a draft guidance on clinical trial data disclosure, which has been received with less enthusiasm, though the agency is still gathering comments.
Agency initiatives to promote development and innovation in the digital health space, however, have been met with more positive feedback.
John Reites, partner and chief product officer at Thread said, “These new regulations and supportive messages from the agency are enabling digital health companies of all sizes to see a more clear path to potentially becoming a standard in health care.”
