The US Food and Drug Administration (FDA) is taking definitive steps towards a more viable framework for adaptive clinical trials. In an effort to clarify the conditions and requirements for adaptive studies, the agency has a series of guidance documents in the pipeline and is encouraging input from product sponsors and the broader scientific community.
Adaptive trials are an umbrella term for more flexible study formats that use interim analyses to fine-tune parameters such as dose selection, treatment duration or sample size. The more sophisticated predictive tools available to drug developers have opened up the possibilities for adjusting trials in the light of emerging safety or efficacy data: for example, randomisation might be tailored to ‘enriched’ populations most likely to respond to treatment.
Addressing the 2006 Conference on Adaptive Trial Design in Washington recently, Scott Gottlieb, the FDA’s deputy commissioner for medical and scientific affairs, said adaptive studies could sharpen the efficiency of the drug development process, reduce exposure of trial participants to inferior therapies, generate better targeted treatments and help doctors to deliver more personalised medicine.
The traditional design model tended to produce clinical trials that were too large, costly, unwieldy and unenlightening – not to say potentially unethical, Gottlieb pointed out. “Establishing that a placebo pill doesn’t treat a cancer better than an active drug in our highly empiric approach often doesn’t maximise our learning about a new medicine, and it surely doesn’t help the patient who gets the sugar pill,” he commented.
Adaptive trials were not a panacea, Gottlieb stressed. They were also more complicated than conventional trials to design and analyse, while the need to make a number of decisions over the course of a study might increase the risk of making the wrong decision. That was why sponsors needed consensus and clarification on pivotal scientific issues around when an adaptive design was most appropriate.
If the FDA was already seeing “a lot of interest” in adaptive approaches, especially for early-stage clinical trials, the lack of clear guidance had also led to “trepidation about the use of adaptive features and reluctance to consider a variety of enrichment and adaptive designs”, Gottlieb said. This might reflect a belief that the FDA had yet to demonstrate its readiness to accept adaptive trial designs or corresponding approval criteria, he acknowledged.
The agency hopes to correct that impression by issuing guidance documents to “help articulate the pathway for developing adaptive approaches to clinical trials”. The two most advanced of these documents address the use of multiple endpoints in the same study and enrichment designs. The guidance on multiple endpoints could be available for discussion by January 2006. Three further documents will tackle non-inferiority trial designs, adaptive designs and how to deal with missing trial data.
The research-based industry association, PhRMA, confirmed its members’ “keen” interest in adaptive clinical trials, although it could not say how many companies were actually using these formats. Adaptive designs were “one of the important new tools” that would help to modernise and accelerate the drug development process, commented spokesman Jeff Trewitt.
He also noted that a technical working group within PhRMA was in the early stages of developing a white paper on adaptive trials in collaboration with the FDA and EU regulators. This should address the technical challenges presented by adaptive studies, as well as concerns raised about potential risks such as early leakage of trial data.