FDA’s Cavazzoni on neuro, accelerated approval
FDA’s approach to neurodegenerative diseases unchanged by Dunn’s departure, CDER director says
The departure of Billy Dunn, who headed FDA’s Office of Neuroscience during controversial approvals of drugs to treat Alzheimer’s disease and ALS, will not change the agency’s approach to reviewing medicines for neurological conditions, Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research, told BioCentury.
Her comments were part of a wide-ranging interview for The BioCentury Show that also covered the CDER director’s perspectives on accelerated approvals, regulatory flexibility, advisory committees, hybrid work and other topics.
Media speculation that Dunn’s departure would affect pending or future approval decisions is based on a “fundamental misunderstanding on how we make decisions,” Cavazzoni said. “There seems to be sort of the impression that one single person, the day before an application is due, says, okay, what am I thinking today? I’m going to push a button, yes or no.”
In fact, she said, decisions are the result of months of deliberations, and “lots of eyes” are involved.
Cavazzoni emphasized that the “trends that we have seen in neuroscience and particularly in neurodegenerative disease are here to stay.”
She also sought to dispel misunderstandings about FDA’s use of “regulatory flexibility.” The agency’s use of the term is predicated on its legal requirement to base approvals, including accelerated approvals, on “substantial evidence of effectiveness,” Cavazzoni said.
“Regulatory flexibility,” she said, “is something that we consider based on the context around that particular drug and that particular application. And some of examples of the context are whether the disease is life-threatening, whether it is very serious, whether it is very rare, whether there are other treatments for the disease or whether there is unmet medical need.”
Those criteria, she added, can lead FDA to determine if the substantial evidence threshold has been met, that it is “appropriate in this case to accept a greater degree of uncertainty for this disease with unmet medical needs, no other treatments, [and that is] very serious or life-threatening, compared to what we would do in a situation where none of that applied.”
FDA approvals of drugs for neurodegenerative diseases, she said, are being driven by advances in scientific understanding of the causes of disease similar to those that, starting two decades ago, started a revolution in the treatment of cancer. And like cancer, biology is revealing biomarkers that can be used as the basis for accelerated approvals, she added.
Cavazzoni also discussed how FDA will use authority over accelerated approvals that Congress provided the agency in legislation passed in December.
The default assumption going forward, she said, will be that trials to confirm clinical benefit will be fully enrolled and ongoing prior to granting accelerated approval. There will, however, be exceptions.
FDA officials have told BioCentury the agency may not require ongoing confirmatory trials when there is a finding of efficacy that could transform patient lives, and it would be unethical to delay access to wait for a sponsor to launch a trial.
In such cases, the agency will press companies to start and complete trials rapidly, Cavazzoni said. “What is inherent to accelerated approval is some residual uncertainty about the clinical benefit, and so it is absolutely essential that those confirmatory trials be completed as quickly as possible.”
Cavazzoni responded favorably to the suggestion that FDA do more to gain scientific consensus by holding public meetings about approvable endpoints, and that it decouple such discussions from specific product applications. FDA is considering this kind of approach, especially for clinical areas such as neurological disorders where she said “we’re beginning for the first time to really make some inroads in understanding the biology of certain diseases.”