fter years of relying on outdated standards for evaluating new drugs for Alzheimer’s and other neurologic diseases, the FDA is finally modernizing its approach. This is good news for researchers working to develop much-needed medications for these conditions.
The change has to do with the endpoints the FDA requires in clinical trials. A loose standard in place since the 1990s required clinical trials to show that a new drug for Alzheimer’s disease improved patients’ cognition and function. But that isn’t in line with our current understanding of the disease and was likely a contributing factor in the high rate of failure in Alzheimer’s trials.
Impairments in cognition — which includes memory, executive function, language, and other aspects of thinking and reasoning — are characteristic features of Alzheimer’s. Functional impairments — problems with daily tasks such as getting dressed, brushing your teeth, cooking, driving, and the like — are generally due to cognitive issues.
Under the dual-endpoint standard, the FDA asked drug developers to demonstrate benefits to cognition among Alzheimer’s patients with symptoms of dementia that were “clinically meaningful” by demonstrating improvements in function. But we can now recognize earlier stages of Alzheimer’s disease, such as mild cognitive impairment, in which patients have no issues with daily function. In this large group of patients, it’s difficult, if not impossible, to show improvements in function because their function is fine.
In other diseases, the FDA requires clinical trials to focus on one endpoint. It is now applying this approach to Alzheimer’s disease. It’s much like the “modernized standard” that my colleague, George Vradenburg, and I called for last year. And the FDA has gone even further for clinical trials including early-stage patients. Its new draft guidelines outline three stages of early Alzheimer’s disease and offer guidance on drug development for each. These forward-thinking guidelines acknowledge advances in our understanding of Alzheimer’s.
Individuals with stage 1 Alzheimer’s have no clinical symptoms of the disease, but do have biomarker evidence of it. These can include positive PET scans of the brain or positive tests for beta-amyloid or tau, two proteins that are hallmarks of Alzheimer’s disease. For clinical trials involving these asymptomatic, cognitively normal patients, the FDA says that improvements in relevant biomarkers could now serve as the basis for accelerated drug approval.
Individuals with stage 2 Alzheimer’s have biomarker evidence of the disease and subtle cognitive impairment, but no problems with function. For trials in this population, the FDA will now consider “strongly justified arguments” for using only cognition as an endpoint.
Individuals with stage 3 Alzheimer’s have biomarker evidence of the disease plus cognitive and functional impairment — in other words, they have what is currently called mild cognitive impairment. The FDA suggests that trials testing therapies in this group should include measures of cognition and function, but encourages new approaches to assessing these outcomes.
The question now is how to design Alzheimer’s clinical trials to meet these guidelines.
It’s clear that trials must now specify and define the stage of Alzheimer’s disease among the population being studied at the time of enrollment, as well as the expected stage at its conclusion. It is also clear that biomarkers should be used as one criteria for trial enrollment, to monitor disease progression, and to indicate responses to the drug.
The new FDA guidelines are a big advance. They define earlier stages of Alzheimer’s, acknowledge the vital role of biomarkers, and open doors for novel drug targets. Exactly how the new guidelines will play out for drug developers remains to be seen. The immediate task is to develop new biomarkers and more sensitive tests of cognition and function.
Now that the FDA has signaled it is ready to accelerate the development of new drugs for Alzheimer’s, the challenge for us is to prove that they work.
Howard M. Fillit, M.D., is the founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation. He also serves as a clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at Icahn School of Medicine at Mount Sinai.
Editor’s note: The author did not initially disclose having received payments for consulting work in pharmacoeconomics for Hoffmann-La Roche; Genentech; Eli Lilly; Otsuka; Lundbeck; and Merck Sharp & Dohme.