FDA Issues New Draft Guidance for Alzheimer’s Trials that Could Open Up Approvals


Merck & Company’s recent failure of verubecestat (MK-8931) in Alzheimer’s underlines just how difficult it has been for researchers to come up with meaningful treatments for the disease. Well over 115 drugs for Alzheimer’s have failed in late-stage trials, what John Carroll of Endpoints News dubbed “an unrelenting disaster zone for 15 years, with nothing available to treat this disease aside from some marginal symptomatic therapies.”

The U.S. Food and Drug Administration (FDA) issued new draft guidance for preclinical trials in Alzheimer’s on February 16, which recognized three stages of pre-dementia sporadic AD and provided suggestions on how to measure trial results for each of them.

Nicholas Doyle and Shana Cyr, with Finnegan, Henderson, Farabow, Garret & Dunner, wrote on Lexology, “FDA identifies four categories as conceptually useful for the design and evaluation of clinical trials in different stages of AD: Stage 1 (characteristic pathophysiologic changes of AD but no evidence of clinical impact), Stage 2 (characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment), Stage 3 (characteristic pathophysiological measures, and mild but detectable functional impairment), and Stage 4 (overt dementia). FDA discusses clinical endpoints for early AD trials in patients with stage 1, 2 or 3.”

In general, Alzheimer’s researchers welcomed the changes. Suzanne Hendrix, president of Pentara Corporation, a pharmaceutical consulstancy for Alzheimer’s clinical trial design in Salt Lake City, Utah, wrote to Alzforum, “This is great news. [The guidance] reflects acceptance of new approaches that are supported by research. … The acknowledgement that large effects in cognition may be important without a co-primary was refreshing.”

Paul Aisen, a researcher at the University of Southern California Alzheimer’s Therapeutic Research Institute (ATRI) in La Jolla, California, told Alzforum, “This is a valuable guide to current regulatory positions on early trial design that will facilitate progress in the field.”

The FDA’s first guidance was published in 2013 and recognized prodromal and preclinical stages of the diseases. The assessments of these stages were based on combinations of cognitive and functional tests like the CDR Sum of Boxes or other cognitive tests.

The new guidance refines this, staying away from “preclinical” and “prodromal,” and defining them in terms of changes in function, cognition and biomarkers. Alzforum writes, “In stage 1, biomarkers are abnormal, but people have no cognitive complaints or detectable decline even on sensitive tests. In stage 2, subtle cognitive effects crop up, but no functional deficits. In stage 3, people begin to have problems with some daily tasks. Lon Schneider, professor of Psychiatry & The Behavioral Sciences at the Keck School of Medicine at the University of Southern California, Los Angeles, said this categorization provides useful structure for trialists, and noted that stage 3 would correspond to mild cognitive impairment due to AD, while the first two are preclinical.”

It might be perceived that the new guidelines are lowering the bar for drug developers, but researchers are saying otherwise. Schneider told the forum, “The 2018 edition of the FDA draft guidance better conceptualizes the 2013 draft guidelines. … The 2018 draft guidelines may be less dramatic than they seem, and they neither lower nor raise barriers for drug approval. They are more a fine-tuning of early Alzheimer’s diagnoses for labeling purposes, a more pragmatic discussion of endpoints, and a finesse of the disease-modification term. The two new features seem to be allowing the potential for approving drugs that show functional benefit without cognitive benefit, and a statement that using a diagnostic biomarker might require its formal development as a companion diagnostic device. One overarching caveat for the guidelines is that early stage diagnostic criteria and trials endpoints may still require validation.”

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