In light of recent failures in high-profile Alzheimer’s disease clinical trials, scientists have turned their attention with increasing urgency toward testing therapies in early-stage patients who have underlying brain pathology but little to no functional impairment. Now, the U.S. Food and Drug Administration is formally recognizing this shift. The agency yesterday held a Webinar on a draft guidance it had issued last month to companies developing AD drugs. In it, the agency acknowledged that testing drugs in the dementia stage of the illness may be too late to have a clinically meaningful effect. “The goals of the guidance are to provide a framework for how drugs might be studied in patients with early-stage AD, and to provide a forum for further discussion,” Nicholas Kozauer told Webinar attendees. Kozauer and Russell Katz, both of the FDA’s Division of Neurology Products, led the Webinar and coauthored an editorial in the March 28 New England Journal of Medicine that describes the guidance and its rationale.
On 7 February 2013, the FDA released the guidance to industry in draft form and welcomes public input until 9 April (electronic comments can be submitted here). The guidance states that traditional criteria—which require drugs to improve performance in both cognitive and functional domains—will not work for early-stage patients who show mild cognitive impairment (MCI) yet still carry on with life normally. The document acknowledges the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and other natural history studies that suggest biological changes can reflect AD in advance of clinical symptoms. The draft guidance recognizes “prodromal AD” (i.e., MCI-like deficits anchored by AD biomarkers) and “preclinical AD” (cognitively normal with AD risk factors or biomarker changes) as part of the disease spectrum. The guidance proposes using continuous outcome measures in clinical trials rather than trying to measure time to dementia. It encourages drug developers to consider taking disease-modifying compounds into late MCI using composite measures that assess cognition and function on the same scale, for example, Clinical Dementia Rating Sum of Boxes (CDR-SB) score. Other scales are under development, for example, cognitive composites as recently discussed in an ARF Webinar and an ARF conference story. Katz said the FDA would consider these as well. For early MCI or preclinical populations, the agency suggests it may be possible to approve a drug based on an isolated cognitive measure through the agency’s accelerated approval pathway. This mechanism speeds approval of drugs for unmet medical needs, and would require post-approval studies to verify the clinical benefit.
“This really launches a new age, and it’s very much built on the ADNI collaborative effort. I just wanted to recognize that,” Paul Aisen of the University of California, San Diego, said at the ADNI steering committee meeting on 18 March during the American Academy of Neurology annual conference in San Diego.
That same day, the New York Times ran an editorial warning ominously that the FDA’s proposal “lowers the bar” for AD drug development. The newspaper editors argue that it could be risky to allow companies to test compounds in people without obvious dementia using biological markers and subtle changes in cognitive performance, instead of improved function, to gauge therapeutic efficacy. “A small decline in scores on cognitive tests may have no bearing on whether patients will progress to serious disease,” the editors wrote. “The test scores might also mistakenly identify people who are not in the early stages of Alzheimer’s and who, if treated, would suffer adverse side effects without receiving any clinical benefit.”
Aisen—along with Ron Petersen of the Mayo Clinic, Rochester, Minnesota; Michael Weiner of UC San Francisco; and Reisa Sperling of Brigham and Women’s Hospital, Boston, Massachusetts—submitted a letter to the New York Times editors declaring the FDA’s proposal “the only feasible drug development plan” and arguing that the “cautious approach suggested by the [New York Times editors] would take an incalculable toll on our health.” The scientists' letter is posted below.
AD researchers praise the FDA’s efforts as a sensible adaptation to new AD drug development challenges. “We herald this as a real shot in the arm with massive implications for the field,” said Marwan Sabbagh of Sun Health Research Institute in Sun City, Arizona. Adam Fleisher of Banner Alzheimer’s Institute in Phoenix, Arizona, says the FDA has been “forward thinking but cautious” in rising to the challenge of finding treatments for AD in its earliest stages while “encouraging cautious scientific diligence.”
They and other scientists disagree with the New York Times editors’ claim that the proposal loosens the rules for drug approval. “The bar is not lower with these new guidelines,” wrote Sterling Johnson of the University of Wisconsin, Madison, in an e-mail to Alzforum (see full comment below).
At the Webinar, Katz said, “It only makes sense to use outcome measures appropriate for the condition being treated. We do that every day with every drug we deal with. We are attempting to tailor the outcome measure to the early-stage AD population. Using a single outcome measure instead of two is just the appropriate thing to do in this population. We absolutely do not believe we are loosening guidelines.”
William Jagust of the University of California, Berkeley, points out that the FDA is “suitably skeptical of using only a biomarker as an endpoint in a clinical trial.” Kozauer and Katz expressed a similar sentiment. “Despite our growing understanding of the relationship between various disease-based biomarkers and the clinical course of Alzheimer’s disease,” they wrote in the NEJM editorial, “it remains unclear whether the effect of a drug on one or more such biomarkers can actually predict a meaningful clinical benefit.” This was borne out in recent clinical trials showing discordant biomarker changes and cognitive endpoints (see ARF conference story).
Even for early MCI trials using a single cognitive measure in lieu of the traditional two-pronged requirement for both cognitive and functional gains, Kozauer told the Webinar audience that the agency “would have to be convinced that patients being identified for treatment are very likely to go on to develop AD dementia. We recognize that number is not going to be 100 percent, but we would have to have a good understanding of the risk before we contemplate using the [accelerated approval] pathway,” he said. Still, even if some amyloid-positive seniors do not develop dementia within their lifetime, “early treatment could have a substantial impact on AD at a population level,” Sperling noted. “Delaying dementia by just five years is estimated to reduce Medicare costs of AD by more than 50 percent.”—Esther Landhuis
To the Editors,
Nearly half of the population over the age of 70 will be affected by Alzheimer’s disease with accumulation of abnormal amyloid protein in brain associated with cognitive decline and eventual dementia and death. Drugs now in development can reduce amyloid accumulation, but such treatments at late stages of AD dementia do not provide substantial clinical benefit. A simple analogy might be trying to treat heart disease by lowering cholesterol at the stage of heart failure in the intensive care unit.
The new anti-amyloid drugs must be tested at the earliest, asymptomatic stage before there is widespread, irreversible loss of nerve cells in the brain. The only feasible drug development plan, as noted in the well-considered draft guidance document by the FDA, must rely on demonstration of slowing subtle cognitive decline, along with evidence of amelioration of the underlying disease pathology. The cautious approach suggested by the Editors [Editorial, 18 March 2013] would take an incalculable toll on our health.
Paul S. Aisen, MD
Director, Alzheimer’s Disease Cooperative Study
Professor of Neurosciences, University of California, San Diego
9500 Gilman Drive M/C 0949
La Jolla, CA 92093
Ronald C. Petersen, MD, PhD
Director, Mayo Clinic Alzheimer’s Disease Research Center
Professor of Neurology, Mayo Clinic
Reisa A. Sperling, MD
Director, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital
Professor of Neurology, Harvard Medical School
Michael W. Weiner, MD
Director, Alzheimer’s Disease Neuroimaging Initiative
Professor of Medicine, Radiology, Psychiatry, and Neurology
University of California, San Francisco
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- Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013 Mar 28;368(13):1169-71. Epub 2013 Mar 13 PubMed.