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In A Game Change, FDA Shifts Criteria for Drug Development to Early-Stage Alzheimer's Disease

Nierengarten, Mary Beth

doi: 10.1097/01.NT.0000429675.93853.a5
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A new FDA policy document relaxes criteria for enrollment for clinical trials for Alzheimer's disease and supports earlier intervention.

In a move that several leading Alzheimer's disease (AD) experts welcomed, the Food and Drug Administration (FDA) issued a new guidance document in February refocusing drug development and treatment for Alzheimer's disease to earlier stages of disease. Among its policy changes, the FDA proposed loosening regulations requiring patients to have both cognitive and functional impairment to be eligible for clinical trials.

The proposed changes, which were explained further in a Mar. 13 paper in the New England Journal of Medicine, reflect an emerging consensus among AD clinicians and investigators that treating the disease at earlier stages may be more effective than the current approach of providing therapies once the disease is diagnosed and at a later stage.

Commenting on the FDA policy document, David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN, noted that many people in the field think the failure of current therapies in mild cognitive impairment or dementia due to AD is that its neurodegeneration is too far along, even in people with mild cognitive impairment. Current theoretical and empirical work suggests, he said, that some of these treatment approaches, especially those geared toward lowering brain amyloid-beta (Abeta) should only work in at-risk people who are asymptomatic.

Targeting people at risk for AD who are asymptomatic is a completely different approach than the FDA has previously considered for the disease, Dr. Knopman said, adding that he applauds the change.

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The guidance document also attempts to address several challenges that have made it difficult to assess the efficacy of drugs for people with early disease — such as identifying patients with early AD or who are at risk of developing AD to enroll in clinical trials, as well as selecting endpoints to measure in people with early disease who do not show clinical signs of disease.

Under the new proposed suggestions, the FDA proposes potential strategies for demonstrating clinical efficacy in trials that enroll patients with early stage disease. One strategy is to use a composite scale that assesses both cognition and function as a single primary efficacy outcome measure in patients with early disease, such as the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score.

For patients with the earliest symptomatic stages of the disease who may have subtle cognitive deficits without any detectable functional impairment, the FDA says it could consider marketing approval of a drug through the accelerated approval mechanism using one single primary efficacy measurement based on a valid and reliable cognitive assessment. The agency would require post-marketing follow-up studies, however, to ensure continued benefit over time.

The FDA stipulated that it will not yet consider approval of a drug based on a beneficial treatment effect on a biomarker used as a surrogate outcome measure of AD until there is widespread evidence-based agreement that the biomarker is reasonably likely to predict a clinical benefit.



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The FDA statement reflects what has been going on behind the scenes for several years, said John C. Morris, MD, Friedman distinguished professor of neurology at Washington University School of Medicine in St. Louis, MO, and the principal investigator of the Dominantly Inherited Alzheimer Network (DIAN).

Dr. Morris said that he and his DIAN co-investigators, including Randy Bateman, MD, Knight distinguished professor of neurology at Washington University School of Medicine, have been meeting frequently with the FDA to discuss ways to design clinical trials to test drug efficacy in patients with no clinical symptoms of disease. The FDA has been supportive in all these discussions, said Dr. Morris. He noted that the FDA enabled the DIAN Trials Unit to launch this month the first ever “prevention” trial that will evaluate three anti-Abeta agents in individuals from families with a causative mutation for AD. The FDA support extends to other prevention trials soon to launch that also will evaluate anti-Abeta strategies in asymptomatic patients. [See related coverage in Neurology Today:]

One of these trials will be done in older patients with evidence of Abeta plaques but with no clinical symptoms and, unlike the DIAN study, who do not have the genetic mutation that predicts the future development of AD. These patients represent the majority of patients who develop AD, according to Ronald C. Petersen, MD, professor of neurology and director of the Mayo Alzheimer's Disease Research Center in Rochester, MN. Although the clinical picture may be similar between people with a genetic mutation for AD and those with the anti-Abeta component, the underlying cause of that clinical picture may be quite different between these groups of patients, he said.

“In all likelihood, there are many other factors that come into play to produce the same clinical picture in a sporadic, nongenetic 85-year-old man with the disease than you see with a 45-year-old man with a genetic mutation with the disease,” he said.



Dr. Petersen is less convinced, therefore, that data concerning markers in the early onset cases will translate directly to the late onset non-genetic cases. “I think it is a great idea, but treatments that may be effective in early-onset cases may be less effective in late-onset cases, but the strategy is worth pursuing.”

Dr. Petersen also questioned the validity of using a composite scale such as the CDR-SB suggested by the FDA, particularly for patients with mild cognitive impairment in whom, in his opinion, the test may be insensitive in picking up subtle changes of the disease. “It may not be the best clinical marker in that stage of the disease,” he said.

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Just as the FDA is often criticized for moving slowly in approving drugs, an equally strong pressure comes from those who warn about the risks of approving drugs too fast to ensure their safety. Days after publication of the FDA statement, the editorial board of The New York Times on Mar. 17 questioned whether patient safety could be compromised by giving patients with no evidence of disease drugs that may be effective, but have side effects.

Saying he thought the editorial was somewhat shortsighted and inappropriately conservative given the challenges of finding effective treatments for AD, Dr. Knopman emphasized that safety and risk-benefit ratios are always an important issue. “Nobody is going to approve a drug for use in cognitively normal people unless it is safe and unless there is strong evidence that it can delay the biological progression of Alzheimer's disease,” he said. “I don't think the FDA criteria pose a risk.”



Dr. Morris also emphasized the need for safety, but noted that by study design, the current prevention trials will only give anti-Abeta therapy to people who are at high risk of developing AD and already have Abeta abnormalities.

Dr. Petersen acknowledged the risk of giving a drug with potential inflammatory side effects to people without symptoms of the disease, but said some bold and perhaps risky steps are needed.

Despite some reservations about the details of the FDA proposal, he emphasized that he agrees with its essence. “I support this approach because there has not been a new drug approved for AD by the FDA in 10 years,” he said, adding that perhaps one reason for this could be a flaw in the design of clinical trials that have not permitted intervening earlier in the course of disease.

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•. Kozauer N, Katz R.Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med 2013; 368:1169–1171.
    •. New York Times Editorial Board. “Drugs for early-stage Alzheimer's.” Mar.17, 2013.
      •. Guidance for industry: Alzheimer's disease: Developing drugs for the treatment of early stage disease. Washington, DC: Center for Drug Evaluation and Research, February 2013:
        •. The Dominantly Inherited Alzheimer Network:
          •. Neurology Today archive on Alzheimer's disease:
            ©2013 American Academy of Neurology