FDA Modifies Approval Standards for Early Alzheimer’s Drugs

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The FDA announced this week that it is modifying its approval criteria for drugs targeting early stage Alzheimer’s disease.  The announcement highlights the fact that many researchers are refocusing their efforts to find drugs that prevent, rather than cure, Alzheimer’s disease.

Alzheimer’s disease is defined as a progressive, degenerative disorder of the brain, resulting in

  • a decline in cognitive functions, and
  • interference with normal activities of daily living

Relying on this definition, the FDA has required clinical trials to establish that the test drug improves both cognition and functionality.

Trial Failures with Late Stage Subjects.  As discussed in other blogs, there were several phase 3 clinical trials that ended last fall in failure.  The trial participants all had moderate to severe Alzheimer’s. Based in part on those results, the Alzheimer’s research community has increasingly considered the possibility that pharmacological interventions must begin before people show symptoms of the disease.

Trials with Early Stage Subjects.  Trials are now being started which will limit the participant pool to those with 1) very mild symptoms, or 2) no symptoms, but with high levels of protein associated with Alzheimer’s shown in brain scans or spinal fluid.  The shift toward trials using asymptomatic populations makes it difficult, if not impossible to measure a drug’s effect on function.  The FDA is proposing to relax its criteria in light of this development.

Proposed guidelines.  The proposed guidelines modify approval criteria for trials using asymptomatic or mildly symptomatic participants.  Trials using patients with mild symptoms will be allowed to use one composite measure that combines assessment of cognitive and functional ability.  Trials using asymptomatic patients will be allowed to submit data on cognition only.  If the data shows cognitive benefits, the FDA would be able to approve the drug on an accelerated basis. The approval would be subject to additional (phase 4) testing to confirm that the drug provides the expected clinical benefit.

Benefits.  The FDA’s modifications reflect the realization that the standard criteria cannot be applied to an asymptomatic population.  The shift toward prevention means that it will take a very long time to know with certainty whether a drug is effective in delaying, slowing, or preventing the course of Alzheimer’s disease.  One benefit of the FDA’s proposed approach is that it will make promising therapies available to patients sooner than under the current system.  A second benefit is that, by relaxing the initial criteria and accelerating the approval process, the FDA will encourage more pharmaceutical companies to participate in Alzheimer’s research.

Risks.  There are potential risks to the modification of the standards.  The draft guidelines do not specify what cognitive improvement must be shown to warrant accelerated approval.  Will slight cognitive improvement be sufficient absent other indicators of therapeutic benefit?  Will the initial trials be long enough to identify therapies that offer only temporary benefit?  Will there be requirements to eliminate from the study those asymptomatic individuals who do not have Alzheimer’s?  How will the phase 4 trials be structured and how long will pharmaceutical companies be required to report data?

The FDA is to be applauded for responding to the unique circumstances of Alzheimer’s research.  However, it would be an extreme disservice to patients if drugs (presumably expensive and possibly with side effects) were approved that provided minimal benefit, and were allowed to be left on the market for an indeterminate period.  The FDA must make sure that its relaxed standards are balanced with rigorous follow up requirements to protect patients and to insure that the goal of effective treatment is advanced.


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