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7 March 2018

What does the new FDA guidance mean for clinical trials in early Alzheimer’s disease?

The latest FDA draft guidance for clinical trials in early Alzheimer’s disease presents many new opportunities and challenges for drug development. 

With rising life-expectancy, and no treatments to prevent or slow disease progression, the Alzheimer’s disease pandemic is set to reach crisis point. Research and development efforts by the biopharmaceutical industry have been moving clinical trials into the earliest stages of the disease process, prior to the onset of overt cognitive and functional symptoms.

The US Food and Drug Administration (FDA) has recognised this evolving trend and in February 2018 released a draft guidance document on how to meaningfully include patients with very early-stage Alzheimer’s disease in clinical trials. Importantly, for the first time, the FDA has suggested that for patients with very early stage Alzheimer’s disease, sensitive neuropsychological tests can be used as a primary endpoint to provide adequate support for marketing approval. 

Discover cognitive endpoints 


The current landscape of clinical trials in Alzheimer’s disease

The therapeutic development process for Alzheimer’s disease has been plagued with late-stage failures for the last 20 years, and so far 2018 has been no exception. In January, Lundbeck, Eli Lilly, and Axovant all experienced drug failures. With Boehringer Ingelheim and Merck swiftly following suit in February, and Pfizer ditching their neuroscience programme all together, something has to be done to invigorate novel drug development efforts in Alzheimer’s disease.


The latest FDA guidance aligns early disease stages with appropriate endpoints and trial designs

For the last two decades, clinical trials have largely been conducted with patients who have a definitive diagnosis of Alzheimer’s dementia – but is this too late in the disease process? Would the results of some of these drug interventional trials have been different if patients were tested at earlier stages? The catch is there is no clear guidance on how to categorise patients with ‘early stage Alzheimer’s disease’, nor what a successful trial might look like with these patients. The February 2018 guidance document is a major step toward clarifying these issues and providing practical approaches for trial designs that could lead to more successful study outcomes.


“[The move] is a big deal to companies. It is a clear statement that the FDA understands that the science of Alzheimer’s has evolved”

Chief Science Officer at the Alzheimer’s Association, Dr Maria Carrillo, told Bloomberg


The six stages of Alzheimer’s disease

The guidance both defines the early stages of Alzheimer’s disease, and outlines potentially acceptable primary efficacy endpoints for each stage. Furthermore, it suggests that trials may utilize a ‘time to event’ approach: the time it takes for a clinically meaningful event (such as advancing a stage) to occur. In the guidance, the FDA describes six stages of Alzheimer’s disease, of progressing severity and symptomology (low-high: 1-6). The distinction between the stages is described below and visualised in table 1.


Stage 1. Patients with pathological features of Alzheimer’s disease but without clinical symptomology (asymptomatic).

Potential primary endpoints for stage 1.

  • Biomarkers could be used to accelerate drug approval if “biomarker effects would be found to be reasonably likely to predict clinical benefit, with a post-approval requirement for a study to confirm the predicted clinical benefit” (FDA, 2018; pg. 6).
  • Time to event: progression to Stage 2; e.g. cognitive impairment.


Stage 2. Patients with pathological features of Alzheimer’s disease and subtly impaired performance on sensitive neuropsychological measures, but no functional deficits.

Potential primary endpoints for stage 2.

  • Neuropsychological performance “a persuasive effect on sensitive measures of neuropsychological performance may provide adequate support for a marketing approval” (FDA, 2018; pg. 5).
  • Time to event: progression to Stage 3; e.g. mild functional impairment.


Stage 3. Patients with pathological features of Alzheimer’s disease and subtly impaired performance on sensitive neuropsychological measures, and mild functional deficits.

Potential primary endpoints for stage 3.

  • Neuropsychological performance “an effect on a sensitive measure of neuropsychological performance of uncertain independent clinical meaning (e.g. a word-list recall test) should not allow for an overall finding of efficacy in the absence of meaningful functional benefit” (FDA, 2018; pg. 5).
  • Assessment of daily function, which may be measured independently or in a single, combined instrument (cognition + function).


Stages 4, 5, 6. Patients with clinically diagnosed dementia, which is mild (stage 4), moderate (stage 5) or severe (stage 6). 

“a discussion of these disease stages [4,5,6] is not the focus of this guidance” (FDA, 2018; pg. 4).


Table 1. Visualisation of the inclusion/exclusion criteria for each stage of early Alzheimer’s disease.


What are the potential issues for clinical trials in early stage Alzheimer’s disease?

This guidance represents a significant step-change for the FDA’s approach to the drug and product approval process for neurological conditions. However, developing preventative treatments for Alzheimer’s disease will be by no means a simple process. There are many potential barriers, such as:

  • How to confidently identify patients at the early stages of Alzheimer’s disease, in an efficient, cost-effective and non-invasive manner.
  • The ethical implications of testing people who do not have a clinical diagnosis of disease.
  • Conducting appropriate trials which are of sufficient length to ascertain a clinically meaningful effect, yet still pragmatically achievable.
  • Finding neuropsychological measures which are sufficiently sensitive to detect subtle abnormalities in cognitive function.


Next steps 

The Director of Clinical Affairs at Cambridge Cognition, Dr Kenton Zavitz, hosted a webinar to discuss these issues and propose potential strategies to enhance the success of clinical trials in early stage Alzheimer’s disease.  

Contact us 

Tags : clinical trials | cognitive impairment | alzheimer's disease | early alzheimer's disease | prodromal | pre-clinical | fda | guidance | regulations