Monday, March 11, 2024

FDA Guidance for Early Alzheimer's Disease: Key Roles of Biomarkers

Recently, both LA Times (February 14) and NY Times (March 4) have had articles on the debates about how to define the use of biomarkers in early Alzheimer's disease, and at what point the term "Alzheimer's Disease" comes into play for early cases.  

FDA releases for comment a new 11-page draft guidance on early diagnosis of Alzheimer's by biomarkers and subtle cognitive testing.  This is in the spotlight because of the belief that only early intervention will be effective (supported also by subgroups in existing trials.)  The topic also comes to the fore because advances in proteomics make plasma biomarkers practical for the first time as opposed to PET scans or CSF tests.  

  • Article on this shift, here.  
  • See Ashton 2024 in JAMA, data on phospho-tau 217 in plasma.   
  • pTau217 is newly in breakthrough-review at FDA.   
  • See an excellent webinar on pTau217 sponsored by ALZPATH, here.

Find the FDA guidance here:

Wisely, I think, FDA breaks early Alzheimer development into 3 stages, culminating in the earliest  symptoms.

  • Stage 1 is no cognitive symptoms, not even on subtle testing, but Alzheimer biomarkers like tau and amyloid are rising.
  • Stage 2 has biomarkers plus subtle neuropsych changes or subtle/mild complaints.
  • Stage 3 has biomarkers, probably stronger signals, and detectable functional impairment.   

FDA calls these "stages of Early AD" so they're using the D word (disease) but clearly defining it as biomarker only (#1) or biomarker and subtle specialized testing changes (#2). 

I won't belabor it here, but if you're directly interested in this field, the guidance has many complex and  subtle points to make such as regarding functional and cognitive scales as endpoints at different stages, and how this shapes approval processes.  

Comment within 90 days.  Early coverage at RAPS here.

The guidance revises a 2018 draft that was not finalized.  Coverage at Genomeweb.


CMS Tie-In

Read about the CMS "GUIDE" demo care program for enhanced integrated care for Alzheimer patients in FFS Medicare.  Here.


See an article in Bloomberg, "Do you really want to know?" if you'll get Alzheimer's.



From Chat GPT 4.

Let's open with the definitions of Stages 1, 2, and 3 for early Alzheimer's disease (AD) as provided in the FDA's guidance. These stages are identified based on the progression of the disease, marked by pathophysiological changes, and the emergence of clinical symptoms and functional impairment.

Stage Definitions:

Stage 1:

  • Characterized by the presence of pathophysiological changes indicative of AD, without any clinical impact.
  • Patients are asymptomatic with no subjective complaints, functional impairment, or detectable abnormalities on sensitive neuropsychological measures.
  • The diagnosis is primarily based on biomarker evidence, demonstrating the characteristic pathophysiological changes of AD.

Stage 2:

  • Patients exhibit the characteristic pathophysiological changes of AD and may have subtle detectable abnormalities on sensitive neuropsychological measures or subjective complaints of mild cognitive symptoms.
  • However, there is no functional impairment. This stage can be considered a transitional phase where slight cognitive symptoms first become apparent.

The transition to Stage 3 is signaled by the emergence of subtle functional impairments.

Stage 3:

  • Characterized by more apparent pathophysiological changes of AD, more evident abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment.
  • The functional impairment at this stage is not severe enough to warrant a diagnosis of overt dementia. This stage roughly corresponds to the syndrome of "mild cognitive impairment."
  • It is noted that the term "mild cognitive impairment" could also encompass patients in late Stage 2 or early Stage 4, highlighting the continuum of the disease progression.

These stages reflect the evolution of AD from its pathophysiological onset, through initial clinical manifestations, to the point where mild functional impairments begin to emerge, but before overt dementia develops. The FDA emphasizes the importance of accurately identifying these stages in clinical trials to ensure appropriate enrollment and the selection of relevant outcome measures that align with the specific stage of disease progression.

And Overview...

The FDA's draft guidance for developing drugs for the treatment of early Alzheimer's disease (AD) provides a comprehensive framework aimed at guiding sponsors through the clinical development process for drugs targeting stages of sporadic AD that occur before the onset of overt dementia (i.e., Stages 1 through 3). This guidance emphasizes the importance of considering the disease continuum and ensuring that clinical trials are appropriately designed to evaluate potential treatments in the early stages of AD, where intervention might halt or reverse the disease process.

Specific Recommendations for Designing Clinical Trials:

Diagnostic Criteria for Early AD:

  • Enrollment should be based on biologically based diagnostic criteria that reflect the pathophysiological changes of AD. This is crucial for ensuring that trial participants truly have AD, minimizing the inclusion of individuals who do not have the disease.
  • The guidance outlines the staging of AD based on pathophysiological changes and clinical impact, ranging from Stage 1 (asymptomatic but with biomarker evidence of AD) to Stage 3 (mild but detectable functional impairment, not severe enough to warrant a diagnosis of overt dementia).

Outcome Measures:

  • Clinical trials should include both clinical outcome assessments and biomarkers. The primary endpoint selection should aim to measure a clinically meaningful change. Direct measures of clinical benefit or validated surrogate endpoints may support traditional approval, while surrogate endpoints that predict clinical benefit may support an accelerated approval.

  • For stages with detectable cognitive and functional impairments (Stages 3 and higher), a co-primary endpoint approach assessing both cognitive and functional (or global) measures is recommended.
  • In early stages (Stages 1, 2, and early 3), FDA may consider other approaches, including endpoints based on cognitive assessments or surrogate endpoints, which may allow for shorter trial durations.

Stage-specific Considerations:

  • Stage 1: Focus on the effect on the characteristic pathophysiological changes of AD as demonstrated by various biomarkers, considering the challenge of demonstrating a clinically meaningful benefit due to the lack of clinical impairment at baseline.
  • Stage 2: Trials may need sufficient duration to evaluate clinical measures assessing cognition and function. A persuasive effect on cognition, supported by effects on pathophysiological changes, may provide adequate support for marketing approval.
  • Stage 3: Demonstrating a favorable effect on observed impairments in both cognition and daily functioning is important. An integrated scale assessing effects on daily function and cognition could serve as a single primary efficacy outcome measure.

This proposed guidance may serve as a cornerstone for discussions among the FDA, pharmaceutical sponsors, the scientific community, and the public about drug development for early AD, emphasizing the need for early intervention and precise diagnosis in clinical trials.