June 10, 2024
Docket No. FDA-2013-D-0077
The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
There is a great need for research aimed at developing treatments to prevent or slow the progression of early Alzheimer’s disease, but we disagree with several assumptions in the Guidance and have strong concerns about the stages of Alzheimer’s disease as defined in this guidance. Stage 1 is defined on the basis of biomarkers in the absence of any symptoms of cognitive impairment, because the Guidance states that it is “expected that biomarker evidence of disease will establish the reliable diagnosis.” This expectation is inconsistent with clear evidence that there are many individuals who have evidence of amyloid and tau pathology who show no signs of Alzheimer’s disease and will never show signs of the disease even without any medical treatment. For example, a 2015 study estimated that more than 10% of cognitively normal 50-year-olds would test positive based on biomarker evidence, as would almost 16% of 60-year-olds and 23% of 70-year-olds.1 Experts estimate that 40 million asymptomatic Americans could be categorized as Stage 1 Alzheimer’s under the proposed criteria in the FDA guidance, but most of those individuals would never develop dementia. We agree with Dr. Jason Karlawish, a geriatrician who is co-director of the Penn Memory Center in Philadelphia, who states that the evidence is “not yet clear and convincing that amyloid alone defines Alzheimer’s disease.” 2
Although people with two copies of APOE4 are more likely to develop amyloid plaque in a recent study, many do not; moreover, that research was primarily on white people of European ethnicities, and it is known that the risk of amyloid plaque varies for people with different ethnic backgrounds.3 FDA should specify in its Guidance that it would be unethical to include asymptomatic individuals in clinical trials testing an experimental Alzheimer’s drug, especially since all such drugs that have been developed thus far have significant adverse events, including brain bleeds, brain swelling, and shrinking brain volume.4 It is especially problematic that the researchers that found lower brain volume in patients taking these drugs compared to the placebo group did not evaluate the impact of brain volume on the patients’ cognitive functioning. Because of these adverse events, it would also be unethical to encourage asymptomatic people with two copies of APOE4 to participate in such clinical trials until more is known about the other risk factors that increase the chances of developing dementia in people of varying ethnicities. For FDA-approved treatments, the indication on the label should make it clear what the evidence is of benefit and harms for different types of patients, and how strong the evidence is that the benefits outweighed the risks for all individuals with specific biomarkers.
We understand that defining asymptomatic patients as having Stage 1 Alzheimer’s disease was recommended by an Alzheimer’s Association Working Group. However, financial disclosures show that the pharmaceutical and medical testing companies who would benefit from that recommendations employed seven members of the 20-person Working Group and at least seven more members were academics who receive money from those companies for consulting or research.5 The same analysis indicates that four other scientists who were outside advisors to the Working Group were executives from the makers of two new medicines for Alzheimer’s patients, or two companies that were developing similar drugs.
The Guidance definition of Stage 2 is also problematic. It is well documented that many patients who have “subtle detectable abnormalities on sensitive neuropsychological measures or subjective complaints of mild cognitive symptoms but no functional impairment” could have mild symptoms due to side effects of medication, lack of sleep, or other causes that could be rectified without medications that are intended for individuals with Alzheimer’s disease. Many if not most of these patients may never develop Alzheimer’s disease and should not be defined as Stage 2 Alzheimer’s disease.
We agree with the American Geriatrics Society’ warning that the Alzheimer’s Association Working Group proposal could lead to overdiagnosis of Alzheimer’s and subject people to treatments with “limited benefit and high potential for harm.” 5 Unfortunately, the same is true for the FDA’s proposed guidance because of the similarities, especially regarding the definition of Stage 1.
We strongly support the FDA’s acknowledgment that endpoints must demonstrate a tangible clinical impact on daily function and/or cognition. We note, for example, that the Sims et al TRAILBLAZER-ALZ 2 research on donanemab found an average benefit of 3 points on the iADRS scale compared to placebo (out of a total of 144 points) but that in the same article the researchers indicated that a benefit of 5 points was needed to demonstrate clinically meaningful benefits for patients with mild cognitive impairment and 9 points for those with mild dementia.6 This disconnect between what is clinically meaningful and how the benefits of a drug have been hyped by a company is an issue that should be of great concern to the FDA and addressed in the FDA guidance. Moreover, a 76-week study does not provide adequate information about long-term risks for individuals who may live for decades after treatment is intitiated.
The FDA Guidance needs to incorporate the concerns expressed by numerous experts about the ambiguity regarding the exact role of amyloid plaque in Alzheimer’s disease, and the ethical issues raised regarding clinical trials that rely on biomarkers rather than clinically meaningful outcomes. Caution is needed for all such research, but especially those involving asymptomatic patients. FDA notes that the brain changes targeted by recent Alzheimer’s drugs may develop decades prior to symptom onset but fails to adequately consider that symptoms never develop in many patients. Accurately predicting if or when an individual might develop symptoms is not currently possible. Based on the draft Guidance, an unknown proportion of individuals who may never develop symptoms could potentially be exposed to a drug with substantial safety concerns without receiving any benefits. Although biomarkers are correlated with disease progression, it is still unclear whether the prevention or reversal of these markers is necessary or sufficient to reverse or delay disease onset or progression. Therefore, we agree with the statement in the Guidance that any surrogate endpoint that is determined to be appropriate for use in a particular therapeutic clinical development program should not be assumed to be appropriate for use with a different product or trial population. However, the staging proposed in the guidance seems to ignore that cautious approach.
The FDA should be more explicit in its Guidance regarding the magnitude of effect needed to be considered for FDA approval. As illustrated in the Sims et al article cited above, statistically significant changes can lack clinical relevance for patients. Moreover, minor reductions in population-level risk may not be applicable to broader, more diverse patient populations in the real world. At the same time, research clearly indicates that lifestyle modifications often significantly reduce cognitive impairment and also offer additional health and well-being advantages without the risks associated with many medications. The FDA should require that treatments for Alzheimer’s disease have an impact that is clinically meaningful as well as statistically significant; treatments should noticeably improve patients’ lives compared to placebo and non-medical interventions.
It is important to note that even if a drug is intended for a narrow, high-risk population, it may be prescribed to a much broader, lower-risk demographic. This is true regardless of what the label specifies, but the inappropriate inclusion of asymptomatic individuals as Stage 1 Alzheimer’s disease makes that much more likely.
- Jansen, W. J., Ossenkoppele, R., Knol, D. L., et al. (2015). Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA, 313(19), 1924–1938. https://doi.org/10.1001/jama.2015.4668
- Span, P. (2024). Apparently healthy but diagnosed with Alzheimer’s. The New York Times. https://www.nytimes.com/2024/03/04/health/alzheimers-amyloid-diagnosis.html
- Belluck, P. (2024) Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s The New York Times. https://www.nytimes.com/2024/05/06/health/alzheimers-cause-gene-apoe4.html
- Thambisetty, M., & Howard, R. (2024). Conveying Risks of Harm in Alzheimer Disease by Amyloid Lowering. JAMA, 10.1001/jama.2024.7548. Advance online publication. https://doi.org/10.1001/jama.2024.7548
- Petersen, M. LA Times, (2024). Inside the plan to diagnose Alzheimer’s in people with no memory problems — and who stands to benefit. LA Times. https://www.latimes.com/science/story/2024-02-14/inside-controversial-plan-to-diagnose-alzheimers-in-people-without-symptoms
- Sims, J. R., Zimmer, J. A., Evans, C. D., et al. (2023). Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA, 330(6), 512–527. https://doi.org/10.1001/jama.2023.13239