Alzheimer’s Association Panel Offers Considerations for New Definition of Meaningful Change in Drug Trials


Factoring in the complex nature of the disease, a group of experts provided perspectives on how clinically meaningful benefit should be viewed, stressing the importance of early intervention.

Ronald C. Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic

Ronald C. Petersen, MD, PhD

A newly published paper from a group of experts convened by the Alzheimer’s Association provided clarity and direction for the Alzheimer disease (AD) community on the definition of "clinically meaningful benefit" or "meaningful slowing of disease progression" in AD.1 In recent years, discussions have been ongoing about this definition on the heels of recent advances in the therapeutic pipeline.

All told, the group concluded that it is critical to implement a treatment strategy early in the disease, as well as assess change over the course of a relatively brief 18-month clinical trial, as the ways to understand the value of an effective intervention. Study investigators, which included lead author Ronald C. Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, and others, also noted that because of the complexity of AD and its pathology, it is unlikely that any single type of intervention will have a large clinical effect.

The paper comes at a "very exciting and historical point in AD drug development," the authors noted. Most recently, in January 2023, the FDA approved its second antiamyloid therapy lecanemab (Leqembi; Eisai) for patients in early AD stages.2 It joined aducanumab (Aduhelm; Biogen) which gained greenlight in June 2021, in that class of therapies. Recently, the FDA issued a complete response letter to Eli Lilly for its investigational therapy donanemab, citing a lack of participants with long-term data lasting more than 12 months on the agent.3

Trying to understand the true impact of a therapeutic has been a conversation for years in the AD field. The authors pointed to 2 variables that should be considered: the number of points relative to placebo on a cognitive scale, but also the time that it took for that difference to be achieved.

Petersen et al wrote, “during an RCT [randomized controlled trial] for a treatment that slows disease progression, while it remains necessary to achieve statistical significance compared to a placebo on a cognitive measure for the study to be considered positive, another consideration might be the time needed to achieve that difference. A statistically significant difference seen after 6 months would be considered very important, but a statistically significant result of the same magnitude at the end of a hypothetical 60-month study may not be considered clinically meaningful.”

Over the years, the development of accurate biomarkers of disease pathology has improved and will remain a critical aspect of early intervention going forward, the investigators noted. This opens the door to potentially preventing or slowing cognitive, functional, and behavioral decline, and accumulating disability. Although these biomarkers have begun to come into the fold more, the pathological processes underlying AD can take 1 to 2 decades, and trials are typically performed over only 18 to 24 months.

While it’s difficult to pinpoint how much amyloid reduction is considered clinically meaningful, any form of slowing of clinical progression at the early symptomatic stage of the disease might be in consideration. Peterson and his colleagues also continued to press for patient voices in the community when helping understand what is clinically meaningful; however, they felt as though the patient voice has been misapplied when it comes to evaluating clinical trial outcomes for new therapies.

Patients with Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores between 0.5 to 3.0—otherwise the earliest stages of clinical progression—have been typically used in AD drug trials. In the paper, the authors suggested that a change from a CDR score of 0.5 to 1 in a single domain is likely to be of meaningful value to patients and their families. “These differences in a CDR-SB change of 0.5 would constitute the difference between MCI and dementia, or mild neurocognitive disorder and major neurocognitive disorder in DSM-5," Petersen et al wrote. "The field needs to recognize and further validate these outcomes."

AD pathophysiology exists in a complex environment of other medical and neuropathological entities, including amyloid, tau, α-synuclein, TDP43, vascular disease, and possibly other considerations such as cerebrospinal fluid dynamics. Because each of these can produce cognitive impairment, the authors noted that a modest clinical impact expected to be observed over the course of an 18-month trial is probably not reasonable. The authors noted again that the duration of treatment is important, and literature has suggested a cumulative benefit over time. They wrote that 18 months also "may not inform us of how much amyloid would have to be reduced or at what point we are intervening in the disease continuum."

"This argument is not meant to ‘lower the bar’ of expectations of AD RCTs; rather, it is meant to view them from a realistic perspective,” Petersen et al concluded.1 "Again, we are no longer dealing with therapies that are designed to acutely improve cognition and/or clinical function but, rather, to modestly slow the rate of further deterioration. If such therapies are continued long term, and if they sustained their effectiveness at the same ‘modest’ levels to reduce clinical decline, they would be expected to show cumulative benefits that become more readily apparent and meaningful over time."

1. Peterson RC, Aisen PS, Andrews JC, et al. Expectations and clinical meaningfulness of randomized controlled trials. Alzheimers Dement. 2023;1-7. doi:10.1002/alz.12959
2. FDA grants accelerated approval for Alzheimer's disease treatment. FDA. News release. January 6, 2023. Accessed February 6, 2023.
3. US Food and Drug Administration Issues Complete Response Letter for Accelerated Approval of Donanemab. News release. Eli Lilly. January 19, 2022. Accessed January 19, 2022.
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