” It is well documented that for every minute that you exercise, you add one minute to your life. This enables you at 85 years old to spend an additional five months in a nursing home at $5000 per month! ” From Cartalk , the old NPR Radio Show.
Okay, jokes aside, FDA has now approved two IV anti-amyloid beta antibody solutions, aducanumab and lecanemab. Each is controversial in its own way.
Aducanumab’s FDA process and clinical trial result interpretations have been well documented, and the subject of a recent Congressional investigation which called out irregularities. Although the report is negative, evidently no penalties ensued.
The lecanemab trial in NEJM Jan 2023 resulted in a statistically significant result of a clinical endpoint, namely the measurement called the CDR-Sum of Boxes. Both the lecanemab group and placebo group declined over 18 months, but the lecanemab group did so more slowly. The scores run from 0-18; each group started with a mean score of 3.2. The “least-squares mean change” favoring lecanemab was 0.45. Out of 18 points, that’s a 2.5% difference.
The authors themselves write: “A definition of clinically meaningful effects in the primary end point of the CDR-SB score has not been established; however, this trial exceeded the prospectively defined target, with an estimated treatment difference of 0.373 points on a scale range of 18…”
So, given the low risk of adverse events (the main worry, known as ARIA-E (Amyloid Related Imaging Abnormality with Edema, was about 1% in the reported trial), is the magnitude of change worth the time, effort, cost and risk, and to what end? (There have been two or three subsequent associated deaths, at least one disputed by the company).
Well, a bit late perhaps, given how many trials there have been already, the Alz Assoc had a conference to discuss “clinical meaningfulness” in AD trials, July 2022. The fact that they needed a conference shows that opinions abound.
The summary (Feb 2023) of the conference and Alz Assoc position doesn’t really address “meaningful results” directly! The last sentence of the abstract states: “Our expectations of outcomes from therapeutic interventions in AD may need to be modified.” [AlzGadfly editorial comment: hmmmmmmmmm.]
However, the group had “two conclusions”: “First, combination therapies will be a necessity to augment the benefit shown with monotherapy.” [AlzGadfly has been writing of this strategy for years, but nothing seems to be forthcoming.]
“Second, it is critically important to determine the stage of intervention for this putative underlying pathophysiological process.” [AlzGadfly interprets this to say we still don’t understand how or why AD starts or progresses.]
Dr. J. Cummings has also written an editorial about interpreting clinical meaningfulness, He cites an approach (2023, Lansdall) of doing single patient evaluations for meaningfulness, rather than a group in a trial; that group proposes that a 1.0-2.5 change in score would probably be meaingful.
Probably the best summary (“No easy answers…) is from last month on AlzForum, which includes discussions of a webinar sponsored by the nonprofit Us Against Alzheimer’s. The comments after the news article are interesting.
Dr. Lon Schneider, USC: “The title of the Alzheimer’s Association’s presser sums it up: “EXPERTS REDEFINE ‘CLINICAL MEANINGFULNESS’ IN ALZHEIMER’S.” This is straight from the silver linings playbook. If you don’t like an outcome, then change the game plan, make up a rule, and blame the refs for the lousy call. If all else fails, then move the goal posts, kick a field goal, and declare victory…”
Is clinical meaningfulness just in the eye of the beholder, either a Person Living with Dementia or their CareGivers, essentially qualitative rather than quantitative? On the other hand, how can we assess the effectiveness of these very expensive agents over time, especially with “evidence-based” medical decision making?
How much is it like choosing synthetic oil for your old car at the oil change place….how do you really know it’s worth it, and are you likely to notice any difference in performance?
[thanks to A. Bleyer for inspiring this post, since I was trying to ignore the issue]
Late Addenda: I forgot to mention that the NEJM editorial with the lecanemab paper basically called the result “modest,” which was a word used often in the press when clinicians were asked to characterize the paper.
Qualitative measures do have an important role in clinical research and practice. “Quality of Life” i (QoL) in cancer patients is seen more often in the literature, and some practices incorporate quality of life goals with treatment planning to distinguish it form duration of life type goals. AlzGadfly was the PI of a tiny pilot study of QoL in teen cancer patients once upon a time. It would be interesting to compare various measurements of QoL in cancer and dementia patients.