“Real world” eligibility for aducanumab
Open accessAbstract
On June 7, 2021, the U.S. Food and Drug Administration (FDA) approved aducanumab, an amyloid beta-directed monoclonal antibody, as a new treatment for Alzheimer's disease (AD),1 taking advantage of an Accelerated Approval program. The aducanumab effect on amyloid beta plaques2 was deemed to predict benefits for patients and, thus, considered as an approvable surrogate endpoint. Nevertheless, there are residual uncertainties concerning the clinical effectiveness of the drug3-5 that has to be confirmed via post-approval phase 4 studies. As often happening in the design of randomized controlled trials (RCTs), relatively rigid eligibility criteria were adopted in the EMERGE [NCT02484547] and ENGAGE [NCT02477800] phase 3 studies on aducanumab to render more homogeneous the sampled populations. The choice was aimed at reducing the established clinical and biological heterogeneity of the target conditions (i.e., mild cognitive impairment [MCI] and mild AD dementia) and reduce safety/tolerability concerns. At the same time, the stringent criteria may result in the recruitment of patients who are not adequately representative of the overall clinical population, consequently reducing the generalizability of the findings.6 A poor external validity was already documented for the trials leading to the approval of the pharmacological compounds currently marketed for the symptomatic treatment of AD.7, 8 To identify the proportion of patients who would be potentially eligible to receive aducanumab in the "real world", we systematically applied the criteria adopted in the pre-approval research protocols to a representative clinical population referring to a geriatric outpatient unit of a tertiary university hospital in Milan (Italy). A total of 911 patients consecutively attending the unit for cognitive complaints were considered. Patients underwent a comprehensive geriatric assessment, including cognitive and neuropsychological evaluation, frailty assessment (using a 40-item Frailty Index [FI]), routine blood tests, and neuroimaging, as part of standard clinical care. In addition, a minority of these patients (i.e., 11.4%) underwent a lumbar puncture to measure cerebrospinal fluid (CSF) AD biomarkers (i.e., Aβ1–42, total-tau, and phospho-tau). The diagnoses of MCI, AD dementia, and non-AD dementias were formulated according to current international diagnostic criteria. The local Ethics Committee authorized the data collection and use as part of a clinical registry. Written informed consent was obtained from patients (or proxies as appropriate). The inclusion and exclusion criteria of the EMERGE and ENGAGE studies were retrieved from the information registered on the clinicaltrials.org database. These criteria were then operationalized in our clinical database and sequentially applied to the patients to test their potential eligibility to aducanumab. About half of the patients (n = 423) resulted ineligible due to age >85, <6 years of education, and absence of a formal caregiver (Figure 1). Another relevant part of patients (n = 389) would then be excluded because of not meeting the prespecified clinical criteria (e.g., diagnosis of non-AD dementia, Mini-Mental State Examination score <24, and/or evident functional impairment). Most of the remaining subjects (n = 99) would not probably be selected because they were frail (i.e., FI >0.25,9 thus not in the "good health" conditions as required), presenting a major laboratory abnormality, underweight/obesity, or significant brain vascular disease at the neuroimaging. Finally, given that nearly one-third of the patients with MCI or AD in our population did not exhibit a CSF positive amyloid status (i.e., Aß1–42 < 600 pg/ml10), we assumed that three additional subjects would possibly be excluded because they result negative at the amyloid-beta measurement. Thus, only six patients (i.e., 0.66%) of the study population would potentially be candidates to aducanumab. Our findings should be cautiously interpreted since they were derived from a single center experience and obtained by adapting the research criteria to the data routinely collected as part of the clinical activities. Moreover, the eligibility criteria applied in our analyses were those retrieved from clinicaltrial.gov. We cannot be sure that some modifications have been used in the conduction of the EMERGE and ENGAGE studies since no article from these trials has yet been published in a peer-reviewed journal. Our results suggest that only a marginal proportion of patients with cognitive disorders currently attending "real-world" geriatric services would potentially benefit from aducanumab due to the low external validity of pre-approval studies. This observation, together with the unanswered questions concerning the aducanumab efficacy and cost-effectiveness,11, 12 should be considered before planning any reorganization and redistribution of care resources. In this context, the final indications provided by the FDA will b
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The stringent eligibility criteria for clinical trials of drugs for AD made the study population's health better than the general AD population, and historically excluded racial and ethnic backgrounds were under-represented, although there were higher numbers of minoritised groups in the lecanemab trial.
“The stringent eligibility criteria for clinical trials of drugs for AD made study population's health better than the general AD population (511) and historically excluded racial and ethnic backgrounds were under-represented, although there were higher numbers of minoritised groups in the lecanemab trial.”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [511]
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- Authors
- Canevelli, M., Rossi, P. D., Astrone, P., Consorti, E., Vanacore, N., & Cesari, M.
- Affiliations
- Istituto Superiore di Sanità (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Aziende Socio Sanitarie Territoriale Lodi (IT)
- University of Milan (IT)
- Corresponding author
- Canevelli, Marco
- Venue
- Journal of the American Geriatrics Society
- Publisher
- Wiley
- Published
- 2021-07-31
- Volume
- 69
- Issue
- 10
- Pages
- 2995-2998
- ISSN
- 0002-8614 (ISSN-L)
- 1532-5415
- OpenAlex
- W3186239671
- Cited by
- 36
- References
- 8
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 11 · 2023: 9 · 2022: 5 · 2021: 1
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of the American Geriatrics Society (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- aducanumab, Alzheimer's disease, anti-amyloid therapy, inclusion and exclusion criteria, early Alzheimer's disease
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Eligibility Determination, Female, Humans, Male, Antibodies, Monoclonal, Humanized
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