Alzheimer’s disease: FDA guidance had ‘strong influence’ on endpoint selection

Regulatory NewsRegulatory News | 04 April 2022 |  By 

Non-binding guidance from the US Food and Drug Administration (FDA) had a strong impact on the selection of primary endpoints in Alzheimer’s disease clinical trials, a recent analysis finds.
Over the last decade, FDA has released two guidances for Alzheimer’s disease (AD) trials: a draft guidance in 2013 that recommended the use of composite cognitive and functional scores like the Clinical Dementia Rating–Sum of Boxes (CDR-SB) to measure mild cognitive improvement in early-stage Alzheimer’s disease trials, and a 2018 draft guidance that shifted their recommendations to “a broader array of endpoints including biomarkers, coprimary endpoints, and integrated scales” dependent on early Alzheimer’s disease type, the authors of the analysis said.
“It seems clear from this work that these two guidance documents in the field of AD may have had a strong influence on trial design,” Jeffrey Yu, health economics researcher at the Leonard D. Schaeffer Center for Health Policy & Economics, Los Angeles, and colleagues wrote in their paper, which was recently published in the journal Alzheimer’s & Dementia: Translational Research & Clinical Interventions.
The researchers identified 314 Alzheimer’s disease trials conducted between March 2013 and March 2018 consisting of 34 Phase 2/3 trials (10.8%), 279 Phase 3 trials (88.9%), and 1 Phase 3/4 trial (0.3%). Of these, 124 trials (39.5%) evaluated a disease-modifying therapy (DMT), 159 trials (50.6%) had a single primary endpoint, and 155 trials (49.4%) had at least two primary endpoints. The trials examined were conducted with at least one site in North America (58.0%), Europe (47.8%), or Asia (31.9%).
Yu and colleagues found 128 different primary endpoints among all trials, with the most common being the Alzheimer's Disease Assessment Scale (ADAS)-Cog 12 in 145 trials, Mini-Mental State Examination (MMSE) in 45 trials, Clinician’s Interview-Based Impression of Change–Plus Caregiver Input (CIBIC+) in 36 trials, the Neuropsychiatric Inventory (NPI) in 35 trials, and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) in 33 trials.
Over time, the authors discovered FDA’s guidances seemed to influence adoption of certain primary endpoints. For example, selection of CDR-SB as a primary endpoint, which was specifically mentioned in FDA’s 2013 draft guidance, increased from 1.9% to 16.7% following the release of the draft guidance in March 2013. “Among DMT trials, a decline in cognitive/functional composite endpoint use was also seen prior to the March 2013 guidance; however, their use, and the use of CDR-SB, increased sharply in the subsequent period,” Yu and colleagues said.
DMT trials with private sponsors showed a significantly increased use of CDR-SB as a primary endpoint between March 2013 and 2018 (13.3%; P = .005), and a significantly increased use of cognitive/functional composite endpoints each year during that same timeframe (17.0%; P = .001). There was not an increased use of cognitive/functional composite endpoints (– 12.4%; P = .137) or CDR-SB (–5.8%; P = .337) in DMT trials with public sponsors after March 2013.
Following FDA’s 2018 guidance describing use of non-DMT primary endpoints, there was “decreased use of both types of endpoints in the period after March 2018, which reflects the March 2018 guidance that offered alternative options for early AD trials,” the authors noted.
However, not all trials followed suggestions outlined in either draft guidance document. Some trial stakeholders elected to use a cognitive-only endpoint or co-primary endpoint, the authors said. “This observation suggests that non-binding guidance imperfectly influences trialist behavior. These observations are important because they provide quantitative evidence rather than anecdotal observation to demonstrate the effects of regulatory guidance on industry practice,” Yu and colleagues explained.
One reason trials might have followed the suggestions in the draft guidances is because they were interpreted as regulatory requirements despite the documents not being legally enforceable or set as binding requirements by FDA, the authors said.
“Concerns had in fact been expressed that the FDA’s specific suggestion of CDR-SB would drive the adoption of CDR-SB as a standard of efficacy in early AD. Because research practices in early AD have yet to be fully established, FDA suggestions might impact the measurement of clinical benefit and even innovation itself if the standard for trial success is constrained,” they noted. “Thus, how the FDA decides to operationalize the guidances to describe trial design is crucial.”
As guidances from FDA become more common, stakeholders may view the suggestions in the agency’s guidances as a type of “soft law” and are more likely to adopt endpoints in guidances that FDA considers favorable “to increase the likelihood that their efficacy data will be considered acceptable during regulatory reviews.”
“It was therefore unsurprising that the advice from guidances studied here appears most strongly correlated with changes in practice among privately sponsored trials because these types of trials typically are more likely to support marketing applications for AD drugs,” the authors said.


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