FDA updates early Alzheimer’s drug development guidance to add support for biomarkers, surrogate endpoints

The US Food and Drug Administration (FDA) has released a second revision of its draft guidance for developing drugs intended to treat early Alzheimer’s disease.

The draft guidance, a revision of a previous draft guidance released by the agency in February 2018, is a document written for sponsors considering development of drugs for sporadic Alzheimer’s disease (AD) stages prior to a patient developing overt dementia. FDA appears to have reorganized the latest version of the draft guidance in acknowledgment of the changing landscape of AD drug development. (RELATED: Draft and Final FDA Guidances Detail Development of New Drugs for Neurological Disorders, Regulatory Focus 15 February 2018)

“This revision describes FDA’s current thinking regarding the use of biomarkers for the selection of participants with early stages of AD for enrollment in clinical trials, the selection of outcome measures for clinical trials in early AD, and the use of effects on characteristic pathophysiological changes of AD to support approval in these populations,” FDA wrote in a Federal Register notice.

In the 2018 draft guidance, FDA noted that “biomarker evidence of disease will play a role in the reliable identification of patients in trials of early AD.” The agency’s latest revision to the draft guidance changes that language, and FDA said it is now “expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early AD.”

A general section on outcome measures has been changed in the latest revision, now incorporating descriptions surrounding the use of co-primary endpoints and cognition originally found in the background section the 2018 draft guidance. The outcome measures section contains subsections describing clinical endpoints, time-to-event analysis, and surrogate endpoints. Subsections on specific AD disease stages, originally the main focus of the outcomes section of the 2018 draft guidance, have been moved to the end of the guidance in a new subsection containing considerations for early AD stages and have remained largely the same.

While the latest revision notes co-primary endpoints consisting of cognitive and functional measures are still appropriate for patients with AD of stage 3 disease and higher, FDA acknowledges “it may take longer to establish a clinically meaningful treatment effect in early AD due to the minimal or absent cognitive and functional deficits seen in those stages of the disease.” Additionally, assessment tools may not be sensitive enough to detect these changes, FDA noted.

“FDA may consider other approaches, including endpoints based on cognitive assessments or surrogate endpoints, which may allow for shorter trial durations as a basis for approval in the earliest stages of AD,” the agency wrote.

FDA has carried over its assessment that similar findings across multiple individual tests increases the likelihood of persuading the agency towards marketing approval. For patients with AD in its earliest stages, “FDA will consider strong justifications that a persuasive effect, considering both magnitude of effect and statistical robustness of the findings, on cognition alone as assessed by sensitive neuropsychological tests may provide adequate support for a marketing approval,” they said. Persuasiveness of a finding includes the magnitude of effect and robustness, and “a pattern of putatively beneficial effects demonstrated across multiple individual tests” would be more persuasive for supporting marketing approval than findings through a single uncorroborated neurological effect, the agency noted.

“Whether effects on cognitive outcome measures would be capable of providing evidence of effectiveness in the absence of a meaningful change in function to support either traditional or accelerated approval would require detailed discussion with the Agency,” they wrote. “However, in a trial with relatively short-term assessments, such as a trial for a therapy intended to treat symptoms of AD, an effect on sensitive measures of neuropsychological performance of uncertain independent clinical meaning (e.g., a word-list recall test) would generally not allow for an overall finding of efficacy in the absence of meaningful functional benefit.”

Surrogate endpoints, specific AD stage considerations

FDA’s latest version of draft guidance contains a new section on surrogate endpoints, noting that acceptability of a surrogate endpoint depends on factors such as disease stage, trial population, mechanism of action, and current treatment availability.

“Sponsors considering the use of a biomarker as the primary measure of effect should discuss their plans with FDA early in development,” FDA wrote. “In general, even if accelerated approval is considered as the initial approval pathway, clinical outcome assessments should be included in clinical trials for early AD to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.”

With regard to stage 1 AD, a treatment effect pattern across multiple biomarkers would make a putative effect more persuasive in support of marketing approval, as in patterns seen across multiple individual neuropsychological tests. “Whether effects on biomarkers would support accelerated approval would require detailed discussion with the Agency, including a plan for subsequent confirmation of clinical benefit,” they said.

FDA said the same approach to a treatment effect pattern across multiple neuropsychological tests would apply to trials including patients with stage 2 and stage 3 disease. “It would generally be expected that such effects on cognitive measures would be supported by similarly persuasive effects on the characteristic pathophysiological changes of AD,” the agency wrote. “Whether effects on cognitive outcome measures would, in the absence of a meaningful change in function, support either traditional or accelerated approval would require detailed discussion with the Agency.”

Draft guidance

FDA updates early Alzheimer’s drug development guidance to add support for biomarkers, surrogate endpoints

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