The U.S. Food and Drug Administration has revised clinical trial guidelines for Alzheimer’s therapies to help researchers come up with trial objectives that are better suited to patients in the early stages of the disease.
European regulators have also revised their Alzheimer’s trial guidelines.
The early-stage patients that the new FDA guidelines are intended to help include people who have yet to display memory loss or functional impairment.
Both the new FDA and European Medicines Agency (EMA) guidelines reflect many researchers’ goal of developing therapies for early Alzheimer’s, following continued failures in drug development for this disease.
U.S. regulatory documents cover a broad range of subjects, including how to develop new treatments and how to prepare submissions for a combination product — one composed of any combination of a drug and a device.
The new guidance is a revision of a 2013 draft. It addresses FDA’s current thinking on the selection of patients in the early stages of a disease for clinical trials, diagnostic criteria for asymptomatic patients, trial outcome measures, and the selection of endpoints.
In one section, the FDA addressed the historical considerations of functional and cognitive evaluations in clinical studies on Alzheimer’s, which implied that an improvement in memory or thinking was not relevant unless associated with an independent benefit on functional disability.
Regulators find “such usage inappropriate, because it implies that an effect on cognition itself, regardless of the nature of the observed effect and the manner in which it is assessed, cannot be clinically meaningful. This is certainly not the case,” the new draft says.
The 2013 document recommended assessing outcomes at prodromal and preclinical disease stages using measures that combine cognitive and functional tests. The 2018 guidance now refines these ideas. And instead of using the terms “preclinical” and “prodromal,” the FDA defines three stages of early Alzheimer’s in terms of their functional, cognitive, and biomarker changes.
For patients in stage 1 who do not have a detectable disease, the guidance notes that clinical studies may measure effects on biomarkers related to characteristic Alzheimer’s changes, such as levels of amyloid beta, the main component of senile plaque.
In this stage, biomarkers are abnormal, but people have no cognitive complaints or detectable decline even on sensitive tests. These biomarkers “may, in principle, serve as the basis for an accelerated [therapy] approval,” as they would be considered reasonably likely to predict clinical benefit.
Patients in stage 2 are defined as having characteristic pathophysiologic changes in their disease and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment. At this stage the FDA will look for improvements in diverse neuropsychological tests or for a larger effect on just one, besides changes in biomarkers.
Stage 3 patients have characteristic pathophysiologic changes in their disease, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment. This stage is where people begin to have problems with some daily tasks.
The FDA believes clinical endpoints in these patients need to demonstrate that a drug favorably affects their functional deficits. Ideally, the outcome measure used in this stage of the disease will provide an assessment of meaningful cognitive function.
U.S. regulators put a special emphasis on monitoring disease progression in trials. A lasting effect of a treatment candidate must be demonstrated in both biomarkers and clinical tests.
They also recommend using a placebo group rather than historical data on Alzheimer’s progression, due to its variability.
“The guidance documents we’ve issued today are an important step in facilitating efficient development of treatments for patients with serious neurological conditions,” Scott Gottlieb, the FDA’s commissioner, said in a statement.
“These changes, both outward facing and internal, will improve our ability to engage with sponsors, patients, and researchers, and adapt quickly to an environment where the science is changing at a breathtaking speed across many disease areas,” he added.
The EMA revised its clinical trial guidelines to focus on early Alzheimer’s and biomarkers, encouraging the industry to use biomarkers and explore their potential.
“As the biomarker field is evolving, the possibility to detect changes and progression in vivo, opens new regulatory scenarios including the possibility to intervene directly on the neuropathology before the appearance of symptoms,” the EMA’s guidelines say.
The agency highlighted the current focus on disease-modifying treatments, which target the biological mechanisms of the disease. This contrasts with currently available medications, which only treat Alzheimer’s symptoms.
Novel approaches currently in development include biomarkers for brain inflammation, as well as blood or metabolic changes.
EMA now recommends classifying biomarkers according to their potential use, such as diagnostics or prognostics. The agency notes that most biomarkers “still require validation for many of these particular purposes.”
The new EMA guidelines, which will go into effect on Sept. 1, also cover the impact of diagnostic criteria on clinical studies’ design, as well as efficacy and safety considerations, among other parameters.
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