How to Define ‘Clinical Meaningfulness’ and ‘Treatment Success’?
This week, at a meeting in Bethesda, MD, a group of experts pondered what works to measure "clinical meaningfulness" in drug development for early Alzheimer's disease.
This is good news, and indicates that more clinical trials for disease-modifying drugs may be on the horizon. These drugs are targeted towards Alzheimer's at its very earliest stages, years and even decades before forgetfulness and other symptoms appear, and are designed to slow progression. Thus they offer new hope that is beyond the reach of all currently approved treatments (cholinesterase inhibitors), which treat symptoms but do nothing to slow down the course of disease.
Previous trial results have suggested that to attack Alzheimer’s, it has to be done early. Experts have focused on changes at the cellular level that begin up to two decades before recognizable symptoms—problems with memory and cognition—make the disease apparent. In fact, research and clinical science are coming together to describe the disease as a continuum, with a “preclinical” stage, lasting a decade or longer, that is virtually invisible, beginning with no symptoms and even no cellular changes that could be picked up on a biomarker. The preclinical phase of Alzheimer's ends with pathophysiologic changes that could possibly be detected, but with no other outward signs. Currently there is some debate over whether cognition changes could, in fact, be detected and considered “clinically meaningful” at this point, but by and large a person with preclinical Alzheimer’s is indistinguishable from the profile of normal or “typical” aging. The next phase—early or “prodromal” Alzheimer’s—equates with a condition now known as mild cognitive impairment (MCI).
Research evidence to date suggests that the treatment window for disease-modifying drugs is from preclinical through prodromal /MCI phases; by the time individuals are diagnosed using current methods, it’s too late. However, the early treatment of Alzheimer’s, before symptoms appear, creates a conundrum in that the effectiveness of disease-modifying drugs is difficult to measure, preclinically, using traditional yardsticks. Thus, in preclinical Alzheimer's treatment trials, a variety of proposed alternatives are being considered for use, separately or combined, as clinical endpoints (e.g., agreed-upon outcomes indicating treatment success). These range from purely physiologic effects, such as amyloid beta accumulation and hippocampal atrophy; to cognition changes; assessments of social functioning and things like self care and independence (sometimes referred to as "activities of daily living"); and behavioral factors like agitation and anxiety. However, opinions differ about how "clinically meaningful" each of these endpoints would be, and there are questions of reliability, variability, and other uncertainties.
One thing's for sure--with more and more evidence suggesting that Alzheimer's can only be arrested at the very front of its decades-long course, the rule book is changing. Trials designed to test disease-modifying Alzheimer's drugs will probably look a lot different from your typical Phase 3 clinical trials. Besides endpoints, other innovations being looked at by trial designers, in consultation with the FDA, include such things as online cognitive self assessments; enrolling both the person with Alzheimer’s and an individual close to that person, probably a caregiver, as a study partner; measuring functional well being, as opposed to only cognition changes, as an endpoint that might be more “clinically meaningful’; and finding ways to control for all the variables apart from treatment success or failure that might affect a person’s clinical outcome. The latter factors, things like caregiving; baseline cognition and health; lifelong habits; and needing to measure treatment results against a sliding scale of changes associated with “normal aging”; all make the Alzheimer’s population notoriously difficult to study in clinical trials because they can skew results. Statisticians and other researchers refer to these potentially confounding variables as “noise” in otherwise pristine data.
It's a complicated picture, and that's why the Accelerate Cure/Treatments for Alzheimer’s Disease (ACT-AD) coalition, sponsored this recent discussion and holds others like it, on at least a yearly basis. The idea is to bring FDA scientists and officials together with their counterparts in industry and academia to hash out some of the thornier issues behind testing and bringing new Alzheimer’s drugs to market. More than 50 nonprofit organizations, including BrightFocus, make up ACT-AD, all stakeholders in the war on Alzheimer’s disease who are looking to make faster progress. “We’d all love to have one tool [to measure treatment success] that would work across all stages of the disease," said Paul Aisen, MD, of the University of California, San Diego. However, given Alzheimer’s long latency period, that's not going to happen, and it's important to have "as much collaboration as possible in what we call the preclinical space," he said.
A lifelong Alzheimer’s researcher himself, Aisen directs the Alzheimer's Disease Cooperative Study (ADCS), a research consortium formed among the National Institute on Aging (NIA) and academic research institutions. He and Harvard researcher Reisa Sperling, MD, who was a 2010-14 BrightFocus grantee, are responsible for designing the first major Phase 3 clinical trial of a disease-modifying drug for preclinical Alzheimer’s the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4). A4 will test the Lilly drug, solanezumab, an investigational monoclonal antibody designed to protect neurons. Directed by Sperling and due to begin in a few months, A4 is still recruiting participants aged 65-85 years at 60 sites throughout the U.S. and Canada, and one site in Australia. (For more information, read our earlier News Update.]
Currently, 5 million Americans have Alzheimer's, and at least that many more are walking around with the disease in preclinical stages. In his closing remarks, Dan Perry, founder of the ACT-AD coalition, said: "I can't think of a better incentive [for industry and the FDA] to work through the regulatory issues surrounding clinical trials to accelerate drug development."
Prodromal is another term for early Alzheimer’s disease; it equates with a condition also known as mild cognitive impairment (MCI).
Mild cognitive impairment (MCI) is a condition between normal age-related memory loss and dementia. Individuals with MCI have persistent memory problems (for example, difficulty remembering names and following conversations and marked forgetfulness) but are able to perform routine activities without more than usual assistance. Individuals with MCI are at risk of developing Alzheimer's disease or other forms of dementia.
Cholinesterase inhibitors address the low levels of acetylcholine, an important brain chemical, in people with Alzheimer's. The medications slow down this chemical breakdown of acetylcholine, which in turn may slow down the progression of cognitive symptoms.
Amyloid is a general term for protein fragments that the body produces normally. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques.