The first goal of the U.S. national Alzheimer’s plan is that, by 2025, researchers will discover ways to diagnose and treat patients before they have problems performing daily tasks like driving and managing finances, but the plan lacks a strategy to determine whether these treatments provide “meaningful clinical benefit,” two leading researchers argue in a recently published essay.
Drs. Jason Karlawish and Ken Langa wrote in the October 17, 2016, edition of the Journal of the American Medical Association Internal Medicine that, since its creation in 2010, the National Alzheimer’s Project Act (NAPA) has encouraged joint efforts between the National Institutes of Health and pharmaceutical companies to conduct clinical trials aimed at preventing or delaying the onset of Alzheimer’s disease. At least five are planned or under way.
Jason Karlawish is a professor of medicine, medical ethics and health policy, and neurology and co-director of the Penn Memory Center and at the University of Pennsylvania. Ken Langa is a professor of medicine and associate director of the Institute of Gerontology at the University of Michigan and VA Ann Arbor Healthcare System.
Of five trials reviewed by the authors, only one employed measures to determine whether the intervention is deemed clinically beneficial, a term that describes evidence of impact on day-to-day function. The other trials evaluate the disease course using a measure of cognition called “‘an intermediate clinical endpoint’ because it does not establish “meaningful clinical benefit.”
After drugs are approved by the Food and Drug Administration, the FDA’s regulations expect the company that owns the drug will collect evidence to demonstrate the drug’s clinical benefit. The authors note that the nation’s Alzheimer plan has no strategy to determine how this evidence should be collected and analyzed.
The Anti-Amyloid in Asymptomatic Alzheimer’s Study (the A4 Study), for example, is testing whether the drug solanezumab “slows the rate of cognitive decline in cognitively normal adults.” Success in this collaboration between the National Institute of Health and Eli Lilly and Company will be measured using a composite of four cognitive tests. The study is not designed to show whether improved scores on these tests guarantee meaningful clinical improvement in the ability to perform activities like managing finances and driving.
To evaluate whether Alzheimer’s disease prevention trials have significant clinical benefits, Karlawish and Langa argue that researchers, policy makers, and clinicians should design studies that consider three questions:
- Is there a slowing of the trajectory of cognitive decline after the onset of dementia?
- Does treatment lead to a lengthening of the mild or severe stages of dementia?
- Does treatment delay death and, if so, is treatment associated with compression or expansion of the time living with dementia?
Trials such as the three-year long A4 Study cannot effectively address these questions, because it takes more than three years to evaluate whether participants who received the drug maintain independence and the ablity to perform cognitive tasks for longer than those who received no treatment.
The challenges of evaluating efficacy are compounded by the fact that healthy individuals are taking these preventive drugs. Because these interventions would be given to “someone who is feeling fine, with no memory or cognitive problems. This raises the bar to establish evidence of benefit from preventive interventions,” Langa said.
“It would be prohibitively expensive to do the A4 Study for 10 or 15 years to try to get this ultimate answer of whether we’re preventing dementia. So we need to do other kinds of studies,” Langa explained.
Karlawish and Langa propose that participants in Alzheimer’s prevention studies should also participate in long-term observational cohort studies, where functional outcomes can be evaluated and analyzed alongside cognitive test results.
“These studies are one way to address the very high cost and difficulties of getting a read on long term outcomes, and exemplifies collaboration in the area of data sharing, a strategy emphasized in the U.S. Alzheimer plan,” Langa said.
Karlawish explained that issues of competing interests must also be addressed.
“Claims that these treatments have significant clinical benefits will engage both public and private interests, which can be at odds,” he said. “We think the U.S. Advisory Council on Alzheimer’s Research, Care, and Services is the right place for establishing a common set of publically recognized guidelines for the design and interpretation of studies to establish the benefit of an Alzheimer’s prevention therapy.”
The authors recommend three guidelines for these studies:
- In evaluating the potential benefits and risks of preventing dementia, studies need to consider chronic diseases that increase older patients’ risks of cognitive decline and death. Competing risks and the potential for harm are essential topics in the discussion surrounding preventive care.
- Assessments of autonomy and quality of life should be part of evaluating the benefit of a treatment, not just whether life is prolonged.
- The benefit of a prevention therapy will likely decrease if patients stop taking the medications. Estimates of benefit must therefore address variability in adherence to medication.