Two physicians — one at the University of Pennsylvania’s Perelman School of Medicine and the other with the University of Michigan — argue in a recent opinion piece that the National Alzheimer Project Act (NAPA), as it now stands, has resulted in potential treatments for Alzheimer’s disease being tested without a clear requirement that these therapies show proof of meaningful clinical benefit.
In the viewpoint, “Unfinished Business in Preventing Alzheimer’s Disease,” Jason Karlawish, MD, and Kenneth M. Langa, MD, PhD, warned that this failure could lead to treatments being approved that end up being much more costly than they should be. The article was published in JAMA Internal Medicine.
NAPA, signed into law in 2010 by President Barack Obama, calls for new treatments to slow or prevent the disease by 2025 — and five clinical trials are now underway toward that goal, the doctors write. But only one of the five (NCT02565511) is using scientific measures of clinical benefit (defined as demonstrated improvements in day-to-day function). The others are using a “surrogage” measurement that falls under the U.S. Food and Drug Administration’s (FDA) accelerated approval program, established during the early years of HIV research to speed the development of needed drugs. The problem is that this measure looks at therapeutic effect, which is a predictor of clinical benefit rather a measure of it, the authors said, according to a press release.
After receiving accelerated approval, the company that developed the treatment is expected it collect evidence demonstrating its clinical benefit.
The FDA, on its website, noted that treatments given accelerated approval use a surrogate endpoint or “a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. … Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug.” If not, the “FDA has regulatory procedures in place that could lead to removing the drug from the market.”
The authors claim that private interests could shape how a drug’s clinical benefit is established after approval, which works to determine its costs. A similar problem is now happening with cancer treatments, they wrote.
“NAPA is missing an important strategy,” said Karlawish, a professor and co-director of the Penn Memory Center. “We need a strategy for gathering and interpreting information and data to determine if it shows a meaningful clinical benefit to patients — before the FDA approves the drug. Alzheimer’s is a complex, unique disease that needs more a rigorous and expanded set of study endpoints in order to better quantify outcomes.”
To determine if the potential treatments being tested offer clinical benefit, they said that three questions must be asked:
- 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?
Karlawish and Langa also recommend that people taking part in Alzheimer’s prevention studies participate in long-term observational cohort studies, where functional outcomes can be assessed and analyzed together with results from cognitive tests.
“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 Alzheimer plan,” Langa said.
“Claims that these treatments have significant clinical benefits will engage both public and private interests, which can be at odds,” said Karlawish. “We think the U.S. Advisory Council on Alzheimer’s Research, Care, and Services is the right place for establishing a common set of publicly recognized guidelines for the design and interpretation of studies to establish the benefit of an Alzheimer’s prevention therapy.”
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