fter years of relying on outdated standards for evaluating new drugs for Alzheimer’s and other neurologic diseases, the FDA is finally modernizing its approach. This is good news for researchers working to develop much-needed medications for these conditions.

The change has to do with the endpoints the FDA requires in clinical trials. A loose standard in place since the 1990s required clinical trials to show that a new drug for Alzheimer’s disease improved patients’ cognition and function. But that isn’t in line with our current understanding of the disease and was likely a contributing factor in the high rate of failure in Alzheimer’s trials.

Impairments in cognition — which includes memory, executive function, language, and other aspects of thinking and reasoning — are characteristic features of Alzheimer’s. Functional impairments — problems with daily tasks such as getting dressed, brushing your teeth, cooking, driving, and the like — are generally due to cognitive issues.


Under the dual-endpoint standard, the FDA asked drug developers to demonstrate benefits to cognition among Alzheimer’s patients with symptoms of dementia that were “clinically meaningful” by demonstrating improvements in function. But we can now recognize earlier stages of Alzheimer’s disease, such as mild cognitive impairment, in which patients have no issues with daily function. In this large group of patients, it’s difficult, if not impossible, to show improvements in function because their function is fine.

In other diseases, the FDA requires clinical trials to focus on one endpoint. It is now applying this approach to Alzheimer’s disease. It’s much like the “modernized standard” that my colleague, George Vradenburg, and I called for last year. And the FDA has gone even further for clinical trials including early-stage patients. Its new draft guidelines outline three stages of early Alzheimer’s disease and offer guidance on drug development for each. These forward-thinking guidelines acknowledge advances in our understanding of Alzheimer’s.

Individuals with stage 1 Alzheimer’s have no clinical symptoms of the disease, but do have biomarker evidence of it. These can include positive PET scans of the brain or positive tests for beta-amyloid or tau, two proteins that are hallmarks of Alzheimer’s disease. For clinical trials involving these asymptomatic, cognitively normal patients, the FDA says that improvements in relevant biomarkers could now serve as the basis for accelerated drug approval.

Individuals with stage 2 Alzheimer’s have biomarker evidence of the disease and subtle cognitive impairment, but no problems with function. For trials in this population, the FDA will now consider “strongly justified arguments” for using only cognition as an endpoint.

Individuals with stage 3 Alzheimer’s have biomarker evidence of the disease plus cognitive and functional impairment — in other words, they have what is currently called mild cognitive impairment. The FDA suggests that trials testing therapies in this group should include measures of cognition and function, but encourages new approaches to assessing these outcomes.


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The question now is how to design Alzheimer’s clinical trials to meet these guidelines.

It’s clear that trials must now specify and define the stage of Alzheimer’s disease among the population being studied at the time of enrollment, as well as the expected stage at its conclusion. It is also clear that biomarkers should be used as one criteria for trial enrollment, to monitor disease progression, and to indicate responses to the drug.

The new FDA guidelines are a big advance. They define earlier stages of Alzheimer’s, acknowledge the vital role of biomarkers, and open doors for novel drug targets. Exactly how the new guidelines will play out for drug developers remains to be seen. The immediate task is to develop new biomarkers and more sensitive tests of cognition and function.

Now that the FDA has signaled it is ready to accelerate the development of new drugs for Alzheimer’s, the challenge for us is to prove that they work.

Howard M. Fillit, M.D., is the founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation. He also serves as a clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at Icahn School of Medicine at Mount Sinai.

Editor’s note: The author did not initially disclose having received payments for consulting work in pharmacoeconomics for Hoffmann-La Roche; Genentech; Eli Lilly; Otsuka; Lundbeck; and Merck Sharp & Dohme.

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  • My wife has A.D./dementia and I don’t expect the kind of evidence that the FDA rightly considers a requisite for approval before trying a natural remedy that may help in a statistically unmeasurable manner. For example, I had heard that turmeric-curcumin had antioxidant properties and that countries that used it ad a spice in their cuisine had a liw oncidence of Alzheimer’s. That as often happens, im vitro and rodent findings were not found in humans. Could it be because the end points were set too high? After reading a paper that reported BACE-1 inhibition by turmeric I decided to try it, 500 mg bid. Only 2 weeks later and my wife’s caretaker and myself have observed certain reactions that make me feel we are onto something. Does the FDA have a site designed to compile and follow up on such cases? I would like to see the FDA’s position on natural products such as flavenoids, riboside nocotinamide (Elysium Co.). If outside of your legal purview then some other agency should be asked to do it.

    • Note that curcumin is an agonist at the SXR receptor. That means it up-regulates the drug clearance enzymes, like the drug metabolizing enzyme 3YP3A4 and the drug transporter P-glycoprotein. At the level you would get from food, it’s not a problem. But concentrated curcumin extracts do have the potential to interefere with other drugs. This is the same mechanism by which cancer chemotherapy drugs ultimately fail due to the development of multidrug resistance — the drug clearance mechanisms gets boosted into overdrive.

  • Amnestic MCI has been associated with risk of dementia or AD…only a risk…it is not a diagnosis…you shall have more risk regarding to others with MCI…and if you change your lifestyle it is possible that never shall get the disease…

    • Luckily for me it has been a little over 12 yrs since my 1st diagnosis, so that is a good thing that it has not progressed to dementia.

  • “But we can now recognize earlier stages of Alzheimer’s disease, such as mild cognitive impairment, in which patients have no issues with daily function. In this large group of patients, it’s difficult, if not impossible, to show improvements in function because their function is fine.”This is part of the 4th paragraph & I hate that this information is incorrect. MCI is not dementia & not everyone who is diagnosed with MCI will progress to a form a dementia. The other part that makes me made is , ” it’s difficult, if not impossible, to show improvements in function because their function is fine.” Anyone with MCI diagnosis, knows that this info is also inaccurate! I sure wished that the medical professionals would provide information that is accurate! In 2005, at age 47, I was diagnosed with MCI & 12 yrs. later it has not progressed to dementia.

    • Cheryl…I think you have a point…the problem is you have different types of MCI and the challenge is to see the difference between a healthy MCI and a MCI that can go to dementia…even when you have no MCI you can get the disease…if we know all the subtypes of MCI…the pharma can find the wright treatment…again the only solution for this is AI and machine learning…

  • This is very bad news. If an AD drug can get approval on biomarkers alone while having no impact on symptoms or progression, that will mean they can bleed insurers dry for ineffective treatments for this common and increasingly prevalent disease. I do agree that the functional part should be let go, but not the cognitive part. The standard should require improvement or arresting progression on cognitive tests like the MMSE. If it improves biomarkers too, that’s great, but improvement on biomarkers with no improvement or arresting progression on tests like the MMSE should not be a basis for approval.

  • Because Alzheimer’s disease is such a complex disease…the only solution that make sense is AI and machine learning based on different biomarkers. PET, MRI or lumbar punction scans are invasive, costly and can give only static data. That is also the reason why in developed countries only 50% of AD patients can get a diagnosis with 30% misdiagnosis. With the combination of subjective data ( digital neurocognition test) and measurable data (eye tracking, face-emo- recognition) and machine-deep learning you shall get better outcomes.

  • This is just another scam where BIG PHARMA refuses to research for a cure of anything anymore, but stringing patients along with this crap of “progression free disease”. Now they’re applying it to AD. FDA no longer patient focused, but profit focused.

  • Sounds reasonable. However, I would much rather have a focus on research, screening and remediation of some of the triggers for Alzheimers and other dementias, and with attention to those with genetic susceptibility.

    Good candidates of exposures damaging to gut, neural and brain health include chemicals and pesticides, mercury exposure from fillings and fish, low grade dental and jaw infections, Lyme disease, mold exposure, diet leading to diabetes, head trauma leading to CTE, etc. All of these have been reported to have associations with cognitive impairment in the literature.

    The chase for the perfect molecule, while exciting, costly and lucrative to the winners, will not have the return on investment to society and population health that prevention, screening and remediation will yield.

  • Changing the endpoints will make pharmas, and MDs living off it, a pile of money.
    Certainly, they are not going to cure or alleviate AD. But I guess, that is irrelevant

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