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Homing In On a Moving Target: Meeting the Challenges of Alzheimer’s Disease Research

Alzheimer’s disease clinical trials have an exceptionally high failure rate. But that doesn’t mean the research has been a failure.

Over the last few decades, researchers have made tremendous advances in understanding what Alzheimer’s disease does to the brain. That has paved the way for current and future research into therapies that could prevent the disease, or at least delay its onset by a few years.

But although my colleagues and I are optimistic, that doesn’t change the fact that no new AD drug has been approved since 2003. From 2002-2012, drug candidates have had a 99.6 percent failure rate.[i] In some cases, the proposed therapeutic may have been ineffective. But in others, the flaw could be due to the trial execution and/or design.[ii]  The more we learn, the easier it will be to understand that distinction in future trials.

The first few lessons relate to trial design and execution:

Lesson 1: Enrollment often happens too late.

Prevention trials need patients who are pre-symptomatic, or have only the mildest of symptoms. Many Alzheimer’s patients don't get diagnosed until they’re almost past the stage researchers are looking for.

Lesson 2Many individuals participating in AD trials don’t even have the disease.

Up to half of people with mild cognitive impairment and a quarter with mild dementia do not have measurable amyloid plaque development–a key AD biomarker.[iii] Many of these individuals nevertheless end up in AD trials, including anti-amyloid ones. This skews results, especially when it comes to placebo decline.

Lesson 3: Old-school rater training won’t work.

The conventional once-and-done approach simply won’t work for AD prevention trials that can run for years. Because the risk of variability is exceptionally high, raters need consistent training/feedback over the life of the trial.

Lesson 4: Paper assessments are obsolete.

A paper-based approach increases the potential for rater and administrative errors. This effect is often compounded by subjectively reported and scored assessments. In fact, research has found the use of paper-based assessments could be an important factor in failed or inconclusive trials.[iv] Electronic clinical outcome assessment (eCOA) tools–not just digital versions of paper COAs–are essential to the AD trials of today and tomorrow. For example, merely replacing a paper scale with a digital one fails to take advantage of the flexibility and sophistication of a fully computerized platform–especially with respect to pop-up support, built-in clinical guidance, consistency checks, etc.

Lesson 5: Biomarkers will transform research.

In April 2018, the National Institute on Aging and the Alzheimer’s Association released a framework in which biomarkers would define the presence of disease for the purposes of research. It will allow researchers to better identify candidates to enroll in clinical trials. It also provides a more accurate way to measure disease progression. Ideally, this means less time wasted, which could speed development and reduce costs. This approach got a tentative green light from the FDA in early 2017 in the form of draft guidance around the use of biomarkers. In early- stage trials, drug developers would no longer have to prove that their therapy met the endpoints of “cognition and function.” Instead, they can use biomarkers as endpoints. It will be possible to get an expedited approval for a compound that was shown to have an impact on a biomarker.

The last three lessons relate more to the therapies themselves.

Lesson 6: Tau continues to be a promising target.

Research will continue to focus on prevention, and it will continue to assess the role of amyloid and Tau proteins. (In fact, we anticipate more anti-tau trials for Alzheimer’s and other neurodegenerative diseases.)

Lesson 7: We expect a verdict on the amyloid hypothesis soon.

It remains an open question right now whether an anti-amyloid strategy is going to work at any stage of disease, but it seems less likely that it will work after the onset of significant dementia.  Several prevention trials are in the works, and we’ll know about the validity of the amyloid hypothesis by the time these all read out. In the meantime, researchers will focus more on tau. One possibility is that there’s some sort of pathological interface between amyloid and tau and that amyloid may mediate tau-related pathology in some way.

Lesson 8: Monotherapy may not be the way to go.

It’s possible the key to slowing, stopping or preventing AD lies in combination therapies instead of monotherapies. We just don’t know yet. But we soon may, as the use of biomarkers increases.

Moving forward

The science is advancing quickly. Pharmaceutical companies and biopharma organizations need a partner who grasps the particulars of Alzheimer’s clinical trials.

WCG is running–or has run–more than 30 of them, at every stage of the disease. Currently, we’re involved in over 2,000 sites around the world actively researching potential therapies. Our system is established, our raters are the best trained in the industry, and our leadership includes the leading clinicians and researchers in this area.


[i] Cummings JL, Morstorf T, Zhong K. “Alzheimer's disease drug-development pipeline: few candidates, frequent failures.” Alzheimers Res Ther. 2014 Jul3;6(4):37

[ii] Posner H, Curiel R, Edgar C, et al. “Outcomes Assessment in Clinical Trials of Alzheimer’s Disease and its Precursors: Readying for Short-term and Long-term Clinical Trial Needs.” Innovations in Clinical Neuroscience. 2017;14(1-2):22-29.

[iii] Cummings, J. (2018), “Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes.” Clinical And Translational Science, 11: 147-152. doi:10.1111/cts.12491

[iv] Negash S, Böhm P, Steele S, Sorantin P, Randolph C. Virgil Investigative Study Platform Minimizes Scoring Discrepancies to Improve Signal Detection. MedAvante Inc.; Loyola University Medical Center. Poster presentation, 14th Annual Athens/Springfield Symposium on Advances in Alzheimer Therapy, March 2016.