Breast Cancer Approach to Alzheimer’s Trial Design Could Improve Results, Scientists Contend

Research on Alzheimer’s treatments could benefit from the adaptive clinical trial approach used in breast cancer research, three Georgetown University scientists argue in a commentary.

An adaptive approach involves modifying a trial as results come in to find the best way to treat the disease the trial is examining.

The adaptive approach to breast cancer trials requires collaboration and data sharing among pharmaceutical firms, public research organizations, academic institutions, and patient advocacy groups, the Georgetown group noted in their viewpoint piece in the journal JAMA Neurology. 

Scientists Mindi Messmer, Erin Wilhelm and Ira Shoulson acknowledged that an adaptive approach would be far more complicated in Alzheimer’s than in breast cancer research. But it could help overcome the 99.6 percent clinical trial failure rate of Alzheimer’s therapies and the resulting loss in research investment, they said.

“In the face of these challenges, there is global interest to innovate clinical trials that enable more effective outcomes,” they wrote. Their piece was titled “I-SPY 2 Breast Cancer Trial as a Model for Innovation in Alzheimer Disease Therapies.”

Clinical trial failures stem from a number of factors, including poor understanding of disease processes, inappropriate dosing or length of treatment, and patient populations that are too different. But the Georgetown scientists contended that innovative trial designs have overcome some of these obstacles in other diseases.

Collaboration can lead to patient groups that are similar, common placebo groups, and reduced trial costs, they wrote.

The I-SPY 2 breast cancer study could serve as a model for Alzheimer’s research, they maintained. I-SPY 2 stands for Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis.

The trial, which covered women with a difficult-to-treat form of breast cancer, used a hybrid umbrella/basket design. The umbrella part of the term refers to the simultaneous testing of about 12 experimental therapies. Researchers test them in subgroups — or baskets — of patients with similar genetic markers or tumor subtypes.

Another part of the trial design involves using advanced statistical models to predict which therapies are most likely to pass a Phase 3 clinical trial. This approach has led to four therapy candidates being forwarded to Phase 3 trials since 2010, with four or five more expected by 2019.

A key to the success of this approach has been unrestrained sharing of research data, the Georgetown researchers wrote. While some research initiatives — including the Alzheimer’s Disease Neuroimaging Initiative and the Dominantly Inherited Alzheimer Network — have adopted this open approach to data, the collaborations did not include an adaptive trial design.

In addition to cutting costs and making the selection of therapy candidates more efficient, an adaptive Alzheimer’s trial could test multiple ways of evaluating cognition and of validating patient-reported outcomes, the Georgetown group said. Researchers could use the findings not only to design trials but also to select biomarkers and cognition measurements.

Adopting the I-SPY approach to Alzheimer’s research would not be easy, the scientists acknowledged.

One challenge would revolve around the much poorer understanding that researchers have of Alzheimer’s, compared with breast cancer. In addition, researchers could not use brain tissue samples to analyze treatment outcomes. And at the moment researchers lack good biomarkers and ways to measure outcomes.

In addition, different groups of Alzheimer’s patients may respond differently to treatment. For instance, researchers still don’t know whether the APOE4 gene, which increases the risk of Alzheimer’s, can help predict response to treatment.

All these challenges could be overcome, however, the Georgetown scientists contended.

“An adaptive trial for AD [Alzheimer’s disease] is an opportunity for continued learning and progress toward effective therapies for those in need,” they concluded.