Investigative journalists and medical experts are calling for increased scrutiny of Alzheimer's drug trials, particularly in light of concerns surrounding the recently approved drug donanemab (Kisunla). Their concerns include questionable clinical trial results, potential conflicts of interest, and the use of surrogate endpoints that may mislead the public.
Independent Sources and Conflict of Interest
According to experts, journalists must consult with industry experts who have no ties to pharmaceutical companies. Shannon Brownlee suggests that reporters create their own list of independent experts or use resources like The Lown Institute's list. Brownlee also emphasizes the importance of checking the Open Payments database to uncover relationships between healthcare providers, pharma, and medical device manufacturers.
Endpoint Manipulation and Statistical Significance
Concerns have been raised regarding the primary endpoint used in donanemab's clinical trials. Eli Lilly created the integrated Alzheimer’s disease rating scale (iADRS) in 2015 and, according to the FDA, changed the primary endpoint from the clinical dementia rating scale, sum of boxes, or CDR-SB test, to the iADRS during the study. The iADRS scale showed a 2.92 difference between the drug and placebo groups, which is below the five-point threshold for clinical significance. The CDR-SB showed a statistically significant, but clinically insignificant difference of 0.7 points.
Interpreting Statistical Claims
Experts caution against accepting statistical claims at face value. Jeanne Lenzer advises journalists to pay close attention to terms like "significant" and to understand the difference between absolute and relative differences. For example, while Lilly promoted donanemab as slowing disease progression by 22%, this figure represents a relative difference, while the absolute difference on the iADRS scale was only 2.9 points.
The Role of Surrogate Endpoints
The use of surrogate endpoints, such as amyloid reduction, also warrants careful consideration. According to experts, a surrogate endpoint should have a direct tie to the clinical endpoint of interest, such as slowing dementia. However, concerns have been raised that Lilly only met the primary endpoint because the company changed it.
Ethical Considerations
Arthur Caplan, Ph.D., emphasizes the need for demanding journalism in the Alzheimer's space, given the size of the disease, the money involved, and the public's fear. He notes that while Alzheimer's disease is a significant concern, real prevention does not exist, testing is still crude, and treatment is still a hope, not close to a reality.
