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NEW YORK — In the relentless quest for an Alzheimer’s cure, hope can be a dangerous thing. The latest “breakthrough” drug, donanemab, promised to slow the march of this devastating disease. However, a startling investigation has revealed a troubling story behind its approval — one of questionable data, potential conflicts of interest, and a drug that might pose more risks than benefits.
Donanemab, developed by pharmaceutical giant Eli Lilly, belongs to a new class of medications designed to target beta-amyloid, a protein long believed to be the culprit behind Alzheimer’s. The U.S. Food and Drug Administration (FDA) gave it the green light on July 2, 2024, despite initially denying approval just a year earlier. This reversal has raised eyebrows in the medical community and beyond.
The investigation, published in The BMJ and conducted by journalists Jeanne Lenzer and Shannon Brownlee, uncovers a series of red flags that call into question not just donanemab’s safety and efficacy but also the integrity of the approval process itself.
Perhaps most alarming are the safety concerns surrounding the drug. During clinical trials, more patients died while taking donanemab than those on a placebo. Initially, 17 deaths (2.7%) occurred in the donanemab group compared to 10 (1.4%) in the placebo group. When the FDA expressed concern about this “imbalance,” Lilly hired an outside company to gather more data on patients who had dropped out of the study. This additional search narrowed the gap to 19 deaths in the donanemab group and 15 in the placebo group.
However, Steven Goodman, an expert in clinical trial design at Stanford University, raises doubts about the reliability of this new data.
“There was also no information on health outcomes in those patients other than death, nor the causes of the deaths,” Goodman says in a media release. He adds that the “failure to formally follow patients who stopped treatment was a significant design flaw, particularly when that discontinuation was partly due to adverse drug effects.”
Beyond the mortality risk, over one-third of patients taking donanemab experienced brain swelling or bleeding, a side-effect known as amyloid-related imaging abnormalities (ARIA). This occurred in 36.8% of donanemab patients compared to 14.9% of placebo patients. Lilly itself acknowledged that three deaths due to ARIA were directly attributed to the drug.
The drug’s effectiveness is also under scrutiny. Lilly claims that donanemab slowed the progression of Alzheimer’s by 22% compared to placebo. However, this figure is based on a relative difference between test scores. In absolute terms, the difference is much less impressive – patients taking donanemab worsened by 10.2 points on a 144-point scale, while placebo patients worsened by 13.1 points, a difference of just 2.9 points.
“That’s a relative difference that transforms a very tiny absolute difference into a number that seems impressive,” states Alberto J. Espay, a neurologist and specialist in clinical epidemiology and healthcare research at the University of Cincinnati, who calls this framing misleading.
Adding to the controversy, the BMJ investigation uncovered potential conflicts of interest among members of the FDA advisory committee that recommended donanemab’s approval. Seven of the eight doctors appointed to review the drug had received direct payments from drug companies. Three had financial ties to Lilly, two had connections to Roche (Lilly’s partner in developing an Alzheimer’s blood test), and two others hold patents on amyloid antibodies. The eighth doctor had received research funding from Janssen for another Alzheimer’s drug.
These financial ties were substantial. Using public databases and disclosures, The BMJ investigation found that individual advisers received up to $62,000 for consulting and speaking fees and up to $10.5 million in research grants from 2017 through 2023.
When questioned about these conflicts, the FDA responded with a terse statement: “The FDA does not comment on matters related to individual members of an advisory committee.”
The investigation also revealed that Lilly changed the primary outcome measure of its trials midstream. Initially, the company planned to use the widely accepted “clinical dementia rating scale—sum of boxes” (CDR-SB). However, they switched to their own “integrated Alzheimer’s disease rating scale” (iADRS) during the course of the study, a move that the FDA did not agree with.
As donanemab enters the market, patients, families, and healthcare providers are left to grapple with difficult questions. Is the promise of slowing Alzheimer’s progression worth the potential risks? Can we trust the data and the process that led to this drug’s approval? And perhaps most importantly, in our desperate search for an Alzheimer’s cure, are we letting hope cloud our judgment?
The story of donanemab serves as a sobering reminder that in the complex world of drug development and approval, things are not always as they seem. As we continue the fight against Alzheimer’s, the authors of the report say the public must demand transparency, rigorous science, and an approval process free from conflicts of interest.
Paper Summary
Methodology
The BMJ investigation examined FDA approval documents, clinical trial data, and public records to piece together the story of donanemab’s journey to approval. Researchers analyzed safety outcomes and efficacy measures from the clinical trials. To uncover potential conflicts of interest, they used public databases like OpenPayments, along with committee members’ CVs, published article disclosures, and patent ownership records. This allowed them to trace financial connections between advisory committee members and pharmaceutical companies involved in Alzheimer’s drug development.
Key Results
The investigation revealed a higher initial death rate in the donanemab group compared to placebo during clinical trials. There were significant rates of brain swelling and bleeding (ARIA) in patients taking donanemab.
Questions arose about the drug’s effectiveness, as there was a small absolute difference in cognitive decline between treatment and placebo groups. The team found extensive financial ties between FDA advisory committee members and Eli Lilly or other companies developing similar drugs.
There are now concerns about the methods used to gather additional mortality data after the initial trial period. The primary outcome measure changed during the clinical trials.
Study Limitations
This investigation relied primarily on publicly available data and documents. Some financial relationships or additional clinical data may not have been captured. The full details of the third-party company’s methods for finding missing patient data were not disclosed, limiting the ability to assess its reliability. The investigation focused on one specific drug approval process, so its findings may not be generalizable to all FDA decisions or other Alzheimer’s treatments.
Discussion & Takeaways
The donanemab approval process highlights broader issues in drug development and regulation for Alzheimer’s disease. It raises questions about the use of surrogate endpoints versus clear clinical benefits, the balance between urgent need for treatments and ensuring drug safety, and the management of conflicts of interest in the approval process. For patients and healthcare providers, the key takeaway is the importance of carefully weighing the risks and potential benefits of new Alzheimer’s treatments, considering both relative and absolute measures of effectiveness.
Funding & Disclosures
The BMJ investigation was conducted in partnership with the McGraw Center for Business Journalism at City University of New York’s Craig Newmark Graduate School of Journalism. The authors declared no competing interests related to this specific investigation. The BMJ, as a medical journal, has a long-standing interest in issues of drug safety, efficacy, and regulatory processes. The investigation itself did not receive direct funding from any pharmaceutical companies or organizations involved in Alzheimer’s drug development.
