Re: Donanemab: Conflicts of interest found in FDA committee that approved new Alzheimer’s drug
Dear Editor,
Although it is important to evaluate the potential for bias in the approval of a new drug, the recent article by Lenzer and Brownlee itself provides a biased characterization of the approval of donanemab by the U.S. Food and Drug Administration (FDA) and of the participating members of the advisory committee meeting at which donanemab was discussed.
It is essential that advisory committee members have scientific and technical expertise in the evaluation of data from clinical trials. All members participating in the donanemab advisory committee meeting underwent thorough screening procedures consistent with U.S. federal conflict of interest laws and regulations, and they were determined to be eligible to serve [1, 2]. In some instances, a waiver was granted pursuant to those laws and regulations if the applicable criteria were met.
We also note that the FDA’s evaluation of drug safety continues in the postmarketing setting. The FDA has required for each approved anti-amyloid therapy, including donanemab, a postmarketing registry study that will evaluate safety outcomes of amyloid-related imaging abnormalities (ARIA) and associated symptoms in patients taking the drug. Review of this data is a continuous process that includes interim progress reports every 6 months until study completion approximately 10 years after study initiation, at which time a final report is submitted. In addition to the registry, the agency has a pharmacovigilance strategy for ongoing safety surveillance of this class of drugs through the FDA Adverse Event Reporting System (FAERS), ongoing clinical trials, periodic safety reports [3], and enhanced pharmacovigilance reporting that is described in the donanemab approval letter [4].
The agency carefully considered the findings of decreases in brain volume on MRI in our reviews of the approved anti-amyloid therapies. Many hypotheses have been proposed for these changes, including neurodegeneration, but the etiology remains unclear [5]. Clinical trials have demonstrated a slowing of decline on measures of cognition and daily function, and importantly, these benefits occurred in the context of the observed brain volume changes. In our review, we note the need for longer-term data to fully understand the clinical implications, if any, of the observed brain volume changes [6].
The agency views the results from the clinical trials to be clinically meaningful. In assessing treatment response, one important consideration is what is important to patients, and in a progressive neurodegenerative disease, reducing the rate of progression - prolonging a patient’s current state of functioning - is meaningful. Additionally, we do not limit our assessment to only the primary endpoint, but we look at the consistency and robustness of the findings across all endpoints in the study. For both the lecanemab and donanemab approvals, there were very robust and highly consistent findings across endpoints. The unanimous positive feedback from the members at both advisory committee meetings reflects their assessment of the clinical value of the treatment effect. The article provides quotations from some who minimize the importance of the treatment effects; however, missing from the article are broader perspectives, including those from patient communities.
Rapid Response:
Re: Donanemab: Conflicts of interest found in FDA committee that approved new Alzheimer’s drug
Dear Editor,
Although it is important to evaluate the potential for bias in the approval of a new drug, the recent article by Lenzer and Brownlee itself provides a biased characterization of the approval of donanemab by the U.S. Food and Drug Administration (FDA) and of the participating members of the advisory committee meeting at which donanemab was discussed.
It is essential that advisory committee members have scientific and technical expertise in the evaluation of data from clinical trials. All members participating in the donanemab advisory committee meeting underwent thorough screening procedures consistent with U.S. federal conflict of interest laws and regulations, and they were determined to be eligible to serve [1, 2]. In some instances, a waiver was granted pursuant to those laws and regulations if the applicable criteria were met.
We also note that the FDA’s evaluation of drug safety continues in the postmarketing setting. The FDA has required for each approved anti-amyloid therapy, including donanemab, a postmarketing registry study that will evaluate safety outcomes of amyloid-related imaging abnormalities (ARIA) and associated symptoms in patients taking the drug. Review of this data is a continuous process that includes interim progress reports every 6 months until study completion approximately 10 years after study initiation, at which time a final report is submitted. In addition to the registry, the agency has a pharmacovigilance strategy for ongoing safety surveillance of this class of drugs through the FDA Adverse Event Reporting System (FAERS), ongoing clinical trials, periodic safety reports [3], and enhanced pharmacovigilance reporting that is described in the donanemab approval letter [4].
The agency carefully considered the findings of decreases in brain volume on MRI in our reviews of the approved anti-amyloid therapies. Many hypotheses have been proposed for these changes, including neurodegeneration, but the etiology remains unclear [5]. Clinical trials have demonstrated a slowing of decline on measures of cognition and daily function, and importantly, these benefits occurred in the context of the observed brain volume changes. In our review, we note the need for longer-term data to fully understand the clinical implications, if any, of the observed brain volume changes [6].
The agency views the results from the clinical trials to be clinically meaningful. In assessing treatment response, one important consideration is what is important to patients, and in a progressive neurodegenerative disease, reducing the rate of progression - prolonging a patient’s current state of functioning - is meaningful. Additionally, we do not limit our assessment to only the primary endpoint, but we look at the consistency and robustness of the findings across all endpoints in the study. For both the lecanemab and donanemab approvals, there were very robust and highly consistent findings across endpoints. The unanimous positive feedback from the members at both advisory committee meetings reflects their assessment of the clinical value of the treatment effect. The article provides quotations from some who minimize the importance of the treatment effects; however, missing from the article are broader perspectives, including those from patient communities.
[1] 18 U.S.C. 208; 5 CFR 2640.103
[2] 18 U.S.C. 208(b); 5 CFR 2640.103; 5 CFR 2640.301
[3] 21 CFR 600.80(c)(2)
[4] https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/761248Orig...
[5] Belder et al. Lancet Neurol 2024; 23: 1025–34
[6] FDA reviews of donanemab. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/761248Orig1s000T...
Competing interests: No competing interests