An insider's perspective on FDA approval of aducanumab.

Introduction: Aducanumab was approved in 2021 by the US Food and Drug Administration (FDA) under the accelerated approval pathway. Since then, there have been many misconceptions about the approval decision despite multiple publications from the FDA to explain the rationale. Methods: Even though the FDA's final decision was accelerated approval, the Office of Clinical Pharmacology recommended regular/full approval based on its own analyses. Exposure-response analyses were conducted to quantify the relationship between aducanumab longitudinal exposure and responses (standardized uptake values ratios for amyloid beta and various clinical endpoints) in all clinical trials. To explain the difference between aducanumab and other compounds with negative results in the past, publicly available data were combined with the aducanumab data to demonstrate the relationship between amyloid reduction and clinical endpoint change across multiple compounds with similar mechanism of action. The probability to observe the overall positive findings in the aducanumab program was quantified under the assumption that aducanumab is ineffective. Results: Positive exposure-response (disease progression) relationship for multiple clinical endpoints from all clinical trials was identified. Positive exposure-amyloid reduction relationship was established. Consistent amyloid reduction-clinical endpoint change relationship across multiple compounds was observed. If aducanumab is assumed to be ineffective, it is extremely unlikely we would observe the overall positive findings in the aducanumab program. Conclusion: These results provided convincing evidence to support aducanumab's effectiveness. In addition, the observed effect size in the studied patient population represents a clinically meaningful benefit given the magnitude of disease progression within the trial duration. Highlights: Totality of evidence supports the Food and Drug Administration (FDA)'s approval decision for aducanumab.Different opinions were clearly explained in the FDA's public reviews from different disciplines.Readers are encouraged to read the FDA's reviews to understand the FDA's rationale to approve aducanumab.