TABLE 1.

Milestones of aducanumab drug development and regulatory process. ²¹ , ²³

Date	Event
December 16, 2014	A Type B End of Phase 2 Meeting was held. The meeting included preliminary discussion regarding study population, endpoints, and dosing for the applicant's two proposed phase 3 studies, and the Division suggested a SPA be requested for an in‐depth review of the protocols. The Division and applicant agreed to the safety monitoring plan and the safety database.
September 28, 2015	SPA agreements for Study 301 and Study 302 were reached with the Division and the trials were initiated. During the trials, the target dose for all apolipoprotein E ε4 carriers in the high‐dose arm was increased from 6 to 10 mg/kg. This protocol change was called Protocol Version 4 (PV4). The rationale for this change can be found on page 121 of the FDA's medical review. 15
March 21, 2019	Biogen announces the termination of the Phase 3 program (Studies 301 and 302) based on results of a prespecified interim futility analysis (data generated up to December 26, 2018). The first formal request from Biogen to the FDA regarding a discussion of the decision to terminate the studies came on May 15, 2019, in the form of a Type C Meeting Request.
June 14, 2019	A Type C Meeting was held to discuss the applicant's analysis of the intent to treat populations of Study 301 and Study 302 including all data prior to the March 21, 2019, announcement of the termination of the studies. The Division advised the applicant that the development of aducanumab should not be abandoned as the available clinical data suggested the drug may be clinically active and did not provide convincing evidence that the drug is ineffective. The Division recommended that further analyses of the available data should be conducted to understand the effect of early termination of the studies on the interpretability of the data and to address the partially conflicting results for Study 301 compared to those for Study 302.
October 21, 2019	A Type C Meeting was held to discuss the additional analyses proposed at the June 14, 2019, meeting. Based on these analyses, the Division agreed that the results of Study 301 and Study 302 are interpretable and suitable for additional consideration. The Division further advised that planning for submission of a marketing application was a reasonable option.
February 20, 2020	The applicant opened BLA 761178 and submitted nonclinical information.
July 7, 2020	BLA submission complete.
November 6, 2020	AC meeting (Yes: 0; No: 10; Uncertain: 1).
January 28, 2021	The Division notified the applicant that their January 27, 2021, submission constituted a major amendment to the application. PDUFA date was changed to June 7, 2021.
March 31, 2021, and April 7, 2021 (additional internal Agency meetings to discuss the application and differences of opinion on approvability)	MPPRC meetings. This meeting provided an opportunity to discuss the reviews conducted by the review team and receive input and feedback from the members of the committee. At the MPPRC meetings, many different perspectives were discussed extensively as to whether there is substantial evidence of effectiveness for aducanumab's intended use to treat Alzheimer's disease.
April 26, 2021 (additional internal Agency meeting to discuss the application and differences of opinion on approvability)	Center director briefing meeting. The meeting included CDER senior leaders, as well as Dr. Peter Marks, Director of the CBER, and Dr. Rick Pazdur, Director of the OCE. The meeting reviewed the approach to approval the Office of Neuroscience and the Office of New Drugs supported, specifically, using the accelerated approval pathway based on substantial evidence of the effect of aducanumab on reduction in brain amyloid plaques, an effect that is reasonably likely to predict clinical benefit. This approach was supported by Dr. Cavazzoni, Dr. Marks, Dr. Pazdur, and the Office Directors for Clinical Pharmacology (OCP; Dr. Issam Zineh) and Medical Policy (Dr. Jacqueline Corrigan‐Curay). The Director of the Office of Translational Sciences (which includes both the Office of Biostatistics and the Office of Clinical Pharmacology), Dr. Shahvree Buckman‐Garner, commented that she understood the arguments for and against approval. Dr. Sylva Collins, Director of the Office of Biostatistics (OB), dissented on the approach, stating her belief that there is insufficient evidence to support accelerated approval or any other type of approval.
June 7, 2021	Accelerated approval by the FDA.

Abbreviations: AC, Advisory Committee; BLA, Biologics License Application; CBER, Center for Biologics Evaluation and Research; CDER, Center for Drug Evaluation and Research; FDA, US Food and Drug Administration; MPPRC, Medical Policy and Program Review Council; OCE, Oncology Center of Excellence; PDUFA, Prescription Drug User Fee Act; SPA, Special Protocol Assessment.