What the sponsor asked the agency to accept
As the FDA restates it.
The applicant’s proposed indication is to delay clinical decline in patients with Alzheimer’s disease.
Clinical review · PDF p. 12 · action of · fda.gov ↗
What the agency said
T1 · SurrogateOrigin
ADU-T1-1
I concur with ON that the BLA has met the requirements for accelerated approval, including with ON’s conclusion that Biogen has provided substantial evidence of effectiveness on the surrogate endpoint of reduction in brain amyloid plaque and that the surrogate endpoint is reasonably likely to predict clinical benefit, for the reasons set forth in ON’s summary memorandum.
Office Director memorandum · PDF p. 3 · action of · fda.gov ↗
Origin: the first agency position on T1 in this record.
T1 · SurrogateOrigin
ADU-T1-2
Finally, a surrogate outcome for which there is substantial evidence of effectiveness, reduction in amyloid beta plaques on PET imaging, has been assessed in the aducanumab development program, and is reasonably likely to predict clinical benefit, as demonstrated in the reviews discussing the relationship of amyloid plaque reduction to clinical outcome.
Summary review · PDF p. 8 · action of · fda.gov ↗
Origin: the first agency position on T1 in this record.
T2 · Effect sizeOrigin
ADU-T2-1
Study 302 provides the primary evidence of effectiveness as a robust and exceptionally persuasive study demonstrating a treatment effect on a clinically meaningful endpoint and reinforced by effects on secondary endpoints, biomarkers, and in relevant subgroups.
Clinical review · PDF p. 14 · action of · fda.gov ↗
Origin: the first agency position on T2 in this record.
T2 · Effect sizeOrigin
ADU-T2-2
A p-value < .05 doesn’t necessarily reflect a clinically meaningful effect especially if there would be connotations of disease modification but the actual evidence supporting that is lacking and there is a failed study calling that p-value into question.
Statistical review · PDF p. 111 · action of · fda.gov ↗
Origin: the first agency position on T2 in this record.
T3 · ARIAOrigin
ADU-T3-1
The incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoE ε4) carriers than in ApoE ε4 non-carriers (42% and 20%, respectively).
Prescribing information (label) · PDF p. 5 · action of · fda.gov ↗
Origin: the first agency position on T3 in this record.
T3 · ARIAOrigin
ADU-T3-2
Obtain brain MRIs prior to the 7th infusion (first dose of 10 mg/kg) and 12th infusion (sixth dose of 10 mg/kg) of ADUHELM to evaluate for the presence of asymptomatic ARIA.
Prescribing information (label) · PDF p. 6 · action of · fda.gov ↗
Origin: the first agency position on T3 in this record.
T4 · DataOrigin
ADU-T4-1
The only valid analysis of Study 301 is the prespecified randomization supported analysis of study 301 which failed for the high dose (p=0.83) and this study outcome should not be discounted without an extremely compelling reason (which there is not).
Statistical review · PDF p. 9 · action of · fda.gov ↗
Origin: the first agency position on T4 in this record.
T4 · DataOrigin
ADU-T4-2
Based on the considerations above, the applicant has provided substantial evidence of effectiveness to support approval.
Clinical review · PDF p. 133 · action of · fda.gov ↗
Origin: the first agency position on T4 in this record.
T4 · DataOrigin
ADU-T4-3
Studies 301 and 302 meet ICH E1A guidelines for exposure of at least 300 subjects at 6 months and 100 subjects at 12 months at the proposed doses.
Clinical review · PDF p. 240 · action of · fda.gov ↗
Origin: the first agency position on T4 in this record.
T5 · ConfirmatoryOrigin
ADU-T5-1
In order to verify the clinical benefit of aducanumab, conduct a randomized, controlled trial to evaluate the efficacy of aducanumab-avwa compared to an appropriate control for the treatment of Alzheimer’s disease.
Approval letter · PDF p. 6 · action of · fda.gov ↗
Origin: the first agency position on T5 in this record.
T5 · ConfirmatoryOrigin
ADU-T5-2
When residual uncertainty exists about the clinical benefit of a drug, it is important to address that uncertainty, and accelerated approval provides an opportunity to address the uncertainty associated with a surrogate outcome that is reasonably likely to predict clinical benefit by requiring a post-approval study to verify the clinical benefit predicted by the effect on the surrogate.
Summary review · PDF p. 8 · action of · fda.gov ↗
Origin: the first agency position on T5 in this record.
Committee votes
Peripheral and Central Nervous System Drugs Advisory Committee, . Read from Clinical review, which reproduces the questions and results.
| Question | Yes | No | Uncertain | Source |
|---|---|---|---|---|
| Q2 Does Study 302, viewed independently and without regard for Study 301, provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease? | 1 | 8 | 2 | p. 133 ↗ |
| Q4 Does Study 103 provide supportive evidence of the effectiveness of aducanumab for the treatment of Alzheimer’s disease? | 0 | 7 | 4 | p. 134 ↗ |
| Q6 Has the Applicant presented strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology? | 5 | 0 | 6 | p. 134 ↗ |
| Q8 it is reasonable to consider Study 302 as primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease? | 0 | 10 | 1 | p. 134 ↗ |