{
 "decision": {
  "id": "aduhelm-2021-aa",
  "title": "Aduhelm, accelerated approval",
  "outcome": "approved",
  "pathway": "Accelerated approval",
  "case": "BUILT",
  "action_date": "2021-06-07",
  "incomplete": false
 },
 "package": "aducanumab_bla761178",
 "documents": [
  {
   "code": "Approv",
   "title": "Approval letter",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Approv.pdf",
   "pages": 12,
   "sha256": "0e858c46904084b21f0570c127d553cb9b9ac83a94f743773734edd01cefef51",
   "cited": true
  },
  {
   "code": "SumR",
   "title": "Summary review",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000SumR.pdf",
   "pages": 70,
   "sha256": "236a7a9d873a2021cfc9838bae0de9425fe37e491730b1f0dd538a2fc18b60b1",
   "cited": true
  },
  {
   "code": "ODMemo",
   "title": "Office Director memorandum",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000ODMemo.pdf",
   "pages": 15,
   "sha256": "294669838bea203b4dd8ee1da9baa83ff92d44b8cb433acdaecfe65664827981",
   "cited": true
  },
  {
   "code": "MedR",
   "title": "Clinical review",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf",
   "pages": 392,
   "sha256": "4a457dcbec58bfc631ca4bb84e48ac9e0ef1bd805619e038a317097580566225",
   "cited": true
  },
  {
   "code": "StatR",
   "title": "Statistical review",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000StatR.pdf",
   "pages": 113,
   "sha256": "0aa0829e3ad0ce98e990a87cfeb39f588fa789206feae04e35263d965aec3563",
   "cited": true
  },
  {
   "code": "Lbl",
   "title": "Prescribing information (label)",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Lbl.pdf",
   "pages": 24,
   "sha256": "b3e7a6ef236d2fa10dc19f6e2499acf963fabb2ed8cfa9f53d4adaf59aad5925",
   "cited": true
  },
  {
   "code": "AdComBriefing",
   "title": "Advisory committee briefing document (FDA and Biogen, November 6, 2020)",
   "url": "https://www.fda.gov/media/143502/download",
   "pages": 343,
   "sha256": "3f86f3d94f7810af32376570aebf692d0792ca2d3c26c563eb55cdaf7a84d588",
   "cited": false,
   "archived_copy": "https://web.archive.org/web/20210919225355id_/https://www.fda.gov/media/143502/download",
   "note": "No longer served by fda.gov; this is the Internet Archive's capture of the original file."
  },
  {
   "code": "AdComTranscript",
   "title": "Advisory committee transcript (November 6, 2020)",
   "url": "https://www.fda.gov/media/145691/download",
   "pages": 325,
   "sha256": "6bd6b905d80fb83afca903f42e7335fe0fe4d56c039acc8b7fec217dd6d45180",
   "cited": false,
   "archived_copy": "https://web.archive.org/web/20210919225355id_/https://www.fda.gov/media/145691/download",
   "note": "No longer served by fda.gov; this is the Internet Archive's capture of the original file."
  },
  {
   "code": "AdComMinutes",
   "title": "Advisory committee minutes (November 6, 2020)",
   "url": "https://www.fda.gov/media/145690/download",
   "pages": 6,
   "sha256": "c632c51b032bb7ee27859558f577d8ac7d3c862a1b5252405c28a9ae3c18fe81",
   "cited": false,
   "archived_copy": "https://web.archive.org/web/20210919225355id_/https://www.fda.gov/media/145690/download",
   "note": "No longer served by fda.gov; this is the Internet Archive's capture of the original file."
  }
 ],
 "missing_documents": [],
 "facts": {
  "action_date": {
   "doc": "Approv",
   "page": 1,
   "excerpt": "Approval Date: 06/07/21",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Approv.pdf#page=1",
   "value": "2021-06-07"
  },
  "sponsor": {
   "doc": "Approv",
   "page": 1,
   "excerpt": "Sponsor: Biogen Inc.",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Approv.pdf#page=1",
   "value": "Biogen Inc."
  },
  "basis": {
   "quote": "This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM.",
   "doc": "Lbl",
   "page": 2,
   "sid": "Lbl:p2:s10",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Lbl.pdf#page=2",
   "label": "Reduction in amyloid beta plaques"
  },
  "committee": {
   "doc": "MedR",
   "page": 133,
   "excerpt": "Peripheral and Central Nervous System Drugs Advisory Committee was held via an online teleconference on November 6, 2020",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=133",
   "name": "Peripheral and Central Nervous System Drugs Advisory Committee",
   "date": "2020-11-06",
   "votes": [
    {
     "doc": "MedR",
     "page": 133,
     "excerpt": "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? Vote Results: Yes: 1 No: 8 Uncertain: 2",
     "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=133",
     "question": "2",
     "yes": 1,
     "no": 8,
     "uncertain": 2,
     "third_label": "uncertain",
     "headline": false
    },
    {
     "doc": "MedR",
     "page": 134,
     "excerpt": "Does Study 103 provide supportive evidence of the effectiveness of aducanumab for the treatment of Alzheimer’s disease? Vote Results: Yes: 0 No: 7 Uncertain: 4",
     "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=134",
     "question": "4",
     "yes": 0,
     "no": 7,
     "uncertain": 4,
     "third_label": "uncertain",
     "headline": false
    },
    {
     "doc": "MedR",
     "page": 134,
     "excerpt": "Has the Applicant presented strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology? Vote Results: Yes: 5 No: 0 Uncertain: 6",
     "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=134",
     "question": "6",
     "yes": 5,
     "no": 0,
     "uncertain": 6,
     "third_label": "uncertain",
     "headline": false
    },
    {
     "doc": "MedR",
     "page": 134,
     "excerpt": "it is reasonable to consider Study 302 as primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease? Vote Results: Yes: 0 No: 10 Uncertain: 1",
     "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=134",
     "question": "8",
     "yes": 0,
     "no": 10,
     "uncertain": 1,
     "third_label": "uncertain",
     "headline": true
    }
   ]
  },
  "confirmatory": {
   "quote": "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.",
   "doc": "Approv",
   "page": 6,
   "sid": "Approv:p6:s18",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Approv.pdf#page=6",
   "label": "PMR 3971-1: randomized, controlled trial",
   "completion": {
    "doc": "Approv",
    "page": 6,
    "excerpt": "Trial Completion: 08/2029",
    "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Approv.pdf#page=6",
    "value": "08/2029"
   }
  }
 },
 "sponsor_ask": {
  "quote": "The applicant’s proposed indication is to delay clinical decline in patients with Alzheimer’s disease.",
  "doc": "MedR",
  "page": 12,
  "sid": "MedR:p12:s12",
  "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=12"
 },
 "positions": [
  {
   "quote": "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.",
   "doc": "ODMemo",
   "page": 3,
   "sid": "ODMemo:p3:s2",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000ODMemo.pdf#page=3",
   "id": "ADU-T1-1",
   "thread": "T1",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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.",
   "doc": "SumR",
   "page": 8,
   "sid": "SumR:p8:s10",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000SumR.pdf#page=8",
   "id": "ADU-T1-2",
   "thread": "T1",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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.",
   "doc": "MedR",
   "page": 14,
   "sid": "MedR:p14:s14",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=14",
   "id": "ADU-T2-1",
   "thread": "T2",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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.",
   "doc": "StatR",
   "page": 111,
   "sid": "StatR:p111:s1",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000StatR.pdf#page=111",
   "id": "ADU-T2-2",
   "thread": "T2",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "The incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoE ε4) carriers than in ApoE ε4 non-carriers (42% and 20%, respectively).",
   "doc": "Lbl",
   "page": 5,
   "sid": "Lbl:p5:s37",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Lbl.pdf#page=5",
   "id": "ADU-T3-1",
   "thread": "T3",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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.",
   "doc": "Lbl",
   "page": 6,
   "sid": "Lbl:p6:s15",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Lbl.pdf#page=6",
   "id": "ADU-T3-2",
   "thread": "T3",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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).",
   "doc": "StatR",
   "page": 9,
   "sid": "StatR:p9:s14",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000StatR.pdf#page=9",
   "id": "ADU-T4-1",
   "thread": "T4",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "Based on the considerations above, the applicant has provided substantial evidence of effectiveness to support approval.",
   "doc": "MedR",
   "page": 133,
   "sid": "MedR:p133:s5",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=133",
   "id": "ADU-T4-2",
   "thread": "T4",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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.",
   "doc": "MedR",
   "page": 240,
   "sid": "MedR:p240:s27",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR.pdf#page=240",
   "id": "ADU-T4-3",
   "thread": "T4",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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.",
   "doc": "Approv",
   "page": 6,
   "sid": "Approv:p6:s18",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000Approv.pdf#page=6",
   "id": "ADU-T5-1",
   "thread": "T5",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  },
  {
   "quote": "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.",
   "doc": "SumR",
   "page": 8,
   "sid": "SumR:p8:s11",
   "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000SumR.pdf#page=8",
   "id": "ADU-T5-2",
   "thread": "T5",
   "status": "Origin",
   "compares_to": null,
   "status_review": "reviewed"
  }
 ],
 "edges": [
  {
   "from": "LEQ-T1-1",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T1-1",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T1"
  },
  {
   "from": "LEQ-T1-2",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T1-2",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T1"
  },
  {
   "from": "LEQ-T2-1",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T2-1",
   "to_decision": "aduhelm-2021-aa",
   "status": "Conditional",
   "thread": "T2"
  },
  {
   "from": "LEQ-T3-1",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T3-1",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T3"
  },
  {
   "from": "LEQ-T3-2",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T3-2",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T3"
  },
  {
   "from": "LEQ-T3-3",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T3-1",
   "to_decision": "aduhelm-2021-aa",
   "status": "Departs",
   "thread": "T3"
  },
  {
   "from": "LEQ-T4-1",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T4-2",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T4"
  },
  {
   "from": "LEQ-T4-2",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T4-3",
   "to_decision": "aduhelm-2021-aa",
   "status": "Conditional",
   "thread": "T4"
  },
  {
   "from": "LEQ-T5-1",
   "from_decision": "leqembi-2023-aa",
   "to": "ADU-T5-1",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T5"
  },
  {
   "from": "DON-T4-1",
   "from_decision": "donanemab-2023-crl",
   "to": "ADU-T4-3",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T4"
  },
  {
   "from": "DON-T4-2",
   "from_decision": "donanemab-2023-crl",
   "to": "ADU-T4-3",
   "to_decision": "aduhelm-2021-aa",
   "status": "Consistent",
   "thread": "T4"
  }
 ]
}