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Ignoring the Experts: Implications of the FDA’s Aduhelm Approval

Published online by Cambridge University Press:  11 July 2022

Alexandra Maulden
Alexandra Maulden*
Affiliation:
Boston University School of Law, Boston, MA
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Abstract

In early June 2021, the U.S. Food and Drug Administration (“FDA”) granted Accelerated Approval to Aducanumab (“Aduhelm”) for treating Alzheimer’s disease. The decision was immediately engulfed in controversy because the agency ignored the Scientific Drugs Advisory Committee’s unanimous recommendation not to approve the drug. The FDA granted the approval based on Aduhelm’s ability to lower beta-amyloid levels. However, the agency had not previously indicated this as a surrogate clinical end for the trial, and its own scientific analysis failed to show that amyloid changes correlate with cognitive or functional changes for Alzheimer’s patients. This decision sets dangerous precedent and has the potential to transform the approval process for new drugs including, but not limited to, those meant to treat Alzheimer’s.

Type
Student notes
Information
American Journal of Law & Medicine , Volume 48 , Issue 1 , March 2022 , pp. 108 - 133
Copyright
© 2022 The Author(s)

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Footnotes

†

J.D. Candidate 2022,; concentration in Health Law; B.A. in Biology, Colgate University. Thank you to Professor Fran Miller for providing invaluable feedback on various drafts of this paper and my fiancée for encouraging me throughout my writing process. The author can be contacted at [email protected]

References

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11 Id.

12 Id. at 11.

13 Id at 9.

14 National Institute on Aging, supra note 9.

15 Id.

16 Patrizia Cavazzoni, FDA’s Decision to Approve New Treatment for Alzheimer’s Disease, U.S. Food & Drug Admin. (June 7, 2021), https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease [https://perma.cc/M8XK-SQ56].

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19 U.S. Food & Drug Admin., Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products 3 (May 1998), https://www.fda.gov/media/71655/download [https://perma.cc/A2MK-D963].

20 Kelly Servick, Alzheimer’s Drug Approved Despite Murky Results, 372 Science 1141, 1141 (2021); Lewis Kuller & Oscar L. Lopez, Engage and Emerge: Truth and Consequences?, 17 Alzheimer’s & Dementia 692, 692 (2021).

21 Feuerstein et al., supra note 18.

22 Id.

23 Id.

24 Id.

25 Biologics are defined as “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” 42 U.S.C. § 262 (2016).

26 Id.

27 Originally, the regulatory system varied greatly between biologics and nonbiologic drugs. In 1997, however, the Food and Drug Administration Modernization Act (FDAMA) amended the Public Health Service Act (PHSA) to establish a single biologics license and specified that the Food, Drug, Cosmetic Act (FD&C Act) applies to Biologics. FDA Modernization Act of 1997, Pub. L. No. 105-115, §123, 111 Stat. 2296, 2323 (1997). Typically, the BLA process has four defined phases: preclinical investigation, clinical investigation, FDA review, and post marketing study. Food & Drug L. Inst., A Practical Guide to FDA’s Food and Drug Law and Regulation 169 (Stephen M. Kanovsky & Wayne L. Pines eds., 2020).

28 Food & Drug L. Inst., supra note 27.

29 Phase 1 studies are meant to establish the safety of the product as well as understand the metabolism and pharmacological actions of the drug, side effects and possible early evidence of effectiveness. Food & Drug L. Inst., supra note 27, at 172.

30 The purpose of Phase 2 trials is to gather evidence of the medication’s effectiveness on the particular disease. Id.

31 Id.

32 A CDER team evaluating the NDA or BLA usually involves a wide array of experts, including physicians, statisticians, chemists, pharmacologists and other scientists. The NDA or BLA requires a large amount of data so that the FDA can complete a thorough evaluation of the drug. How Drugs are Developed and Approved, U.S. Food & Drug Admin. (Jan. 7, 2019), https://www.fda.gov/drugs/development-approval-process-drugs/how-drugs-are-developed-and-approved [https://perma.cc/2GMQ-UFPA].

33 21 U.S.C. §355(d).

34 Id.

35 Development & Approval Process, U.S. Food & Drug Admin. (Oct. 28, 2019). https://www.fda.gov/drugs/development-approval-process-drugs [https://perma.cc/7A8T-RLHV]. However, in guidance document describing the substantial evidence standard, the FDA cautions that reliance on a single large multicenter trial to establish effectiveness should be limited to when the trial has demonstrated a “clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be impractical or unethical. U.S. Food & Drug Admin., supra note 19.

36 21 U.S.C. §355(d).

37 The FDA acknowledges that all drugs come with risks and no drug can be completely safe. This risk/benefit analysis may not always be straightforward and could suffer from imperfect data or differences in opinions within the FDA team. Id.

38 U.S. Food & Drug Admin., supra note 34.

39 New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval, 57 Fed. Reg. 58942 (Dec. 11, 1992).

40 21 C.F.R. §314.510 (2016).

41 Id. (emphasis added).

42 Some examples of a surrogate endpoint are a laboratory measurement, radiographic image, physical sign or another type of measure. 21 U.S.C. § 357(e)(9) (2021).

43 Accelerated Approval, U.S. Food & Drug Admin. (Jan. 4, 2018), https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval [https://perma.cc/TD6G-QLCC].

44 Id.

45 Elisabeth Rosenthal, Why We May Never Know Whether the $56,000-a-year Alzheimer’s Drug Actually Works, KHN (July 12, 2021), https://khn.org/news/article/commentary-aduhelm-alzheimers-drug-effectiveness/ [https://perma.cc/F89K-3JVW].

46 Brian P. Dunleavy, 64% of FDA-Approved Meds Pass Through Streamlined Processes, UPI (Apr. 21, 2020), https://www.upi.com/Health_News/2020/04/21/64-of-FDA-approved-meds-pass-through-streamlined-processes/9821587475020/ [https://perma.cc/K6HT-DJQH].

47 Id.

48 Id.

49 Rosenthal, supra note 45.

50 FDA-TRACK: Advisory Committees Dashboard, U.S. Food & Drug Admin. (Sept. 30, 2021), https://www.fda.gov/about-fda/fda-track-agency-wide-program-performance/fda-track-advisory-committees-dashboard [https://perma.cc/38DV-ZL9K].

51 Generally, a majority of advisory committees consists of research and clinical specialists who are considered experts in the field, but they also include a consumer representative, industry representative and at least two specialists in the disease or condition for which the drug is meant to treat. The Food and Drug Administration Safety and Innovation Act (FDASIA) amended conflict of interest rules to improve outside expert recruitment and expand the number of experts who qualify to sit on the advisory committees. Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144,126 Stat. 993 (2012). This was done to ensure advisory committees reflected the most current expert guidance. Food & Drug L. Inst., supra note 27.

52 U.S. FOOD & DRUG ADMIN., FINAL SUMMARY MINUTES OF THE PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS ADVISORY COMMITTEE MEETING 2 (Nov. 6, 2020).

53 Id.

54 Inst. Med. & Comm. to Study Use Advisory Comms., Food and Drug Administration Advisory Committees (Richard A. Rettig, Laurence E. Earley, & Richard A. Merrill eds., 1992).

55 Id.

56 Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 STAT 823. Even when CDER is not required to use advisory committees, it tends to use them more frequently when the new drug is therapeutically significant or has particularly complex data. Food & Drug L. Inst., supra note 27, at 183.

57 Food & Drug L. Inst., supra note 27.

58 The Federal Advisory Committee Act requires that all advisory committee’s decisions, not just those operating in the FDA, must be reviewed by a government official. Pub. L. 92-463, Oct. 6, 1972, 86 Stat. 770 (5 U.S.C. App.) (2022).

59 FDA Modernization Act of 1997, Pub. L. No. 105-115, § 120, 111 Stat. 2296, 2320.

60 Feuerstein et al., supra note 18.

61 Id.

62 Id.

63 Id.

64 Id.

65 Id.

66 This FDA-written memo was previously undisclosed and only read aloud to a STAT reporter. Id.

67 Id.

68 Id.

69 Id.

70 See Samantha Budd Haeberlein, Vice President of Late Stage Clinical Development, Biogen, Remarks during Biogen Third Quarter 2019 Financial Results and Business Update (Oct. 22, 2019), as transcribed by The Motley Fool, https://www.fool.com/earnings/call-transcripts/2019/10/22/biogen-inc-biib-q3-2019-earnings-call-transcript.aspx [https://perma.cc/YLC8-S9J7] (last visited Mar. 2, 2022)

71 See Alfred Sandrock, Executive Vice President of Research & Development and Chief Medical Officer, Biogen, Remarks during Biogen Third Quarter 2019 Financial Results and Business Update (Oct. 22, 2019), as transcribed by The Motley Fool, https://www.fool.com/earnings/call-transcripts/2019/10/22/biogen-inc-biib-q3-2019-earnings-call-transcript.aspx [https://perma.cc/VV6Y-526C] (last visited Mar. 2, 2022).

72 Although Biogen didn’t reveal actual participant data, EMRGE patients showed a 23% reduction in decline on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score, a 27% reduction of the AD assessment Scale-Cognitive Subscale 13 items (ADAS-Cog-13) and a 40% reduction on the AD Cooperative Study activities of Daily Living Inventory for Mild Cognitive Impairment (ADCS-ADL-MCI) compared to the placebo group. Robert Howard & Kathy Y Liu, Questions EMERGE as Biogen Claims Aducanumab Turnaround, 16 Nature Revs. Neurology 63, 63 (2020).

73 Id.

74 Id. at 63-64.

75 Id.

76 Subjects were randomized into 1 of 3 treatment groups: Aduhelm high dose, Aduhelm low dose and placebo. However, in each treatment group, the dose level varied based on whether the participant carrier status for a specific gene, ApoE ε4. Originally, ApoE ε4 carriers in the high dose treatment arm received 6mg/kg before the mid study protocol amendment raised the dosage to 10mg/kg. Food & Drug Admin., Ct r. Drug Evaluation & Rs ch., Application Number: 761178Orig1s000 Statistical Review(s) 9 (July 7, 2020); Ned Pagliarulo & Jonathan Gardner, 7 Questions on Biogen’s Revival of a Failed Alzheimer’s Drug, BioPharmaDive (Oct. 22, 2019), https://www.biopharmadive.com/news/biogen-alzheimers-aducanumab-revival-7-questions/565609/ [https://perma.cc/AC6Z-PZT2].

77 Pagliarulo & Gardner, supra note 76.

78 Howard & Liu, supra note 71, at 64; see Lon Schneider, A Resurrection of Aducanumab for Alzheimer’s Disease, 19 Lancet Neurology 111 (Feb. 2020) (arguing the difference in study results “could just as likely been due to greater worsening in the placebo group” rather than greater exposure to the higher dose in the larger dataset).

79 One study had a statistically significant effect for the high dose (p=0.01), but the other study did not have a statistically significant effect (p=0.83). Food & Drug Admin., supra note 75, at 7.

80 Id. at 9.

81 The 2019 draft guidance on substantial evidence states that “poor execution can render a trial of any design to be not adequate or not well-controlled and, therefore, unable to provide substantial evidence of effectiveness. Examples of this include a randomized, double-blind, placebocontrolled trial in which unblinding is common due to an effect of the test drug, and where a modest treatment effect is found on a primary endpoint that is subject to bias when drug assignment is known (e.g., a physician global impression). In these cases, the trials might not be considered adequate and well-controlled.” Food & Drug Admin., Ct r. for Biologics Evaluation & Rs ch., Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products 7 (Dec. 2019).

82 Food and Drug Admin., supra note 75, at 111.

83 Feuerstein et al., supra note 18.

84 U.S. Food & Drug Admin., Final Summary minutes of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting 4 (Nov. 6, 2020).

85 Id.

86 Id.

87 Id.

88 U.S. Food & Drug Admin., Summary Memorandum 55 (June 7, 2021) (on file with journal); see also Feuerstein et al., supra note 18.

89 U.S. Food & Drug Admin., supra note 87; see also Feuerstein et al., supra note 18.

90 Id.

91 Id.

92 Ctr. Drug Evaluation & Rsch., supra note 75.

93 Rowan Walrath, For Alzheimer’s Patient Advocates, Biogen’s Drug Approval Opens the Door, Bos. Bus. J., (June 10, 2021, 5:33 AM) https://www.bizjournals.com/boston/news/2021/06/10/alzheimers-drug-patient-advocate-reactions-biogen.html [https://perma.cc/6SU8-KCAC].

94 Laurie McGinley, The Controversial Approval of an Alzheimer’s Drug Reignites the Battle over the Underlying Cause of the Disease, Wash. Post (July 16, 2021, 5:10 PM), https://www.washingtonpost.com/health/2021/07/05/aduhelm-new-alzheimers-drug-amyloid/ [https://perma.cc/TY5D-PUQY].

95 Jeffrey Toobin, The Road to Aduhelm: What One ex-FDA Adviser Called ‘Probably the Worst Drug Approval Decision in Recent US History’ for an Alzheimer’s Treatment, CNN (Sept. 27, 2021, 10:01 AM), https://www.cnn.com/2021/09/26/politics/alzheimers-drug-aduhelm-fda-approval/index.html [https://perma.cc/H6D5-FQDM].

96 Memorandum from Billy Dunn, Director of Office of Neuroscience, FDA, to Nathan Fountain, Chairperson, Peripheral and Central Nervous System Drugs Advisory Committee (June 7, 2021).

97 Id.

98 Alexander et al., supra note 5; U.S. Food & Drug Admin., Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) Meeting, 140 (Nov. 6, 2020 10:00 to 5:06p.m.), https://www.fda.gov/media/145691/download [https://perma.cc/3E9H-C7MH].

99 Feuerstein et al., supra note 18.

100 Alexander et al., supra note 5 at 770.

101 U.S. Food & Drug Admin., Early Alzheimer’s Disease: Developing Drugs for Treatment 6 (Feb. 2018), https://www.fda.gov/files/drugs/published/Alzheimer’s-Disease---Developing-Drugs-for-Treatment-Guidance-for-Industy.pdf [https://perma.cc/A2TL-ARNU].

102 U.S. Food & Drug Admin., Full Prescribing Information 2, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf [https://perma.cc/6L5C-NPBE] (revised June 2021).

103 Andrew Joseph, An Extra Twist in the FDA’s Alzheimer’s Decision: No Limits on Which Patients Can Get The Drug, STAT (June 7, 2021), https://www.statnews.com/2021/06/07/twist-fda-alzheimers-decision-no-limits-on-patients/ [https://perma.cc/F6D7-Z9K3].

104 Id.

105 Id.

106 Id.

107 Adam Feuerstein, Under Fire from Critics, Revises Prescribing Information for Biogen’s Alzheimer’s Drug, STAT (July 8, 2021) https://www.statnews.com/2021/07/08/fda-under-fire-from-critics-revises-prescribing-information-for-biogens-alzheimers-drug/ [https://perma.cc/U5A7-MRS6]; U.S. Food & Drug Admin., supra note 101.

108 Feuerstein, supra note 107.

109 Id. at 5.

110 Mark Terry, JAMA Paper Withdrawal Adds One More Layer to Aduhelm Controversy, BioSpace (July 28, 2021), https://www.biospace.com/article/biogen-withdraws-aduhelm-clinical-trial-paper-from-jama/ [https://perma.cc/K6VZ-FR3L].

111 Bob Herman, Biogen Pulled Aduhelm Paper after JAMA Demanded Edits, Axios (July 27, 2021), https://www.axios.com/biogen-jama-aduhelm-clinical-trial-results-publish-fc7c2876-a684-4bfc-8462-4165f57d735a.html [https://perma.cc/2PAV-S5DN].

112 Id.

113 Id.

114 Damian Garde & Adam Feuerstein, Biogen CEO: Company was ‘Wrong’ About Initial Aduhelm Price, ‘Courageous’ to Lower It, STAT (Jan. 10, 2022), https://www.statnews.com/2022/01/10/biogen-ceo-company-was-wrong-about-initial-aduhelm-price-courageous-to-lower-it/ [https://perma.cc/BQF8-EF4M].

115 Id.

116 Feuerstein et al., supra note 18.

117 Toobin, supra note 95.

118 Alexander et al. supra note 5, at 771.

119 Feuerstein et al., supra note 18.

120 Id.

121 Andrew Joseph, Third Member of FDA Expert Committee Resigns over Controversial Alzheimer’s Therapy Decision, STAT (June 10, 2021), https://www.statnews.com/2021/06/10/third-member-of-fda-expert-committee-resigns-over-controversial-alzheimers-therapy-decision/ [https://perma.cc/9SYY-LQDQ].

122 Id.

123 Moira McCarthy, FDA Panel Member Tells Healthline Why he Resigned Over Alzheimer’s Drug Approval, Healthline (July 1, 2021), https://www.healthline.com/health-news/qa-with-fda-panel-member-who-resigned#1 [https://perma.cc/ER24-5UJB].

124 Ed Silverman, FDA Approves Sarepta’s Controversial Drug for Duchenne Muscular Dystrophy, STAT (Sept. 19, 2016), https://www.statnews.com/pharmalot/2016/09/19/sarepta-wins-dmd-drug-approval/ [https://perma.cc/2CWA-CYU9].

125 FDA Panel Does not Support Approval of Eteplirsen, Innovative Sci. Sols. (Aug. 15, 2016), https://innovativescience.net/fda-panel-does-not-support-approval-of-eteplirsen/ [https://perma.cc/X6CQ-FUZK].

126 Id.

127 U.S. Food & Drug Admin., NDA 206488 Accelerated Approval (2016); Silverman, supra note 124.

128 Annemieke Aartsma-Rus & Nathalie Goemans, A Sequel to the Eteplirsen Saga: Eteplirsen is Approved in the United States but was not Approved in Europe, 29 Nucleic Acid Therapeutics 13, 13 (2019).

129 Id.

130 Update on Regulatory Submission for Aducanumab in the European Union, Biogen (Dec. 17, 2021) https://investors.biogen.com/news-releases/news-release-details/update-regulatory-submission-aducanumab-european-union [https://perma.cc/8NHV-KQBK].

131 McCarthy, supra note 122; Letter from Aaron Kesselheim, Professor of Medicine, Brigham and Women’s Hospital, to Janet Woodcock, Acting Commissioner of Food and Drugs (June 10, 2021).

132 Aaron Kesselheim & Jerry Avorn, Approving a Problematic Muscular Dystrophy Drug: Implication for FDA Policy, 315 JAMA 2357, 2357 (2016); U.S. Food & Drug Admin., Scientific Dispute Regarding Accelerated Approval of Sarepta Therapeutics’ Eteplirsen (NDA 206488) 2-5 (Sept. 16, 2016); Toobin, supra note 95.

133 Kesselheim & Avorn, supra note 132; U.S. Food & Drug Admin., supra note 132.

134 Audrey D. Zhang, Jason Schwartz & Joseph Ross, Association Between Food and Drug Administration Advisory Committee Recommendations and Agency Actions 2008—2015, 97 Milbank Q. 796, 796 (2019).

135 Letter from Aaron Kesselheim, Professor of Medicine, Brigham and Women’s Hospital, to Janet Woodcock, Acting Commissioner of Food and Drugs (June 10, 2021).

136 Dr. Janet Woodcock (@DrWoodcockFDA), Twitter (Jul. 9, 2021, 12:49 PM) https://twitter.com/DrWoodcockFDA/status/1413540801934774283 [https://perma.cc/R9K2-UUG6].

137 Letter from Carolyn B Maloney & Frank Pallone, Committee on Oversight and Reform and the Committee on Energy and Commerce to Michel Vounatsos, (July 12, 2021) https://oversight.house.gov/sites/democrats.oversight.house.gov/files/2021-07-12.CBM%20Pallone%20to%20Vounatsos-Biogen%20re%20Aduhelm.pdf [https://perma.cc/UF2D-7A6X].

138 Letter from Carolyn B Maloney & Frank Pallone, Committee on Oversight and Reform and the Committee on Energy and Commerce to Michel Vounatsos, (Sept. 1, 2021) https://energycommerce.house.gov/sites/democrats.energycommerce.house.gov/files/documents/EC%20COR%20FDA%20Aduhelm%20Letter%209.1.21.pdf [https://perma.cc/XH5K-8HAU].

139 Id.

140 Aducanumab for Alzheimer’s Disease: Effectiveness and Value, Inst. for Clinical & Econ. Rev. (June 30, 2021) https://icer.org/wp-content/uploads/2020/10/ICER_ALZ_Revised_Evidence_Report_06302021.pdf [https://perma.cc/D4VZ-UVCB].

141 Berkeley Lovelace Jr., Biogen Faces Tough Questions Over $56k-a-year Price of Newly Approved Alzheimer’s Drug, CNBC (June 8, 2021) https://www.cnbc.com/2021/06/08/biogen-faces-tough-questions-over-56k-a-year-price-of-newly-approved-alzheimers-drug.html [https://perma.cc/6APQ-H6X7].

142 Id.

143 Id.

144 Id.

145 Garde & Feuerstein, supra note 114.

146 Andrew Joseph & Rachel Cohrs, Alzheimer’s Patients are in Limbo as Hospitals, Insurers Grapple with Whether to Offer Aduhelm, STAT (Aug. 4, 2021), https://www.statnews.com/2021/08/04/alzheimers-patients-in-limbo-as-hospitals-insurers-grapple-aduhelm/ [https://perma.cc/7XD9-6TD4].

147 The FDA decision to overrule the advisory committee and grant approval has caused many insurance companies to pause. CeCi Connolly, president and CEO of the Alliance of Community Health Plans, has said “at a minimum [it]suggests [that] we’ve got to keep digging.” Id.

148 Initially, Massachusetts’s second biggest health insurer threatened to limit or not cover Aduhelm unless the price is lowered. In a statement, they accused Biogen of “putting excessive corporate profits ahead of patients.” Jonathan Saltzman, State’s Second-largest Health Insurer Slams Biogen for Costly Alzheimer’s Drug, Bos. Globe, (June 23, 2021), https://www.bostonglobe.com/2021/06/23/business/states-second-largest-health-insurer-slams-biogen-costly-alzheimers-drug/ [https://perma.cc/7A4N-CF95]. In August 2021, they released another statement confirming that they would not cover the drug. Joseph O’Riordan, Aducanumab (Aduhelm) is Considered Experimental and Investigational, Harvard Pilgrim HealthCare (Aug. 2021), https://www.harvardpilgrim.org/provider/aducanumab-aduhelm-is-considered-experimental-and-investigational/ [https://perma.cc/V2EM-73RB].

149 Jonathan Saltzman, ‘This is Unprecedented’: Several Private Insurers Won’t Cover Biogen’s Alzheimer’s Drug, Bos. Globe (July 13, 2021, 7:08 PM), https://www.bostonglobe.com/2021/07/13/business/this-is-unprecedented-several-private-insurers-wont-cover-biogens-alzheimers-drug/?p1=BGSearch_Overlay_Results [https://perma.cc/BML7-PMQJ].

150 Id.

151 Ned Pagliarulo, VA Leaves Aduhelm off Coverage List, Recommending Against Controversial Alzheimer’s Drug, BIOPHARMADIVE (Aug. 12, 2021), https://www.biopharmadive.com/news/va-aduhelm-formulary-coverage-alzheimers/604884/ [https://perma.cc/B3AY-FLM2].

152 Rebecca Robbins, Sales of Biogen’s Costly New Alzheimer’s Drug Fall Far Short of Expectation, N.Y. Times (Oct. 20, 2021), https://www.nytimes.com/2021/10/20/business/biogen-aduhelm-sales-q3-2021.html [https://perma.cc/5XSV-C3MW].

153 As part of the policy, VA providers are asked to conduct obtain braining scans to confirm amyloid plaques and recommends gene testing to determine if patients have the gene associated with higher risk of brain swelling. Pagliarulo, supra note 143.

154 Rachel Dolan & Elizabeth Williams, How Might the FDA’s Approval of a New Alzheimer’s Drug Impact Medicaid?, Kaiser Fam. Found. (July 13, 2021), https://www.kff.org/medicaid/issue-brief/how-might-the-fdas-approval-of-a-new-alzheimers-drug-impact-medicaid/ [https://perma.cc/WUK8-6BS6].

155 Paige Minemyer, CMS Official Says Medicaid Must Cover Aduhelm as Industry Awaits National Coverage Decision, Fierce Healthcare, (Sept. 23, 2021, 12:12 PM), https://www.fiercehealthcare.com/payer/cms-says-medicaid-must-cover-aduhelm-as-industry-awaits-its-national-coverage-decision [https://perma.cc62YP-S7HW].

156 Juliette Cubanski & Tricia Neuman, FDA’s Approval of Biogen’s New Alzheimer’s Drug Has Huge Cost Implications for Medicare and Beneficiaries, Kaiser Fam. Found. (June 10, 2021), https://www.kff.org/medicare/issue-brief/fdas-approval-of-biogens-new-alzheimers-drug-has-huge-cost-implications-for-medicare-and-beneficiaries/ [https://perma.cc/T2LS-9QR5].

157 Id.

158 Matt Salo, Opinion, Much Adu(helm) About Nothing: New Alzheimer’s Drug Threatens State Medicaid Budgets, STAT (Oct. 12, 2021), https://www.statnews.com/2021/10/12/new-alzheimers-drug-threatens-state-medicaid-budgets/ [https://perma.cc/L2JM-NFVE].

159 Letter from Jami Snyder & Allison Taylor, Nat’l Assoc. of Medicaid Dirs., to Chiquita Brooks-LaSure, Administrator, Ctr. for Medicare & Medicaid Servs. (Aug. 11, 2021), https://medicaid_directors.org/wp-content/uploads/2022/02/NAMD-Urges-Medicare-to-Not-to-Shift-Cost-of-Alzheimers-Drug-to-Medicaid-updated_pdf.pdf [https://perma.cc/2AJX-5XV6].

160 Ed Silverman, A Looming Decision on Medicare Coverage for Biogen’s Alzheimer’s Drug Could Shock State Medicaid Programs, STAT (Jan. 10, 2022), https://www.statnews.com/pharmalot/2022/01/10/alzheimers-biogen-medicare-medicaid-hepatitis/ [https://perma.cc/58ZN-3VTA].

161 Id.

162 Id.

163 Ctrs. for Medicare & Medicaid Servs., CAG-00460N, Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease, https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&ncaid=305&keyword=aduhelm&keywordType=starts&areaId=all&docType=NCA%2cCAL%2cNCD%2cMEDCAC%2cTA%2cMCD%2c6%2c3%2c5%2c1%2cF%2cP&contractOption=all&sortBy=relevance&bc=1 [https://perma.cc/SS85-3DWU] (last visited Feb. 27, 2022).

164 Rachel Cohrs, Medicare Plans to Restrict Access to Controversial, Pricey Alzheimer’s drug Aduhelm to Patients in Clinical Trials, STAT (Jan. 11, 2022), https://www.statnews.com/2022/01/11/medicare-aduhelm-proposed-decision/ [https://perma.cc/VQD7-9F7D].

165 Nicholas Florko, With its Aduhelm proposal, Medicare is Stepping into a Heated Debate About How Best to Improve Equity in Alzheimer’s Treatment, Stat (Jan. 13, 2022), https://www.statnews.com/2022/01/13/medicare-aduhelm-proposal-debate-equity-alzheimers-treatment/ [https://perma.cc/8J2C-6VTH].

166 Katherine Ellen Foley & Megan Wilson, ‘Not a Tolerable Situation’: Patient Groups Take AIM at CMS over Alzheimer’s Coverage Decision, Politico (Jan. 17, 2022, 7:00 AM), https://www.politico.com/news/2022/01/17/alzheimers-coverage-patient-groups-cms-527170 [https://perma.cc/6P9L-EJYH].

167 Letter from Comm. on Energy & Com. to Xavier Becerra & Chiquita Brooks-Lasure, Dep’t of Health & Hum. Servs., (Feb. 8, 2022), https://republicans-energycommerce.house.gov/wp-content/uploads/2022/02/02.08.22-Letter-to-Becerra-re-CMS-NCD.pdf?utm_campaign=pharmalittle&utm_medium=email&_hsmi=203520149&_hsenc=p2ANqtz-_G57M0675zDT_XBfjTIWpQ-6otLcvcsqlHOD2DNoeBdmQYfxa5Owugugc9t46-KgVKGxkaT3g8MWIDgHqZDurXNVt1Fw&utm_content=203520149&utm_source=hs_email [https://perma.cc/SKY5-33EZ].

168 Letter from Biogen to Tamara Syrek Jensen, Director, Coverage & Analysis Grp., Ctrs. for Medicare & Medicaid Servs., (Feb. 10, 2022), https://investors.biogen.com/static-files/48bc8500-bf36-4be1-ae87-81d4bab2d05f [https://perma.cc/XCC8-6XTD] (Public comment in response to CMS draft decision, supra note 155, titled, “Proposed Decision Memorandum for Monoclonal Antibodies Directed Amyloid for the Treatment of Alzheimer’s Disease”).

169 Id.

170 Id.

171 Id.

172 Id.

173 Nicholas Florko, Biogen Pushes Back on Medicare’s Limits on Alzheimer’s Drug Coverage—And Advances a Counter Offer, STAT (Feb. 10, 2022), https://www.statnews.com/2022/02/10/biogen-pushes-back-on-medicares-limits-on-alzheimers-drug-coverage-and-advances-a-counteroffer/ [https://perma.cc/JJ83-AS84].

174 Rachel Cohrs, Medicare Finalizes its Restrictions on new Alzheimer’s Drug, Despite Pressure from Drugmakers, STAT (Apr 7, 2022), https://www.statnews.com/2022/04/07/medicare-final-decision-alzheimers-coverage-biogen-aduhelm/?utm_campaign=pharmalittle&utm_medium=email&_hsmi=209433325&_hsenc=p2ANqtz--wOxAfI409ZSPBV4DqCodQobAyUiugEjIb0_AHL08hkCHWCj04xTZeps9He2DZDIIUPJAiVRBmv-Exmr3-ovyhAjTl3g&utm_content=209433325&utm_source=hs_email [https://perma.cc/5JCX-S8YN].

175 Id.

176 Press Release, CMS Finalizes Medicare Coverage Policy for Monoclonal Antibodies Directed Qagainst Amyloid for the Treatment of Alzheimer’s Disease, Ctrs for Medicare & Medicaid Services (April 07, 2022), https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment [https://perma.cc/5S3A-G8JA].

177 Id.

178 Rachel Cohrs, supra note 164.

179 John N. Mafi & Catherine Sarkisian, Medicare got it Right: Unproven Alzheimer’s Drug would have Threatened the Financial Stability of 60 Million Americans, STAT (April 8, 2022), https://www.statnews.com/2022/04/08/medicare-right-decision-limit-coverage-aduhelm/ [https://perma.cc/7AKR-J3HX].

180 Id.

181 Megan Wilson, Narrow Aduhelm Coverage Sparks Debate over Viability of Future Treatments, Politico, (04/09/2022 0:700am), https://www.politico.com/news/2022/04/09/alzheimer-drug-aduhelm-medicare-coverage-00024222 [https://perma.cc/54EU-9ZQP].

182 The Cleveland Clinic, Mount Sinai Health System and Mass General Brigham have announced they would not cover the drug. Joseph & Cohrs, supra note 138; Information on the Drug Aduhelm (Aducanumab) for Alzheimer’s Disease, Brigham & Woman’s Hospital, https://www.brighamandwomens.org/neurology/cognitive-and-behavioral-neurology/alzheimers-disease-drug-aducanumab [https://perma.cc/9LCT-SXNP] (last visited 10/29/21).

183 Pam Belluck, Cleveland Clinic and Mount Sinai Won’t Administer Aduhelm to Patients, N.Y. Times (Sept. 2, 2021), https://www.nytimes.com/2021/07/14/health/cleveland-clinic-aduhelm.html#:~:text=the%20main%20story-,Cleveland%20Clinic%20and%20Mount%20Sinai%20Won’t%20Administer%20Aduhelm%20to,its%20approval%20by%20the%20F.D.A [https://perma.cc/AX2U-W8UA].

184 Id.

185 Ed Silverman, Poll: Most Neurologists and Primary Care Doctors Disagree with FDA’s Approval of Alzheimer’s Drug, STAT (June 30, 2021), https://www.statnews.com/2021/06/30/biogen-alzheimers-fda-neurologists-primary-care/ [https://perma.cc/3PU9-QY8P].

186 Id.

187 Damian Garde & Adam Feuerstein, Biogen’s Aduhelm Sales Fall Dramatically Below Wall Street’s Expectation, STAT (Oct. 20, 2021), https://www.statnews.com/2021/10/20/biogens-aduhelm-sales-dramatically-below-wall-street-expectation/ [https://perma.cc/SE6U-UWTU].

188 Biogen only made about $300,000 from Aduhelm. This is significantly lower than both Wall Street’s expectation and Biogen’s own goal. Id.

189 Rebecca Robbins, Sales of Biogen’s Costly New Alzheimer’s Drug Fall Far Short of Expectations, N.Y. Times (Oct. 20, 2021), https://www.nytimes.com/2021/10/20/business/biogen-aduhelm-sales-q3-2021.html [https://perma.cc/MQB9-TVB2].

190 Garde & Feuerstein, supra note 172.

191 See generally Francesco Panza et al., A Critical Appraisal of Amyloid β-targeting therapies for Alzheimer Disease, 15 Nature Revs. Neurology 73 (2019).

192 See Adam Adam Feuerstein, Biogen, Eisai Seek Fast Approval for Second Alzheimer’s Drug, Relying on Relaxed FDA Standard, STAT (Sept. 28, 2021) [hereinafter Biogen, Eisai], https://www.statnews.com/2021/09/28/biogen-eisai-seek-fast-approval-for-second-alzheimers-drug-relying-on-relaxed-fda-standard/ [https://perma.cc/7R4K-5X3Y].

193 Adam Feuerstein, In Reversal, Eli Lilly Now Intends to Seek Fast Approval for Alzheimer’s Treatment, STAT (June 24, 2021), https://www.statnews.com/2021/06/24/eli-lilly-seek-fast-approval-for-alzheimers-treatment/ [https://perma.cc/49BD-CCR2].

194 Id.

195 Biogen, Eisai, supra note 192.

196 Unlike Aduhelm, Eisai and Biogen only completed a phase 2 clinical trial. A Phase 3 clinical trial has been fully enrolled, but the study will not end until Fall 2022. Id.

197 Andrew Joseph, Member of FDA’s Expert Panel Resigns Over Controversial Alzheimer’s Therapy Approval, STAT (June 8, 2021), https://www.statnews.com/2021/06/08/fda-expert-panel-resigns-alzheimers-approval/ [https://perma.cc/635Y-FSB4].

198 Id.

199 FDA’s drug center chief Patrizia Cavazzoni argued there aren’t comparable surrogate endpoints for ALS to use the Accelerated Approval pathway and any Phase 3 trial that does not reach its primary endpoint would not be enough to gain its endpoint. Since there is still uncertainty whether amyloid plaques cause Alzheimer’s, this decision (and comment) has outraged many members of the ALS community. Nicholas Florko, Advocates Blast the FDA For Not Moving as Fast on ALS as on Alzheimer’s, STAT (June 11, 2021), https://www.statnews.com/2021/06/11/advocates-blast-fda-for-not-fast-als-alzheimers/ [https://perma.cc/S676-VMVY].

200 Darryl C. Murphy, New Hope for ALS Patients After FDA Reverses Course On Possible Treatment, WBUR (Sept. 17, 2021), https://www.wbur.org/news/2021/09/17/amylyx-early-approval-fda [https://perma.cc/62T3-4ZDH].

201 Id.

202 Id.

203 Ed Silverman et al., The Biggest Losers from Medicare’s Decision on Aduhelm may be Biogen’s Competitors, STAT (Jan. 12, 2022), https://www.statnews.com/pharmalot/2022/01/12/biggest-losers-biogen-competitors-medicare-aduhelm/ [https://perma.cc/A6JJ-SRA8].

204 Id.

205 Centers for Medicare & Medicaid Services, supra note 168.

206 Many top FDA officials have strong ties with the pharmaceutical industry. Additionally, under the Prescription Drug User Fee Act (PDUFA), much of the FDA’s budget comes from the pharmaceutical companies paying the FDA to review new drug applications. In this way they are somewhat beholden to the industry they are meant to regulate. See David S. Hilzenrath, Drug Money: FDA Depends on Industry Funding; Money Comes with “Strings Attached”, Project on Gov’t Oversight, (Dec. 01, 2016), https://www.pogo.org/investigation/2016/12/fda-depends-on-industry-funding-money-comes-with-strings-attached/#:~:text=Currently%2C%20the%20fees%20drug%20companies%20pay%20for%20the,guarantee%20that%20the%20FDA%20will%20approve%20the%20drug [https://perma.cc/3NG6-WU5E]; Massimo Calabresi, Candidate to Lead FDA has Close Ties to Big Pharma, Time (Feb. 19, 2015, 5:00 AM), https://time.com/3714242/candidate-to-lead-fda-has-close-ties-to-big-pharma/ [https://perma.cc/7Z4A-3EK R]; Katie Thomas, F.D.A. Official Under Bush Is Trump’s Choice to Lead Agency, N.Y. Times (Mar. 10, 2017), https://www.nytimes.com/2017/03/10/health/fda-scott-gottlieb.html [https://perma.cc/U6JG-USEU].

207 Looking purely at numbers, it is clear the FDA has consulted advisory committees less in recent years despite approving more novel therapies. This trend should be reversed. Mark Senak, AdComms—Is FDA Getting Less Advice?, Eye on FDA (Aug. 5, 2021), http://eyeonfda.com/2021/08/adcomms-is-fda-getting-less-advice/ [https://perma.cc/GM9R-A7UC].

208 Audrey D. Zhang et al., Association Between Food and Drug Administration Advisory Committee Recommendations and Agency Actions 2008—2015, 97 Milbank Q. 796, 803 (2019).

209 Id.

210 See, e.g., Cary Funk et al., 5 Key Findings About Public Trust in Scientists in the U.S., Pew Rsch. (Aug. 5, 2019), https://www.pewresearch.org/fact-tank/2019/08/05/5-key-findings-about-public-trust-in-scientists-in-the-u-s/ [https://perma.cc/449B-HTFZ] (“More than half of Americans (57%) say they trust research findings more if the data from the study is openly available to the public, and 52% say they trust research findings more if they have been reviewed by an independent committee.”).

211 18 U.S.C. §208 (2020).

212 U.S. Food & Drug Admin., Procedures for Evaluating Appearance Issues and Granting Authorizations for Participation in FDA Advisory Committees (June 2016), https://www.fda.gov/media/98852/download [https://perma.cc/H3LK-2TMW]; Michael Mezher, FDA Issues New Guidance on Conflict of Interest for Advisory Committee Members, Regul. Affs. Pro. Soc’y (June 28, 2016), https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/6/fda-issues-new-guidance-on-conflict-of-interest-for-advisory-committee-members [https://perma.cc/CZ9B-Z59Y].

213 U.S. Food & Drug Admin., supra note 211, at 13.