Btobioinnovation.com 

Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT #22.12.5

US Congressional report faults FDA and Biogen for Alzheimer’s drug approval

You will find below the Executive Summary of the US Congressional Report on the Investigation into FDA’s Atypical Review Process and Biogen’s Aggressive Launch Plans prepared by the Staffs of the Committee on Oversight and Reform and Committee on Energy and Commerce  (December 2022)

EXECUTIVE SUMMARY

This staff report presents the findings of an 18-month investigation conducted by the Committees on Oversight and Reform, and Energy and Commerce (the Committees) into the regulatory review and approval, pricing, and marketing of biotechnology company Biogen Inc.’s Alzheimer’s disease drug, aducanumab, known more commonly by its trade name, Aduhelm.

More than six million people in the United States live with Alzheimer’s disease, a number projected to increase to as many as 14 million people by 2060.To best support patients and families impacted by Alzheimer’s disease, advance brain health equity, and eradicate this devastating disease, treatments must be effective, safe, accessible to patients, and affordable for federal health care programs.

The Food and Drug Administration (FDA) granted accelerated approval for Aduhelm on the basis that the drug reduces amyloid beta plaque in the brain. The FDA’s action came despite the fact that Biogen cancelled clinical trials for Aduhelm in March 2019 due to an independent report indicating the drug was unlikely to effectively slow cognitive and functional impairment and that further clinical study would be futile.

In June 2019, FDA and Biogen began a “working group” collaboration to examine data from Biogen’s failed clinical trials.3 New evidence obtained by the Committees shows that the FDA-Biogen working group engaged in at least 115 meetings, calls, and substantive email discussions over the course of a year, from July 2019 to July 2020, including convening more than 40 meetings to guide Aduhelm’s potential approval.

In November 2020, FDA and Biogen prepared and presented a joint briefing document to FDA’s Peripheral and Central Nervous Systems Drugs Advisory Committee (PCNS Advisory Committee)—a joint process that had previously only been used for oncological drugs under circumstances of broad consensus. None of the empaneled PCNS Advisory Committee members voted to recommend traditional approval for Aduhelm. Despite the PCNS Advisory Committee’s lack of recommendation, and internal concerns raised by experts in FDA’s Center for Drug Evaluation and Research’s (CDER) Office of Biostatistics (OB) about the inconsistency of the drug’s clinical data, the agency granted accelerated approval to Aduhelm on June 7, 2021.6

Oversight and Reform Committee Chairwoman Carolyn B. Maloney and Energy and Commerce Committee Chairman Frank Pallone, Jr., announced a joint investigation of the approval and pricing of Aduhelm on June 25, 2021, following concerns about FDA’s review of Aduhelm, significant questions about the drug’s clinical benefit, and the high price of Aduhelm set by Biogen.

This report is intended to provide policymakers, relevant agencies, and the public with an understanding of Aduhelm’s approval process and Biogen’s pricing of Aduhelm. This report also provides recommendations intended to ensure and increase public confidence in the continued safety, efficacy, and affordability of FDA-approved drugs.

Over the course of the investigation, the Committees’ staff held multiple briefings with FDA and reviewed more than 500,000 pages of documents and information from FDA and Biogen, including internal Biogen strategy documents; Biogen’s Board of Directors materials and launch plans; communications among and between senior Biogen and FDA leaders; and internal FDA correspondence and materials. These materials included FDA’s internal review of its interactions with Biogen in preparation for and during the PCNS Advisory Committee meeting, which was conducted in the Spring of 2021 and resulted in a report dated May 30, 2021. Though the internal review concluded the interactions between FDA and Biogen prior to the PCNS Advisory Committee meeting were appropriate, it presented three findings of atypical, processes, and four recommendations for improvement to prevent the situation that prompted the internal review moving forward.

The Committees’ review of these materials reveals that FDA’s review and approval of Aduhelm consisted of atypical procedures and deviated from the agency’s own guidance. These materials also reveal that Biogen had aggressive launch plans for Aduhelm—including in its label and pricing—despite concerns about efficacy, safety, and affordability. The Committees’ investigation found:

● FDA’s Interactions with Biogen Were Atypical and Failed to Follow the Agency’s Own Documentation Protocol: Documents obtained by the Committees show that FDA staff and Biogen engaged in at least 115 meetings, calls, and substantive email exchanges over a 12-month period beginning in July 2019. These exchanges included at least 40 FDA-Biogen “working group” meetings. FDA’s own internal review of the agency’s approval process for Aduhelm found that the extent of collaboration between FDA and Biogen was atypical and “exceeded the norm in some respects.” FDA confirmed that the total number of meetings between FDA staff and Biogen during this time is unknown because FDA lacked a “clear record” of the informal meetings and other interactions between agency staff and Biogen. Of the more than 40 working group meetings between FDA staff and Biogen that were memorialized, not all were properly documented according to internal FDA procedures. The Committees identified an additional 66 calls and substantive email exchanges among the subgroups of the working group that were not memorialized.

● FDA and Biogen Inappropriately Collaborated on a Joint Briefing Document for the PCNS Advisory Committee That Did Not Adequately Represent Differing Views Within FDA: The Committees obtained evidence that FDA and Biogen staff worked closely for several months ahead of the November 6, 2020, PCNS Advisory Committee meeting to prepare the joint briefing document for the Committee’s review. Documents show that using a joint briefing document afforded Biogen advance insight into FDA’s responses and direct guidance from the agency in drafting the company’s own sections. For example, in an exchange of the draft briefing document on October 9, 2020, FDA staff asked Biogen to move a paragraph drafted by the agency into Biogen’s section of the memorandum—a change reflected when the document was finalized. FDA’s internal review determined that the Office of Neuroscience (ON) within CDER’s Office of New Drugs (OND) had failed to obtain internal OND consensus on FDA’s position prior to working with Biogen on the document. The review concluded that “the use of the joint briefing document was not an appropriate approach in this instance” given the substantial disagreement between FDA offices.

● FDA Pivoted to Using the Accelerated Approval Pathway for Aduhelm on a Substantially Abbreviated Timeline: Despite considering Aduhelm under the traditional approval pathway for nine months, documents and information obtained by the Committees show that FDA abruptly changed course and granted approval under the accelerated approval pathway—which allows the use of surrogate clinical endpoints to demonstrate effectiveness—after just three weeks of review. According to senior FDA leadership, the shift in approval pathway from traditional approval to accelerated approval only occurred after an FDA expert council meeting on April 7, 2021, resulted in unfavorable feedback for Aduhelm’s traditional approval. Meeting minutes and FDA’s responses to the Committees show FDA informed Biogen on April 28, 2021, that Aduhelm would be considered under the accelerated approval pathway.

● FDA Approved and Biogen Accepted a Broad Label Indication for Aduhelm Despite Lack of Clinical Data on All Alzheimer’s Disease Stages and Biogen’s Reservations: FDA approved Aduhelm for treatment of “people with Alzheimer’s disease”—a far broader population than Biogen studied in its clinical trials. Materials obtained by the Committees demonstrate that FDA recommended this broad label indication despite the lack of clinical data on disease stages other than mild cognitive impairment (MCI) and mild dementia stage of disease. Internal documents obtained by the Committees show that Biogen accepted this broad indication statement for Aduhelm despite internal reservations about the lack of evidence of clinical benefit for patients at disease stages outside of the clinical trials and an unknown safety profile. In documents, Biogen’s Alzheimer’s disease team leaders expressed concern that the company could lose credibility by advocating for a broad label that exceeded the clinical trial population, and the company even developed a communications strategy to deal with the anticipated fallout. However, company materials noted that Biogen had “NO plan to push back on broad label indication internally or with the regulators,” and Biogen only sought a label update to clarify the appropriate patient population after patient and provider confusion and public criticism when the drug came to market.

• Biogen Set an Unjustifiably High Price for Aduhelm to “Make History” for the Company Despite the Impact on Patients and the Medicare Program: Documents obtained by the Committees show that Biogen viewed Aduhelm as an unprecedented financial opportunity—estimating a potential peak revenue of $18 billion per year—and developed aggressive launch and marketing plans to maximize revenue throughout the drug’s lifecycle. These internal documents show that Biogen initially set Aduhelm’s price at $56,000 per year despite a lack of demonstrated clinical benefit in a broad patient population, and the anticipated financial impact on patients and the Medicare program. A September 2020 5 presentation to the Board stated, “Our ambition is to make history” and “establish ADUHELM as one of the top pharmaceutical launches of all time.” Documents provided to the Committees show that Biogen fully expected the high price would spur “pushback” from providers and payers and that, in anticipation of this backlash, Biogen developed an external narrative about the drug’s value to sell to patients and the public.

● Biogen Expected Aduhelm to Be a Burden to Medicare and Costly to Patients: Internal company documents show that Biogen was aware that the financial burden of its high price for Aduhelm would fall primarily on Medicare. Documents show that Biogen projected Medicare would account for more than 85 percent of the drug’s target patient population at the time of its launch—and that government programs would collectively account for 90 percent of the patient population. A November 2020 presentation to the Board noted, “Aducanumab has the potential to be a significant part of the Medicare Part B budget” and calculated that Aduhelm could cost Medicare $12 billion in one year— representing 36 percent of Medicare’s 2018 Part B budget. Internal company documents also show that Biogen knew based off of previous pricing models that some Medicare patients would struggle to afford Aduhelm. Analyses conducted by Biogen estimated that some Medicare patients could face out-of-pocket costs for Aduhelm of up to 20 percent of their income.

● Biogen Planned to Spend Billions to Market Aduhelm Despite the Financial Impact on Patients and the Health Care System: Internal documents show that Biogen planned an aggressive outreach and marketing campaign to launch Aduhelm, focusing on direct outreach to providers, patients, patient advocacy groups, payers, and even policymakers. In some long-range plans, Biogen anticipated spending more than $3.3 billion on sales and marketing for Aduhelm from 2020 to 2024—more than two and a half times what Biogen spent in total development costs for aducanumab from 2007 until approval in June 2021. In September 2020, Biogen anticipated spending between $500 million and $600 million to build out its sales force, with a focus on targeting physicians. Biogen also aimed to activate patients directly through a variety of strategies, including marketing, media, and patient services.

Given these findings, the Committees recommend FDA take three immediate actions to help restore the American people’s trust in the agency’s processes and assurances of drug safety and efficacy:

1. Ensure that all substantive FDA interactions with drug sponsors are properly memorialized;
2. Establish a protocol for joint FDA-Drug Sponsor Briefing Documents for Advisory Committees; and
3. Update its Guidance for Industry Regarding Development and Review of New Alzheimer’s Drugs.

While FDA’s own internal review conclusions in May 2021 consisted of similar recommendations related to meeting memorialization and use of joint briefing documents, as of August 2022, FDA reported to the Committees that it is still in the process of implementing these recommendations.

In addition, as a result of the Committees’ findings, the Committees also recommend actions that Biogen, and other drug sponsors, take in the future to fulfill their responsibility to the patients and families who may come to rely on their treatments. Biogen and other drug sponsors should:

1. Communicate safety and efficacy concerns clearly to FDA; and
2. Consider the value assessment made by outside experts, including patient access, when setting drug prices.

The American people rely on FDA for assurance on the safety and efficacy of the medications they take. The number of patients and families impacted by Alzheimer’s disease will continue to increase, and it is crucial that FDA and drug companies adhere to established procedures and conduct themselves with the transparency necessary to earn public trust. The Committees urge FDA, Biogen, and other drug sponsors seeking to develop treatments for Alzheimer’s disease and other diseases to follow guidance and protocols, provide transparency into the drug evaluation process and drug pricing, and work to better ensure public trust in future drug approvals.

Paris, December 30, 2022.

This document has been prepared by btobioinnovation and is provided to you for information purposes only.  The information contained in this document has been obtained from sources that btobioinnovation believes are reliable but btobioinnovation does not warrant that it is accurate or complete. The views presented in this document are those of btobioinnovation’s editor at the time of writing and are subject to change.  btobioinnovation has no obligation to update its opinions or the information in this document.