FDA’s Alzheimer’s Drug Decision Clouds House User Fee Discussion

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In a fairly standard discussion about renewal of FDA’s user fees, House lawmakers used the opportunity to query the agency’s officials about the controversial approval of the Alzheimer’s drug aducanumab (Aduhelm).

During a hearing of a House Committee on Energy & Commerce’s Subcommittee on Health on Thursday, aducanumab was the proverbial elephant in the room, as members questioned FDA’s leadership surrounding the drug’s approval, and the effect of the Centers for Medicare & Medicaid Services’ (CMS) equally contentious coverage decision regarding the drug.

Critics of the FDA’s decision charged that the drug’s approval will encourage “bad innovation,” while proponents of the drug claim Medicare’s proposed coverage restrictions will have a “chilling effect” on research and development in the Alzheimer’s space.

Accelerated Approval: Aducanumab Looms Large

Reshma Ramachandran, MD, a physician-fellow at the Yale National Clinician Scholars Program and a witness for the committee, said the FDA’s decision on aducanumab illustrates how the agency was “putting industry interests before that of patients.”

Ramachandran, who is also chair of the Doctors for America FDA Task Force, was especially critical of the accelerated approval process used in the aducanumab decision. As part of this expedited process, drug sponsors are able to seek approvals based on shorter clinical trials and surrogate endpoints “hypothesized to be associated with clinically meaningful outcomes.”

Sponsors, in turn, are required to conduct post-approval trials to confirm clinical benefit. However, as of 2020, close to half of the drugs that received accelerated approval have not yet demonstrated clinical benefit for patients, she said.

In the case of aducanumab, Ramachandran said the surrogate endpoint used — reduction of amyloid beta plaque in the brain — across two dozen clinical trials “found no association with a clinically meaningful outcome for patients,” she added.

Despite an FDA advisory committee voting 0-10, against the data presented about the drug in November 2020, the agency greenlighted it in June 2021. Then in January 2022, CMS announced Medicare would restrict coverage of the new drug to patients in qualifying clinical trials.

In the end, the agency’s decision will encourage “bad innovation” by industry, she said, as it has spurred more manufacturers to make similar drugs using the same “unproven” mechanism of action.

She called on the FDA to take a page from Europe, where sponsors are required to renew accelerated approvals each year and to submit interim progress reports. If a manufacturer fails to comply, approval should expire and if a confirmatory trial shows negative results, approval should be withdrawn, Ramachandran suggested.

Pharma’s Influence on FDA Approval

Questions around aducanumab’s approval also focused on the agency’s culture and its closeness with industry.

Rep. Debbie Dingell (D-Mich.) questioned FDA witnesses about alleged “off the books” meetings between the agency and aducanumab’s sponsor, Biogen, and “almost daily working group collaboration” between company employees and FDA’s review staff.

Asked what efforts the agency is making to ensure staff are not “inappropriately influenced by industry,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said the agency’s decisions are made independent of industry’s influence.

“[W]e agree that it is very important to maintain that independence as has been the case in past decisions,” she noted.

When Dingell asked Cavazzoni to commit to maintaining strict “guardrails” around conflicts of interest, Cavazzoni replied that “the guardrails have been in existence and upheld throughout, and we will continue to maintain our high standards and independence in decision-making.”

CMS Restrictions: A ‘Chilling Effect’ on Innovation?

Other committee members were more concerned with CMS’s restrictions for coverage of aducanumab, than the FDA’s decision to approve it.

The subcommittee’s ranking member, Brett Guthrie (R-Ky.) asked what impact CMS’s decision to restrict coverage for the Alzheimer’s drug to patients in qualifying clinical trials could have on innovation in the industry.

Cartier Esham, PhD, chief scientific officer and the executive vice president of the Biotechnology Innovation Organization, the world’s largest biotechnology advocacy organization, responded that CMS’s decision “would have a chilling effect not just on the future of investment in the research and development for innovative Alzheimer’s treatments, but for other treatments to treat difficult diseases.”

Venture capital investment in the small companies researching these important new drugs relies on there being a “stable and understood pathway from approval to access.” FDA makes a decision based on safety and effectiveness and CMS makes its determination based on coverage being “reasonable and necessary” and “where coverage is provided for treatments to be used as indicated on FDA approved labels,” Esham added.

“The assertions to and impact on an entire class of drugs as proposed under this current [national coverage determination] proposal really is untenable from an investment standpoint,” she noted.

Enhancements to User Fees

In between the discussion about aducanumab, the hearing also focused on policies and procedures. Its original purpose was to discuss user fees, which support the review of drugs and devices, enable investments in new technologies, and allow the FDA to recruit and retain staff. The agreements must be reauthorized every five years and the deadline for the next reauthorization is September 30.

Stated goals of changes to the new user agreements included:

  • Accelerating development of complex generics by issuing product specific guidance and increasing communication with manufacturers via the Generic Drug User Fee Amendments
  • Making the Biosimilar User Fee Amendments more efficient and increasing the approval of interchangeable biosimilars
  • Changes to the Prescription Drug User Fee Amendments to allow earlier meetings with manufacturers to receive feedback on their development programs, more timely review of supplements, and an increase in cell and gene therapy staff, to help speed the review process for these products
  • A new rare disease endpoint pilot program, so staff and manufacturers can work together to identify endpoints that can be used in clinical trials, leveraging the accelerated approval pathway

FDA officials also discussed the challenges in identifying surrogate markers for rare diseases, and the progress they made with patient-focused drug development, holding meetings to better understand patients’ views of a particular drug or illness.

They also said the new user agreements would include provisions to leverage “decentralized trials” using digital health tools or bringing the trial directly to the patient, such as a nurse going to a patient’s home to administer a drug or take a measurement.

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    Shannon Firth has been reporting on health policy as MedPage Today’s Washington correspondent since 2014. She is also a member of the site’s Enterprise & Investigative Reporting team. Follow

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