Ahh, aducanumab ... While clinicians wrestle with administering the drug, finding out if it works, whether insurance will cover it, and how it will affect other trials (Part 1, Part 4, Part 5, and Part 7 of this series), the regulatory and U.S. public policy worlds are experiencing their own aftershocks from the FDA’s June 7 decision. The agency’s irregular process, in which it granted an accelerated approval based on biomarker data, has sparked investigations both in the U.S. House and at the Department of Health and Human Services. The latter probe will review the use of accelerated approvals more broadly, as other approvals have also come under scrutiny of late. The consequences may be felt far beyond the Alzheimer’s field.

  • AdCom continues to challenge the basis for aducanumab approval.
  • Controversy over the FDA’s decision has sparked investigation in the U.S. House.
  • Department of Health and Human Services probe will examine FDA accelerated licensing in general.

The FDA has drawn fire from multiple sides for giving Aduhelm the nod despite inadequate efficacy data and a unanimous “no” vote from its Advisory Committee (Jun 2021 news). In the face of opposition from AdComs and its own statisticians, the agency pivoted from having considered full approval with the AdComs to granting accelerated approval based on plaque removal. On July 28 in the New England Journal of Medicine, seven AdComs members wrote that the committee was never told accelerated approval was on the table, nor asked to weigh in on that possibility. The authors, led by Caleb Alexander at Johns Hopkins Bloomberg School of Public Health, Baltimore, maintain that evidence was lacking for plaque removal as a surrogate endpoint for clinical benefit, and note that the FDA has not produced a solid scientific rationale for taking this position. “An effective surrogate should strongly correlate with a clinical endpoint in clinical studies, but an FDA statistical review … found no evidence that amyloid changes correlated with cognitive or functional changes,” they wrote. The authors took the agency to task for not seeking input on this question from the committee.

In addition, Alexander and colleagues called out that only a small number of accelerated approvals in other disease indications have subsequently produced the required evidence of clinical efficacy in post-market studies. In the case of Aduhelm, they noted that the overly broad FDA label, which does not require doctors to verify the presence of amyloid plaques, could result in Medicare wasting billions of dollars on unnecessary treatment. The authors applauded the HHS investigation as timely and needed to prevent future regulatory failures. “The overwhelming unmet need in this common and devastating disease should drive research investments, not lowering of regulatory standards that Americans rely on for safe and effective medicines,” they concluded (Alexander et al., 2021). 

Scrutiny of the FDA’s process was heightened by revelations that the agency’s Billy Dunn may have had an “off-the-books,” one-on-one meeting with Biogen executive Al Sandrock at a neurology conference in May 2019, after Biogen had announced the failure of its Phase 3 trials based on an ill-advised futility analysis. As reported elsewhere, Sandrock showed Dunn the company’s updated, more-promising efficacy data, and engaged his support. After the meeting, the company established “Project Onyx,” an internal strategic effort to get the drug approved that was withheld from the agency’s advisory committee (STAT newsEndpoints News). 

Other reports indicate Biogen also had a “Project Javelin,” a campaign to persuade treatment centers to administer the antibody once approved (Endpoints News).

Is all this proper? Some in Congress, such as Rep. Katie Porter (D-CA), want to find out. Porter led calls for the HHS inspector general to examine the relationship between the FDA and Biogen, and determine if rules were broken (Endpoints News). The FDA’s acting commissioner, Janet Woodcock, acknowledged the approval process had been poorly handled, and on July 9 also requested the HHS IG begin such an investigation (STAT news; Washington Post). On August 4, the IG’s office announced it would review the use of accelerated approvals more broadly, not just of aducanumab (BloombergSTAT news). In recent months, the accelerated approval mechanism has been criticized for greenlighting some drugs that never prove themselves, yet stay on the market (STAT news). 

The HHS investigation is not the only one. Two Congressional House committees, Oversight and Reform as well as Energy and Commerce, on June 25 launched a joint probe to examine the aducanumab approval process (CNN). On July 12, the committees sent Biogen a letter demanding an exhaustive list of documentation, including all communications with the FDA, internal discussions of Project Onyx, and all documents regarding how aducanumab’s price was set (U.S. Congress, Committee on Oversight and Reform and Committee on Energy and Commerce, letter to  Michel Vounatsos, chief executive officer of Biogen Inc., July 12, 2021Endpoints News). 

On June 15, Rep. Peter Welch (D-VT), wrote in an open letter to Vounatsos that “as a strong supporter of our Medicare program and an advocate for affordable as well as accessible health care, I am shocked at the price Biogen set for Aduhelm” (see Welch’s House website for the full letter).

Not to be outdone, on June 23 Sens. Elizabeth Warren (D-MA) and Bill Cassidy (R-LA) demanded their chamber’s Finance Committee hold a hearing to examine aducanumab’s price and how it will affect Medicare (full text). Thus far, the U.S. Senate has not taken up Warren and Cassidy’s call for a hearing on aducanumab. However, Senate Finance Committee Chairman Ron Wyden (D-OR) cited aducanumab while outlining principles for drug-pricing reform. “For some drugs, prices may be justified based on the remarkable clinical benefits they offer. But many, like the recently-approved Alzheimer’s drug Aduhelm, launch at prices far beyond any reasonable justification of the clinical value to patients, caregivers, or society,” Wyden wrote (Senate Committee on Finance, 2021). 

All this has fueled speculation that aducanumab’s price will revive interest in drug price control legislation, and on August 12, President Biden spoke to the issue of drug prices (Washington Post; Washington Post; Washington Post). 

Separately, the Aduhelm approval may damage Woodcock’s career prospects, as it has deepened Sen. Joe Manchin’s (D-WV) opposition to her appointment as FDA commissioner (Jun 2021 Manchin letter to the White House).

In response to the controversies, Dunn and drug evaluation director Patrizia Cavazzoni at the FDA have defended their decision in editorials in The Washington Post and JAMA. In the Post, they argued that such approvals have helped speed cancer research. “In a high proportion of instances, we have found that subsequent studies confirmed clinical benefit. Even though not every drug worked as expected, these approvals have propelled progress forward,” they wrote.

For its part, Biogen also pushed back on the criticism, with Sandrock penning an open letter to the AD community (Axios news). “We welcome a formal review into the interactions between the FDA and Biogen,” Sandrock wrote.—Madolyn Bowman Rogers


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Therapeutics Citations

  1. Aduhelm

News Citations

  1. Aducanumab: Will Appropriate-Use Recommendations Speed Uptake?
  2. Seeking Real-World Data on Whether Aducanumab Works
  3. Will Insurance Cover Aducanumab? Jury Is Out
  4. Aduhelm Approval Reverberates Through Research
  5. Aducanumab Approval Sparks Backlash

Paper Citations

  1. . Revisiting FDA Approval of Aducanumab. N Engl J Med. 2021 Aug 26;385(9):769-771. Epub 2021 Jul 28 PubMed.

External Citations

  1. STAT news
  2. Endpoints News
  3. Endpoints News
  4. Endpoints News
  5. STAT news
  6. Washington Post
  7. Bloomberg
  8. STAT news
  9. STAT news
  10. CNN
  11. U.S. Congress, Committee on Oversight and Reform and Committee on Energy and Commerce, letter to  Michel Vounatsos, chief executive officer of Biogen Inc., July 12, 2021
  12. Endpoints News
  13. Welch’s House website
  14. full text
  15. Senate Committee on Finance, 2021
  16. Washington Post
  17. Washington Post
  18. Washington Post
  19. Jun 2021 Manchin letter to the White House
  20. The Washington Post 
  21. open letter
  22. Axios news

Further Reading