Outrage of the Month: FDA’s Inappropriate Close Collaboration with Biogen on Alzheimer’s Disease Drug

Health Letter, January 2021

By Michael Carome, M.D.

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Regulatory capture occurs when a regulatory agency becomes dominated by the industries that the agency is charged with regulating. This can lead the agency to act in ways that benefit the interests of regulated companies, rather than the public interest.

The dangers of regulatory capture were exemplified by the regulatory capture on the part of the Federal Aviation Administration that resulted in grossly insufficient regulatory oversight of the Boeing 737 MAX aircraft and contributed to the chain of errors that led to the crashes of Lion Air flight 610 in 2018 and Ethiopian Airlines flight 302 in 2019, causing the preventable deaths of 346 people.

Regulatory capture has now infiltrated the Food and Drug Administration (FDA). Exhibit A of this regulatory capture is the unprecedented and inappropriate close collaboration between the FDA and Biogen regarding the company’s biologics license application (BLA) for approval of the Alzheimer’s disease drug aducanumab for the treatment of Alzheimer’s disease.

Such close collaboration dangerously compromised the independence and objectivity of senior staff and clinical reviewers in the FDA’s Office of Neuroscience (ON) in the Center for Drug Evaluation and Research’s (CDER’s) Office of New Drugs during the agency’s review of Biogen’s BLA for aducanumab and key data from two identical pivotal phase 3 clinical trials of the drug. ON Director Billy Dunn, M.D., supervised the FDA team conducting this review and likely played a key role in the close FDA–Biogen collaboration.

After aducanumab’s two identical phase 3 trials were stopped in 2019 at the halfway point because a preliminary analysis found that they were unlikely to show the drug benefitted Alzheimer’s patients, the FDA and Biogen worked collaboratively to salvage the drug. They jointly relied on dubious analyses that over-emphasized the results of one phase 3 trial suggesting the drug may work at a high dose but disregarded data from the other phase 3 trial showing no benefit of the drug at any dose. The FDA and Biogen co-authored an unprecedented joint briefing document on aducanumab that was heavily biased in favor of the drug.

A lone FDA statistician, who evidently was not involved in FDA’s close collaboration with Biogen, authored a scathing critique of the biased analyses conducted collaboratively by the agency and the company. He concluded there was insufficient evidence that aducanumab was effective.

In early November, members of an FDA advisory committee that was convened to consider whether there was sufficient evidence of the effectiveness of aducanumab harshly criticized the analyses of clinical trial data conducted by FDA clinical reviewers and Biogen, the collaborative review process and the biased joint briefing document. Ten out of 11 members of the committee concluded there was not sufficient evidence of effectiveness to support approval of the drug. It appears that without the intervention of the committee, the FDA was prepared to rush to market a drug lacking substantial evidence of effectiveness for treating Alzheimer’s disease.

On Dec. 9, Public Citizen’s Health Research Group sent a letter to the U.S. Department of Health and Human Service’s Office of Inspector General (OIG) demanding an investigation of the close collaboration between the FDA and Biogen. In our letter, we highlighted that a decision by the FDA to approve aducanumab now would have several wide-ranging adverse consequences. First, approving a drug for Alzheimer’s disease that has not been shown to be effective — and that in the end may turn out to be ineffective, assuming another phase 3 trial is conducted appropriately and completed — would provide false hope to millions of desperate patients with the disease and their families.

Second, because the drug would be exorbitantly expensive (therapy would be priced at about $50,000 per year,[1] and that does not include the cost of the serial brain imaging tests, such as magnetic resonance imaging, that patients would need to undergo) and used by potentially millions of patients for years, it would have a massive impact on health-care economics and potentially bankrupt the Medicare program, as well as many patients and their families. Such economic costs would only be justifiable for a drug that has definitive evidence of significant, clinically meaningful benefit.

Finally, the premature approval of aducanumab could impede the development of other experimental treatments for Alzheimer’s disease for many years, potentially delaying progress on drugs that actually may turn out to be beneficial.

As we noted in a separate Dec. 9 letter to FDA Commissioner Stephen Hahn, we asserted that the circumstances surrounding the FDA’s collaboration with Biogen before and after the submission of the BLA for aducanumab are a black eye for the agency. To begin restoring public confidence in the FDA and its review of aducanumab, we urged the commissioner to, among other things, immediately assign all further review and decision-making related to aducanumab to FDA staff who were not involved in the close collaboration with Biogen and temporarily remove Dr. Dunn from his position as ON Director until the requested OIG investigation is completed.

Regulatory agencies, like the FDA, must maintain their independence and objectivity when overseeing regulated industries to avoid disastrous consequences. In the case of the FDA, breaches of the agency’s independence and objectivity undoubtedly could lead to approval of drugs and medical devices that are unsafe or ineffective, which could result in substantial harm to public health and to the private and public institutions and individuals who pay for health care. The American people deserve better from the FDA.


References

[1] Belluck P. F.D.A. panel declines to endorse controversial Alzheimer’s drug. The New York Times. November 6, 2020. https://www.nytimes.com/2020/11/06/health/aducanumab-alzheimers-drug-fda-panel.html. Accessed November 29, 2020.