The New England Journal of Medicine has retracted its article, published in 2021, evaluating avacopan for antineutrophil cytoplasmic antibody-associated vasculitis because of undisclosed changes to primary end point assessments following database lock and trial unblinding According to the journal, the changes were identified through an ongoing US Food and Drug Administration investigation conducted following publication and were made without the knowledge of the two academic authors without the knowledge of the two academic authors.

"[T]he primary end-point assessments in nine patients were readjudicated after database lock and trial unblinding," wrote Eric J. Rubin, MD, PhD, Editor-in-Chief of The New England Journal of Medicine. Dr. Rubin continued, "This was not disclosed in the article and is inconsistent with proper research conduct." The editorial states that the two academic authors requested retraction after an ongoing FDA investigation found the undisclosed readjudication 

Separately, the FDA’s Center for Drug Evaluation and Research has proposed withdrawing approval of Tavneos (avacopan) from the market. The FDA alleged that new information that became available more than 3 years after approval showed that unblinded study personnel manipulated the results of the pivotal clinical study so the drug looked effective when the original analysis did not support that conclusion. The FDA also alleges that the original analysis was not disclosed to the agency and states that it can no longer conclude that there has ever been a valid demonstration that the drug is effective for its approved use.

Tavneos remains on the market while the withdrawal process proceeds. According to the FDA, the applicant may request a hearing before the FDA Commissioner decides whether to withdraw the drug's approval. The FDA advises health care professionals to discuss available treatment options with patients, including whether continuing Tavneos remains appropriate while the agency's review is ongoing.

The retracted article reported findings from the ADVOCATE phase 3 randomized, double-blind, double-dummy trial conducted at 143 international centers. Researchers randomly assigned 331 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis to receive oral avacopan 30 mg twice daily or a tapering regimen of oral prednisone. All patients also received rituximab or cyclophosphamide, with patients receiving cyclophosphamide transitioning to azathioprine.

The study's coprimary end points were remission at week 26, defined as a Birmingham Vasculitis Activity Score of 0 with no glucocorticoid use during the previous 4 weeks, and sustained remission at both weeks 26 and 52. The published article reported that avacopan was noninferior, but not superior, to prednisone for remission at week 26 and was superior to prednisone for sustained remission at week 52. The article has since been retracted by The New England Journal of Medicine.

The retraction follows a correction published in January 2024 that revised glucocorticoid dose conversions after errors underestimated prednisone-equivalent doses in both treatment groups. The correction states that, after those revisions, the article was correct. The current retraction cites undisclosed readjudication of primary end point assessments in nine patients following database lock and trial unblinding.

The ADVOCATE trial was funded by ChemoCentryx. Two authors were employees of ChemoCentryx, and several authors reported financial relationships with pharmaceutical companies. 

Source: The New England Journal of Medicine; US Food and Drug Administration