Drug for Severe Sepsis Is Withdrawn From Market, Fails to Reduce Mortality

Abstract

A DRUG ONCE BELIEVED TO IMprove mortality rates of patients with severe sepsis has been withdrawn from the market because new evidence has revealed it fails to do so—10 years after the drug was approved by the US Food and Drug Administration (FDA). Eli Lilly and Company announced on October 25 that it was withdrawing drotrecogin alfa (activated) [Xigris, a recombinant human activated protein C (rhAPC)]. The withdrawal marks the end of a checkered history for rhAPC that began while the drug was initially under review during the FDA’s approval process. At that time, an advisory committee for the agency rendered a split vote on whether to recommend approval. This ambivalence prompted the agency to limit the indication for the drug to adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who were at high risk of death. Even with the restriction, the drug—the only agent thought to reduce mortality in patients with severe sepsis—has been estimated to have generated more than $1 billion in sales in the decade it remained on the market. The FDA’s counterpart in Europe, the European Medicines Agency (EMA), has also been ambivalent about rhAPC. The EMA approved the drug in 2002, but by 2007, its Committee for Medicinal Products for Human Use (CHMP) noted that the initial efficacy results of the trial that served as the basis for the drug’s approval—the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study (Bernard GR et al. N Engl J Med. 2001;344[10]:699-709)—had not been replicated in further studies. At the CHMP’s request, Lilly agreed to conduct a new placebo-controlled study to confirm that the benefits of rhAPC outweighed its risks in patients with septic shock—the latter being an indication similar but not identical to severe sepsis with multiple organ failure.