Controversy Brews Over Xigris' Role in Treating Sepsis

Laurie Barclay, MD

September 30, 2002

Oct. 1, 2002 — Sounding board articles in the Sept. 26 issue of the New England Journal of Medicine generated significant media controversy about Xigris, or recombinant human activated protein C (HAP-C; drotrecogin alfa), which acts within blood vessels to treat severe sepsis. The authors stated that the data are encouraging but insufficient to make Xigris the standard of care.

The drug's manufacturer Eli Lilly and Co. countered that this opinion is out of line with the Food and Drug Administration (FDA)'s position and that of other regulatory agencies in multiple countries. Both the FDA and Virginia Commonwealth University (VCU) jumped into the fray, issuing news releases promoting their viewpoints.

"Controversy surrounds both the drug study itself and the FDA approval," writes NEJM editor-at-large Richard P. Wenzel, MD, from VCU, recalling criticism from the medical community when the FDA approved Xigris in January 2002 in a split vote by a 20-member advisory panel. Re-evaluation of the original Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial and of updated information and new research findings may help resolve the controversy.

"The Holy Grail for sepsis has always been to find a drug that targets the real biology of sepsis — where the action is on the inside of the blood vessels," Wenzel says in a news release. "This is the first drug that actually works not directly on the organism causing the infection, but on the body's response to the organism, particularly at the level of the blood vessel."

In the PROWESS phase III trial involving 1,690 patients, 24.7% of patients taking Xigris and 30.8% in the placebo group died. Because most of the patients who benefited from the drug had severe sepsis with reduced levels of activated protein C, FDA approval in November 2001 was limited to adult patients with severe sepsis associated with acute organ dysfunction who have a high risk of death, as determined by an APACHE II score of 25 or greater. Relative risk of death for these patients was reduced by 29% ( P=.002) in the PROWESS trial.

According to the NEJM article by H. Shaw Warren, MD, from Massachusetts General Hospital in Boston, and fellow consultants to the FDA, the study protocol changed during the PROWESS trial, shifting the study population composition toward patients with less severe underlying disease and more acute infectious illnesses. Other changes included use of a different placebo and elimination of protein C deficiency status as a primary variable. Around the same time, Lilly began producing the drug using a new master cell bank. Cumulative mortality curves suggest an improvement in protective efficacy of Xigris after these changes were made.

"Although the data regarding activated protein C are very encouraging, we believe that there is not sufficient evidence at present for it to become the standard of care," Warren and colleagues write. They recommend a new trial to confirm the post hoc analyses, preferably one that prospectively incorporates a prognostic scoring system such as APACHE II.

To counteract these claims, a NEJM article by Jay P. Siegel, MD, from the FDA Center for Biologics Evaluation and Research in Rockville, Maryland, notes that "exhaustive comparisons" of the two product lots by the FDA and Lilly revealed similar activated protein C structure, pharmacokinetics, enzyme kinetics and binding affinity. Not only were results consistent for patients with severe disease throughout the trial, but protocol changes actually excluded patients who were more likely to benefit from Xigris.

According to Siegel, for Warren and colleagues to cast doubt on conclusions from this trial contradicts the decisions of the multiple independent authorities that analyzed Xigris clinical data, incccluding the FDA, the Centers for Medicare and Medicaid Services (CMS), regulatory authorities in 11 other countries, and the European Committee for Proprietary Medicinal Products responsible for Xigris approval in its 15 member countries.

"These are brand new issues for us in the drug approval process, so the Journal decided to bring out the controversy and bring on the debate," Wenzel says. "The best possible outcome would be to see more data, more studies and then we could be much more confident on the question of whether we really have a drug that works. And in this NEJM series, [Lilly] has announced that they plan to do just that."

At the FDA's request, Lilly will conduct postapproval controlled trials enrolling more than 13,000 patients to determine the role of Xigris in lower-risk patients with severe sepsis, in children with severe sepsis, and in conjunction with low-dose heparin. In Siegel's view, bolstered by currently available data, Xigris "as labeled will save many lives as we gather the information necessary to refine its use further."

"Xigris is a proven lifesaving advance for the treatment of adult patients with life-threatening severe sepsis. To imply otherwise in the pages of one of the world's most prestigious medical journals — 10 months after the FDA approved this therapy based on the strength of our clinical data — attempts to turn back the clock on the treatment of severe sepsis. The opinion article's assertions serve only to confuse physicians who are attempting to make the best treatment decisions for their patients with severe sepsis, " says August M. Watanabe, MD, executive vice president of science and technology for Lilly. "We disagree with the authors' suggestion that we should contemplate denying severe sepsis patients fighting for their lives access to an FDA-approved therapy in order to replicate the proven findings from the largest trial of its kind ever conducted. In our viewpoint, that would be unethical."

CMS apparently agrees; it has designated Xigris as the first and only medical product to be granted new technology status for the substantial improvement in treatment it offers Medicare patients with life-threatening severe sepsis. As of Oct. 1, 2002, hospitals using Xigris in Medicare patients with life-threatening severe sepsis will receive additional reimbursement.

"In an era of unprecedented scientific breakthroughs, we must do all we can to ensure that all patients have access to the latest in medical innovations," Department of Health and Human Services Secretary Tommy G. Thompson says in a statement on this decision. Among other considerations are contraindications and cost-benefit analysis. Patients with profound thrombocytopenia or markedly prolonged prothrombin times should not receive this drug, according to a letter to the editor of NEJM by E. Wesley Ely, from Vanderbilt University in Nashville, Tennessee, and fellow PROWESS study investigators.

In controlled and open-label trials of Xigris in more than 2,786 patients with severe sepsis, there were 13 suspected cases (0.5%) of intracranial hemorrhages occurring during infusion. Independent review by Ely's group showed that nine of the 13 patients had platelet counts less than 30,000/mm 3 or meningitis or both.

The Medical Letter summarizing the PROWESS trial and rationale for FDA approval of Xigris noted that in an ongoing, open-label trial, intracranial hemorrhage occurred in 13 (2.5%) of 520 patients treated with Xigris. Contraindications to Xigris use include active, recent, or high risk of bleeding.

Even at $7,000 per dose, Xigris can be relatively cost-effective when targeted to patients with severe sepsis but without coexisting conditions that substantially limit life expectancy, according to Reuters Health reports published on Medscape Sept. 18 and 26. Braden J.Manns, of the University of Calgary in Alberta, and colleagues, determined that the cost per life-year gained by treating sepsis patients with an APACHE II score of 25 or more would be $19,723, or $16,309 per life-year for patients younger than 40 years. However, the cost exceeds $575,000 per life-year gained for patients with less severe disease.

"Severe sepsis shows no mercy, so I want to offer my patients every advantage in their struggle to survive," Greg A. Schmidt, MD, from the University of Chicago in Illinois, says in Lilly's news release. "There is no doubt in my mind that Xigris, when used appropriately, is an unprecedented, lifesaving advance for this vulnerable patient population."

N Engl J Med. 2002;347(13):1027-1030,1030-1034,1035-1036
Med Letter. 2002;44:17-18

Reviewed by Gary D. Vogin, MD

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