Friday, November 18, 2011

Drug withdrawal sends critical care specialists back to basics : Asher Mullard in The Lancet

The withdrawal of Lilly's antisepsis drug marks the latest U-turn in the treatment of severe sepsis, an area of critical care plagued by starts, stops, and confusion. Asher Mullard reports.
Lilly has pulled its antisepsis drug Xigris (drotrecogin alfa) from markets worldwide because the results of the post-marketing PROWESS SHOCK trial did not show efficacy. The move, which comes nearly 10 years after the drug was initially approved in the USA, brings a long controversial story to a close, but draws attention to the slow pace of progress for the treatment of sepsis.
“This was an interesting saga for the field of critical care. It really brought out the relationship between pharma and physicians”, says Anthony Suffredini, Associate Chief of the Critical Care Medicine Department at the US National Institutes of Health.
Xigris, also known as activated protein C, took off to a bright start in 2000 when the phase 3 PROWESS trial was stopped early because of the drug's high efficacy (reducing the relative risk of death by 20% compared with placebo). Despite the early optimism, the anti-inflammatory drug's promise began to unravel at a 2001 US Food and Drug Administration (FDA) advisory meeting. Experts raised several concerns including worries over why Lilly changed the enrolment criteria half way through the trial. Faced with a lack of therapeutics on the one hand and insufficient clinical data on the other, ten panellists voted to approve the drug and ten voted to reject it.
Regulators hedged their bets. The FDA approved the drug in 2001 for patients at high risk (but not low risk) of death, on the basis of a post-hoc subgroup analysis of PROWESS. European regulators followed with a similar approval a year later.
But subsequent findings continued to divide the community. An analysis of the 3-month mortality rates in PROWESS did not find a treatment effect. An FDA-mandated trial in patients at low risk of death was stopped early because of futility, and a subgroup analysis of high-risk patients who had inadvertently been enrolled into the trial was discouragingly negative. The drug also seemed to confer a higher risk of severe bleeding than originally noted.
Lilly, moreover, was accused of running an aggressive marketing campaign for the drug and attempting to manipulate the development of the Surviving Sepsis Campaign's 2004 sepsis treatment guidelines.
Faced with increasing scepticism, Lilly launched the PROWESS SHOCK trial in 2008 to re-assess the drug in high-risk patients, at the behest of the European Medicine Agency. Recent top-line results did not show efficacy of Xigris, prompting Lilly to pull the drug. Detailed trial results are expected in early 2012.
Guido Bertolini, a clinical epidemiologist who specialises in intensive care at Mario Negri Institute for Pharmacological Research, Bergamo, Italy, views the history of Xigris as a scandal. “I'm angry with the regulators in both the US and Europe, who in this case failed to defend citizens”, he says. “They repeatedly ignored the guidelines that they themselves set.”
The implications of the withdrawal of an infrequently used (sales in 2010 were US$104 million), and ultimately ineffective, product might be minimal for patients. And because the high mortality of severe sepsis remains a clinical challenge, industry interest in bringing severe sepsis to heel persists. “It's a double edged sword”, explains Phil Dellinger, intensivist at Cooper University Hospital, NJ, USA, and a leader of the Surviving Sepsis Campaign. “We've been discouraged by all the negative trials, but if there is a positive trial there's not going to be a lot of competition.”
Ongoing efforts include Aggenix's immunomodulator talactoferrin alfa, which is in a phase 2/3 trial that is due to report next year. Other firms are hunting for biomarkers that can be used to stratify the highly heterogeneous severe sepsis patient population or are developing devices to remove cytokines or endotoxins from the blood. In the meantime, says Suffredini, clinicians are “falling back on the tried and true: good antibiotic stewardship”.
But the withdrawal also draws attention to a problem that has repeatedly reared its head in critical care: the inability to reproduce initially positive findings. Centocor's Centoxin, an endotoxin-targeting monoclonal antibody, was marketed in Europe in 1992 for severe sepsis on the basis of a single trial but was withdrawn when a second trial to support FDA approval raised safety flags. Other promising treatment models—including intensive insulin therapy and high-dose steroid use—have been rapidly adopted only to be found ineffective or harmful years later.
“As a speciality, we might just be too quick to jump on the bandwagon”, suggests Suffredini. Bertolini takes the argument a step further: “Science needs replication. The approval of sepsis drugs needs to be based on more than a single trial.”

Posted via email from Jack's posterous

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