Critical care and resuscitation

ED I T O R I A LS
“Those who cannot remember the past are condemned hence Viagra and Zyprexa), was launched in 2001 to the same hype and with even more sophisticated marketing tech “Scepticism is the chastity of the intellect, and it is By late 2005, it had recorded sales of $214.6 mspite the release of a negative second studynd about $100 million despite growing concerns about its efficacy.
If only to confirm the sense of deja vu, the same group at the Crit Care Resusc ISSN: 1441-2772 1 December In February of 1991, what was considered a pivotal article was NIH was once again at the forefront of those concerne This England Journal of Medicine The article time, these sceptics were joined by other voices in Eur reported the life-saving effects of Centoxin (nebacumab), an www.jficm.anzca.edu.au/aaccm/journal/publica- HA-1A human monoclonal antibody against endotoxin in 543 • the second trial was terminated because of futility;
with sepsis and presumed gram-negative bacteraemia.
• in that trial, surgical patients with severe sepsis and single-
Centoxin did not decrease overall mortality, but, among organ failure were more likely to die; that 90-day mortality patients with gram-negative bacteraemia, it decreased 28-day was not significantly different even in the first trial; mortality from 49% to 30% — a significant improvement.
• the original trial may not have been adequately blinded;
Centoxin did not receive United States Food and Drug Admin- • there was an unexpected reduction in do-not-resuscitate
istration approval; the trial used multiple end points without (DNR) orders in the Xigris arm after a change of protocol adjustment for multiple comparisons; the company (CentocorBiotech) had access to the interim analysis and consequently halfway through the study,hile the DNR rate remained modified the end points; and, if the preset end points had not been changed, the difference would not have been significa • halfway through the trial, 20 sites were removed and 45
Yet the usual frenzy of hype and hope followed, and new sites added; that the dropped sites showed a worldwide use of Centoxin was substantial, with significant negative effect of Xigris but the new ones showed a initial financial benefits to Centocor. Concern about the wisdom of such use was raised by Natanson’s critical care • the trial was stopped on interim analysis; and
team at the US National Institutes of Health (NIH)ey • patients aged under 50 years had no benefit,hose
demonstrated that Centoxin had adverse effects in a caninemodel of gram-negative bacteraemia, and that the drug between 80 and 90 years of age or with chronic morbidi- failed to alter levels of bacteraemia or endotoxaemiaTwo ties (common candidates for DNR orders) seemed to do large trials of monoclonal antibodies against endotoxin fol- better for the primary 28-day mortality outcome.
lowed in 1994 and in 1995, and their negative results spelled The demand for another trial in patients who were most likely to be treated with Xigris (those with septic shock) grew Many lessons could have been learned from this experience.
stronger and, finally, continued registration by the European Some of these lessons might have reasonably included the Medicines Agency became contingent upon the conduct of need to exert caution when evaluating the results of a study sponsored by a pharmaceutical company, where data control On 25 October 2011, Lilly announced that it was withdraw- and analysis was not fully in the hands of an independent data ing Xigris from the market in response to the negative results of collection, analysis and publication system; the need to remain the PROWESS-SHOCK trial. As this issue of Critical Care and sceptical in the presence of implausibly good results; the Resuscitation went to press, the only trial-related information wisdom of requiring a confirmatory trial before embracing the available was that mortality was 26.4% with Xigris and 24.2% use of a novel drug with poorly understood mechanisms and with placebo, and that serious bleeding occurred in 1.2% of no published phase I, IIa or IIb studies; and the need to remain patients with Xigris and 1% of patients with placebo. Although vigilant to the risks of mid-trial changes in protocol or drug many will be interested in the trial details and much is likely to be learnt from its findings, with the removal of the drug from In light of the Centoxin experience, one might have expected worldwide markets, the Xigris story is over.
the critical care community to be particularly “critical” when Will the medical, and, in particular, the Australian and New another Centoxin-like drug appeared — but it was not. Ten Zealand intensive care community learn from this? We hope years later, ironically almost to the month, another pivotal trial and think so. The Australian and New Zealand intensive care (Recombinant Activated Human Protein C Worldwide Evalua- community has evolved remarkably during the decade that saw tion in Severe Sepsis [PROWESS]) was published in the same Xigris come and go. Its understanding of the difficulties of remarkable deja vu for those of us old enough to designing, conducting, analysing and interpreting randomised remember Centoxin. The new drug, Xigris (drotrecogin alfa) controlled trials in critically ill patients has increased markedly, (named in the period when Lilly marketing experts preferred and is likely to continue to progress in the coming decade.
drug names starting with letters from the end of the alphabet, Pharmaceutical trials will be viewed with much greater scrutiny Critical Care and Resuscitation  Volume 13 Number 4  December 2011 ED I T O R I A LS
and understanding. Convincing animal studies, encouraging 2 Quezado ZM, Natanson C, Ailing DW, et al. A controlled trail of HA-1A phase I investigations, positive phase II work with evidence of in a canine model of gram-negative septic shock. JAMA 1993; 269: benefits using surrogate markers, and at least two independent confirmatory phase II trials will increasingly be demanded 3 McCloskey RV, Straube RC, Sanders C, et al. Treatment of septic shock with human monoclonal antibody HA-1A: a randomized, double- before costly experimental treatments are implemented in daily blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern In the immortal words of Oscar Wilde, “the truth is rarely 4 Bone RC, Balk RA, Fein AM, et al. A second large controlled clinical pure and never simple”. A good dose of scepticism is study of E5, a monoclonal antibody to endotoxin: results of a advisable, and Wilde’s words should surely serve as a useful prospective, multicentre randomized controlled trial. The E5 Sepsis mantra in medicine, and justify the future careful and reflec- Study Group. Crit Care Med 1995; 23: 994-1006.
tive intellectual stance that the saga of Centoxin and Xigris 5 Bernard GR, Vincent JL, Laterre PF, et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group.
Efficacy and safety of recombinant human activated protein C forsevere sepsis. N Engl J Med 2001; 344: 699-709.
Author details
6 Eichacker PQ, Natanson C, Danner RL. Surviving sepsis — practice guidelines, marketing campaigns and Eli Lilly. N Engl J Med 2006; 355: Miklós Lipcsey, Specialist Physician in Anaesthesia and Intensive Care2 7 Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for 1 Department of Intensive Care, Austin Health, Melbourne, VIC, Australia.
adults with severe sepsis and a low risk of death. N Engl J Med 2005; 2 Section of Anaesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
8 Armstrong D. Lilly pulls Xigris off markets after sepsis drug fails study.
Correspondence: [email protected] Bloomberg Business Week 2011; 25 Oct. http://www.business-week.com/news/2011-10-25/lilly-pulls-xigris-off-markets-after-sepsis-drug-fails-study.html (accessed Nov 2011).
References
9 Mackenzie AF. Activated protein C: do more survive? Intensive Care 1 Ziegler EJ, Fisher CJ Jr, Sprung CL, et al. Treatment of gram negative 10 Finfer S, Ranieri VM, Thompson BT, et al. Design, conduct, analysis and bacteremia and septic shock with HA-1A human monoclonal antibody reporting of a multi-national placebo-controlled trial of activated against endotoxin. A randomized, double blind placebo-controlled protein C for persistent septic shock. Intensive Care Med 2008; 34: trail. The HA-1A Sepsis Study Group. N Engl J Med 1991; 324: 429-36.
Critical Care and Resuscitation  Volume 13 Number 4  December 2011

Source: http://www.cicm.org.nz/journal/2011/december/ccr_13_4_011211-211.pdf