Evidence-based Backlash: The Xigris eXample

Rich Savel, has a wonderful editorial in this month's issue of the American Journal of Critical Care (AJCC) discussing the importance and dangers of evidence-based medicine as currently practiced. He and co-author Cindy Munro use the rise and fall of Drotrecogin Alfa (Xigris, activated protein C) as an example for what can go wrong and why.

Rich Savel in the center

Their key conclusions:

1) "Though the results of a single, large RCT are important, they clearly are not sufficient for future agents to be rapidly integrated into national guidelines or consensus statements."

2) "Another important lesson is that pharmaceutical companies should stay as far removed as possible from development of guidelines promulgated by national medical societies. One of the most important things such a society has is its reputation, which it must be careful not to tarnish. Although this can often be a great challenge, it has become quite clear from the controversies surrounding APC that the relationship between pharmaceutical corporations on the one hand and academia and national medical societies on the other should be kept distinct and transparent."

3) and finally - “... the single most important lesson from the rise and fall of APC is that we should maintain skepticism: maintain it until the trial can be reproduced; maintain it in the face of trusted medical societies integrating recommendations for agents before sufficient evidence is presented; and maintain it until all potential conflicts of interest have been shared. EBM is not merely one way to practice; it is the only way. In addition to understanding all of the dynamic complexities and nuances of EBM, we must develop a healthy skepticism toward new research results and apply that approach liberally as the scientific method does its important job of confirming the validity of those results."

Full Disclosure: Rich and I were residents at NYH-Cornell back in the 1990s and we were also co-Assistant Chief Residents at Memorial Sloan Kettering under Kent Sepkowitz. Rich has gone on to great things as co-editor of the AJCC and medical directorship of the surgical intensive care unit at Montefiore Medical Center, Albert Einstein College of Medicine in NYC. Rich is also the editor and founder of the SCCM iCritical Care Podcast - which rocks.

Conflicting Results in Clinical Trials: the APC Example

Dan posted last week on activated protein C (Xigris) being withdrawn from the market.  David Rind (Evidence in Medicine blog) has posted his thoughts on what might have been behind the initial positive study in 2001 and subsequent negative studies.  It is worth a read.

David Rind: APC and Conflicting Trials (10/29/2011)

Headline of the day

This is my favorite headline about the demise of drotrecogin alpha (a.k.a. activated protein C, Xigris), which was withdrawn from the market yesterday after the PROWESS-SHOCK study results revealed it to be no better than placebo in the treatment of severe sepsis. The headline, of course, implies that Xigris once was effective, it just isn’t any more…and from the quotes in this story, it appears that Lilly is arguing that improvements in sepsis management have now made it impossible to detect the incremental benefit that Xigris provided (you know, back when we were super-terrible at treating sepsis).

Fair enough, but that explanation ignores the controversial history of this drug and the role of Eli Lilly in the surviving sepsis campaign. It also ignores one of the most important lessons we should learn from this debacle: the perils of the subgroup analysis. Eli, our in-house methodologist, may wish to chime in, but you can start here with a nice review that points out why subgroup analyses of clinical trials should be treated with extreme caution, and used only to generate hypotheses, not for clinical decision making (or drug approval!).