Story of Xigris (Protein C) for Sepsis

Xigris, also called Drotrecogin Alfa (Activated) or Protein C, was the only approved drug for severe sepsis indication and it was withdrawn from the market last week (Oct 25, 2011). In a recently completed clinical trial (PROWESS-SHOCK trial), Xigris failed to show a survival benefit. Due to the early controversies over Xigris’s approval and the continuous debate on Xigris’s risk benefit, PROWESS-SHOCK trial has been under watch since its start. The study design, statistical analysis plan, and unblinding plan have all been published way before the completion of the trial.

A decade ago, prior to the approval of Xigris for sepsis indication, the risk-benefit had been debated quite a bit. Xigris was know to be linked to the increased risk of serious bleeding in patients. there was "controversy surrounds both the drug study itself and the FDA approval," wrote NEJM editor-at-large Richard P. Wenzel, MD in 2002. FDA held the anti-infective advisory committee meeting for Xigris in treating sepsis. The FDA approved the drug despite the advisory committee's split vote (10 to 10) due to concerns about the validity of the claimed efficacy and safety findings on the basis of a single trial. At that time, Xigris was approved based on a single pivotal trial (PROWESS trial) that was also stopped early for efficacy. At that time, the FDA reviewers certainly believed that Xigris was beneficial and could save a lot of lives.

PROWESS trial has been the model for other clinical trials in Sepsis even though the PROWESS trial itself has been criticized for changes in the protocol during the 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.

Subsequent trials have now shown that Xigris has no benefit and has unfavorable risk-benefit profiles. The ADDRESS trial (published in 2005) showed the absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications. The result indicates that Xigris should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25. Now the PROWESS-SHOCK trial further confirmed that the risk of bleeding outweigh the benefit in reducing the mortality – unfortunately it is a decade after Xigris has been on the market.

The market practice for Xigris has also been criticized. Several years ago, there were a lot of talks about Lilly’s influence on a committee in defining the sepsis treatment guidelines which was in favor of using Xigris.

Retrospectively, we can have something to learn from the Xigris story: 1) a single pivotal trial may be insufficient in confirming the treatment benefit; 2) change the protocol during the trial could have bias to the trial results; 3) stop a trial for efficacy may be risky.

New drugs for life-threatening disease such as sepsis are desperately needed, however, to demonstrate the benefit of any drug in the complicated sepsis treatment is a challenging task. The diversities in sepsis treatment in various institutes make the clinical trials in sepsis very difficult and the sample size for sepsis trials need to be sufficiently large to show the benefit.

A medical joke to share

Not sure where the origin is. It is circulated quite a bit. 

Best friends graduated from medical school at the same time and decided that, in spite of two different specialties, they would open a practice together to share office space and personnel.

Dr. Smith was the psychiatrist and Dr. Jones was the proctologist; they put up a sign reading: "Dr. Smith and Dr. Jones: Hysterias and Posteriors". The town council was livid and insisted they change it.

So, the docs changed it to read: "Schizoids and Hemorrhoids". This was also not acceptable, so they again changed the sign. "Catatonics and High Colonics" - No go.

Next, they tried "Manic Depressives and Anal Retentives" - thumbs down again. Then came "Minds and Behinds" - still no good. Another attempt resulted in "Lost Souls and Butt Holes" - unacceptable again! So they tried "Analysis and Anal Cysts" - not a chance. "Nuts and Butts" - no way. "Freaks and Cheeks" - still no good. "Loons and Moons" - forget it.

Almost at their wit's end, the docs finally came up with: "Dr. Smith and Dr. Jones - Specializing in Odds and Ends". Everyone loved it.

Will Electronic Data Capture be always better than Paper-CRF?

The traditional way to do the clinical trial data management is to use the paper based case report forms (CRFs). The blank paper CRFs are distributed to the investigator sites. The investigator or study coordinator fills out the CRFs. CRFs will then be monitored and collected from the investigator sites. CRFs will subsequently be handled by a centralized group - data management group where the activities include the clinical database building, data entry, data cleaning, data clarification,...

The industry trend has been gradually moving away from the paper-based CRFs and moving toward to the electronic data capture (EDC). In EDC world, the database was built prior to the study start (significant longer leading time prior to the study study is needed) . The data will be directly entered into the database by the investigator site (investigator or study coordinator). EDC has been touted by many vendors as the preferred way for conducting clinical trials: getting the data fast, saving timeline, saving cost, minimizing data transcription errors... While this is generally true, it is not universal.


In some situations, the trial using the traditional paper-based CRFs is a better way than EDC. For example, in a clinical trial for a rare disease, there are many investigator sites and each site may only enroll very few subjects or not enroll any subject. The EDC will not be an efficient way in data collection. Many site staff will be trained on EDC and never have chance to enroll any patient into the study and never have a chance to use EDC. When a site finally has a chance to enroll a subject, the initial training on using EDC may be a distant memory.

The EDC trial is not always cheap. With EDC trial, significant cost could be spent on the EDC system hosting and EDC system help desk support. Imagining a slow enrollment trial running for 7-8 years, the cost for hosting EDC system and providing the help desk support will be too much comparing to a paper-based study.

While EDC is a trend, the adoption of EDC is not universal. In some situations, the traditional paper CRFs may be better.