Column organized by Evan Schwarz, MD
Washington University in St. Louis
Division of Emergency Medicine
Over the past few years, the emergency department treatment of septic patients has dramatically changed. Much of this is due to the implementation of early goal directed therapy which emphasizes aggressive fluid resuscitation, early antibiotic initiation, vasopressors, and transfusion as needed. Another innovation in the treatment of sepsis was the development of Xigris (recombinant human activated protein C or drotrecogin alfa) by Eli Lilly. This medication was approved with much controversy by the FDA in 2001 based on a single phase 3 randomized control study known as the PROWESS study, which showed overall survival benefits at 28 days with Xigris (Phase 3 studies compare the newer treatment or regimen with the pre-existing standard for treatment while phase 1 and 2 trials focus on the safety, kinetics, and dosages of the new treatment). The medication was approved in septic patients with minimum APACHE II scores of 25 or 2 sepsis induced organ dysfunction. There was, however, some controversy regarding the methodology of the study. Because of this, sales of Xigris did not meet expectations despite its approval. As a result Eli Lilly hired a public relations firm to develop a marketing strategy to improve sales.
In recent years there has been a drive to put evidence-based intervention into “bundles” which are used to develop a protocol for physicians to follow. While this practice has a measureable effect on patient outcomes, it may have some harmful effects as well. One such effect is that some pharmaceutical companies may use these guidelines to promote their own products. Another effect of bundles is that they make it very easy to develop pay-for-performance packages in which compensation is dependent on compliance with the entire bundle. In the authors’ opinion, Eli Lilly took advantage of such protocols to promote their drug Xigris in the sepsis protocol.
The marketing strategy consisted of “3 prongs” or phases. The first phase involved establishing a Surviving Sepsis Campaign to raise physicians and the medical media’s awareness of sepsis. Second, Eli Lilly heightened the demand for Xigris by spreading the word that it was being rationed because of its high cost and physicians were being forced to decide who would receive it, and in turn, survive. The company provided a $1.8 million grant to establish the Values, Ethics, and Rationing in Critical Care (VERICC) task force to address the ethics behind rationing a potentially life threatening drug such as Xigris. Eli Lilly also helped to fund the international panel of critical experts which gathered to develop the guidelines for management of sepsis which were published in Critical Care Medicine in 2004. Lastly the Surviving Sepsis campaign was established to promote treatment of sepsis. Lilly provided more than 90% of the funding for the first 2 phases of the campaign.
Even though many proponents will argue that despite their funding, Lilly did not influence the establishment of the sepsis guidelines, the fact that these recommendations are largely based on randomized controlled trials, automatically tends to favor newer treatments, such as Xigris, which need such trials for approval. Frequently already established practices such as antibiotics and fluid, are ranked less highly in such guidelines because they lack randomized controlled studies as established standards of care.
Furthermore, the original PROWESS study, also demonstrated an increased risk in bleeding (approximately 3.5% of patients) with Xigris which again manifest in the ADDRESS and RESOLVE studies. In the ENHANCE trial the risk was found to be even greater. These results, however, were not included in the Surviving Sepsis Campaign Guidelines. In fact, the efficacy of rhAPC has not been prospectively shown even though the FDA had asked for further testing when Xigris was approved. While the PROWESS study showed a significant overall survival benefit at 28 days, the FDA only approved it for patients with APACHE scores greater than 25 even though the efficacy of Xigris has not been demonstrated in a prospective trial consisting of these patients.
In their final marketing phase, Eli Lily established the “Implementing the Surviving Sepsis Campaign” program in 2004 in order to create performance bundles based on recommendations from the campaign guidelines. One branch of this bundle included a recommendation of Xigris even though the results of the ADDRESS and RESOLVE studies were not mentioned. These bundles are now being implemented internationally by the Society for Critical Care Medicine with funding from Eli Lilly. It should be mentioned that the Infectious Diseases Society of America has declined to endorse the guidelines.
In conclusion , practice guidelines can be helpful in standardization of practices across diverse international health care settings improving patient outcomes. To minimize bias and ulterior motives, pharmaceutical industry involvement in guideline development must be closely scrutinized.