In 2001, the Food and Drug Administration (FDA) approved Eli Lilly's Xigris (recombinant human activated protein C, or rhAPC, also known as drotrecogin alfa [activated]) for the treatment of sepsis. This approval was based primarily on a single phase 3 randomized, controlled trial — the Recombinant Activated Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study, published the same year — which showed a significant overall survival benefit at 28 days. The FDA acknowledged that there was controversy surrounding this decision, and half the members of the agency's advisory panel, pointing to methodologic and other important problems with the PROWESS study, voted to require that a confirmatory trial be performed before approval was granted.The authors' conclusions were:
To improve sales of rhAPC, in 2002, Lilly hired Belsito and Company, a public relations firm, to develop and help implement a three-pronged marketing strategy. First, the product's sales were to be supported by marketing initiatives targeted to physicians and the medical trade media. Second, because rhAPC was relatively expensive, word would be spread that the drug was being rationed and physicians were being "systematically forced" to decide who would live and who would die. As part of this effort, Lilly provided a group of physicians and bioethicists with a $1.8 million grant to form the Values, Ethics, and Rationing in Critical Care (VERICC) Task Force, purportedly to address ethical issues raised by rationing in the intensive care unit. Finally, the Surviving Sepsis Campaign was established, in theory to raise awareness of severe sepsis and generate momentum toward the development of treatment guidelines.
In the second phase [of the Surviving Sepsis campaign], launched in June 2003, international experts in critical care and infectious diseases were convened to create guidelines for sepsis management, which were published in Critical Care Medicine in March 2004. Lilly provided more than 90% of the funding for these two phases, and many participants had financial or other relationships with the company. According to the Council of Public Relations Firms, Belsito helped to assemble the VERICC Task Force and launch the campaign, and initiated a media-outreach program to 'raise awareness' of alleged rationing in severe sepsis with the intent of generating demand for rhAPC.
[In the guidelines,] rhAPC was given a highly favorable rating (grade B), whereas established therapies for sepsis (such as antibiotics, fluids, and vasopressors), though included in the recommendations, received lower ratings (grade D or E), because most had not undergone randomized, controlled trials owing to a lack of equipoise.
This imbalance is made more troubling by the campaign's failure to discuss persisting concern about rhAPC, which has been reinforced by recent trials. After the PROWESS study, which had demonstrated an increased risk of serious bleeding, two other controlled trials — the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) study and the Resolution of Organ Failure in Pediatric Patients with Severe Sepsis (RESOLVE) study — both of which were terminated early because they were deemed unlikely to show a significant difference in their primary end points, confirmed that increase in risk and resulted in warnings submitted by Lilly to the FDA regarding the use of rhAPC. ...No mention of the [ADDRESS] study was included in a supplement to the Surviving Sepsis Campaign Guidelines.... Although data from the ENHANCE trial were available and are included in the guideline supplement, the possible magnitude of this increased risk (a 28-day incidence of serious bleeding of 6.5%, as compared with 3.5% in the PROWESS study) is not noted.
The Infectious Diseases Society of America (IDSA), however, declined to endorse [the guidelines].... According to Dante L. Landucci, an intensivist at East Carolina University, Critical Care Medicine, which published the guidelines, removed mention of the IDSA's rejection from his invited editorial on the subject that appeared in print 3 months after the guidelines did.
As part of the third phase of the campaign, Lilly awarded unrestricted grants for an 'Implementing the Surviving Sepsis Campaign' program. The main goal of this phase, launched in mid-2004, is the creation of performance bundles based on selected recommendations from the campaign guidelines. Again, many participants have self-reported financial or other relationships with Lilly. Despite the persisting scientific controversy surrounding its safety and efficacy, rhAPC is included in one of these performance bundles. Neither the campaign's manual on bundle implementation nor a cover letter from the president of the Society of Critical Care Medicine mentions the ADDRESS and RESOLVE trials or the warnings they precipitated. In formulating and promoting the bundles, the campaign sought to collaborate with public, not-for-profit arbiters of the quality of health care, including the Voluntary Hospital Association, the Institute for Healthcare Improvement, and the Joint Commission on Accreditation of Healthcare Organizations.
Implementation of the bundles is being advocated nationally in workshops organized under the auspices of the Society of Critical Care Medicine and funded by Lilly. Furthermore, the campaign has lobbied state governments to adopt the bundles. Efforts to institute these measures internationally are being promoted in a program called the "Surviving Sepsis Campaign Roadshow," also subsidized by Lilly.
Professional societies and other stakeholders must work together to promote a consistent guideline-development process, a robust rating system for guidelines that is applicable to all subspecialties, and a policy that prohibits the pharmaceutical and medical-device industries from directly or indirectly funding or influencing practice standards. The challenges involved in producing first-rate guidelines and performance standards are only exacerbated by the intrusion of marketing strategies masquerading as evidence-based medicine.We have previously discussed how guidelines may be written by authors who have financial interests in relevant products (here and here). This current case suggests how this may come to pass in the context of a detailed stealth marketing campaign (and see posts here and here about stealth marketing.) It is particularly notable that these issues are now appearing in the most mainstream of mainstream medical journals.
Maybe with increasing realization how pervasive conflicts of interest fuel deceptive marketing and promotion will come some increased skepticism and a will to address this problem.