Saturday, August 16, 2008

More Questions About Conflicts of Interest and "Surviving Sepsis"

Two years ago, we posted about questions whether the "Surviving Sepsis" campaign was driven by marketing as well as science. Then, we discussed a commentary in the New England Journal of Medicine which asserted that the campaign was part of an effort by Eli Lilly & Co to market Xigris (recombinant human activated protein C, or rhAPC, also known as drotrecogin alfa [activated]) for the treatment of sepsis.(1)

The Wall Street Journal just published an article questioning another aspect of that campaign. In 2001 a clinical trial in the New England Journal of Medicine by Rivers et al reported favorable results for early goal-directed therapy in the treatment of sepsis.(2) This therapy incorporated continuous monitoring of oxygen in the blood using a special central venous catheter capable of measuring oxygen saturation. The WSJ article first raised concerns that some of the patients initially entered into the study were excluded after randomization.

The medical-journal article analyzed 263. But it also said that 288 patients were 'evaluated,' of whom 25 'were excluded or did not consent to participate.'

Dr. Rivers, in an April interview describing how he proceeded, said 'all 288 are randomized' -- that is, placed into either the standard-therapy group or the other group -- 'and then some are excluded because they're not considered severe septic shock.'

But once patients are randomly placed in a group, they must be included in a final analysis, according to a fundamental principle of medical research. Twenty-five were not, the medical-journal article makes clear.

Further muddying the waters, Dr. Rivers, despite having said all 288 patients were 'randomized," stated in a later email that 'there were absolutely no patients pulled out before the analysis.'

The result appears to be a lack of clarity about exactly how this seminal study was done.

Hospital statisticians who worked on it had concerns about the data and recalculated the results with all 288 patients, according to people familiar with the events. When they did, these people say, the death-rate gap wasn't statistically significant.

Statisticians were especially concerned when they noticed that a relatively high proportion of the other 25 -- those not included in the final analysis -- were either conventional-therapy patients who survived or patients on aggressive therapy who died, say the people familiar with the events.

In 2005, a medical resident at Henry Ford doing follow-up research complained to senior hospital officials about the data in Dr. Rivers's study. The hospital convened a panel of inquiry, which concluded the issues had been satisfactorily resolved, hospital officials say.

The panel did a 'thorough investigation' and 'unanimously supported the conclusions,' the hospital said, adding that Dr. Rivers is 'an outstanding clinical investigator whom we support.'

The hospital declined to make the panel's report available. The medical resident who complained, Michael Donnino, declined to discuss the issue of the other 25 patients not included in the final analysis.

Dr. Rivers said that 'randomization was valid,' that 'all patients enrolled in the [early goal-directed therapy] study were appropriately selected, randomized and examined statistically,' and that 'there are no scientific integrity issues in the study.'
I should note that ideally randomized controlled trials should account for all patients randomized, and attribute their results to the group in which they were randomized, even if they did not complete the treatment to which they were randomized. Eliminating patients after randomization could bias the results of analysis, especially if patients particularly likely to have good or bad outcomes were selectively eliminated from one group or the other. The WSJ article raises questions about the occurrence of such bias, but does not prove it occurred.

Further complicating things, the WSJ article suggested that the authors of the article also had undisclosed conflicts of interest.

At the time the study at Henry Ford Hospital was published, in late 2001, the hospital was the owner of patents on the catheter used in the new treatment. Dr. Rivers had transferred the rights to the institution.

The New England Journal of Medicine didn't mention the patents when publishing the study. According to its editor, its policy at the time was to ask only whether an investigator had financial ties to companies involved, and Dr. Rivers said, correctly, that he had none.

Since the publication, catheter maker Edwards Lifesciences has made various payments to Dr. Rivers and his hospital. Such arrangements aren't unusual in medicine, but their existence can raise doubts about findings.

Dr. Rivers and the hospital over the years have received at least $404,000 from Edwards, the Irvine, Calif., company says.

For instance, Edwards paid $150,000 between 2001 and 2003 to Henry Ford Hospital for what Edwards terms 'nonexclusive patent rights [and] ongoing research' into blood oxygen and the mechanism of shock. Dr. Rivers, in an interview, described this as 'money I've gotten from the catheter...all for research.'

In addition, Edwards said, it has paid Dr. Rivers $158,000 to make speeches about his research, $20,000 to reimburse him for patent legal fees, $36,000 in reimbursed expenses and $40,000 in consulting fees.

Edwards Lifesciences said medical evidence has 'demonstrated that early goal-directed therapy yields significant reductions in sepsis-related mortality, lower organ failure rates and/or reduced health-care costs, particularly due to reduced stays.' In recent articles he has written, Dr. Rivers has disclosed receiving support from Edwards.

Also, Edwards Lifesciences was, along with Eli Lilly, a major sponsor of the Surviving Sepsis campaign.

In 2002, critical-care doctors from several specialties joined together to recommend treatments, calling themselves the Surviving Sepsis Campaign. Leading it were R. Phillip Dellinger of Cooper University Hospital in Camden, N.J., and Mitchell M. Levy of Brown University Medical School. Both, plus four others in the group, received consulting fees, honoraria or research-grant support from catheter maker Edwards.

Edwards helped pay for overseas meetings of the group in 2002 and 2004, which cost $861,000 in all. Surviving Sepsis endorsed Dr. Rivers's protocol as well as a drug made by another funder of the conferences, Eli Lilly & Co. Edwards said such support is 'routinely given to advance science and treatments for the benefit of patients.'

Finally, Dr Rivers also has also recently disclosed that he has been receiving money from Eli Lilly, for example, in a 2006 article, "Dr. Rivers has done consultant work for Biosite, Inc., Chiron, the Lilly Corporation, and Edwards Lifesciences over the last year."(3)

So, for an interval summary, recent guidelines promulgated by the "Surviving Sepsis" campaign include fairly enthusiastic endorsements for use of Xigris, made by Eli Lilly & Co, and early goal directed therapy, which requires use of a specific catheter made by Edwards Lifesciences (and other companies). These guidelines were based on research sponsored by these two companies which the guidelines touted as more definitive than it now appears to be. Furthermore, there is a web of financial links, that now appears increasingly complex, tying together these two companies, some researchers involved in these studies, their institutions, and the guideline writing process. These apparent conflicts of interest have raised questions about the integrity of the research on which the guidelines were based, and bias influencing the writing and deployment of the guidelines.

So it is becoming more difficult to determine the extent that marketing considerations influenced the "Surviving Sepsis" campaign, and some of the medical research on which its guidelines were based. Thus, the issue of how best to manage sepsis, already a complex one, now becomes more complex and less clear.

The larger lessons, again, are that there is a growing and ever more pervasive web of financial ties among academic medicine and commercial firms that make drugs and devices and provide various health care services. The resulting conflicts of interest suggest patients, physicians and policy-makers should be ever more skeptical about seemingly authoritative medical research, and medical education, practice guidelines, and health care policy based on this research.

To make better decisions for individual patients, and better policies for populations, people, patients, physicians and policy-makers at least need clearer and more detailed information about all conflicts that may affect the evidence and opinions that influence their decisions. But might it not be simpler and ultimately better for people, patients, physicians and policy-makers to eliminate some of these conflicts so that we can begin to believe that researchers and academics are paid only to take care of patients, and create and disseminate new knowledge?


1. Eichacker PQ, Natanson C, Danner RL. Surviving sepsis - practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med 2006; 335: 1640-1642. Link here.

2. Rivers E, Nguyen B, Havstad S et al for the Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377. Link here.

3. Rivers EP. Early goal-directed therapy in severe sepsis and septic shock: converting science to reality. Chest 2006;129:217-218. Link here.


Anonymous said...

I read the WSJ article and wondered if there was anything special about this catheter other than it's ability to make money for certain individuals.

If paying attention to oxygen capacity is indeed important in sepsis, what about simply following Hgb closely and transfusing earlier than usual? What about being more aggressive with dobutamine in general in sepsis? The control group in any study looking at the catheter should do those two things, then we'll see if the catheter adds anything.

Anonymous said...

Edwards Lifesciences should be under investigation for the under the table deals. I have seen monies from Edwards go to hospitals for research. Then the hospitals turn a round a by their products. Donations by Edwards is just a marketing stunt to get the hospitals to buy their products.

Anonymous said...

Early goal directed therapy isn't about O2 capacity so much as O2 extraction in setting of hypotention. High mixed venous O2's are consistent with septic shock and do correct with aggressive resuscitation. If you don't believe early aggressive resuscitation improves outcomes because the study had commercial support, then it's time for someone to repeat the study. I do use the Edwards CVP with continuous SvO2 monitoring sometimes but more often I just follow venous blood gases drawn from CVP lines in the SVC. I appreciate skepticism with conflicts of interest but the physiology is appealing and anecdotally I do see shorter ICU stays when complete resuscitation is provided early and SvO2s seem to be good markers of this.
As for Edwards funding research, I think we should look at it as part of their ethical responsibility to continue to fund research. The sort of scrutiny given to Rivers demonstrates that academics are held accountable for their research / recommendations and it remains the prescribing provider's responsibility to choose how / how not to utilize it.
BTW, I have NO affiliation with Rivers or Edwards or anyone else.