December 26th, 2006

Medical Journal Spikes Article On Industry Ties of Kidney Group

By David Armstrong
Wall Street Journal

The New England Journal of Medicine last month published studies warning that aggressive efforts to treat anemia in kidney-disease patients with the drug erythropoietin, or EPO, as recommended by the National Kidney Foundation, appear to increase the risk of heart failure and the need for dialysis. But the medical journal spiked an opinion piece commissioned from one of its senior writers that was critical of the foundation’s reliance on multimillion-dollar donations from the companies that make such drugs.

The journal did run a less-critical editorial on the studies co-authored by Julie Ingelfinger, a nephrologist and deputy editor at the journal who is the immediate past president of the Massachusetts-based chapter of the National Kidney Foundation and a member of the state group’s medical advisory board. The editorial that ran made no mention of the foundation’s industry funding, and Dr. Ingelfinger’s relationship with the foundation wasn’t disclosed.

Meanwhile, the author of the spiked editorial, Dr. Robert Steinbrook, submitted it to one of the journal’s chief rivals, the British medical journal Lancet, which ran a version on its Web site on Nov. 17, a day after the New England Journal published its reports on the matter.

Dr. Steinbrook’s article said that the foundation’s guidelines have been questioned because of the group’s close relationship with the drug industry. The article also noted that in fiscal 2005, the foundation received more than half of its support from “corporate and organizational partners,” and, in the calendar-year 2005, it received $4.1 million from Amgen Inc. and $3.6 million from Johnson & Johnson’s Ortho Biotech, the current marketers of EPO in the U.S. Of the 18 members of the group that formulated the guidelines, two-thirds disclosed financial associations with Amgen or other EPO manufacturers or marketers, he noted.

Dr. Steinbrook commented that “given the billions of dollars at stake for the drug and dialysis, such guidance is likely to receive the broadest acceptance if developed without industry support and by experts without relevant financial associations.”

The editorial that was published in the New England Journal also expressed doubt about the kidney foundation guidelines—saying “these recommendations are not based on persuasive randomized, controlled trials”—but made no mention of the industry funding of the kidney foundation.

The handling of the two articles has reignited debate about the journal’s standards and whether it is tough enough on issues involving industry funding of research and treatment guidelines. Considered the most influential medical journal in the world, the publication is closely watched for what it says, or doesn’t say, about industry influence on medicine.

Earlier this year, the journal was faulted for not being more aggressive in rooting out problems with a 2000 study it published on Merck & Co.’s painkiller Vioxx, which was removed from the market in 2004 because of safety concerns.

The journal in 2002 relaxed its conflict-of-interest policy for editorial writers. Complaining that it was difficult to find qualified editorial writers who didn’t have a conflict of interest, it loosened its policy to forbid only writers who have a “significant” stake in the research they opine on.

By contrast, earlier this year, the rival Journal of the American Medical Association toughened its disclosure rules, telling study authors it wanted more information about their relationships with drug and medical-device companies. This followed a series of gaffes in which authors of studies published in the medical journal failed to reveal their financial ties with pharmaceutical companies.

The incident also highlighted the uncertainty over how aggressively to treat anemia, a shortfall in the body’s hemoglobin or oxygen-carrying red blood cells, in patients with kidney disease. The EPO drugs, such as Amgen’s Epogen, have become best-sellers for their ability to relieve anemia-related fatigue and allow kidney patients to forestall regular blood transfusions. The foundation has issued guidelines encouraging doctors to keep hemoglobin levels in such patients even higher than the level approved by the Food and Drug Administration. But two clinical trials published in the New England Journal found that such aggressive efforts to treat anemia appeared to increase the risk of heart failure in one study, and to accelerate the need for dialysis in the other.

In one of the studies—led by Ajay Singh, clinical director of the renal division of Brigham and Women’s Hospital in Boston, and sponsored by J&J’s Ortho unit—one set of patients received EPO treatments designed to raise hemoglobin to the near-normal level of 13.5 grams per deciliter. Doctors targeted a lower hemoglobin level of 11.3 grams per deciliter for the remaining patients, within the FDA’s approved target range of 10 to 12 grams per deciliter. The kidney foundation’s guidelines encompass a hemoglobin range of 11 to 13 grams per deciliter. The researchers found that patients in the high-hemoglobin group were nearly 50% more likely to experience heart problems than patients in the low-hemoglobin group.

The second study, sponsored by Roche and led by Tilman Drueke, a nephrologist with Necker Hospital in Paris, assigned kidney patients either to aggressive anemia treatment with a target hemoglobin range of 13 to 15 grams per deciliter or to a more traditional range of 10.5 to 11.5 grams per deciliter. The team found no significant difference in heart problems between the groups, although the high-hemoglobin patients reported better general health and vitality. However, more of the intensively treated patients had to start dialysis treatment than their counterparts, and tended to do so more quickly.

The kidney foundation, which issued its recommendations earlier this year, credits Amgen as the “founding and principal sponsor” of the guidelines. Such sponsorship is unusual—the American Diabetes Association, for instance, says it doesn’t “receive or allow for any corporate contributions for our clinical practice recommendations.”

Ellie Schlam, a foundation spokeswoman, says Amgen’s sponsorship money paid for guideline-development staffers, a $3,000 grant to each member for travel to meetings and other expenses, plus phone, faxing, copying and other administrative expenses. A disclosure on the foundation’s Web site noted that most members of the guideline group have a financial relationship with either Amgen or dialysis providers, who resell EPO and stand to profit from its increased use. Still, the foundation says sponsors aren’t informed or involved in any aspect of guideline development.

A spokesman for Amgen said the company is “not involved in the creation and design of the guidelines we sponsor.” He said the company promotes the anemia levels approved by the FDA and not the higher levels suggested by the guideline committee. Ortho didn’t provide financial support for the development of guidelines, a spokesman says, adding that money it donated has been used to fund patient screening and medical education programs.

The New England Journal declined to discuss Dr. Steinbrook’s article, saying “we discuss only content that we have published.” Dr. Steinbrook, a former deputy editor of the New England Journal, has been a national correspondent since 2002. According to a person familiar with the matter, he was told his manuscript lacked balance because it suggested that the commercial support of the guidelines influenced the medical recommendations made by that group. New England Journal editors also criticized the piece for failing to credit the guideline writers for striving to find the right balance when it comes to anemia guidelines.

Meanwhile, Richard Horton, editor of the Lancet, said “I was surprised Robert came to us because I have admired his work for the New England Journal of Medicine.” Dr. Horton said of the article: “We thought it extremely important—because of the significant clinical implications and because of the questions it raised about the propriety of the arrangements over funding and guideline development.”

Asked why Dr. Ingelfinger’s roles at the Massachusetts Kidney Foundation weren’t listed along with the article she co-authored, a spokeswoman for the New England Journal said, “We publish financial associations that are relevant to the content of the article. We tend to be inclusive, rather than exclusive.”

The article did disclose that Dr. Ingelfinger’s co-author, Giuseppe Remuzzi, had received lecture fees from Abbott Laboratories, Sanofi-Aventis, and AstraZeneca PLC, none of which make EPO. Dr. Remuzzi was unavailable for comment.

The Web site of the Massachusetts chapter listed Dr. Ingelfinger as president and chairman of its medical board at the time her editorial was published last month. But the New England Journal spokeswoman said Dr. Ingelfinger wasn’t in a leadership role there at the time she wrote the editorial and that her positions have been unpaid.

Calls to Dr. Ingelfinger were returned by public relations staff at the medical journal, who declined to say whether Dr. Ingelfinger was involved in vetting Dr. Steinbrook’s piece or if her superiors were aware of her roles at the kidney foundation.

Frank Davidoff, the editor emeritus of the Annals of Internal Medicine, says Dr. Ingelfinger’s association with the kidney foundation should have been made known to readers. “She should have disclosed that, even if she is the best person to write the editorial,” he said. Dr. Davidoff said medical journals historically have paid less attention to the potential conflicts of editorial writers than they have to researchers publishing original studies.

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