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US: Strengthening Bones, Raising Questions

by Denise GelleneNew York Times
April 23rd, 2004

Last fall, the National Kidney Foundation for the first time set treatment guidelines to prevent a complication from kidney failure that causes damage to bones. The guidelines were tough, and there was no drug on the market that would easily help a patient meet them.

Five months later, the Food and Drug Administration gave Amgen Inc. the OK to sell cinacalcet, an $8-a-day pill its sells under the name Sensipar to people on kidney dialysis. The drug, something of a breakthrough, can stem the loss of key minerals that keep such patients' bones strong, the same minerals the Kidney Foundation set target levels for in its guidelines.

In fact, Amgen's research and development chief, Roger Perlmutter, told investors on Wall Street last month: "You can't get to the guidelines without using Sensipar, it seems to me."

What Perlmutter didn't mention and what the investment and medical community knew was that Amgen helped sponsor the Kidney Foundation's research. The company contributed $150,000 to support research that led to the guidelines, and seven of the 14 experts who wrote the guidelines had ties to the Thousand Oaks company, according to the Kidney Foundation.

To some in the medical community, the guidelines are, at best, suspect.

"The guidelines could be very good or they could be very bad. That is the problem: It is impossible to tell," said Marcia Angell, a former editor of the New England Journal of Medicine, who said she believed the Kidney Foundation's recommendations "can't be trusted" because pharmaceutical companies sponsored the panel's work.

Amgen wasn't the only financial backer. Abbott Laboratories and Genzyme Corp. also were sponsors, to the tune of $450,000 and $150,000, respectively. And the panel specifically mentioned drugs sold by Abbott and Genzyme, as well as drugs made by companies that weren't sponsors.

Though the panel did not mention Sensipar, it is the drug that will probably benefit most if the guidelines are followed. "It is very difficult to meet the recommendations without it," said analyst Geoffrey Porges of Sanford Bernstein & Co.

Amgen isn't secretive about its connections to the foundation and says it gives unrestricted grant money to the organization. However, the company could not confirm the specific amount that it contributed to sponsor the guideline research.

Amgen, which gave the foundation information about its drug, saw nothing unethical in supporting an effort "to raise physician standards to provide the best healthcare delivery," spokeswoman Kelly Stoddard said. "It was an independent process," she said of the panel's work.

For its part, the New York-based Kidney Foundation, whose members include patients and healthcare professionals, stands by its guidelines and maintains its work was independent. Amgen has sponsored some of its studies before: Its first clinical recommendations, in 1997, have been credited with helping to reduce anemia in dialysis patients and were sponsored by Amgen, which sells a multibillion-dollar anemia drug.

Any potential conflicts of interest associated with the latest guidelines were disclosed to the public, said Kidney Foundation spokeswoman Karen Glowacki.

Sheldon Krimsky, a Tufts University professor and author of "Science in the Private Interest," said that wasn't enough.

"It is like having a judge disclose that he is sentencing a felon to a for-profit prison in which the judge has a stake," Krimsky said. "That doesn't make it acceptable."

There's no question that the foundation's treatment goals could give Amgen a marketing tool for a drug that faces some challenges.

One problem for Amgen is that because cinacalcet is a pill, it isn't covered by the federal Medicare program, which otherwise picks up most dialysis-related costs. Many patients will be reluctant or unable to pay for the drug, which would typically cost nearly $3,000 a year. And in clinical trials, some patients needed a dose that would cost nearly $9,000 a year.

Moreover, patients may lack motivation to take cinacalcet because they don't feel ill when their mineral levels are out of whack. Bone disease "doesn't hurt until it's too late," said Robert Provenzano, president of the Renal Physicians Assn.

In its press materials for Sensipar, Amgen cites the Kidney Foundation guidelines, which set targets for calcium and phosphorous, minerals that can get out of control in people with kidney failure. They can't effectively remove excess phosphorous, a mineral found in many foods, and as phosphorous accumulates in the blood, it soaks up calcium. So the parathyroid gland, sensing more calcium is needed, releases a hormone that signals the bones to release the mineral. As the cycle continues, the bones weaken and blood vessels stiffen.

The guidelines also set targets on parathyroid hormone. Cinacalcet reduces the hormone and slows the rate at which calcium leaves the bones. It also reduces phosphorous.

The Amgen drug "is a new tool in the armamentarium," said Dr. William G. Goodman, a UCLA kidney specialist who tested cinacalcet in human trials. "We can treat patients better than in the past."

However, Goodman said that though the Kidney Foundation's calcium targets were probably good news for Amgen, they might not be ideal for all patients. The guidelines say calcium should be at the "low end" of what is normal in healthy people a range Goodman called "too rigid."

Calcium levels vary among individuals, and the amount needed for bone renewal and repair also varies, he said. In fact, the target in Europe is 12% higher than what the foundation recommends.

"What are the long-term effects of keeping calcium lower than what is normal for these people?" Goodman, an expert on calcium in dialysis patients, asked. "We really don't have the answer."

Dr. Adeera Levin, a kidney specialist at the University of British Columbia in Canada, said she agreed that the calcium targets were too narrow. "Why not have higher calcium than it says in the [guideline] document if nothing bad happens?" she said.Physicians aren't required to follow guidelines issued by the Kidney Foundation, but its recommendations are influential. "Clinicians want to know what the experts think," said Levin, a top medical advisor to the foundation on all guideline development. "It is better than just guessing."

The Kidney Foundation said it started working on the latest guidelines in 1999. The foundation's experts sifted through hundreds of articles from medical journals related to bone disease in kidney failure patients. Before being published last year, the guidelines were broadly circulated among kidney specialists for comment.

Dr. Shaul G. Massry, a USC kidney specialist who chaired the panel, said none of the members were influenced by the corporate sponsorships or their relationships to the companies. "I told everyone to be objective and fair," he said.

One panelist was a member of Amgen's medical advisory board and four panel members had been consultants or advisors to Amgen in the past. A sixth had attended past Amgen advisory board meetings as an observer. And a seventh panelist had received a research grant from Amgen.

An equal number of panelists also had similar connections to Abbott and Genzyme. Representatives of those companies said they did not help write the guidelines and respected the independence of the panel.

Although the panel evaluated drugs made by those two companies, it didn't do so with cinacalcet, because too few studies had been published on it, Massry said. The calcium target was chosen because the experts considered "low normal" safer for patients, he said.

"We did not have cinacalcet in mind," Massry said.

Studies show the guidelines are tough to meet with standard dialysis drugs alone. A recent analysis of 30,000 patients found that 50% of them had more phosphorous and 30% more calcium than recommended by the Kidney Foundation.

"These patients are not going to meet the guidelines on what was standard therapy," said University of Louisville kidney specialist Rosemary Ouseph, who analyzed the data.

Amgen made a similar point at a medical conference in November. It presented results of several clinical trials of hundreds of patients that all pointed to the benefits of taking cinacalcet. In fact, one Amgen study said only 8% of dialysis patients would meet the guidelines for minerals and parathyroid hormone without its drug.

Amgen said Thursday that it had given the Kidney Foundation $150,000 to purchase copies of the guidelines to distribute to the medical community.

The guidelines should be a big help to Sensipar's sales efforts, said analyst Porges. "They are terrifically meaningful to Amgen."





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