Doctors Reaping Millions for Use of Anemia Drugs

[Guest guest]

Doctors Reaping Millions for Use of Anemia Drugs

by ALEX BERENSON and ANDREW POLLACK

Published: May 9, 2007

Two of the world’s largest drug companies are paying hundreds of millions of

dollars to doctors every year in return for giving their patients anemia

medicines, which regulators now say may be unsafe at commonly used doses.

The payments are legal, but very few people outside of the doctors who receive

them are aware of their size. Critics, including prominent cancer and kidney

doctors, say the payments give physicians an incentive to prescribe the

medicines at levels that might increase patients’ risks of heart attacks or

strokes.

Industry analysts estimate that such payments — to cancer doctors and the

other big users of the drugs, kidney dialysis centers — total hundreds of

millions of dollars a year and are an important source of profit for doctors and

the centers. The payments have risen over the last several years, as the makers

of the drugs, Amgen and Johnson & Johnson, compete for market share and try to

expand the overall business.

Neither Amgen nor Johnson & Johnson has disclosed the total amount of the

payments. But documents given to The New York Times show that at just one

practice in the Pacific Northwest, a group of six cancer doctors received $2.7

million from Amgen for prescribing $9 million worth of its drugs last year.

Yesterday, the Food and Drug Administration added to concerns about the drugs,

releasing a report that suggested that their use might need to be curtailed in

cancer patients. The report, prepared by F.D.A. staff scientists, said no

evidence indicated that the medicines either improved quality of life in

patients or extended their survival, while several studies suggested that the

drugs can shorten patients’ lives when used at high doses. Yesterday’s report

followed the F.D.A.’s decision in March to strengthen warnings on the drugs’

labels.

The report was released in advance of a hearing scheduled for tomorrow, during

which an F.D.A. advisory panel will consider whether the drugs are overused.

The medicines — Aranesp and Epogen, from Amgen; and Procrit, from Johnson &

Johnson — are among the world’s top-selling drugs, with combined sales of $10

billion last year. In this country, they represent the single biggest drug

expense for Medicare and are given to about a million patients each year to

treat anemia caused by kidney disease or cancer chemotherapy.

Dr. Len Lichtenfeld, the deputy chief medical officer of the American Cancer

Society, said that both patients and doctors would benefit from fuller

disclosure about the payments and the profits that doctors can make from them.

" I suspect that Medicare is going to take a very careful look at what is going

on here, " he said.

Still, the anemia drugs can help patients’ quality of life, when used

appropriately, he said. " We shouldn’t condemn every oncologist; we shouldn’t

condemn the drugs, because of the situation we’re in now. "

Federal laws bar drug companies from paying doctors to prescribe medicines

that are given in pill form and purchased by patients from pharmacies. But

companies can rebate part of the price that doctors pay for drugs, like the

anemia medicines, which they dispense in their offices as part of treatment. The

anemia drugs are injected or given intravenously in physicians’ offices or

dialysis centers. Doctors receive the rebates after they buy the drugs from the

companies. But they also receive reimbursement from Medicare or private insurers

for the drugs, often at a markup over the doctors’ purchase price.

Medicare has changed its payment structure since 2003 to reduce the markup,

but private insurers still often pay more. Combined with those insurance

reimbursements, the rebates enable many doctors to profit substantially on the

medicines they buy and then give to patients.

The rebates are related to the amount of drugs that doctors buy, and

physicians that agree to use one company’s drugs exclusively typically receive

higher rebates.

Johnson & Johnson said yesterday in a statement that its rebates were not

intended to induce doctors to use more medicine. Instead, the rebates " reflect

intense competition " in the market for the drugs, the company said.

Amgen said that rebates were a normal commercial practice and that it had

always properly promoted its drugs.

" Amgen is dedicated to patient safety, " said David Polk, a spokesman. " We

believe our contracts support appropriate anemia management and our product

promotion is always strictly within the label. "

Both companies’ stocks fell yesterday after release of the F.D.A. report.

Amgen executives may face questions about the controversy from investors today

when the company holds its annual meeting in Providence, R.I.

Since 1991, when the first of the drugs was still relatively new, the average

dose given to dialysis patients in this country has nearly tripled. About 50

percent of dialysis patients now receive enough of the drugs to raise their red

blood cell counts above the level considered risky by the F.D.A.

American patients receive far more of the anemia drugs than patients

elsewhere, with dialysis patients in this country getting doses more than twice

as high as their counterparts in Europe. Cancer care shows a similar pattern.

American cancer patients are about three times as likely as those in Europe to

get the drugs, and they receive somewhat higher doses.

The rebates inevitably encourage use of the drugs, said Michael Sullivan, who

for nine years worked as a business manager for the group of six cancer doctors

in the Pacific Northwest, before losing his job last year. He provided The Times

with documentation that shows the size of the rebates, on the condition that the

group not be identified.

" Personally, I think rebates should go away, " said Mr. Sullivan, whose father

was a kidney dialysis patient who died of a heart attack while taking one of the

anemia drugs. " The whole problem with it, I guess, is that you’re playing with

people’s health. It’s not the same as buying widgets. "

For doctors who use less of the drugs, the rebates may make the difference

between losing money on the drugs or breaking even. Mr. Sullivan said that as

result of the rebates from Amgen, the six doctors in his group made about $1.8

million in net profit on the drugs they prescribed.

Unlike most drugs, the anemia medicines do not come in fixed doses. Therefore,

doctors have great flexibility to increase dosing — and profits. Critics say

that the companies have contributed to the confusion by failing to test whether

lower doses of the medicines might work better than higher doses.

" The burden of proof is for companies and industry to demonstrate that a drug

is safe at a certain level, " Dr. Ajay Singh, an associate professor at Harvard

Medical School. Dr. Singh headed a clinical trial that indicated last year that

the drugs might be unsafe in kidney patients at commonly used doses.

Known generically as epoetin and darbepoetin, and often referred to simply as

EPO, the drugs are genetically engineered versions of a human protein that

stimulates the bone marrow to produce more red blood cells and increase the

body’s ability to carry oxygen.

Most doctors and patients agree the drugs are very helpful for patients when

used to correct severe anemia, which can be debilitating and even

life-threatening. The drugs reduce the need for risky blood transfusions and can

give patients more energy and improve their quality of life.

" We have transformed the lives of patients with chronic kidney disease, " said

Dr. Norman Muirhead, a professor at the University of Western Ontario who has

given talks and consulted for Amgen and Johnson & Johnson.

But there is little evidence that the drugs make much difference for patients

with moderate anemia, and federal statistics show that the increased use of the

drugs has not improved survival in dialysis patients. About 23 percent of

American patients on dialysis die each year, a rate that has not changed since

Epogen was introduced.

Anemia is measured by a patient’s level of hemoglobin, the molecule the body

uses to transport oxygen to its cells. Healthy people have around 14 grams of

hemoglobin per deciliter of blood. Patients with fewer than 12 grams are

considered mildly anemic, and those with fewer than 10 as moderately or severely

anemic.

The labels on the drugs, as currently approved by the F.D.A., encourage

doctors to aim for a hemoglobin level of 10 to 12. But about half of all

dialysis patients now have their hemoglobin levels raised to above 12.

Critics of the drugs say their increased use has been driven by profit.

DaVita, one of the two large dialysis chains, and the most aggressive user of

epoetin, gets 25 percent of its revenue from the anemia drugs — and even more of

its profit, according to some analysts.

Dr. David Van Wyck, senior associate to the chief medical officer of DaVita,

said the company did not overuse the medicines.

Doctors determine how much to use, Dr. Van Wyck said. " To say that somebody is

encouraging a doc to use more EPO is just outrageous. "

Although the safety debate has heated up only recently, the first sign that

the drugs might be dangerous came more than a decade ago. That evidence emerged

in a trial sponsored by Amgen that was set up to show that dialysis patients

would benefit from having their hemoglobin raised to 14, the level in a healthy

person.

But the trial, which was stopped in 1996, found that patients in that group

had more deaths and heart attacks than a group treated with a hemoglobin goal of

10.

That trial should have discouraged doctors from using too much epoetin and

encouraged Amgen to study the risks further, said Dr. Steven Fishbane, a

nephrologist at Winthrop-University Hospital on Long Island.

Instead, use of epoetin continued to soar. No one conducted a trial to

determine whether the optimal hemoglobin target in kidney patients might be 10

or 11, instead of 12 or 13 — a crucial question that remains unanswered even

today.

Dr. Anatole Besarab of the Henry Ford Hospital in Michigan, the lead author of

the study that was stopped in 1996, said that Amgen and Johnson & Johnson had

little incentive to conduct such a trial.

Dr. Robert M. Brenner, head of nephrology medical affairs for Amgen, said

there was ample data from previous trials showing that treating up to hemoglobin

of 12 was safe and effective.

Some hospitals and doctors have used epoetin more conservatively than the big

dialysis chains.

Dr. Ronald A. Paulus, chief health technology officer at Geisinger Health

System, a nonprofit group that includes three hospitals in Pennsylvania, said

Geisinger had lowered its use of epoetin by 40 percent. Its doctors did do so

simply by monitoring patients more closely and giving them more iron, without

which the body cannot make hemoglobin.

Dr. N. D. Vaziri, the chief of nephrology at the University of California,

Irvine, said some clinics had been too aggressive about giving extremely high

doses of epoetin to people who did not initially respond to lower levels. The

United States is virtually the only country in which patients get super-high

doses.

" You create a toxicity situation, " said Dr. Vaziri, who has done studies in

animals showing how epoetin contributes to hypertension and blood clots.

In cancer patients, concerns were raised in 2003 by clinical trials meant to

show that raising hemoglobin to high levels would make chemotherapy or radiation

therapy more effective. Instead, several trials showed the drugs appeared to

worsen cancer or hasten death, although one recent study by Amgen showed that

its drug Aranesp had no effect on patient survival.

The conflicting studies are among the issues the F.D.A. advisory committee is

expected to discuss tomorrow. Already, some cancer doctors are moderating their

use of the anemia drugs.

Dr. Peter Eisenberg, an oncologist in Marin County, Calif., said many doctors

had been induced to use more epoetin by the financial incentives and the belief

that the drug was helpful.

" The deal was so good, " he said. " The indication was so clear and the downside

was so small that docs just worked it into their practice easily.

" Now it’s much scarier than that, " he said. " We could really be doing harm. "