Cancer Doctors Are Paid To Prescribe Dubious Drugs
Procrit, Epogen and Aranesp – known collectively as epoetins or ESAs (erythropoiesis stimulating agents) – are among the world's best-selling drugs, with combined sales of $10 billion last year. In the US, they constitute the single biggest drug expense for Medicare and are given to about a million patients each year to treat the anemia that is caused by cancer chemotherapy or by kidney disease. Two of the world's largest drug companies, Amgen and Johnson & Johnson, have been paying hundreds of millions of dollars in incentive bonuses to doctors – including medical oncologists – who prescribe the anti-anemia drugs.
Procrit and Aranesp can be very effective in correcting the severe anemia that often accompanies cancer. Epogen is widely used in the treatment of patients with renal (kidney) failure, another situation in which anemia is extremely common. Epoetins have been heavily marketed to both physicians and patients on the basis of their ability to reduce the need for blood transfusions, give patients more energy and improve their quality of life. However, there is an emerging downside to the use of these drugs.
An increasing number of researchers have become concerned that the drugs may increase a patient's risk of heart attack and strokes. Furthermore, they do not improve the outcome of cancer treatment. In fact, there is growing evidence that they may actually shorten, rather than lengthen, survival. In the light of mounting concern over the dangers of these drugs, the US Food and Drug Administration (FDA) last month belatedly cautioned that epoetins may be unsafe at the commonly used dose levels, and insisted that a "black box" warning be added to the labels and prescribing information for Aranesp, Epogen and Procrit. In mid-May, an FDA advisory committee urged that additional restrictions be put on the use of drugs that treat anemia in cancer patients (Pollack 2007).
The FDA has been very slow to move on the question of epoetin safety. The first indication that the drugs might in fact be harmful came in 1996. A clinical trial sponsored by Amgen was set up to show that dialysis patients would benefit from having their hemoglobin raised to 14 g/dL, which is the level in a healthy person But the trial found instead that patients who were given epoetins to raise their hemoglobin to 14 g/dL suffered more deaths and heart attacks than a group treated with a hemoglobin goal of 10 g/dL. The trail was prematurely stopped. Dr. Anatole Besarab of the Henry Ford Hospital in Michigan, the lead author of that study, told the Times that Amgen and Johnson & Johnson had little incentive to conduct a definitive trial.
A full decade elapsed before FDA finally was spurred to act. On March 9th, 2007 it issued an advisory warning that "an increased number of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots [occurred] when ESAs were adjusted to maintain…hemoglobin more than 12 g/dL" (FDA 2007).
The FDA acknowledged that there is a higher chance of death and an increased rate of tumor growth when patients with advanced head and neck cancer who are receiving radiation therapy are given epoetins. Similarly, in patients undergoing chemotherapy for advanced breast cancer, epoetins such as Procrit, when given to push their hemoglobin levels above 12 g/dL, are associated with an increased rate of tumor progression. In addition, patients scheduled for major surgery who were given epoetin showed a higher rate of thromboembolism (blood clots).
FDA also says that when epoetins are given to anemic cancer patients who are not receiving chemotherapy, the need for blood transfusions is not reduced, and there is actually a higher chance of death. Similarly, patients with chronic renal failure have a higher chance of death and an increased risk of blood clots, strokes, heart failure, and heart attacks when epoetin is given to maintain hemoglobin levels of more than 12 g/dL.
Overall, the FDA has explicitly acknowledged that there is no evidence to indicate that epoetins such as Procrit, Epogen or Aranesp either improve patients' quality of life or extend their survival. Meanwhile, several studies suggest that the drugs actually shorten patients' lives when used at high doses.
Double Dipping
Drug company kickbacks to doctors who prescribe epoetins such as Aranesp, Procrit and Epogen total hundreds of millions of dollars per year and are considered an important source of income for oncologists. "The payments have risen over the last several years," said an article in the New York Times, "as the makers of the drugs, Amgen and Johnson & Johnson, compete for market share and try to expand the overall business."
Illustrating the scope of the problem, just one group of six oncologists in the Pacific Northwest received $2.7 million from Amgen alone for prescribing $9 million worth of its drugs last year (2006). Thus, doctors pocketed about one-third of the gross cost of the drugs in hush-hush rebates from the companies.
But doctors actually get paid two ways for using these drugs. Although Federal law bans drug companies from paying doctors to prescribe medicines given in pill form and purchased by patients from pharmacies, companies are allowed to rebate part of the price that doctors themselves pay for drugs such as the epoetins, which are then dispensed in their offices as part of treatment. Doctors receive their rebates after they buy the drugs directly from the manufacturer. They also receive reimbursement from insurance companies or Medicare for the drugs, often at a markup over the doctors' purchase price. While Medicare in 2003 changed its payment structure, private insurers generally continue to pay more. Needless to say, when such payments are combined with the aforementioned rebates, it adds considerably to oncologists' salaries.
The size of rebates is related to the quantity of drugs that the doctors buy. Rebates increase if doctors also agree to use one company's drugs exclusively. Johnson & Johnson said in a statement that the rebates were not intended to induce doctors to use more medicine, but simply "reflect intense competition" in the market for the drugs. "Amgen is dedicated to patient safety," said David Polk, a spokesman for that company. "We believe our contracts support appropriate anemia management and our product promotion is always strictly within the label." But the Times notes that American cancer patients are about three times as likely as those in Europe to get these drugs. US patients also receive higher doses.
As a result of the rebates from Amgen, six US doctors alone made about $1.8 million in net profit on the drugs they prescribed. Doctors have great flexibility in the amount of any drug they prescribe and in the profits they derive, and so there is little to stop them from using higher doses and thereby garnering higher rebates. The companies in question have generally failed to test whether or not lower doses of the medicine might work as well as these higher doses. In the period 2002-2003, for instance, the average EPO dose per week for an American patient was 17.4 thousand units compared to 10.8 in Canada, 8.0 in Britain, 6.8 in Germany and 5.3 in Japan. In addition, while 32 percent of American patients received doses over 18,000 units per week, only 1 percent of German patients did so.
Dr. Ajay Singh, an associate professor at Harvard Medical School, headed a clinical trial that indicated last year that the drugs might be unsafe in kidney patients at commonly used doses. "The burden of proof is for companies and industry to demonstrate that a drug is safe at a certain level," Singh said. Although epoetins were shown to be unsafe as far back as 1996, their use has continued to soar.
Dr. Ronald A. Paulus of Geisinger Health System of Pennsylvania said the three-hospital chain had lowered its use of epoetins by 40 percent. It did this by monitoring patients closely and by the simple expedient of giving patients supplemental iron when necessary, in order to support the body's ability to make hemoglobin. An iron supplement costs pennies per day. (Nevertheless, cancer patients should NOT self-medicate with iron supplements. Such supplements can be toxic and can actually encourage the growth of cancer in some situations. The decision to supplement with iron should only be made by an experienced medical professional.)
Further concerns were raised in 2003 by clinical trials that were meant to show that raising hemoglobin to high levels would make chemo- or radiation therapy more effective. Instead, the trials showed that epoetin usage was capable of accelerating patients' cancer, and may in some cases have been associated with shorter survival, although a recent study financed by Amgen claimed that Aranesp had no effect on patient survival. At the May 10th meeting of the FDA Advisory panel one of the members asked company representatives, "What data do you have to assure me that this is not Miracle-Gro for cancer?"
Dr. Peter Eisenberg, a Marin County oncologist, said that many doctors had been induced to use more epoetins by the financial incentives the company offered, as well as their belief that these drugs were 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."
The Times' excellent articles on the subject have sparked widespread revulsion and outrage. There are at this writing over 200 reader comments at the Times Web site alone. A few doctors have written to say that they had already changed their prescribing practices before the Times' latest revelations and to assure readers they did not personally profit from the use of the drug. But that does not change the fact that the rebate program continues apace, and is apparently widespread. More typical responses are that it is "scary" and "disgusting" for physicians to profit from a potentially dangerous treatment in this way.
As long as oncologists continue to derive a considerable amount of their income from drug company rebates of this kind, their clinical judgment will be suspect. Cancer patients will have no way to know whether a particular drug is being prescribed because it is the right and proper treatment or because it lines the pockets of the doctor who gives it. Oncologists whose prescribing habits are influenced by potential personal gain are engaging in unprofessional behavior, since they are putting their own financial interests above the well-being of their patients. Furthermore, even those who are not themselves deriving an income from the rebated sale of drugs, but who fail to speak out against the practice, are guilty of enabling their more greedy colleagues.
All in all, it is an intolerable situation and FDA's recent warnings, while welcome, hardly make a dent in the overall problem.
–Ralph W. Moss, Ph.D.
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References:
FDA Public Health Advisory: erythropoiesis-stimulating agents (ESAs). March 13, 2007. Available at: http://www.fda.gov/cder/drug/advisory/RHE2007.htm
Berenson, Alex and Pollack, Andrew. Doctors reap millions for anemia drugs. New York Times, May 9, 2007. Available at: http://www.nytimes.com/2007/05/09/business/09anemia.html?pagewanted=1
Birnbaum S. CT scanning: too much of a good thing. British Medical Journal 2007; 334(7601): 1006.
Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII – Phase 2 Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, National Research Council available from the National Academies Press at: http://www.nap.edu/catalog/11340.html
Jefford M, Tattersall MH. Informing and involving cancer patients in their own care. Lancet Oncology 2002;3(10):629-37.
Pollack, Andrew. F.D.A. panel seeks limits on cancer patient drugs. New York Times, May 11, 2007. Available at: http://select.nytimes.com/mem/tnt.html?emc=tnt&tntget=2007/05/11/health/11anemia.html&tntemail0=y
