Evelyn Pringle January 2008
Concern about the incentives to overuse injectable cancer drugs, created by the Medicare reimbursement system that paid a markup of 20% to 100%, caused rates to be changed to more closely align with what doctors actually paid for the drugs, and reimbursement is now supposed to amount to only 6% more than the average price paid by all doctors.
In 2005, all totaled, cancer doctors billed about $4.4 billion for chemotherapy and anemia medications, down from $5.6 billion in 2004, and Medicare covered 80% of the bills, according to a report by Alex Berenson in the June 12, 2007, New York Times.
Since the new reimbursement rates went into effect, cancer doctors have been lobbying Medicare officials and lawmakers to raise the prices paid for drugs, and some physicians say that doctors responded to the changes by performing treatments that got them the best reimbursement, regardless of whether the treatment benefited the patients or not.
In general, oncologists make money by providing chemotherapy, even when it has little chance of success. With the new limits on profits, some doctors are performing chemotherapy more often or installing multimillion-dollar imaging machines where they profit when patients receive diagnostic scans, according to the report in the Times.
"There's pretty good evidence at this point," Dr Richard Deyo, professor of medicine at the University of Washington and an expert on health care spending, told the Times, "that there are plenty of patients for whom there's little hope, who are terminally ill, whom chemotherapy is not going to help, who get chemotherapy."
Dr Robert Geller, an oncologist in private practice from 1996 to 2005, before becoming a senior medical director at Alexion, a biotech company, told the Times that, as long as oncologists continue to be paid by the procedure instead of for spending time with patients, they will find ways to game the system, regardless of how much money they make or lose on prescribing drugs.
"People go where the money is, and you'd like to believe it's different in medicine, but it's really no different in medicine," Dr Geller said. "When you start thinking of oncology as a business, then all these decisions make sense."
Some doctors are also now requiring cancer patients to make co-payments, which can amount to hundreds of dollars a month. Medicare calls for a 20% co-pay for chemotherapy drugs, but before the reimbursement cuts in 2005, doctors often forgave the co-pays.
In the spring of 2007, reports appeared in the media about cancer doctors receiving rebates of millions of dollars if they purchased bulk supplies of anemia drugs. Doctors were purchasing the drugs directly from Amgen and Johnson & Johnson and then collecting payments from Medicare and private insurers above the price they paid.
The drugs, known as Erythropoiesis Stimulating Agents, or ESA's, are administered in a doctor's office. According to the FDA, ESA's are approved to treat anemia in patients with chronic kidney failure and in patients with cancer whose anemia is caused by chemotherapy, to reduce need for blood transfusions.
On May 9, 2007, a New York Times article titled, "Doctors Reap Millions for Anemia Drugs," by Alex Berenson and Andrew Pollack, reported that documents given to the Times showed that at one practice in the Pacific northwest, a group of 6 cancer doctors received $2.7 million from Amgen for prescribing $9 million worth of drugs in 2006.
The FDA-approved labeling for ESA's says patients should have a hemoglobin level of 10-12 grams per deciliter of blood, and patients are considered to need treatment if their levels fall below 10. Doctors determine whether a patient is anemic and decide on ESA dosing by measuring how much hemoglobin is present in a patient's red blood cells.
The ESA's approved for cancer patients are made by Amgen and sell under the brand names Procrit and Aranesp. Although Amgen manufactures Procrit, the firm licenses a Johnson & Johnson subsidiary to sell it.
Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, told United Press International, "Probably more than a billion dollars is spent on erythropoietin each year, which makes it one of the most expensive cancer drugs." A six-month course of treatment per patient can cost more than $10,000.
In November 2006, the FDA issued a public health advisory on all ESA's, based on a study in the New England Journal of Medicine, which found that patients treated with Procrit, whose hemoglobin levels were raised above the FDA-recommended level, had a higher risk of heart attack, heart failure, stroke or death.
However, in fact, Johnson & Johnson had halted several studies of Procrit in cancer patients in 2003, after they experienced a higher than expected number of blood clots, according to the January 26, 2007, New York Times.
ESA's are not FDA approved for use with anemic cancer patients who are not undergoing chemotherapy, but doctors have been administering the drugs off-label for that condition. To increase off-label sales, the drug companies used direct-to-consumer advertising to claim that ESA's could restore energy and reduce fatigue in chemotherapy patients.
However, the FDA says there has never been any evidence to support claims that ESA's could increase energy or ease fatigue in patients undergoing cancer treatment.
In January 2007, Amgen itself released the results of study conducted in hopes of supporting the approval of Aranesp for use with cancer patients who were not receiving chemotherapy which found that Aranesp did not reduce the need for transfusions and showed an increase in mortality in patients receiving Aranesp by the end of 16 weeks by a statistically significant amount, compared to patients who did not receive the drug.
In March 2007, Representative, John Dingell, (D-MI) chairman of the House Committee on Energy and Commerce, sent letters to Amgen and J&J, saying that the off-label use of the drugs "appear to cause increases in blood clots, seem to grow tumors and are associated with significantly higher mortality rates than placebo," and told the drug makers to stop all DTC advertising and physician incentives until the FDA determines whether any measures "need to be taken to protect the public from unnecessary risks to human life from these products."
In March 2007, the FDA added black box warnings to the labels about tumor progression and a decreased survival in patients undergoing cancer treatment. On March 9, 2007, the agency issued a public health advisory to warn doctors treating patients with kidney disease or cancer not to push hemoglobin levels over 12 grams per deciliter of blood.
The FDA again warned that ESA's were not indicated for anemic cancer patients not undergoing chemotherapy and that mortality was increased when ESA's were used by this population. The FDA pointed out that ESA's are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer.
During a March 9, 2007, press briefing, Dr Karen Weiss, deputy director of the Office of Oncology Drug Products, said the FDA became concerned after receiving the results from several trials evaluating the aggressive use of ESA's to raise hemoglobin levels higher than listed on their approved labels.
In the March 10, 2007, Wall Street Journal, Dr Weiss was quoted as saying, the "bulk of the data that has raised concerns" came when patients were given higher doses, whether they were experiencing anemia from kidney disease or cancer treatment.
The evidence is that "this type of strategy is not beneficial and in fact has some evidence of harm," she said.
On April 10, 2007, The Wall Street Journal reported that Amgen conducted some studies
which failed to show that the use of Aranesp improved a patient's quality of life. On May 10, 2007, the Journal reported that J&J had "urged" doctors to enroll patients in "mini" trials using a once-a-week 40,000-unit dose of Procrit instead of three 10,000-unit doses a week.
There were $500 million a year in sales from doctors who prescribed Aranesp "off label" to treat anemia in cancer patients who were no longer receiving chemotherapy, according to the Journal.
On May 10, 2007, the FDA's Oncology Drug Advisory Panel held a meeting and voted 15-2 in favor of new restrictions for the use of ESA's, and 17-0 in favor of requiring the drug makers to conduct new clinical trials.
But on May 11, 2007, Bloomberg News reported that the FDA was only given limited access to results from company studies on the drugs. Amgen informed the FDA that the study data requested prior to the meeting of the advisory panel did not belong to the company and because the studies were conducted by third party researchers, Amgen did not have access to the data.
Amgen claimed that attempts were made to obtain the data and informed the FDA that the company would not be able to meet the deadline for submission to the FDA for review prior to the meeting on May 10, 2007.
FDA documents show that three years earlier, at a public meeting of the Advisory Committee on May 4, 2004, Amgen had claimed that 5 studies were being conducted to further investigate the risks of ESA's in cancer patients, including 4 independent, third-party-sponsored clinical trials.
However, Amgen did not initiate discussions with the independent researchers to obtain the primary data for the studies until several months before the May 2007 advisory panel meeting, according to the FDA.
The FDA wanted the primary data in order to perform its own independent analysis of the results, since the studies were being used by Amgen to address safety issues that were raised by the May 2004 panel.
Concerns over the over-prescribing of ESA's and the adverse effects on cancer patients prompted the Centers for Medicare and Medicaid Services to review Medicare coverage of their use. On May 14, 2007, CMS released its proposed coverage decision memorandum regarding the clinical conditions for Medicare reimbursement for ESA's.
CMS found that increased thrombotic-vascular disease, tumor progression, and decreased survival occurred with ESA used to prevent or treat anemia secondary to cancer, cancer chemotherapy, or radiotherapy or to improve tissue hypoxia in an attempt to enhance tumor sensitivity to therapy.
When considering Medicare coverage of ESA's, CMS opened the issue up for comments, and several commenters noted that it had been difficult if not impossible to obtain access to primary data from ESA clinical trials, making it difficult to conduct an independent analysis of the data.
Dr Marcia Angell, senior lecturer in Social Medicine at Harvard Medical School and former Editor in Chief of the New England Journal of Medicine, expressed concern about the lack of transparency and access of clinical trial data on ESA's and stated in part:
"Medicare should have access to all the clinical trial information that the FDA has. Currently, companies seeking marketing approval must submit to the FDA all trials, not just the positive ones, but the agency generally does not share this information without the permission of the sponsoring company. That puts the proprietary interests of drug companies ahead of the public interest. Medicare should require full disclosure from the FDA as a condition of its support."
Many commentators supported non-coverage for treatment of anemia in cancer patients not related to chemotherapy, stating that this was the setting in which much of the adverse outcomes were reported.
According to the CMS report, some beneficiaries with cancer stated that they had received ESA therapy continuously for years, and others stated that they continued to receive ESA's even after their cancer was in remission.
The agency noted that there was also no evidence to support the off-label use of ESA's in the treatment of anemia associated with radiotherapy. "The evidence reviewed and the comments received support the determination that ESA's are not reasonable and necessary for the treatment of anemia associated only with radiotherapy," the CMS report states.
On July 30, 2007, CMS released a final coverage determination which said that Medicare would cover the drugs for chemotherapy patients only if their hemoglobin levels were less than 10 and coverage would stop if it exceeds that level after 4 weeks of treatment.
In the Decision Memorandum, CMS determined that ESA treatment was not reasonable and necessary for conditions that include: any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis; anemia associated with the treatment of acute and chronic myelogenous leukemias, or erythroid cancers; anemia of cancer not related to cancer treatment; patients with erythropoietin-type resistance due to neutralizing antibodies, and anemia due to cancer treatment if patients have uncontrolled hypertension.
Additionally, CMS will only provide coverage for ESA treatment for the anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia, if the hemoglobin level immediately prior to initiation or maintenance of ESA therapy is below 10.
Under the old policy, Medicare allowed doctors to get paid even if cancer patients exceeded the recommended hemoglobin levels but normally physicians only transfuse patients when the hemoglobin level approaches or drops below 8, so the use of ESA's should begin at a level most likely to prevent the hemoglobin from dropping to 8, according to the CMS report.
CMS reiterated the FDA's warning that ESA's increased the risk for death and serious cardiovascular events in trials when administered to target hemoglobin greater than 12, as well as an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure and hemodialysis graft occlusion.
In the midst of all the complaining about the reduced coverage rates, on August 31, 2007, Senator Charles Grassley (R-Iowa), ranking member of the Senate Committee on Finance, sent a letter to Amgen CEO Kevin Sharer requesting information on the company's rebates to health care providers.
The letter notes that the overuse of ESA's is not only a financial concern, but also a major patient safety concern, given that recent clinical studies have identified increased risks of death, blood clots, strokes, heart attacks and tumor growths when ESA's are given in higher than recommended doses.
As part of the Committee's ongoing inquiry into the impact of pricing practices on the utilization of ESA's, the Senator asked Amgen to provide:
(1) the total, average amounts and range of rebates made to physicians, group practices, physician clinics, hospital outpatient departments, skilled nursing facilities and home health agencies which purchased Aranesp and/or Epogen for calendar years 2004, 2005 and 2006 by state; and,
(2) the number of physicians, group practices, physician clinics, hospital outpatient
departments, skilled nursing facilities and home health agencies in each state which received rebates for Aranesp and Epogen in calendar years 2004, 2005 and 2006.
"As a preliminary response to this request," the letter instructed, "identify the five physicians, group practices, physician clinics, hospital outpatient departments, skilled nursing facilities and home health agencies that received the highest rebate payments in each state in calendar years 2004, 2005 and 2006."
Amgen's latest SEC filing shows that Aranesp sales fell to $460 million for the 3rd quarter of 2007, compared to $720 million in the same period last year, and overall profits are down 82%. On October 17, 2007, Bloomberg News reported that Amgen has lost $18 billion in market value this year.
Not surprisingly, on November 13, 2007, the Wall Street Journal reported that Amgen was pouring millions of dollars into a lobbying campaign in an attempt to get Congress to change the Medicare coverage decision.
"The push," the Journal says, "underscores Amgen's dependence on Epogen and Aranesp, which together accounted for 48% of its revenue last year -- and the fact that the federal government pays for the biggest share of Epogen."
Amgen spent $9 million in the first half of 2007, nearly twice the amount that was spent in the previous 6 months. The company has a dozen in-house lobbyists and more than 100 external lobbyists, including former aides to Democratic House Speaker Nancy Pelosi and former Republican Senate Majority Leader Bill Frist, the Journal reports.
California Democrat Representative Pete Stark told the Journal that the integrity of Medicare decisions are at stake. If Congress overturns the new guidelines, the effect would be to tell the "industry they can spend millions of dollars and hire lobbyists all over town to push Congress to overrule sound science," he warned.
Back on August 17, 2007, Fierce Biotech pointed out that Amgen had racked up $10.2 million in lobbying bills in 2006, "and is now second only to Pfizer in the amount of contributions it makes to federal candidates and parties."
On November 9, 2007, Pharmalot's Ed Silverman reported that Amgen was "funding a site called ProtectCancerPatients.org, which was devoted to overturning a recent Medicare decision to reduce reimbursement for Amgen's big sellers, Aranesp and Epogen," until November 9, 2007, when it disappeared.
"This website is the online headquarters of a national campaign to protect cancer patients on Medicare from a decision denying them needed medicines," Mr Silverman quoted the site as saying.
"Our goal is to convince the Administration to reverse a recent decision which would effectively deny senior citizen cancer patients' coverage and access to drugs prescribed by their doctors to combat anemia and reduce transfusions due to strong chemotherapy," the site said.
According to Mr Silverman, site visitors were instructed on ways to contact their elected representatives and to write testimonials about the anemia drugs.
On November 13, 2007, the Wall Street Journal reported that J&J had launched a similar effort for its anemia-fighting drug, with a website "that allows individuals to send emails to the Center for Medicare and Medicaid Services and contact their representatives in Washington."
The Journal noted that cancer doctors, "who benefit from Medicare's unusually high reimbursement rate for anemia drugs, are also in Amgen's corner."
On that subject, it should be pointed out that the investigations by lawmakers are conspicuously missing when it comes to all the health care providers who engaged in the over-prescribing schemes for profit involving ESA's.
The Journal reports that, unlike doctors, all patient groups are not on Amgen's side. "I am astounded that this has been reduced to, 'We want to protect patients,' " Frances Visco, president of the National Breast Cancer Coalition and a 20-year cancer survivor, told the Journal.
Ms Visco says the campaign has confused cancer patients who "feel used by this," and she has urged Congress to reject what she calls Amgen's "abusive" efforts. "Amgen is primarily interested in protecting Amgen," she said in the Journal article.
All that said, the millions of dollars spent on lobbying and political contributions should not have any effect on the decision to limit coverage for ESA's because new studies with reports of adverse effects in cancer patients using the drugs continue unabated. On November 8, 2007, the FDA announced new boxed warnings and labeling changes for ESA's with statements about the risks that the drugs pose to patients with cancer.
In a press release, the FDA once again notes that ESA's are approved to treat anemia caused by chemotherapy and says the new boxed warning clarifies that ESA's should only be used when treating anemia specifically caused by chemotherapy and that ESA's should be discontinued once the patient's chemotherapy course has been completed.
The FDA repeats that an earlier boxed warning in March 2007 described the results of six studies demonstrating that survival was shorter and tumors progressed faster when ESA's were used to achieve hemoglobin levels of 12 or greater in cancer patients.
For patients with cancer, the new warnings advises that ESA's caused tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid and non-small cell lung cancer when they received a dose that attempted to achieve a hemoglobin level of 12 or greater.
The warnings also emphasize that no clinical data are available to determine whether there is a similar risk of shortened survival or increased tumor growth for patients with cancer who receive an ESA dose that attempts to achieve a level of less than 12, the hemoglobin level commonly achieved in clinical practice.
"Health care professionals need to consider the risks of increased tumor progression and decreased survival in patients with cancer when prescribing ESA's," said Janet Woodcock, the FDA's deputy commissioner for scientific and medical programs, chief medical officer and acting director of its Center for Drug Evaluation and Research, in a press release.
On January 3, 2008, the FDA announced that the agency was reviewing more new data from two studies that provide further evidence of the risks of anemia drugs and show that patients with breast or advanced cervical cancers who received ESA's to treat anemia caused by chemotherapy died sooner or had more rapid tumor growth than similar patients who did not receive the drug.
The agency notes that these studies were not among the 6 that were described in revised labeling on November 8, 2007. Taken together, all 8 studies show more rapid tumor growth or shortened survival when patients with breast, non-small cell lung, head and neck, lymphoid or cervical cancers received ESA's, compared to patients who did not receive the treatment, according to the agency.
In its November 9, 2007, third quarter SEC filing, Amgen explains fairly clearly why the company is so worried about the Medicare coverage decision, in stating:
"The Decision Memorandum establishes the ESA reimbursement policy for Medicare and other government beneficiaries who are treated for CIA and who all together accounted for approximately 50% of the U.S. cancer patients receiving Aranesp prior to its issuance."