Procrit, Epogen and Aranesp are known as erythropoiesis-stimulating agents (ESAs). ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. They are used to treat anemia in patients with chronic kidney disease, while Procrit and Aranesp are also approved to treat anemia in cancer patients undergoing chemotherapy.
ESAs have long been the subject of safety concerns, and have had their safety labeling updated several times since 2007. In addition to being linked to blood clots, ESAs have been associated with the promotion of tumor growth when they are used at high doses to increase hemoglobin levels higher than label recommendations.
According to The New York Times, The FDA's decision to subject Procrit, Epogen and Aranesp to yet another advisory panel review was prompted by another study that suggested that high doses of one of the drugs might cause strokes. That study, called "Treat" was published in October in the New England Journal of Medicine. The goal of Treat was to see if using Aranesp to increase the red blood cell levels of people with diabetes and kidney disease would prevent death and cardiovascular problems. No statistically significant difference was found in deaths and cardiovascular problems between the study's Aranesp and placebo groups. However, those who took Aranesp had double the risk of stroke.
According to the Times, in a commentary published this week in the online version of the New England Journal of Medicine, FDA officials said that they anticipated convening an advisory panel meeting sometime in 2010 to re-evaluate the use of ESAs in patients with kidney disease and to consider new ways to control dosage. The officials wrote that the results of Treat “raise major concerns” about the use of the drugs to treat the anemia caused by chronic kidney disease. They also said that the "pronounced difference" in the stroke rate seen in the study was "very troublesome."
The commentary noted that "optimal hemoglobin targets have never been established" for patients with chronic kidney disease." The authors also said that "more frequent hemoglobin monitoring" and other dosing changes might "improve outcomes" for patients treated with the drugs.
Epogen, Procrit and Aranesp are known as erythropoiesis-stimulating agents (ESAs). ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. They are approved in the U.S. to treat anemia in cancer patients undergoing chemotherapy.
ESAs have long been the subject of safety concerns. Last summer, the Food & Drug Administration (FDA) ordered the labeling changes because several studies have shown that Procrit and other ESAs increased tumor growth and shortened survival time in some cancer patients. Among other things, the agency mandated that the labeling be modified to say that the drugs shouldn’t be used in cancer patients receiving chemotherapy when a cure of their cancer is anticipated.
In the first study, researchers from the University of Alberta, Canada, analyzed data from 52 clinical trials that included more than 12,000 people. According to MedicineNet.com, they found that patients treated with ESAs increased the risk of death and serious adverse events such as blood clots by 15% to 16%.
The report, published in the April 30 online edition of the Canadian Medical Association Journal, concluded that ESAs should not routinely be used as an alternative to blood transfusions in patients with anemia related to cancer.
The second study, published in the May 2 issue of The Lancet, was conducted by scientists at the University of Bern in Switzerland. They looked at the findings from 53 cancer trials that included a total of almost 14,000 patients. More than 1,500 patients died during the study period, and almost 5,000 patients died overall, MediciNet.com said. That translated to a 17% increase in deaths during the study period. Patients undergoing chemotherapy had a 10% increased risk of dying.
The authors wrote that the findings "show that erythropoiesis-stimulating agents increase mortality in all patients with cancer, and a similar increase might exist in patients on chemotherapy." They advised that the risks of ESA be balanced against the benefits of treatment. They also said more study is needed to address the drugs' impact on tumor progression and quality of life, MedicineNet.com said.Ticker move Palermo Shooting video
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Wyeth, co-marketer of Enbrel was named as a defendant, as was AmerisourceBergen Corporation, a wholesale drug distributor, and WebMD Health Corporation, an Internet health information source, among others, said Dow Jones.
Enbrel is a rheumatoid arthritis and psoriasis medication and Aransep—which has been found to increase cardiac problems—is prescribed for the treatment of anemia.
This is not the first time in recent days that whistleblower suits—known legally as qui tam suits—filed against drug makers for illegal marketing have made headlines. Most recently, The United States Justice Department (DOJ) joined in two whistleblower lawsuits against drug maker Scios Inc. and Johnson & Johnson Inc. (J&J); J&J is Scios’ parent company. In that case, the lawsuit alleged the drug makers marketed cardiac drug Natrecor for a use not approved by the U.S. Food and Drug Administration (FDA).
Physicians are permitted to prescribe medications off-label; however, off-label marketing is illegal. Medicare does not cover drugs used for off-label uses unless such off-label use is established to be medically necessary. The DOJ explained in an earlier release, that under the Food, Drug and Cosmetic Act, a company must specify the intended uses of a product in its new drug application to the FDA. Before approval, the FDA must determine a drug’s safety and efficacy and, once approved, the drug company may not market or promote the drug off-label.
A revised version of the Amgen suit—which was filed on behalf of the U.S. and some states—was filed in 2007, but remained sealed to protect the whistleblower under federal law, said Dow Jones; often, qui tams are filed by former employees. Dow Jones reported that the lawsuit alleges that:
The drug makers violated federal and state false-claim laws, Medicare and Medicaid anti-kickback laws, and the U.S. Food, Drug and
Cosmetic Act "by engaging in numerous unlawful activities in their marketing of Aranesp and/or Enbrel";
Amgen “improperly marketed the attractive economics of Aranesp to customers”;
Amgen provided price discounts to customers, hiding such discounts from government health programs, such as Medicare and Medicaid;
Aranesp and Enbrel were marketed off-label for uses not approved by the FDA;
Some off-label marketing occurred on Medscape, a WebMD-owned Internet site; and
Amgen intentionally took these steps to beat out its rival drug, Procrit.
Procrit is marketed by Johnson & Johnson and is the same as Amgen’s Epogen, said Dow Jones, which noted that J&J markets Procrit under a license arrangement with Amgen. Last year, Amgen agreed to pay $200 million to J&J to settle allegations it violated antitrust laws. Amgen was accused of offering discounts to cancer clinics that would use Aranesp and other Amgen drugs. Meanwhile, another whistleblower suit was filed against J&J in 2003 by former sales representatives and claimed J&J offered kickbacks to health-care providers and encouraged off-label Procrit use.
Qui tams allow for private persons to file whistleblower suits to provide the government information about wrongdoing. If it is found a person has submitted or caused others to submit false or fraudulent claims to the U.S.—such as federal health care programs and Medicare—the government can recover treble damages and $5,500 to $11,000 for every false or fraudulent claim filed. Whistleblowers can receive 15-to-25 percent of damages awarded.
Aranesp is an erythropoiesis-stimulating agent (ESA). Two other ESA's, Epogen and Procrit, are also currently available. All are made by Amgen, but Procrit is sold by Johnson & Johnson subsidiary Ortho Biotech under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells.
In March 2007, the Food & Drug Administration (FDA) added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. This past November, that black box warning was modified to include more specific dosing information.
Then in March 2008, Amgen and Johnson & Johnson announced that they would be including another black box warning on the drug’s labels. The latest black box warned of the medications’ association with increased tumor growth and shortened survival time in some cancer patients.
Amgen has long offered rebates and discount to oncology clinics for their use of Aranesp. Oncology practices typically buy the drugs they use and then are reimbursed for them by patients and insurers. If doctors pay less for the drugs because of discounts and rebates, they can make a higher profit.
Critics say that such marketing programs encourage doctors to overuse ESAs. The criticism has gotten the attention of Congress, where a probe of the practice is ongoing. In April, Reps. John Dingell and Bart Stupak, both Michigan Democrats, sent letters to Amgen and Johnson & Johnson on Monday, suggesting their marketing campaigns for Procrit, Aranesp and Epogen convinced physicians to prescribe the drugs at unsafe dosages. Senator Charles E. Grassley, Republican of Iowa, said in April that Amgen had provided nearly $800 million in rebates to more than 6,000 facilities in 2006.
Amgen once offered discounts and rebates to doctors based on how much Aranesp they bought. But that program was changed in February, and the company started to offer the discounts and rebates based on the share of a clinic’s anemia drug purchases were represented by Aranesp as opposed to Procrit. At the time, the company maintained that the marketing program was to help Aranesp compete with Procrit, not increase its overall use.
But now, the company has decided to end the rebate program all together. It also said it would stop offering discounts on two other drugs, Neulasta and Neupogen, based on a doctor’s purchase of Aranesp.
But the discount aren't being halted completely. In place of the rebate program, Amgen will now offer bigger discounts at the time of purchase to doctors who buy at least 50 percent of their anemia drugs from Amgen rather than Johnson & Johnson.
Procrit, Aranesp and Epogen are known as erythropoiesis-stimulating agent (ESA). All are made by Amgen, but Procrit is sold by Johnson & Johnson subsidiary Ortho Biotech under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. When Procrit was first approved in 1989, the drug was touted as a treatment to lessen fatigue and improve quality of life among cancer and HIV patients with anemia. But since then Procrit has been forced to undergo five label changes, and the label now states that there was no evidence to back that claim.
This past March, Amgen and Johnson & Johnson announced that they would be including another black box warning on the drug’s labels. The black box warned of the medications’ association with increased tumor growth and shortened survival time in some cancer patients. The warning came on the heels of the PREPARE breast cancer study. That breast cancer study was one of 5 clinical trials that Amgen had agreed to after the safety of Aranesp was called into question. PREPARE showed patients had a higher risk of death on Aranesp. The warning also noted danger for patients with cervical cancer, based on results in December from a study called GOG-191.
That same month, an FDA advisory panel recommended new limits be placed on the drugs. Yesterday's announcement that the agency was requiring further label changes and restrictions is the first time FDA using authority granted to it in 2007 to force a drug maker to change a drug's label. Apparently, the FDA and Amgen were not able to reach agreement over the label changes. According to The New York Times, Amgen had wanted the label to give doctors discretion to initiate therapy before hemoglobin levels dropped to 10 in patients who could not tolerate that degree of anemia. And it wanted mention of the 12 gram upper limit for stopping therapy.
The new label will say that say that the drugs shouldn't be used in cancer patients receiving chemotherapy when a cure of their cancer is anticipated. The FDA also ordered inclusion of a statement that the drugs aren't to be administered when hemoglobin levels are greater than or equal to 10 grams per deciliter. Language is being removed that seemed to imply that it was safe to continue treating patients until their hemoglobin rose to 12 grams per deciliter.
Despite the FDA's tough stance regarding the anemia drug's, the new labeling does not incorporate all of the recommendations the advisory panel made in March. The panel had also advised that patients with advanced breast cancer and head-and-neck cancer shouldn't get the medicines.
Procrit and Aranesp are known as erythropoiesis-stimulating agents (ESA). All are made by Amgen, but Procrit - marketed as Eprex in Europe - is sold by Johnson & Johnson subsidiary Ortho Biotech under a licensing agreement. In the United States, Amgen markets a third ESA, called Epogen.
ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. Over the past 18 months, eight late-stage clinical trials have shown that treatment with ESAs can have an adverse impact on cancer survival.
In the United States, Amgen and Johnson & Johnson announced in March that they would be including a black box warning on the drug’s labels about their association with increased tumor growth and shortened survival time in some cancer patients. The latest black box to be included on the labeling of Procrit and Aranesp came on the heels of the PREPARE breast cancer study. That breast cancer study was one of 5 clinical trials that Amgen had agreed to after the safety of Aranesp was called into question. The new black box cites information from PREPARE which showed patients had a higher risk of death on Aranesp. It also notes danger for patients with cervical cancer, based on results in December from a study called GOG-191.
A week later, a US Food & Drug Administration (FDA) advisory panel voted 13 to 1 in favor of allowing the continued sale of the ESAs for use in cancer patients undergoing chemotherapy. However, the panel voted 11 to 2 in recommending that the drugs not be used in cancer patients who are likely to be cured from their treatments, which suggests the drugs should only be used as part of a best-supportive care regimen for patients with advanced cancer or those expected to die from the cancer. The panel also voted 9 to 5 that the shouldn’t be used in patients with breast cancer as well as patients with head and neck cancer.
On Thursday, the EMEA's Committee for Medicinal Products for Human Use (CHMP) said it had reviewed new data from studies that showed an increased risk of tumor progression, venous thromboembolism and shorter overall survival in cancer patients who received Aranesp and Procrit.
Following this review, the CHMP concluded that the benefits of ESA “continue to outweigh their risks in the approved indications”. However, in cancer patients with a “reasonably long life-expectancy”, the risk/benefit ratio switches and transfusions provide the best option, though the committee agreed that there is no problem of epoetin-containing medicines for the treatment of anemia in patients with chronic kidney failure.
Procrit, Aranesp and Epogen are known as an erythropoiesis-stimulating agent (ESA). All are made by Amgen, but Procrit is sold by Johnson & Johnson subsidiary Ortho Biotech under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. Over the past 18 months, eight late-stage clinical trials have shown that treatment with ESAs can have an adverse impact on cancer survival.
In March, Amgen and Johnson & Johnson announced that they would be including a black box warning on the drug’s labels about their association with increased tumor growth and shortened survival time in some cancer patients. The latest black box to be included on the labeling of Procrit, Aranesp and Epogen came on the heels of the PREPARE breast cancer study. That breast cancer study was one of 5 clinical trials that Amgen had agreed to after the safety of Aranesp was called into question. The new black box will cite information from PREPARE which showed patients had a higher risk of death on Aranesp. It also notes danger for patients with cervical cancer, based on results in December from a study called GOG-191.
A week later, an FDA advisory panel voted 13 to 1 in favor of allowing the continued sale of the ESAs for use in cancer patients undergoing chemotherapy. However, the panel voted 11 to 2 in recommending that the drugs not be used in cancer patients who are likely to be cured from their treatments, which suggests the drugs should only be used as part of a best-supportive care regimen for patients with advanced cancer or those expected to die from the cancer. The panel also voted 9 to 5 that the shouldn’t be used in patients with breast cancer as well as patients with head and neck cancer.
Sales of the anemia drugs have slumped amid the safety concerns. But on Sunday, researchers from the University of Washington presented a study at the American Society of Clinical Oncology in Chicago that indicated a genetic test may help predict whether giving cancer patients anemia drugs could make their cancer worse. In the study, the research group measured levels of erythropoietin receptor messenger RNA in tumor samples from 101 patients with head and neck cancer who took part in a trial of Aranesp. The aim was to test whether the drug might be acting on tumor blood vessels and other membranes as well as red blood cells.
Among patients treated with radiation therapy alone, without prior surgery, tumors with high-levels of this type of RNA messenger progressed faster in patients who received the anemia drug compared with patients given a placebo. Testing for the RNA messenger gene could allow the anemia drugs to be used in a target way, the researchers said.
However, the researchers emphasized that the findings were preliminary and need to be confirmed with a larger analysis of tumor specimens.
Two members of Congress are looking into to allegations that the marketing of Procrit, Aranesp and Epogen encouraged overuse of the anemia drugs, placing some patients in danger. Reps. John Dingell and Bart Stupak, both Michigan Democrats, sent letters to Amgen and Johnson & Johnson on Monday, suggesting their marketing campaigns for Procrit, Aranesp and Epogen convinced physicians to prescribe the drugs at unsafe dosages.
Procrit, Aranesp and Epogen are known as an erythropoiesis-stimulating agent (ESA). All are made by Amgen, but Procrit is sold by Johnson & Johnson subsidiary Ortho Biotech under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. Procrit, Aranesp and Epogen have been touted as treatments to lessen fatigue and improve quality of life among cancer and HIV patients with anemia. But since then the drugs has been forced to undergo five label changes, and the labels now state that there was no evidence to back that claim. Rather, the drugs are only approved to raise red blood cell counts high enough to avoid transfusions.
Last March, the Food & Drug Administration (FDA) added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. This past November, that black box warning was modified to include more specific dosing information.
Last month, Amgen and Johnson & Johnson announced that they would be including another black box warning on the drug’s labels. The latest black box warned of the medications’ association with increased tumor growth and shortened survival time in some cancer patients. A week after those warnings were added, the FDA cancer-drugs advisory committee voted 13 to 1 in favor of allowing the continued sale of the ESAs for use in cancer patients undergoing chemotherapy. However, the panel voted 11 to 2 in recommending that the drugs not be used in cancer patients who are likely to be cured from their treatments. The panel also voted 9 to 5 that the shouldn’t be used in patients with breast cancer as well as patients with head and neck cancer. The FDA is not bound by the recommendations of its advisory panels, however, it usually does follow them.
Reps. Dingell and Stupak want Johnson & Johnson to turn over information regarding its promotion of Procrit. Some of the company's television advertisements suggested Procrit improved quality of life by showing patients who appeared healthy and active. The Congressmen said such promotions encouraged "excessive and dangerous off-label use of the drug." Prior to last year's warnings on dosage, many doctors would prescribe unapproved high doses of the drugs. Johnson & Johnson stopped direct-to-consumer Procrit ads in 2005.
For its part, Amgen never engaged in direct-to-consumer marketing of Aranesp or Epogen. However, the Congressmen's letter questioned whether the company's practice of granting higher rebates to doctors who ordered more vials of Amgen drugs might have led to overuse.
Procrit, Aranesp and Epogen are known as an erythropoiesis-stimulating agent (ESA). All are made by Amgen, but Procrit is sold by Johnson & Johnson subsidiary Ortho Biotech under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. When Procrit was first approved in 1989, the drug was touted as a treatment to lessen fatigue and improve quality of life among cancer and HIV patients with anemia. But since then Procrit has been forced to undergo five label changes, and the label now states that there was no evidence to back that claim.
Last Friday, Amgen and Johnson & Johnson announced that they would be including another black box warning on the drug's labels. The latest black box warned of the medications' association with increased tumor growth and shortened survival time in some cancer patients. The latest black box to be included on the labeling of Procrit, Aranesp and Epogen came on the heels of the PREPARE breast cancer study. That breast cancer study was one of 5 clinical trials that Amgen had agreed to after the safety of Aranesp was called into question. The new black box will cite information from PREPARE which showed patients had a higher risk of death on Aranesp. It also notes danger for patients with cervical cancer, based on results in December from a study called GOG-191.
Last March, the FDA also added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. This past November, that black box warning was modified to include more specific dosing information.
Today, the FDA convened a meeting of its cancer-drugs advisory committee to recommend what additional action the regulator should take in regards to Procrit, Aranesp and Epogen. The panel ultimately voted 13 to 1 in favor of allowing the continued sale of the ESAs for use in cancer patients undergoing chemotherapy. However, the panel voted 11 to 2 in recommending that the drugs not be used in cancer patients who are likely to be cured from their treatments, which suggests the drugs should only be used as part of a best-supportive care regimen for patients with advanced cancer or those expected to die from the cancer. The panel also voted 9 to 5 that the shouldn't be used in patients with breast cancer as well as patients with head and neck cancer. The FDA is not bound by the recommendations of its advisory panels, however, it usually does follow them.
Aranesp, Epogen and Procrit are known as erythropoiesis-stimulating agents (ESAs). All are made by Amgen, but Procrit is sold by Johnson & Johnson under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. Approved uses of ESAs are for the treatment of anemia in patients with chronic kidney failure; for cancer patients whose anemia is caused by chemotherapy; and for those infected with the human immunodeficiency virus (HIV) whose anemia is caused by the HIV drug AZT (zidovudine). ESAs are also approved to reduce the number of transfusions during and after major surgery.
The latest black box to be included on the labeling of Procrit, Aranesp and Epogen came on the heels of the PREPARE breast cancer study. That breast cancer study was one of 5 clinical trials that Amgen had agreed to after the safety of Aranesp was called into question. The new black box will cite information from PREPARE which showed patients had a higher risk of death on Aranesp. It also notes danger for patients with cervical cancer, based on results in December from a study called GOG-191.
That warning followed the addition of two other black box warnings for the drugs. The FDA ordered a black box warning regarding cardiovascular problems and other safety issues posed by the drugs be included on their labels. Last March, the FDA also added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. This past November, that black box warning was modified to include more specific dosing information.
Tomorrow, the FDA's cancer-drugs advisory committee will recommend what action the regulator should take. According to The Wall Street Journal, the FDA will ask the advisory panel to consider several restrictions on Procrit, Aranesp and Epogen beyond the black box warnings. According to documents made public by the FDA yesterday, this could include eliminating their approval for cancer patients. If that happened, the drugs would remain on the market for other uses, particularly in kidney failure. And doctors could still choose to prescribe Procrit, Aranesp and Epogen for cancer patients as an off-label use, as physicians are free to use approved drugs in any way they see fit.
Other restrictions the FDA could impose on Procrit, Aranesp and Epogen include requiring cancer patients to sign informed consents before they take the medicines, confining distribution of the drugs, or asking the drugs' makers to voluntarily limit their advertising and promotion. The FDA is also asking advisors to weigh targeted limits, such as recommending the drugs' use only in small-cell-lung-cancer patients.
Aranesp, Epogen and Procrit are known as erythropoiesis-stimulating agents (ESAs). All are made by Amgen, but Procrit is sold by Johnson & Johnson under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. Approved uses of ESAs are for the treatment of anemia in patients with chronic kidney failure; for cancer patients whose anemia is caused by chemotherapy; and for those infected with the human immunodeficiency virus (HIV) whose anemia is caused by the HIV drug AZT (zidovudine). ESAs are also approved to reduce the number of transfusions during and after major surgery.
A year ago, the Food & Drug Administration (FDA) ordered a “black box” warning regarding cardiovascular problems and other safety issues posed by the drugs be included on their labels. Last March, the FDA added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. This past November, that black box warning was modified to include more specific dosing information.
The new black box warnings on Aranesp, Epogen and Procrit comes on the heels of the PREPARE breast cancer study. That breast cancer study was one of 5 clinical trials that Amgen had agreed to after the safety of Aranesp was called into question. The new black box will cite information from PREPARE which showed patients had a higher risk of death on Aranesp. It also notes danger for patients with cervical cancer, based on results in December from a study called GOG-191.
The new warning for the anemia drugs is being added to precautions outlined in a black box at the top of prescribing information for the medicines. Amgen and Johnson & Johnson are also sending a letter to doctors informing them of the added warning.
The FDA has scheduled an advisory panel meeting for March to further discuss the safety issues surrounding Aranesp, Epogen and Procrit. At that meeting, the FDA could place more restrictions on the drugs, including a recommendation to lower the dose or that doctors stop prescribing the drugs for certain cancers.
The U.S. National Institutes of Health explains that ESAs—erythropoietin (Epogen, Procrit) and darbepoetin (Aranesp)—work by stimulating bone marrow to produce new red blood cells. Epogen, Aranesp and Procrit are used in the treatment of chemotherapy-related anemia and to treat anemia in people with chronic kidney disease who are also on dialysis.
Health experts have raised concerns about Epogen, Aranesp and Procrit before. In kidney patients, past research showed that if ESAs are used to raise hemoglobin levels above 12 grams per deciliter of blood, the risk of death increases. Also, past cancer research revealed that ESAs may be associated with more rapid tumor growth in addition to an increased risk of death. Because of this, the U.S. Food and Drug Administration (FDA) last year had the drugs' manufacturers add a "black box" warning to the medications. The black box—the strongest drug warning—indicates that the medications should be used at the lowest possible doses to avoid risks such as blood clots, heart attacks, stroke, congestive heart failure, increased tumor growth, and an increased risk of death. The FDA also recommended that ESAs be prescribed at the lowest possible doses since trials generally indicated an increased risk when blood levels were raised above 12 grams per deciliter.
But there are critics to these findings. "If you use ESAs the way they're supposed to be used, I really don't see clinically what they're talking about in the trials," said Dr. Jay Brooks, chairman of hematology/oncology at Ochsner Health System in Baton Rouge, Louisiana. "Many of the trials that changed the FDA prescribing guidelines were done in Europe and outside the guidelines of the US. I still think ESAs are extraordinarily useful and safe medications when used in an efficacious manner. I would be treated with these agents if I had cancer," Brooks said.
The study included 51 phase 3 clinical trials completed in the 20-year period between 1985 and 2005. Survival was evaluated in 13,613 cancer patients; the risk of VTE was evaluated in 8,172 people with cancer. The type of cancer varied widely from study to study. "At the end of the day, these data are very provocative and it's important for people [that] make clinical guidelines to review the data," said Bennett, who's also a hematologist/oncologist at Northwestern Memorial Hospital and the Jesse Brown VA Medical Center in Chicago. "Patients should be informed of the risks and benefits of these drugs," he added.
Studies continue to question the drugs' safety and back the policy Straube, chief medical officer at CMS, enacted. "I think that our national coverage decision has been shown, with even more evidence coming out since we made it, to have been the right thing to do," Straube said. The drugs are erythropoietin-stimulating agents, also known as ESAs, and include Amgen's Aranesp and Johnson & Johnson's Procrit. Both medications are multi-billion-dollar selling drugs. CMS issued payment restrictions in 2007 after four large studies raised safety concerns and the Food and Drug Administration (FDA) required a stronger warning on the drugs' labels. The drugs can boost risk of heart problems and even death, especially at high doses.
Labels for Aranesp, Epogen, and Procit were updated to include revised dosage guidelines and information on the drugs’ cardiovascular side effects. The modifications followed the FDA ordering of a black box warning—the strongest drug labeling—about cardiovascular problems and other safety issues. Amgen manufactures all three medications although Johnson & Johnson sells Procrit under a licensing agreement. The drugs are part of a class of drugs known as ESAs that treat anemia in patients with kidney disease or certain cancers by boosting red blood cells. Several studies linked the drugs to cardiovascular problems and deaths and have been tied to worsening tumors when used in cancer patients. Soon after Epogen was introduced, some doctors attempted to use it to increase patients’ hemoglobin—the part of the blood cell that carries oxygen—to levels as high as those in healthy patients (14). Two clinical trials showed the large dosage required to reach these levels could lead to heart problems and death and the black box warning cautioned doctors that the medications should be administered at the lowest dose possible to bring blood counts to the lowest level needed to avoid transfusions. The modified black box warning has more specific dosing information stating dosing should be individualized. For kidney patients, the revised warning reads that patients experienced greater risks for death and serious cardiovascular events when administered ESAs to target higher versus lower hemoglobin levels in two clinical studies’ rather than the more generic warning that risks were seen when hemoglobin levels of greater than 12 were targeted. Following the revised warning, Medicare announced it would not pay for Aranesp, Epogen, and Procrit in patients whose hemoglobin levels were at 10 grams per deciliter.
Straube said he believes the FDA will consider restricting use of the drug in some cancer patients. The entire drug class has been under review as debates continue over whether anemia drugs increase the risk of heart attack and stroke and fuel the growth of cancer.
Aranesp, Epogen and Procrit are known as erythropoiesis-stimulating agents (ESAs). All are made by Amgen, but Procrit is sold by Johnson & Johnson under a licensing agreement. ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. FDA-approved uses of ESAs are for the treatment of anemia in patients with chronic kidney failure; for cancer patients whose anemia is caused by chemotherapy; and for those infected with the human immunodeficiency virus (HIV) whose anemia is caused by the HIV drug AZT (zidovudine). ESAs are also approved to reduce the number of transfusions during and after major surgery.
Recently, several studies have linked the anemia drugs to cardiovascular problems and deaths. They have also been tied to worsening tumors when used in cancer patients. A year ago, FDA ordered a “black box” warning regarding cardiovascular problems and other safety issues posed by the drugs be included on their labels. In March, the FDA added another black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. Last month, that black box warning was modified to include more specific dosing information.
The latest ESA studies showed that patients with breast or advanced cervical cancers who received ESAs to treat anemia caused by chemotherapy died sooner or had more rapid tumor growth than similar patients who didn't receive the anemia drug. The agency said the two new studies, along with six that are included in the current drug labels "show more rapid tumor growth or shortened survival when patients with breast, non-small cell lung, head and neck, lymphoid or cervical cancers received ESAs compared to patients who did not receive this treatment.” The FDA said ESAs were administered in an attempt to achieve a hemoglobin level of 12 grams per deciliter or greater in the studies, which is higher than current dosing recommendations.
Myelofibrosis is a bone marrow disorder that interrupts the body's normal production of blood cells, leading to severe anemia and enlargement of the spleen. While myleofibrosis can progress to leukemia on its own, researchers at the Mayo Clinic found that patients treated with ESAs were far more likely to develop the blood cancer. They examined the records of 311 patients with primary myelofibrosis from 1976 to 2006 to see what factors led some of them to advance to acute leukemia. They found that patients in the study who took ESAs tended to be sicker, and were more likely to develop leukemia.
ESAs like Aranesp, Epogen and Procrit treat anemia in patients with kidney disease or certain cancers by boosting red blood cells. However, several studies have linked the anemia drugs to cardiovascular problems and deaths. They have also been tied to worsening tumors when used in cancer patients. A year ago, the FDA ordered that a “black box” warning regarding cardiovascular problems and other safety issues posed by the drugs be included on their labels. In March, the FDA added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. Last month, that black box warning was modified to include stronger language and more specific dosing information.
Last week, Amgen, the manufacturer of all three drugs, said a study done on breast cancer patients treated with the Aranesp showed that it offered them little help, and also placed them at a higher risk of death. Amgen said it was considering further warnings for the drugs. Aranesp and Epogen are marketed by Amgen, while Procrit is sold by Johnson & Johnson under a licensing agreement with Amgen.
Following the release of the Aranesp breast cancer study, the FDA announced that it would be holding yet another advisory panel meeting in March to discuss the safety of Aranesp, Epogen and Procrit. The March meeting will be the fourth time the FDA has held such a meeting to discuss ESAs. Following one of these meetings in May, the Centers for Medicare and Medicaid Services changed the reimbursement policy for Aranesp and other ESAs. Now doctors will only be paid for using a low dose of the drug.
Since safety concerns over Aranesp, Epogen and Procrit first surfaces, Amgen has lost nearly $19 billion in market value.
The Aranesp breast cancer study was one of 5 clinical trials that Amgen had agreed to after the safety of Aranesp was called into question. Aranesp, and two other drugs made by Amgen, Epogen and Procrit, are all part of a class of drugs known as erythropoiesis-stimulating agents (ESAs). Procrit is marketed by Johnson & Johnson under a licensing agreement with Amgen.
ESAs treat anemia in patients with kidney disease or certain cancers by boosting red blood cells. However, several studies have linked the anemia drugs to cardiovascular problems and deaths. They have also been tied to worsening tumors when used in cancer patients. A year ago, the Food & Drug Administration (FDA) ordered a “black box” warning regarding cardiovascular problems and other safety issues posed by the drugs be included on their labels. In March, the FDA added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. Last month, that black box warning was modified to include more specific dosing information.
Following the release of the Aranesp breast cancer study, the FDA announced that it would be holding yet another advisory panel meeting in March to discuss the safety of Aranesp, Epogen and Procrit. The March meeting will be the fourth time the FDA has held such a meeting to discuss ESAs. Following one of these meetings in May, the Centers for Medicare and Medicaid Services changed the reimbursement policy for Aranesp and other ESAs. Now doctors will only be paid for using a low dose of the drug.
None of this is good news for Amgen, as Aranesp is its biggest selling product. Amgen, based in Thousand Oaks, Calif., has lost about $19 billion in market value this year after studies showed its anemia drugs raised the risk of heart attack, stroke and death at high doses. Last week, after it announced that it was considering more label changes, Amgen stock dropped more than 5 percent. The worst possible outcome for Amgen would be if the latest breast cancer data convinced the FDA panel to vote to recommend against using ESAs to treat other cancers where there's been negative data as well, such as neck and head cancer.
Amgen also reported that participants who received Aranesp had numerically more deaths and reports of tumor growth than control group patients. Amgen cautioned that the results-revealed amid concerns about the overuse and safety of the anemia drug class-were preliminary and conclusions should not be made until completion of the final study report. A formal statistical analysis of survival is anticipated in early 2009. The interim analysis shows the use of Aranesp to support neo-adjuvant chemotherapy has no significant impact on tumor response to chemotherapy at the time of surgery. There were no deaths during the treatment period, researchers said; however, preliminary long-term, follow-up data revealed more deaths in the group receiving Aranesp, with more tumor progression events versus the control group.
The entire drug class, called erythropoiesis-stimulating agents (ESAs), has been under a microscope as debates rage over whether anemia drugs increase the risk of heart attack and stroke, and whether they may play a role in fueling the growth of cancer.
Labels for Aranesp, Epogen, and Procit had been updated to include revised dosage guidelines and information on the drugs' cardiovascular side effects. The modifications followed the Food and Drug Administration's (FDA) ordering of a black box warning-the strongest drug labeling-about cardiovascular problems and other safety. Amgen manufactures all three medications although Johnson & Johnson sells Procrit under a licensing agreement. The drugs are part of a class of drugs known as erythropoiesis-stimulating agents (ESAs) that treat anemia in patients with kidney disease or certain cancers by boosting red blood cells. Several studies linked the drugs to cardiovascular problems and deaths and have been tied to worsening tumors when used in cancer patients. Soon after Epogen was introduced, some doctors attempted to use it to increase patients' hemoglobin-the part of the blood cell that carries oxygen-to levels as high as those in healthy patients (14). Two clinical trials showed the large dosage required to reach these levels could lead to heart problems and death and the black box warning cautioned doctors that the medications should be administered at the lowest dose possible to bring blood counts to the lowest level needed to avoid transfusions. The modified black box warning now has more specific dosing information and states dosing should be individualized. For kidney patients, the revised warning read that patients experienced greater risks for death and serious cardiovascular events when administered ESAs to target higher versus lower hemoglobin levels in two clinical studies' rather than the more generic warning that risks were seen when hemoglobin levels of greater than 12 were target. Following the revised black box warning, Medicare announced it would not pay for Aranesp, Epogen and Procrit in patients whose hemoglobin levels were at 10 grams per deciliter.
Aranesp, Epogen and Procrit are all part of a class of drugs known as erythropoiesis-stimulating agents (ESAs). ESAs treat anemia in patients with kidney disease or certain cancers by boosting red blood cells. However, several studies have linked the anemia drugs to cardiovascular problems and deaths. They have also been tied to worsening tumors when used in cancer patients. Soon after Epogen was introduced, some doctors attempted to use it to increase patients’ hemoglobin (the part of the blood cell that carries oxygen) to levels as high as14 grams. A healthy person would normally have a hemoglobin level between 13.5 and 14. Two clinical trials showed that the large dosage required to attain such high hemoglobin levels could lead to heart problems and death. In March, the FDA added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. The warning labels said hemoglobin levels should not be allowed to go above 12 grams per deciliter of blood.
The modified black box warning on Aranesp, Epogen and Procrit now has more specific dosing information. It now states that dosing should be individualized to "achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL." For kidney patients, the new warning now reads that “patients experienced greater risks for death and serious cardiovascular events when administered ESAs to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies' rather than the more generic warning that risks were seen when hemoglobin levels of greater than 12 were target.
Amgen also announced that it planned to ask the Centers for Medicare and Medicaid Services to loosen payment restrictions for Aranesp, Epogen and Procrit. Shortly after the FDA added the black box warning in March, Medicare announced that program would not pay for Aranesp, Epogen and Procrit in patients whose hemoglobin levels were at 10 grams per deciliter.
Several studies have linked the anemia drugs to cardiovascular problems and deaths. They have also been tied to worsening tumors when used in cancer patients. The drugs improve anemia by increasing red blood cells, something that had previously been accomplished with blood transfusions. But soon after Epogen was introduced, some doctors attempted to use it to increase patients’ hemoglobin (the part of the blood cell that carries oxygen) to levels as high as 14 grams. A healthy person would normally have a hemoglobin level between 13.5 and 14. Two clinical trials showed that the large dosage required to attain such high hemoglobin levels could lead to heart problems and death. In March, the FDA added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. The warning labels said hemoglobin levels should not be allowed to go above 12 grams per deciliter of blood.
Shortly after the FDA added the black box warning, Medicare announced that program would not pay for Aranesp, Epogen and Procrit in patients whose hemoglobin levels were at 10 grams per deciliter. That decision sparked controversy among doctors and members of Congress. As a result, Medicare had been waiting for the outcome of yesterday’s advisory panel meeting before enforcing its new dosing regulations.
Prior to the meeting, the FDA had proposed setting a target hemoglobin level of 11 for the medications. The panel heard from representatives from Amgen, as well as patient representatives and kidney specialists. They expressed fears that the proposed limit would leave many patients under-treated, and at risk for blood transfusions. Many panelists who voted against the proposed level of 11 said that more flexibility in dosing was needed, although most agreed that some guidelines were necessary. Several backed Amgen’s proposed hemoglobin range of 10- to-12 grams. While higher than the FDA proposed limit, that range is still lower than the 11-to-13 range found in some kidney treatment guidelines. At least one panel member expressed concern that 18 years after Epogen received its approval, dosage was still as subject of controversy. He criticized Amgen for not conducting more clinical trails.
Despite the vote in Amgen’s favor, Aranesp, Epogen and Procrit could still face additional changes to their labels. The FDA says that claims made on the labels that the drugs improve patient’s quality of life did not stand up to clinical scrutiny. The FDA is considering removing those statements from the products’ labels; however the advisory panel was not asked to vote on that issue.
Aranesp, Epogen and Procrit are all erythropoiesis-stimulating agents (ESAs) given to anemia patients suffering kidney failure and undergoing chemotherapy treatment. Prior to the development of these drugs, such anemia was treated with blood transfusions. In March, a black box warning was added to the drugs’ labels after the FDA discovered that doctors were using the medications to increase red blood cell counts to unsafe levels. The new warning labels advised that the ESAs should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. The warning labels said hemoglobin (red blood cell) levels should not be allowed to go above 12 grams per deciliter of blood. But the label recommendation did not specify what the lowest hemoglobin should be. Now, no one can agree on what the lowest possible hemoglobin level is, and the FDA is looking to the advisory panel for answers.
The FDA has not pinpointed a proper dosing for ESAs, but has said that there is evidence that a minimum hemoglobin level of 11 could benefit patients. However, an FDA review of the drugs’ safety found that more research focusing on proper dosing is needed. Amgen, the maker of Aranesp and Epogen, claims that a target hemoglobin range should be 11 to 12 grams per deciliter for kidney patients, and that hemoglobin in kidney failure patients should not be allowed to fall below 10.
The dispute over proper ESA dosing came to head a month after the black box warning was added. Because the treatment of kidney patients is a major expense for Medicare, the addition of the warning prompted the program to decide that it would not pay for Aranesp, Epogen and Procrit in patients whose hemoglobin levels were at 10 grams per deciliter. That decision sparked controversy among doctors and members of Congress. As a result, Medicare has been waiting for the outcome of tomorrow’s FDA advisory panel meeting before enforcing its new dosing regulations.
Muddying the waters even more, the FDA says that studies indicating that ESAs significantly improved a patient’s quality of life did not “supply sufficient evidence of efficacy to retain these claims” on the drug labels. The FDA also said that those studies may not meet current regulatory guidelines. But Amgen insists that the data involving quality of life is conclusive.
€œRecently completed studies describe an increased risk of death, blood clots, strokes, and heart attacks in patients with chronic kidney failure when ESAs were given at higher than recommended doses, € the FDA said. €œIn other studies, more rapid tumor growth occurred in patients with head and neck cancer who received these higher doses.
€œIn studies where ESAs were given at recommended doses, an increased risk of death was reported in patients with cancer who were not receiving chemotherapy and an increased risk of blood clots was observed in patients following orthopedic surgery. €
This new labeling change marks the fourth time in the past decade that the products €™ label warnings were forced to be updated. €œThe agency is in the process of re-evaluating the safety of Aranesp, Epogen, and Procrit on the basis of the results of recent clinical studies, € said Dr. Steven Galson, director of FDA €™s Center for Drug Evaluation and Research. €œThe new studies provide significant new information for both prescribers and patients, and the new information applies to all ESAs, which share the same mechanism of action. The safety of these products will be discussed when the Oncologic Drugs Advisory Committee (ODAC) meets in May and further revisions to the labeling may occur after that meeting. €
The FDA is asking the drug makers to add a black-box warning, the agency €™s most serious alert, that €œadvises physicians to monitor red blood cell levels (hemoglobin) and to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid the need for blood transfusions. €
According to the FDA, ESAs are €œgenetically engineered forms of the naturally occurring human protein, erythropoietin. € Erythropoietin is produced by the kidneys and increases red-blood-cell levels. Currently, the FDA has approved these drugs for treating anemia in patients with chronic kidney failure and in patients whose anemia is a result of chemotherapy. Combined domestic sales of the three drugs reached approximately $10 billion last year alone.
In January, Amgen sent a letter to medical professionals warning them of an elevated risk of fatalities associated with the use of Aranesp in cancer patients. Amgen conducted a clinical trial to test the safety and efficacy of Aranesp on patients whose anemia was caused by the cancer itself, not by chemotherapy. While the drug is not currently approved for this usage, corporate estimates say that approximately 10 to 12 percent of all Aranesp sales are for that exact off-label (unapproved) usage.
The safety of Epogen has also been questioned by the medical community. Last November, two studies in the New England Journal of Medicine cited the overuse of anemia drugs in the treatment of kidney patients. Scientists have found that anemic kidney patients are susceptible to heart problems or death when aggressively treated with these drugs. Epogen has also been under attack by Congress because of the strain it places on Medicare. Anemia drugs are currently Medicare €™s largest drug expenditure.
Amgen warned that €œAranesp was ineffective in reducing RBC [red blood cell] transfusions in patients with cancer who have anemia that is not due to concurrent chemotherapy. In addition, this study showed higher mortality in patients receiving Aranesp. € The Phase 3, double-blind, randomized, placebo-controlled study included 989 patients with active cancer and low hemoglobin levels, but who weren €™t receiving chemotherapy or radiotherapy. In the 16-week treatment phase, more deaths were reported in the Aranesp treatment group (26 percent) than the placebo group (20 percent).
Amgen also notes, €œAranesp is not approved for use in this population. Aranesp is approved for the treatment of patients with anemia, which is caused by chemotherapy treatment of their malignant disease, rather than the underlying malignant disease itself. € However, corporate estimates say that approximately 10 to 12 percent of all Aranesp sales are for that exact off-label (unapproved) usage. The clinical trial was set up in order to get the drug approved for use in those patients whose anemia was caused by cancer directly (as opposed to chemotherapy).
Epogen, Amgen €™s other anemia drug, has come under fire as well. In November, two studies in the New England Journal of Medicine called into question the overuse of anemia drugs in the treatment of kidney patients. Scientists have found that anemic kidney patients are susceptible to heart problems or death when aggressively treated with these drugs. The drugs are intended to boost hemoglobin in anemic patients, but the increase in hemoglobin is associated with other serious risks.
Epogen has also been under attack by Congress because of the strain it places on Medicare. Anemia drugs are currently Medicare €™s largest drug expenditure. Epogen and Aranesp account for approximately $6 billion in revenue and $2 billion in profit for Amgen.