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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Procrit and Epogen are known as erythropoiesis-stimulating agent (ESA). They 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 and Epogen are approved in the U.S. to treat anemia in cancer patients undergoing chemotherapy.
The German study involved a version of epoetin alfa called Eprex, made by Johnson & Johnson, which is not marketed in the U.S. According to the FDA, Johnson & Johnson made it aware of preliminary safety findings from a clinical trial conducted in Germany investigating the use of epoetin alfa to treat acute ischemic stroke. Treatment of anemia was not a goal of the trial and most patients were not anemic.
According to the FDA, the clinical trial was a double-blind, placebo-controlled, multicenter investigation in 522 adult patients with an MRI-confirmed ischemic stroke in the area of the middle cerebral artery. Patients were randomized to either receive treatment with a placebo or epoetin alfa administered as an intravenous dose of 40,000 units - a relatively high dose - daily for three days. R-tPA, a medication used to help dissolve blood clots, and often used for acute strokes, was also used when clinically indicated. The FDA said the goal of the clinical trial was to determine whether a high dose of epoetin alfa administered for three days would improve the ability of patients to care for themselves after their strokes.
Over a period of ninety days after the start of the trial, 16 percent of the patients who received epoetin alfa died, compared to only 9 percent of patients in the placebo group. Roughly half of all deaths in both groups occurred within the first seven days after starting the drug, with death from intracranial hemorrhage (bleeding within the brain) occurring among approximately 4 percent of epoetin alfa patients compared to percent of patients in the placebo group.
The FDA said that it is aware of other clinical trials investigating the use of epoetin alfa to improve the functional outcomes of patients after stroke. The agency said that the finding of increased mortality in patients receiving epoetin alfa in the German trial suggests the need to closely monitor patients enrolled in these trials for adverse outcomes and to evaluate whether the potential benefits for enrolled patients outweigh the risks in these trials.
The FDA will work with the manufacturers of ESAs and other sponsors of clinical studies to evaluate the risks and benefits associated with the investigational uses of these ESA products as potential “neuroprotective agents.”
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, 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.
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.
At issue is the fact that Medicare has separate reimbursement methods for dialysis treatments and drug prescriptions. Dialysis centers can currently charge a 6 percent premium on Epogen, raising fears that doctors are over-prescribing the anemia drugs in order to increase profits. Panel members suggested bundling dialysis and drug reimbursement together into a single fee so that the incentive for overusing the drug is diminished. The Government Accountability Office offered a similar recommendation.
Critics of the current Medicare system claim that it is set up to encourage aggressive use of Epogen, which has clear financial costs and, as recent studies have shown, growing health concerns as well. Two studies in the New England Journal of Medicine last month have called into question the overuse of drugs in the treatment of anemia in 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.
Earlier in November, California Congressmen Bill Thomas and Pete Stark, both members of the House Ways and Means Committee, accused Medicare of failing to €œstem the systemic abuse of Epogen, resulting in costs to taxpayers and potential health dangers to patients, € according to the Boston Globe.