In a supplementary "Question and Answer" document released yesterday, the FDA provided more information on the types of cancers seen in children and teens treated with TNF blockers. According to the document, the following types of pediatric malignancies were reported between 2001 and 2008:
Hepatosplenic T-cell lymphoma, 10 cases
Non-Hodgkin’s lymphoma, 7 cases
Hodgkin's lymphoma, 6 cases
Leukemia, 6 cases
Malignant Melanoma, 3 cases
Thyroid cancer, 3 cases
Basal cell carcinoma, 1 case
Lymphoma and AML, 1 case
Leiomyosarcoma, 1 case
Nephroblastoma, 1 case
Renal cell carcinoma, 1 case
Metastatic hepatocellular cancer, 1 case
Malignant mastocytosis, 1 case
Neuroblastoma, 1 case
Colorectal cancer, 1 case
Yolk sac tumor, 1 case
Myelodysplasia, 1 case
Bladder cancer, 1 case
These 48 cases of pediatric cancers included both U.S. (32) and non-U.S. (16) cases. According to the document, 31 cases of malignancy were reported in children taking Remicade, including 10 cases of hepatosplenic T-cell lymphoma in patients with inflammatory bowel disorder; 15 cases of malignancy in children receiving Enbrel were reported; and two cases of malignancy in children receiving Humira were reported. The FDA also said that the 48 cases of pediatric cancers did not confirm a dose association with malignancy.
Last month, the FDA had said that there were 11 deaths among the 48 cases of cancer. The causes of death included hepatosplenic T-cell lymphoma (9 cases) and T-cell lymphoma (1 case). In the remaining case, the patient died from sepsis after achieving remission of the lymphoma.
In children, TNF blockers are used to treat rheumatoid arthritis, inflammatory bowel disorder and Crohn’s disease. They are also approved to treat a variety of chronic, inflammatory and autoimmune system diseases including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF blockers work by neutralizing a protein that, when overproduced, causes inflammation and damage to bones, cartilage and other tissue.
The FDA had been studying the link between the pediatric uses of TNF blockers and cancer since 2008.
The FDA had been studying the link between the pediatric uses of TNF blockers and cancer since 2008. The safety review was prompted by approximately 30 reports of cancer in children and adolescents treated with TNF blockers.
According to a notice posted on the FDA's Website on yesterday, the agency has identified 48 cases of malignancies in children and adolescents treated with TNF blockers. Approximately half were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. Other malignancies reported include leukemia, melanoma, and solid organ cancers. Malignancies such as leiomyosarcoma, hepatic malignancies, and renal cell carcinoma, which are rare in children, were also reported.
Of the 48 cases of cancer, there were 11 deaths, the FDA said. The causes of death included hepatosplenic T-cell lymphoma (9 cases) and T-cell lymphoma (1 case). In the remaining case, the patient died from sepsis after achieving remission of the lymphoma.
Cimzia, approved in April 2008, and Simponi, approved in April 2009, were not included in the FDA’s review because they are not approved for use in children and were minimally used during the review period.
The FDA is requiring manufacturers of TNF blockers to update the Boxed Warning in the prescribing information to alert healthcare professionals of an increased risk of lymphoma and other malignancies in children and adolescents treated with TNF blockers. Along with updating the drugs' labels, the FDA is requiring companies to add information about cancer risks to patient medication guides. The FDA said it is also working with the manufacturers to further define the scope of the cancer risk.
In addition to the updated Boxed Warning, the FDA also required several other changes to the prescribing information for TNF blockers to warn of and mitigate the risks associated with these drugs. These changes are based on additional safety reviews and include:
* Update to the Warnings section describing reported cases of leukemia in adults, adolescents, and children. Changes to the Warnings section of the labeling will also include additional information on malignancies in children and adolescents (see also Boxed Warning information above).
* Update to the Adverse Events section to include information on reported cases of new-onset psoriasis.
* Revised Medication Guide to reflect this new safety information.
In children, TNF blockers are used to treat rheumatoid arthritis, inflammatory bowel disorder and Crohn's disease. They are also approved to treat a variety of chronic, inflammatory and autoimmune system diseases including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF blockers work by neutralizing a protein that, when overproduced, causes inflammation and damage to bones, cartilage and other tissue.
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.
Humira, Cimzia, Enbrel and Remicade are known as tumor necrosis factor (TNF) blockers. They are used to treat rheumatoid arthritis, Crohn's disease and other conditions. The drugs work by suppressing the immune system. It has long been known that people taking TNF blockers run a risk of developing opportunistic infections, and the prescribing information for the drugs has included this information. But now the FDA says that current warnings are inadequate.
The FDA's order came after the agency reviewed 240 reports of histoplasmosis, an infection caused by the fungusHistoplasma capsulatum, in patients being treated with Enbrel, Humira, or Remicade. The majority of the reports involved people in the Ohio River and Mississippi River valleys (the fungus is commonly found in those areas). In at least 21 of the reports, histoplasmosis was initially not recognized by health care professionals, and antifungal treatment was delayed. Twelve of those patients died.
The FDA reviewed one reported case of histoplasmosis in a patient taking Cimzia. The FDA also has received reports of cases of coccidioidomycosis and blastomycosis, including deaths, in patients treated with TNF blockers.
The agency has given the makers of Humira, Cimzia, Enbrel and Remicade 30 days to submit the required safety labeling changes, including strengthened warnings and revisions to the Medication Guides, or to provide a reason why they do not believe labeling changes are necessary. If they do not submit new language, or if the FDA disagrees with the new language the company proposes, the Food and Drug Administration Amendments Act of 2007 provides strict timelines for resolving the labeling changes and allows the agency to issue an order directing the labeling change as deemed appropriate to address the new safety information.
The FDA is also reviewing TNF blockers over a possible link to cancer. In June, the agency said it was investigating about 30 reports of leukemia, lymphoma and other cancers in children and young adults submitted between 1998, after the approval of the first TNF blocker, through April of this year. Approximately half of the reports were lymphomas, cancer of the immune system cells, that were both Hodgkin’s and non-Hodgkin’s based.
In April, the FDA had Amgen and Wyeth include a new black box warning on the Enbrel label stating that the drug has been associated with serious infections, including tuberculosis in some patients. The Enbrel black box warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people.
Enbrel is made from a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance made by the body’s immune system called TNF. People with an immune disease, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, have too much TNF in their bodies. The FDA first approved Enbrel in 2000 for treating rheumatoid arthritis, and its approved uses where expanded several times to include psoriasis and other conditions.
In April, the FDA requested a new black box warning for the Enbrel label stating that the drug has been associated with serious infections, including tuberculosis in some patients. The new Enbrel black box warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people.
Earlier this week, the FDA said it would seek a stronger label on the drug to include warnings that its use could lead to children's deaths as well as moderate-to-severe infections. Reports submitted to the agency linked Enbrel to infections that sometimes led to hospitalization and death. Of the 14 deaths recorded by the FDA, more than half were in children taking Enbrel for arthritis, while the others were among children taking the drug for unapproved uses. The FDA scientists also recommended that stronger warnings about the possibly-fatal infections be added to Enbrel’s label.
The FDA is also reviewing Enbrel and other TNF blockers over a possible link to cancer. The FDA is investigating about 30 reports of leukemia, lymphoma and other cancers in children and young adults submitted between 1998, after the approval of the first TNF blocker, through April of this year. Approximately half of the reports were lymphomas, cancer of the immune system cells, that were both Hodgkin’s and non-Hodgkin’s based.
Ultimately, the FDA advisory panel voted 7-5 with one abstention to recommend expanding Enbrel's approval. The panel of outside medical experts said that Enbrel appears effective in treating psoriasis in children, but it expressed concern about whether the medicine will increase risks of malignancy and serious infections such as tuberculosis. Some panel members expressed concern about giving a drug with unknown side effects to children with only moderate psoriasis. However, they did not recommend that Enbrel be approved only to treat severe psoriasis, saying that might limit whether insurance companies will cover the drug's costs.
The FDA is not bound to follow the recommendations of advisory panels, but the agency usually does so.
Enbrel is made from a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance made by the body’s immune system called TNF. People with an immune disease, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, have too much TNF in their bodies. The FDA first approved Enbrel in 2000 for treating rheumatoid arthritis, and its approved uses where expanded several times to include psoriasis and other conditions.
In April, the FDA had Amgen and Wyeth include a new black box warning on the Enbrel label stating that the drug has been associated with serious infections, including tuberculosis in some patients. The new Enbrel black box warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people.
Today, FDA scientists expressed concern about broadening the drug's approval, citing reports of dangerous side effects in children who have already taken the drug. Reports submitted to the agency linked to infections that sometimes led to hospitalization and death. Of the 14 deaths recorded by the FDA, more than half were in children taking Enbrel for arthritis, while the others were among children taking the drug for unapproved uses. The FDA scientists also recommended that stronger warnings about the possibly-fatal infections be added to Enbrel's label.
On Wednesday, an FDA advisory panel will vote on whether Enbrel should be cleared for the new use. The FDA is not required to follow the panel's advice, though it usually does.
The FDA is also reviewing Enbrel and other TNF blockers over a possible link to cancer. The FDA is investigating about 30 reports of leukemia, lymphoma and other cancers in children and young adults submitted between 1998, after the approval of the first TNF blocker, through April of this year. Approximately half of the reports were lymphomas, cancer of the immune system cells, that were both Hodgkin’s and non-Hodgkin’s based.
In addition to Humira, which is made by Abbott Laboratories, four other TNF blockers are currently on the market in the US. They are Enbrel, marketed by Wyeth and Amgen; Remicade sold by Schering-Plough; and Cimizia, made by UCB of Belgium. TNF blockers impede the action of a substance made by the body’s immune system called TNF. People with an autoimmune disease, such as rheumatoid arthritis, have too much TNF in their bodies.
The FDA said its review will focus on Humira, Enbrel and Remicade. Remicade is approved for use in children with Crohn's disease. Enbrel and Humira are approved to treat children with juvenile rheumatoid arthritis, according to the FDA. The FDA is requiring the maker of Cimzia to conduct a study to assess long-term risks of the product, including lymphoma and other cancers. This study will begin in 2009 and take about 10 years to complete.All of the labels for the drugs currently address the possible risk of cancer when taking the drug.
The FDA is investigating about 30 reports of leukemia, lymphoma and other cancers in children and young adults submitted between 1998, after the approval of the first TNF blocker, through April of this year. Approximately half of the reports were lymphomas, cancer of the immune system cells, that were both Hodgkin's and non-Hodgkin's based.
The FDA has requested that makers of TNF blockers approved for use in children and young adults supply information about all reported cases of cancer among patients in these age groups taking the drugs. The FDA has also asked health-care professionals to weigh the possible risks against the benefits when prescribing TNF blockers.
In addition to the possible cancer risk, TNF blockers have been associated with an increased risk of some infections. In May, Enbrel had its label modified to include a black box warning - the FDA's strictest safety alert - about its association with serious infections, including tuberculosis. The warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people.
Enbrel, manufactured by Amgen and Wyeth, is made from a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance made by the body’s immune system called TNF. People with an immune disease, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, have too much TNF in their bodies. The FDA first approved Enbrel in 2000 for treating rheumatoid arthritis, and its approved uses where expanded several times to include psoriasis and other conditions.
The new Enbrel black box warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people. Approximately 14,000 Americans were diagnosed with tuberculosis last year. Tuberculosis is a bacterial lung infection, and according to the federal Centers for Disease Control and Prevention (CDC), people with weakened immune systems are more likely to contract the disease.
The new Enbrel label says that patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to starting and during treatment with Enbrel. In cases of latent tuberculosis infection, treatment should be initiated prior to therapy with Enbrel. The Enbrel black box warning also says some patients who tested negative for latent tuberculosis prior to receiving Enbrel have developed active tuberculosis. The black box warns physicians to monitor patients receiving Enbrel for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection.
The Enbrel Patient Package Insert is also being converted to a Medication Guide. The Medication Guide is designed to provide important patient safety information and increase the awareness about the proper use of Enbrel. The companies said that the Medication Guide will be distributed when a prescription for Enbrel is dispensed in the US.
In global studies of over 20,000 patients taking Enbrel, tuberculosis was observed in about 200 people. Approximately 14,000 Americans were diagnosed with tuberculosis last year. Tuberculosis is a bacterial lung infection, and according to the federal Centers for Disease Control and Prevention (CDC), people with weakened immune systems are more likely to contract the disease. Enbrel and other medicines in the same class work by blocking a type of immune system protein. The prescribing information warns about new cases and reactivated latent infections, the companies said.
In addition, Moody’s Investors Service placed Amgen’s long-term and short- term debt ratings under review for a possible downgrade. The rating action follows last week’s recommendation by an FDA advisory panel for additional restrictions on the use of Amgen’s anemia drugs, including its top-seller Aranesp, in cancer patients, Moody’s said yesterday. Interim results from a recent, independent study involving breast cancer patients found Aranesp did not enhance the effect of chemotherapy prior to surgery. The study involved over 700 patients and evaluated whether Aranesp prevented anemia and augmented the therapeutic effects of chemotherapy regimens.
Amgen also reported that participants who received Aranesp had numerically more deaths and reports of tumor growth than control group patients. 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 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. Aranesp labels were updated to include revised dosage guidelines and information on the drugs’ cardiovascular side effects following the FDA’s ordering of a black box warning about cardiovascular problems and other safety.
About $11.2 billion of Amgen’s A2 long-term and Prime-1 short-term rated debt will be affected, the rating agency said. Aranesp sales fell at least 50 percent last year after the medicines were tied to greater risks of heart attacks, stroke, and death at high doses. Reduced demand caused Amgen to lose $29 billion in market value last year. “Amgen’s key credit ratios may not have sufficient cushion to absorb any further decline in Aranesp sales at the current rating level,” Moody’s said in the statement. Enbrel was the world’s fifth-best-selling drug last year, with $5.28 billion in revenue. Wyeth and Amgen’s drug competes with Johnson & Johnson’s Remicade, which generated $5.21 billion.
Enbrel, an injection, is designed to work by soaking up an excess inflammatory protein called TNF. The protein can attack the skin and lead to psoriasis, or it can attack joints, causing rheumatoid arthritis, researchers say.
The New Jersey Attorney General’s office began its Enbrel probe after two former Amgen employees charged that the drug maker engaged in illegal marketing practices. Elena Ferrante of Montvale, New Jersey, who was terminated by Amgen in 2005, and Mark Engelman of Laguna Niguel, California, who resigned from the company last year, is suing Amgen for lost wages and other compensation after refusing to participate in improper promotion of Enbrel. Enbrel is approved only for treating moderate to severe psoriasis, but the former employees say they were expected to engage in promotion efforts that sometimes included patients with less severe disease. Enbrel has not been approved for patients with less severe psoriasis.
Ferrante and Niguel claim that Amgen sales reps were instructed to go into dermatologists’ offices and get permission to go through files to identify patients with psoriasis based on the diagnostic coding system insurers use for reimbursement. The representatives were told to then call insurers covering patients with mild psoriasis to seek approval for reimbursement of Enbrel, which costs $20,000 to $50,000 per year, depending on the severity of the sometimes-painful skin condition. When calling the insurance companies, they were instructed not to identify themselves as Amgen sales reps. Rather, they allege that they were told to say that they were “calling on behalf of Dr. So-and-So”.
The Health Insurance Portability and Accountability Act (HIPAA) contains very tough sanctions for disclosing someone’s health information — up to 10 years in jail and a $250,000 fine if the information was transferred or used for commercial advantage. Promoting Enbrel to treat less severe psoriasis could also land Amgen in hot water. Although doctors are free to prescribe approved drugs in any manner they see fit, it is illegal for drug companies to actively promote such off label uses.
Enbrel blocks the action of a substance made by the body’s immune system called TNF. People with an immune disease, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, have too much TNF in their bodies. The Food & Drug Administration first approved Enbrel in 2000 for treating rheumatoid arthritis, and its approved uses where expanded several times to include severe psoriasis and other conditions.
According to the drug’s website, Enbrel is a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance made by the body's immune system called TNF. People with an immune disease, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, have too much TNF in their bodies. The Food & Drug Administration (FDA) first approved Enbrel in 2000 for treating rheumatoid arthritis, and its approved uses where expanded several times to include psoriasis and other conditions.
Elena Ferrante of Montvale, New Jersey, who was terminated by Amgen in 2005, and Mark Engelman of Laguna Niguel, California, who resigned from the company last year, is suing Amgen for lost wages and other compensation after refusing to participate in improper promotion of Enbrel. Enbrel is approved only for treating moderate to severe psoriasis, but the former employees say they were expected to engage in promotion efforts that sometimes included patients with less severe disease.
Ferrante and Niguel claim that Amgen sales reps were instructed to go into dermatologists' offices and get permission to go through files to identify patients with psoriasis based on the diagnostic coding system insurers use for reimbursement. The representatives were told to then call insurers covering patients with mild psoriasis to seek approval for reimbursement of Enbrel, which costs $20,000 to $50,000 per year, depending on the severity of the sometimes-painful skin condition. When calling the insurance companies, they were instructed not to identify themselves as Amgen sales reps. Rather, they allege that they were told to say that they weres “calling on behalf of Dr. So-and-so.”
The representatives also allege that the Amgen sales force was told to write letters on behalf of doctors, seeking advance approval so doctors could write prescriptions for Enbrel. Doctors writing prescriptions would benefit from frequent patient visits to have the drug injected.
If proved, the allegations could cause Amgen serious trouble. The Health Insurance Portability and Accountability Act (HIPAA) contains very tough sanctions for disclosing someone's health information — up to 10 years in jail and a $250,000 fine if the information was transferred or used for commercial advantage. Physicians who agreed to participate in the alleged Enbrel marketing scheme could also be in trouble.
An attorney for the two former Amgen employees told the Associated Press that the New Jersey attorney general's office is investigating and has interviewed Ferrante. According to the Associated Press, that office would not confirm or deny any investigation of Amgen or Enbrel. However, last fall, the New Jersey attorney general convened a task force to investigate how the doctor-patient relationship is affected by the widespread practice of drug and medical device makers giving physicians gifts and fees for researching, consulting and speaking about their products.