FDA expects an investigation into the link between tumor necrosis factor blockers and lymphoma and other cancers in children will be completed in about six months.

The agency announced it is reviewing the safety of use of the drugs in pediatric patients to treat juvenile idiopathic arthritis and Crohn's disease June 4 in an early safety communication.

The four TNF blockers approved in the U.S. (Johnson & Johnson's Remicade , Amgen/Wyeth's Enbrel , Abbott's Humira and UCB's Cimzia ) already have been linked with cancer, but now FDA says it is investigating 30 reports of cancer in children and young adults.

The cases were reported to FDA's Adverse Event Reporting System over a 10-year period beginning in 1998 and ending April 29, 2008. These patients also were taking other immunosuppressive medicines such as methotrexate, azathioprine or 6-mercaptopurine.

About half of the reported cancers were lymphomas, a cancer of the immune system, including both Hodgkin's and non-Hodgkin's lymphoma. Leukemia, melanoma and solid organ cancers also were reported.

"Long-term studies are necessary to provide definitive answers about whether TNF blockers increase the occurrence of cancers in children because cancers may take a long time to develop and may not be detected in short-term studies," FDA said.

The agency is asking drug makers to provide information about all cases of cancer reported in children taking TNF blockers, and has contacted medical experts to assess the potential association and determine if certain children with JIA and Crohn's disease may be at a particular risk for developing a lymphoma or cancer.

"At the current time, the FDA believes that the potential benefits of the use of TNF blockers outweigh the potential risks in certain children and young adults having one of the diseases for which the TNF blockers are approved to treat," FDA said.

Only Remicade (infliximab), Humira (adalimumab) and Enbrel (entanercept) are approved for indications in children. Enbrel has the longest history in the patient population, approved for JIA (then called juvenile rheumatoid arthritis) in 1999.

Remicade was approved for Crohn's disease in children in 2006, and most recently, Humira cleared FDA for JIA in February. Amgen is seeking approval of Enbrel for psoriasis in children, an indication that will be discussed by FDA's Dermatologic and Ophthalmic Drugs Advisory Committee on June 18.

By blocking TNF, the agents suppress the immune system, treating inflammation that causes several immune system diseases, including JIA, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ankylosing spondylitis.

But anti-TNFs are not without potential risks. Labeling for all four approved anti-TNFs already includes a warning on the risk of cancer.

Labeling for Enbrel and Humira carries a warning on malignancies, while Remicade's prescribing information includes a black box warning on rare cases of hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease.

The class of drugs also carries a "black box" warning on risk of infections, including tuberculosis.

Cimzia (certolizumab), the first pegylated anti-TNF, was approved for Crohn's disease in April (¹ Also see "Three’s A Crowd: Cimzia Joins Humira, Remicade For Crohn’s Disease" - Pink Sheet, 5 May, 2008., p. 10). As part of its post-marketing requirements, UCB is required to conduct a study assessing long-term risk of the product, including lymphoma and other cancers. The study will begin in 2009 and take 10 years to complete.

Amgen and Wyeth said they support FDA's safety review and have provided the agency with information from both companies' adverse events databases.

The companies maintain an ongoing safety surveillance program to analyze and evaluate reports, including reports of malignancies, from clinical trials and patient registries, as well as from health care professionals and patients, Amgen added. An estimated 12,000 pediatric patients have been treated with Enbrel. J&J's Centocor unit likewise said it is complying with FDA's evaluation.

- Jessica Merrill (j.merrill@elsevier.com)

TNF Blockers’ Link To Cancer In Children Is Under FDA Investigation

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