June 5, 2008
F.D.A. Reviews Arthritis Drugs for Links to Cancer
The Food and Drug Administration said Wednesday that it was investigating whether four drugs used to treat rheumatoid arthritis and other immune system diseases might increase the risk of cancer in children.
The F.D.A. said that it had received reports of 30 cases of cancer over 10 years among children and young adults treated with those drugs, which are sold by Amgen, Abbott Laboratories and other companies.
But the agency did not make clear how many children had taken the drugs or whether the cancer incidence among them was higher than would be expected. And it said that for now, it believed that the potential benefits of the medicines outweighed the potential risks “in certain children and young adults.”
The drugs involved are Enbrel, sold by Amgen and Wyeth; Remicade, sold by Johnson & Johnson and, in Europe, by Schering-Plough; Humira, sold by Abbott Laboratories; and Cimzia, which won approval in April and is sold by UBC, a Belgian company.
All the drugs try to damp inflammation by blocking a protein called tumor necrosis factor, and they are used to treat various immune diseases including rheumatoid arthritis, psoriasis and Crohn’s disease, which is an inflammation of the bowel.
The TNF-blockers, as they are known, represent one of the most successful classes of drugs ever developed using biotechnology. Remicade, Humira and Enbrel had combined sales of more than $13 billion last year.
But use in children constitutes a small part of the total. Dr. Michael Severino, an Amgen executive, said about a half-million patients had been treated with Enbrel since its approval about a decade ago, of which only 12,000 were children.
Remicade is approved to treat Crohn’s disease in children. Enbrel and Humira are approved to treat juvenile idiopathic arthritis, once known as juvenile rheumatoid arthritis. In fact the label on Enbrel was changed in March to allow use in children as young as 2, from a previous suggested lower age of 4.
Amgen is now seeking approval of Enbrel to treat psoriasis in children, an issue that will be discussed by an advisory panel to the F.D.A. on June 18.
Since the drugs block part of the immune system, it has always been known that they might contribute to higher risk of cancers and also infections. The labels for the drugs all contain warnings to that effect — particularly about the risk of lymphomas, which are cancers of immune system cells.
About half the cancers reported in the children getting the drugs were lymphomas, including Hodgkin’s disease and non-Hodgkin’s lymphoma, the F.D.A. said.
A study that pooled data from randomized clinical trials, found that adults given Humira or Remicade to treat rheumatoid arthritis had 2.4 times the cancer rate of those in the control groups. “It’s clearly something we have to be concerned about and discuss with our patients,” said Dr. Eric L. Matteson, chairman of rheumatology at the Mayo Clinic and an author of the study, which was published in The Journal of the American Medical Association. Dr. Matteson has been a consultant to many of the companies developing such drugs.
Dr. Edward H. Giannini, professor of pediatric rheumatology at the University of Cincinnati, said that 70,000 to 100,000 children in the United States had juvenile idiopathic arthritis, and that the biotech drugs were “unequaled” in their ability to control the disease. “This was a disease that put kids in wheelchairs,” he said.
Dr. Giannini, who received consulting fees from the companies for helping to devise their pediatric clinical trials, said that no cases of cancer were seen in the clinical trials that led to Enbrel’s approval for pediatric use. And a subsequent registry that followed 600 children found no cases after more than 800 patient-years of exposure.
Still, he said, “We have to be careful with the safety aspects of giving immune response modifiers to very young children,” whose immune systems might not be mature yet.
Michael Parks, a spokesman for Johnson & Johnson, said the company had already submitted data to the F.D.A. Most of the cancer cases associated with Remicade use were in children with Crohn’s disease or ulcerative colitis. And all but one of those children also received other immune-suppressing drugs with a known cancer risk, he said.
Laureen Cassidy, a spokeswoman for Abbott, said there had been no instances of cancer in children given Humira in clinical trials or in postapproval safety studies. Humira was approved for pediatric use a few months ago.
The F.D.A. announcement had little impact on the stocks of the companies involved.