By Lisa Seachrist
WASHINGTON - Like no other drug, thalidomide engenders controversy. This time the drug has run afoul of regulators as a result of its maker promoting the medicine as a cancer therapy.
The FDA issued a warning letter to Celgene Corp. demanding the company cease promoting its leprosy drug, Thalomid (thalidomide), for unapproved or "off-label" indications.
The sharply worded missive, dated April 21, 2000, details what the agency views as a pattern of violations of the regulations under which Thalomid was approved and compels Celgene to submit a written response to the agency by May 5. If the company fails to respond to the letter, it may face regulatory action, "including seizure, and/or injunction."
Celgene did not return phone calls on Friday.
The warning letter notes Thalomid was approved under restricted distribution provisions and points out, "Perhaps more than any other available drug, the need to provide and distribute thalidomide responsibly is essential to the public health."
Thalidomide's reputation dates to 1957, when it was marketed in Europe as a sedative and morning sickness treatment. The drug was never marketed in the U.S. because the FDA had concerns about the drug's ability to cause neuropathy. It wasn't until 10,000 children were born with long bone deformities as a result of their mothers taking the drug that thalidomide was withdrawn from the rest of the world.
But thalidomide is a potent anti-inflammatory and anti-angiogenesis agent. In 1996, Celgene submitted a new drug application (NDA) for the drug as a treatment and preventative agent for the cutaneous manifestations of leprosy known as erythema nodusum leprosum. The drug was approved in July 1998.
However, that approval came with some unusual stipulations. Celgene agreed to create registration and training procedures for all users in order to minimize the chances of women taking the drug while they were pregnant or attempting to become pregnant. In addition, patients were required to watch a video warning delivered by a thalidomide victim.
The FDA's issue with Celgene, as outlined in the warning letter, comes not with the education program, but with Celgene's promotion of the drug as an anticancer therapy. The letter points out the FDA specifically noted in the original approval letter that any "statements or implications by you that this product may indeed be safe and efficacious in the treatment of diseases or patient populations beyond that approved in your application may be considered a violation of the promotional provisions of the [Food, Drug and Cosmetics] Act.
The agency wrote that it had warned Celgene several times that it was violating that provision of its approval. First, on July 30, 1998, the Division of Drug Marketing, Advertising, and Communications (DDMAC) called the company about off-label promotion concerns. On Nov. 9, 1998, the DDMAC issued a letter to Celgene expressing concerns over three company press releases because, the agency said, they failed to present risk information and the company had failed to submit them to FDA 30 days in advance of their issuance as is required by FDA regulation. The agency reiterated its concerns to Celgene in a Dec. 22, 1998 letter.
The warning letter said that, despite the warnings, Celgene promoted Thalomid to physicians as a means to treat a number of cancers, particularly multiple myeloma, and as a way to deal with cancer patient weight loss. The FDA highlighted two incidents in which Celgene sales representatives either delivered or attempted to deliver third-party press releases and other materials outlining the drug's potential in treating multiple myeloma, stimulating appetite and promoting the feeling of general well-being among cancer patients. In addition, the letter mentioned a report of Celgene stating publicly during an investors' meeting that their sales representatives would be promoting thalidomide for off-label uses in "detail" sessions with physicians.
"Celgene is demonstrating a continuing pattern and practice of violative behavior that evince its failure to comply with the conditions under which Thalomid was approved," the letter said.
The indications Celgene is promoting are areas in which the company is testing the drug. In November, a New England Journal of Medicine article detailed a study of thalidomide in 84 patients with refractory myeloma. The company has a Phase III study of the drug in myeloma in the works as well as a Phase III study of the drug against solid tumors. (See BioWorld Today, Feb. 14, 2000, p. 1.)
To date thalidomide hasn't been approved for any of these new indications, but physicians may prescribe the drug for whatever they choose.
The company's stock (NASDAQ:CELG) closed Friday at $50.75, up $2.75.