DDMAC issues first warning letter of '04: consumer groups not happy with FDA.

Dear Reader,

The Center for Drugs Division of Drug Marketing, Advertising and Communications (DDMAC) issued its first warning letter for 2004 on March 16 to Corixa, Seattle, regarding a promotional video for the company's drug product Bexxar (tositumomab and iodine I 131 tositumomab).

The agency found the video to be misleading because it omitted material risk information and overstated the efficacy of the drug.

Early last month, facing criticism about the decline in warning and untitled letters, and overall enforcement action on misleading advertising, FDA Commissioner Mark McClellan, M.D., personally released three draft guidance documents on direct-to-consumer advertising and addressed media inquiries about them. (See February 23 issue)

Asked about the seemingly lengthy delays between "bad ads" shown on television and actual warning letters sent, McClellan argued that the delays result because the warning letters written for such ads have to stand up in court.

But consumer groups see FDA's decline in warning and "untitled" letters as inaction.

"Last year was FDA's worst year in recent memory for enforcing the advertising regulations; if they keep up this stone-cold pace, they'll break even that record this year," Peter Lurie, M.D., deputy director of Public Citizen Health Research Group said in an interview. "Consumers need to realize that FDA's capacity to protect them from misleading drug company promotions has essentially ground to a halt."

At last month's briefing, McClellan also argued FDA is spending more time working informally with companies to solve issues and thus circumventing, or at the very least, delaying, the issuance of warning letters.

According to the warning letter, FDA objected to Corixa's promotional material for Bexxar--a therapeutic regimen indicated for the treatment of patients with CD20 positive, follicular, non-Hodgkin's lymphoma, with and without transformation, whose disease is refractory to Rituximab and has relapsed after chemotherapy.

DDMAC said that Corixa included effective-ness information but no risk information in a promotional video despite the fact that the approved physician labeling for Bexxar indicated that the product may be associated with serious risks, and clearly states that the majority of patients who received the Bexxar therapeutic regimen experienced severe thrombocytopenia and neutropenia. It also warns that the Bexxar's therapeutic regimen should not be administered to patients with greater than 25% lymphoma marrow involvement or impaired bone marrow reserve.

Other risks associated with Bexxar included hypersensitivity reactions, including anaphylaxis; prolonged and severe cytopenias; and fetal harm when administered to a pregnant woman.

In addition to omitting risks, the company made several false or misleading safety claims to which the agency objected. For example, the video presents the following claims with accompanying visuals of radiation affecting tumor cells:

* "Bexxar is designed to seek out CD20 positive B cells and deliver both immunotherapy and radiotherapy to tumors. tositumomab, the monoclonal antibody component of Bexxar seeks out and binds to CD20 on the cell surface. While the antibody induces immunogenic responses, the isotope emits beta radiation to kill tumor cells not accessible to the antibody."

* "The Bexxar therapeutic regimen has demonstrated efficacy in patients with bulky tumors, yet the relatively short path length is thought to minimize radiation to surrounding healthy tissues."

DDMAC stated that these claims and ac-companying visuals minimize the risks of Bexxar treatment by suggesting minimal harmful effects on surrounding healthy tissue, when in fact, the drug is associated with cytopenia. Moreover, the video fails to disclose that Bexxar has profound adverse effects on normal cells. The antibody portion of Bexxar is directed against the CD20 antigen, which is found on the surface of both normal and malignant B-lymphocytes; therefore, Bexxar is not "targeted" specifically to non-Hodgkin's lymphoma cells.

Further, the video claims: "Because iodine 131 is rapidly eliminated over a few days through renal excretion; residual exposure to radiation is minimized. With the iodine 131 in Bexxar, radioactive material that doesn't attach to targeted cells is rapidly eliminated by the body." The claim suggests that the elimination rate of iodine 131 is the relevant rate with respect to toxicity, the warning letter emphasized. However, the iodine 131 is not lone iodine; it is attached to tositumomab. More-over, iodine I 131 tositumomab is cleared from the body much more slowly than iodine 131. Because cell death is associated with ionizing radiation from the radioisotope, the slower elimination rate allows more time for the ionizing radiation from the iodine I 131 tositumomab to cause cell death in both nor-mal and tumor cells.

The agency also pointed out that clinical studies with Bexxar have documented numerous toxicities from the iodine 131 radiation.

Additionally, the video claims: "First an in-fusion of the unlabeled antibody called tositumomab is administered.... Next, the patient is given a short infusion of the tailored radioactive dose of the Bexxar therapeutic regimen." The agency took is-sue with this claim because the video omits material steps including a material risk-related fact that, to use Bexxar safely, it is necessary to look for altered distribution of the iodine I 131-tositumomab dosimetric dose.

Lastly, DDMAC objected to several unsubstantiated effectiveness claims. For example, the video claims: "Because unlabeled tositumomab is already bound to circulating B cells, the radio labeled antibodies preferentially target tumor cells." That claim, according to the agency, suggests that tositumomab can target tumors when, in fact, it binds to the CD20 antigen on normal pre-B lymphocytes and mature B lymphocytes, as well as malignant B lymphocytes. The purpose of the initial administration of tositumomab is to allow the iodine I 131 tositumomab to stay in the circulation longer. However, DDMAC stated: "We are not aware of substantial evidence or substantial clinical experience demonstrating that iodine I 131 tositumomab preferentially targets tumor cells."

Furthermore, the agency objected to Corixa's claims suggesting that the components of Bexxar may be administered alone and that each component separately has anti-tumor effects for non-Hodgkin's lymphoma, when, to FDA's knowledge, this had not been demonstrated. "The anti-bodies induce immunogenic responses, including apoptosis, complement-dependent cytotoxicity, and antibody-dependent cellular toxicity," the agency said.

"Bexxar is designed to seek out CD20 positive B cells and deliver both immunotherapy and radiotherapy to tumors. As stated in the PI, 'Possible mechanisms of action of the Bexxar therapeutic regimen include induction of apoptosis, complement-dependent cytotoxicity, and antibody-dependent cytotoxicity mediated by the antibody.'"

When reached for comment Jim De Nike, a spokesperson at Corixa, said his firm only received the warning letter March 16, and that it was posted to FDA's website on March 19.

He said the main issue in the letter concerns a Corixa CD-ROM containing an animated representation of Bexxar's mechanism of action. De Nike added: "FDA raised issues regarding content contained in the CD-ROM. While this action is not uncommon, we take this communication very seriously and are currently working with FDA to ad-dress the issues raised."

"Effective immediately, we have discontinued use of the CD-ROM and are reviewing all materials to ensure compliance," added De Nike. "Corixa and GSK continue to market Bexxar and do not anticipate this action to impact the appropriate use of the product."

Following closely on the tail of its first warning letter, DDMAC issued its first untitled letter this year to Wyeth Pharmaceuticals on March 18. (See DDMAC PROMO UNTITLED LETTER, page 4)

Sincerely, The Editors

P.S.--A copy of the warning letter sent to Corixa, Doc. 12927W, is available to subscribers from RECORD-RETRIEVE for $7 plus retrieval.