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Petition to Add a Black Box Warning to Cancer Drug Gefitinib (Iressa)

Mark B. McClellan, M.D., Ph.D.
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20854

Dear Commissioner McClellan:

Public Citizen, representing 125,000 consumers nationwide, hereby petitions the Food and Drug Administration (FDA) pursuant to the Federal Food, Drug and Cosmetic Act 21, U.S.C. Section 355(e)(3), and 21 C.F.R. 10.30, to add a black box warning to the label of the recently approved drug, Iressa (gefitinib; AstraZeneca) so that it will not be used by lung cancer patients with no prior experience of chemotherapy (first-line treatment), a group of patients for whom it has been definitively proved not to work and whom it may harm.

On May 5, 2003, the FDA approved Iressa for third-line treatment of non-small cell lung cancer (NSCLC). Approval was based on the shrinking of lesions in 10% of a small (216 patients), uncontrolled, unblinded Phase II trial. However, Iressa showed no efficacy whatsoever when used as first-line treatment in two large (over 2,000 patients), randomized, well designed, double-blind, placebo-controlled Phase III trials. Importantly, while the study of third-line therapy relied upon subjective measures and surrogate markers, the study of first-line therapy actually used survival as an endpoint. Iressa has thus been proved twice independently not to extend life when used as first-line therapy. (We suspect that it will have little, if any, effect on survival as third-line therapy, as it should be easier to benefit patients with less advanced cancers.) The black box warning label for Iressa needs to state that the drug should be reserved for the same group of patients who were studied in the Phase II trial on which approval was based, i.e., those with NSCLC who have been exposed to at least 2 previous chemotherapy regimens, both platinum-based and docetaxel.

In addition, as of February 2003, there were 173 post-marketing reports of deaths from acute interstitial pneumonia associated with Iressa apparently unrelated to NSCLC in Japanese patients (Japan was then the only country to have approved Iressa). FDA had wanted a black box warning based on interstitial pneumonia associated with Iressa use,[1] but AstraZeneca obviously succeeded in preventing this important addition to the label.

It is in regard to both the potential for misuse in groups in which it is not efficacious, as well as to provide a clear warning to patients that they may be at risk of a fatal lung disease unrelated to NSCLC, that we feel a black box warning in the Iressa label is necessary.

Examples of black box warnings restricting use

The FDA has added black box warnings to a number of drugs with the purpose of restricting use to particular patient groups and preventing scientifically unjustified off-label use. For example, the FDA added an additional paragraph to the black box warning for Premarin (conjugated estrogens) stating that, “Estrogens and progestins should not be used for the prevention of cardiovascular disease.” This change came as a result of the Women’s Health Initiative, a large clinical trial in which it was found that, among women receiving the drug to prevent cardiovascular disease, there were increased risks of myocardial infarction, stroke, invasive breast cancer, endometrial cancer, pulmonary emboli, and deep vein thrombosis. The drug remained indicated for the treatment of hot flashes.

FDA also added a black box warning to the Nolvadex (tamoxifen) label after an analysis of the Breast Cancer Prevention Study revealed that “Serious and life-threatening events associated with NOLVADEX in the risk reduction [of breast cancer] setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism.” In the same black box was the information that “the benefits of Nolvadex outweigh the risks in women already diagnosed with breast cancer” allowing for an important distinction on use based on diagnosis.

Further examples include black box warnings for both Mellaril (thioridazine) and Serentil (mesoridazine) due to their life-threatening lengthening of the QTc interval. In both cases, the black box explicitly warns that these drugs should be reserved for patients with schizophrenia who fail to respond to other antipsychotic drugs (as opposed to use as first-line therapy, which would be an off-label indication).

Our model black box warning would be:

Iressa has been shown to be ineffective in first-line therapy in non-small cell lung cancer (NSCLC) and should only be used in NSLC patients who have failed to respond to two previous treatment regimens, both platinum-based and docetaxel chemotherapies. Because of an increase in deaths from acute interstitial pneumonia in patients taking Iressa, patients need to be closely monitored and warned of the early signs of interstitial pneumonia.


Nothing requested in this petition will have an impact on the environment.


We certify that, to the best of our knowledge and belief, this petition includes all information and views on which this petition relies, and that it includes representative data and information known to the petitioners which are unfavorable to the petition.


Elizabeth Barbehenn, Ph.D.
Research Analyst

Peter Lurie, M.D., M.P.H.
Deputy Director

Sidney M. Wolfe, M.D.
Public Citizen’s Health Research Group


[1] Iressa postmarketing trial modeled on tarceva Phase III under consideration. The Pink Sheet May 5, 2003; 65:27.