Amgen and Johnson & Johnson are no longer able to promote the impact of their respective erythropoiesis-stimulating agents Aranesp and Procrit on symptoms of anemia in cancer patients, FDA said.

FDA released a Public Health Advisory March 9 announcing labeling changes, including a new "black box" warning, for Procrit (epoetin alfa), Aranesp (darbepoetin alfa) and Amgen's Epogen (epoetin alfa) concerning the risk of serious side effects with aggressive EPO dosing.

During a same-day media call, FDA Office of Oncology Drug Products Director Richard Pazdur was asked whether a claim on Procrit.com that Procrit can help patients "find [their] energy during chemo" would be acceptable following the labeling change.

"That would not be appropriate at this time," Pazdur responded. "For oncology patients, these products have not been shown to improve or relieve symptoms of anemia, nor to improve the quality of life in patients with cancer."

"There is no product labeling that exists ... regarding quality of life or fatigue reduction for oncology patients," he added.

During the call Pazdur emphasized that Aranesp and Procrit are approved for reduction in red cell transfusion in oncology patients, not improving symptoms of anemia associated with chemotherapy.

Within a few hours of the announcement, J&J had closed the Procrit Web site for "upgrading" and Amgen's Aranesp site was not available.

While labeling did not include language concerning the products' impact on quality of life in cancer patients, Pazdur noted that there were "vague" quality of life claims in the patient package insert.

"In looking at the product label, there were claims in the patient package insert ... for example, of improvement in symptoms," he explained.

"In light of the risk/benefit relationship," the quality of life claims in the PPI were removed "because we did not believe at this time that they were supported by substantial evidence to further support marketing claims," he said.

Division of Biologic Oncology Products Director Patricia Keegan said that the chemotherapy-induced anemia quality of life information was originally included in the PPI in an effort to educate patients about the benefits of treating anemia.

"Some of the information in the package labeling and perhaps even some of the information on the Web sites ... are in part sort of a merging of education information," she said.

"Much of that information that we looked at in the package insert had to do with explaining what anemia was and talking in what we thought was lay language about why someone would take these drugs for treatment of anemia," she said.

While the information was added for educational reasons, Keagan said it was being distributed more broadly than anticipated. "What we did not expect was the degree to which this extrapolation might be disseminated," she said.

Pazdur added that information on quality of life in cancer patients may also have been an extrapolation from quality of life data in chronic kidney disease patients.

"There obviously also was perhaps the feeling that claims that were made in renal could be extrapolated to that population. That would not be a current position of the agency."

Pazdur noted the quality of life information for the EPO products was generally added to labeling many years ago, prior to changes in how the agency reviews patient reported outcomes data.

"It is important also to realize that this whole area of patient reported outcomes is a field that is an evolving field. It did not exist, for example, when these claims were put in or it was in a very embryonic stage of development at that time," he said.

"Obviously if we applied our current standards for patient reported outcomes, which has developed ... over the last three to five years, the issues in the oncology claims would not be supported," he added.

Consequently, FDA has asked J&J and Amgen to resubmit the primary data supporting the quality of life claims in both the cancer and chronic kidney disease settings, he said. Quality of life data in CKD remains in the label, pending the review.

"The data was submitted many years ago. We want to take a look at that to see if that data will suffice to support marketing claims based on our current standards for patient reported outcomes," Pazdur said.

Pazdur said how available patient reported outcomes data should be interpreted will be one of a number of topics discussed by FDA's Oncologic Drugs Advisory Committee during a May 5 review of EPO products (¹ 'The Pink Sheet' March 5, 2007, In Brief).

The panel will also discuss FDA's labeling changes for the products, Pazdur said. The new black box warning addresses a number of potential serious adverse events, particularly the increased risk of mortality, seen with aggressive EPO dosing.

For example, ² Aranesp labeling states that "Aranesp and other erythropoiesis-stimulating agents increased the risk for death and for serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dL."

The boxed warning recommends that physicians "use the lowest dose of [the product] that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusion."

The warning also notes that EPO agents have been shown in clinical trials to adversely affect outcomes in head and neck cancer patients, breast cancer patients and in patients with active malignant disease.

Pazdur said the decision to revise labeling for the three products comes on the heels of the release in recent months of data from a number of high profile trials, indicating that EPO adversely affects mortality when dosed aggressively in cancer patients. The trials include Amgen's Anemia of Cancer study of Aranesp and J&J's CHOIR study of Procrit (³ Also see "Aranesp Anemia Of Cancer Study Results Show Increased Mortality Risk" - Pink Sheet, 29 January, 2007., p. 9).

The boxed warnings also highlight the risk of deep vein thrombosis in patients receiving EPO products pre-operatively for reduction of allogenic red blood cell transfusions.

In addition, the Warnings and Dosage & Administration sections were updated to reflect the new information.

- Andrew Kasper (a.kasper@elsevier.com)

Amgen, J&J Barred From Marketing Procrit, Aranesp Chemo-Anemia Benefit

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