Washington Editor

Amgen and Johnson & Johnson have traveled a rocky road over the past year as drug regulators reassessed the safety of the firms' erythropoiesis-stimulating agents (ESAs).

And the road could get bumpier on Tuesday when FDA convenes an expert panel to further evaluate ESAs - the second time this year the agency has sought the counsel of its advisers about the safety of the products.

Regulators want advice about whether data exist to support a recommendation to dose ESAs to attain and maintain a specific hemoglobin level or range, and if so, what that level or range should be, according to briefing documents posted Friday on FDA's website.

According to the FDA, Amgen and J&J want labeling to specify that a hemoglobin level of 11 to 12 g/dL is appropriate for patients with chronic renal failure (CRF) with anemia. Amgen's and J&J's joint briefing document stated that the firms believe the lower boundary of the target should not be less than 10 g/dL.

Current labeling advises prescribers to use the lowest dosage of the products that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red-blood-cell transfusion.

Thousand Oaks, Calif.-based Amgen markets darbepoetin alfa as Aranesp and epoetin alfa as Epogen in the U.S. J&J subsidiary Ortho Biotech, of Bridgewater, N.J., markets epoetin alfa as Procrit under an agreement with Amgen.

ESAs were originally developed to replace the deficiency of erythropoiein that frequently develops in patients with CRF. ESA administration has been shown to increase the red-blood-cell count in CRF patients and reduce the need for risky blood transfusions.

However, researchers reported Wednesday in the New England Journal of Medicine that there was not a significant reduction in the need for red-blood-cell transfusions among critically ill patients who were given Procrit.

While the Procrit patients showed a drop in deaths, there also was an increase in the risk of blood clots and other thrombotic vascular events among that group, the researchers reported.

In March, the FDA called for a black-box warning based on results of at least three studies that showed that use of ESAs to attain higher hemoglobin levels was associated with an increased risk of adverse cardiovascular events and death. Results of another study showed an increased risk of rapid tumor growth in patients with head and neck cancer who received high dosages of ESAs.

FDA safety concerns about ESAs prompted the Centers for Medicare & Medicaid Services to recently impose restrictions for payments of the products for use in patients with cancer. On Sept. 4, the Senate passed a "Sense of the Senate" nonbinding resolution asking CMS to reconsider that decision.

Senators pleaded with CMS to consult with and seek advice from the oncology community about treatment protocols concerning ESAs.

Some House and Senate lawmakers over the past year also have scrutinized the safety of ESAs and questioned whether the FDA acted quickly enough to respond to the negative study results.

At Tuesday's joint meeting of the FDA's Cardiovascular and Renal Drugs and Drug Safety and Risk Management advisory committees, regulators are asking panelists to discuss whether there is a need for additional clinical studies of ESAs.

In the FDA's briefing documents, an agency medical reviewer suggested that "Careful, prospective, randomized studies should be conducted to determine the ideal hemoglobin target, recognizing that it may differ depending on a number of factors, such as chronicity of renal disease or other patient-specific characteristics."

The FDA also wants advice about how to define and identify patients with insufficient responses to ESAs, or so-called hypo-responders, and the types of clinical data needed to support labeling changes to optimize safer use of the products in those patients.

An ESA dosing algorithm that is reasonable and safe for one patient, the FDA medical reviewer stated, may be overly aggressive for another.

"A target of 12 g/dL may pose excessive risk to a patient with advanced renal disease and a low hematocrit, who is poorly responsive to ESAs," the reviewer said.

With FDA's focus on hypo-responders and the potential serious cardiovascular risks for these patients, said Baird & Co. analyst Christopher J. Raymond, Tuesday's panel meeting "could result in the restriction of ESA therapy in a patient population which may account for a disproportionate level of ESA use, possibly deleteriously impacting" Amgen's ESA franchise even further.

A wide range of estimates exist as to the proportion of the ESA market represented by hypo-responders, Raymond said in a research report.

He said that one industry contact suggested that 5 percent to 10 percent of dialysis patients fall into the hypo-responder category, yet account for 30 percent of ESA use.

At Tuesday's meeting, the joint panel also is expected to review findings from a recent reassessment of data from the firms that claims to support patient-reported and physician-assessed benefits associated with the treatment of anemic CRF patients.

The FDA said that Amgen admitted that its reevaluation of the claims does not support retention of several of the quality-of-life claims, and the firm has proposed changing the labeling to reflect its reevaluation.

Amgen (NASDAQ:AMGN) shares on Friday fell $1.11, or 2 percent, to close at $50.90.