Washington Editor

The black-box warning added last March to drugs widely used to treat certain types of anemia has been revised to include even stronger warnings, regulators and the product's makers said Thursday.

The drugs, known as erythropoiesis-stimulating agents (ESAs), are marketed in the U.S. by Thousand Oaks, Calif.-based Amgen Inc. as Epogen (epoetin alfa) and Aranesp (darbepoetin alfa) and Bridgewater, N.J.-based Ortho Biotech Products LP as Procrit (epoetin alfa).

Epogen, Procrit and Aranesp are approved to treat anemia in patients with chronic kidney disease (CKD) and anemia caused by chemotherapy in certain patients with cancer. Epogen and Procrit also are approved for use in certain patients with anemia who are scheduled to undergo major surgery to reduce blood transfusions during or shortly after surgery and for the treatment of anemia caused by zidovudine (AZT) therapy in HIV patients.

The labeling changes were based on results of six clinical trials and advice from two FDA advisory committees that met this year to examine safety concerns raised by those studies, said Richard Pazdur, director of the FDA's Office of Oncology Products.

The revised black box identifies specific cancers - advanced breast, head and neck, lymphoid and non-small-cell lung cancer - in which use of ESAs caused tumor growth and shortened survival when patients received a dose that attempted to achieve a hemoglobin level of 12 g/dL or greater, Pazdur said Thursday during a media telebriefing.

The updated boxed warning, he stressed, also states that the risk of shortened survival and cancer progression have not been excluded in patients with cancer who receive an ESA dose that attempts to achieve a hemoglobin level of less than 12 g/dL, which Pazdur said, "probably represents the majority of cancer patients that are receiving these drugs."

The stronger black box alerts prescribers that ESAs only should be used to treat anemia that occurs in patients with cancer while they are undergoing chemotherapy and advises that patients should stop using ESAs following completion of a chemotherapy course, Pazdur explained.

"Given these concerns, FDA strongly recommends that prescribers talk to their patients about the risks that ESAs might cause cancer to grow more quickly or shorten survival before they prescribe these drugs or continue ESA therapy," he said. "This is an individualized discussion that takes into account many clinical determinations, the purpose that the patient is receiving chemotherapy, the type of chemotherapy that the patient is receiving and the duration of therapy."

For patients with CKD, the revised boxed warning states that ESAs should be used to maintain a hemoglobin level between 10 g/dL to 12 g/dL. The updated black box also alerts prescribers that maintaining higher hemoglobin levels increases a patient's risk for death and serious adverse cardiovascular events, such as stroke, heart attack and heart failure.

Changes also were made in the "Dosing and Administration" section of the labeling to include instructions for dosage adjustments and hemoglobin monitoring for patients with CKD who do not respond to ESA treatment with adequate increases in their hemoglobin levels, the so-called hyporesponders.

In a research note, analyst Joel Sendek of Lazard Capital Markets in New York said that the hyporesponder guidelines are "likely to negatively impact ESA revenues, as the new FDA label is more restrictive than previous labels."

Pazdur noted that the "Indications" section of the labeling has been revised to address quality-of-life claims.

The new labeling, he said, emphasizes that there are no data from controlled clinical trials demonstrating that ESAs improve symptoms of anemia, quality of life, fatigue or patient well-being for patients with cancer or patients with HIV undergoing AZT therapy.

Another statement was added that ESAs should not be used in patients with cancer unless they are receiving myelosuppressive chemotherapy, specifically chemotherapy that lowers blood counts, Pazdur explained.

The "Clinical Experience" section of the labeling for Epogen and Procrit to treat anemia due to CKD has been updated to identify improvements in exercise tolerance and functional ability, he noted. However, Pazdur said, "other portions of this section pertaining to clinical outcomes, such as happiness and well-being, have been deleted."

The FDA is in discussions with Amgen about the specific designs of clinical trials needed to further characterize potential tumor progression, he said.

"We would like to see specific trials done in specific tumor types with clearly outlined endpoints of survival or time-to-progression."

Amgen said it has proposed six new clinical trials designed to assess the safety of ESAs when used to treat chemotherapy-induced anemia in specific tumor types.

However, Patricia Keegan, director of the FDA's Division of Biologic Oncology Products, told reporters that the specific designs and numbers of the new trials the agency is seeking is "still a subject for discussion."

During a conference call to investors Thursday, Amgen CEO Kevin Sharer noted that the new studies are in addition to the firm's ongoing pharmacovigilance program agreed to in 2004.

"We will promptly report to the FDA, physicians and patients the results of these programs as we achieve results," Sharer said.

Sendek called Amgen's pharmacovigilance clinical trial commitment "financially onerous" and said the program could "divert R&D dollars away from pipeline development."

Amgen Persists In Reversing CMS Decision

Amgen also is attempting to overturn a decision made in July by the Centers for Medicare & Medicare Services (CMS) to restrict payments for ESAs in patients with cancer to those whose hemoglobin levels decrease to less than 10 g/dL.

Sharer told investors Thursday that his firm plans in the "next few days" to submit a formal request containing new evidence for reconsideration of CMS's National Coverage Decision (NCD) to limit payments for ESAs.

CMS's decision, he charged, has resulted in "two classes of treatment," where Medicare beneficiaries are provided a "lesser standard of care" than patients covered by private payers.

"In this request, we will ask that Medicare patients receiving chemotherapy and identified by their treating physicians to be suffering from the signs and symptoms of anemia be eligible for reimbursement up to a level of 12 g/dL, consistent with the FDA-approved label and clinical practice guidelines," Sharer said. "This will help restore appropriate physician discretion and enable Medicare patients to receive the treatment they need and deserve."

Sharer insisted that the FDA-approved labeling for ESAs "make clear the safety ceiling of ESAs is a hemoglobin level of 12 g/dL and permits physicians to use their clinical discretion in treating patients experiencing chemotherapy-induced anemia up to a level of 12 g/dL."

CMS's decision, he said, "removes that discretion from physicians and is inconsistent with best medical practice guidelines."

However, Pazdur argued that the FDA-approved labeling for ESAs is "consistent" with CMS's decision.

The new labeling, in addition to the previously approved labeling, "has given the requisite flexibility to practicing physicians to provide the optimal decision making in prescribing these drugs," he said. "We have not stipulated in the labeling a hemoglobin to start ESAs on. We have in the labeling that the hemoglobin level should not exceed 12. We would like to emphasize that this is not a target, this is a upper boundary for safety concerns."

John Jenkins, director of the FDA's Office of New Drugs, added that the labeling is consistent with CMS's decision because "in both cases the goal is to use the lowest dose to avoid the need for blood transfusions. The CMS coverage decision is based on the knowledge that blood transfusions are rarely provided to patients who have hemoglobins of 10 or greater. So in that way, the labeling and the CMS coverage decisions are consistent."

Analyst Adam Walsh of Jefferies and Co. in New York said it was "unlikely" that CMS would reverse its decision on ESA payments for cancer patients.

"New data or arguments that CMS misinterpreted the evidence would need to be compelling for CMS to change the current NCD, in our opinion, and we are not convinced that Amgen has the compelling arguments CMS requires," he said in a research note.