Washington Editor

WASHINGTON - Drug regulators have called for more trials to establish the optimal hemoglobin target for use of erythropoiesis-stimulating agents (ESAs), such as Amgen Inc.'s Aranesp (darbepoetin alfa) and Epogen (epoetin alfa) and Centocor Ortho Biotech Inc.'s Procrit (epoetin alfa), in treating anemia in patients with chronic kidney disease.

In an online commentary published Wednesday night in the New England Journal of Medicine, four FDA officials, including Robert Temple, the FDA's deputy director for clinical science and acting director of the agency's Office of Drug Evaluation, said regulators plan to convene an advisory panel sometime this year to reevaluate the use of ESAs in CKD patients.

The FDA already has imposed restrictions on the use of the drugs in cancer patients - advice that came from the agency's Oncologic Drugs Advisory Committee at a March 2008 meeting. (See BioWorld Today, March 14, 2008, and Aug. 1, 2008.)

Regulators ordered the drugmakers in July 2008 to add new warnings to ESA labeling that the drugs should not be used in patients undergoing chemotherapy intended to cure their cancer. In addition, the firms were told to include warnings that patients should not start the anemia therapies if their hemoglobin levels are greater than or equal to 10 g/dL.

The labeling for ESAs already had warned that patients with breast and head and neck cancers, in addition to those with non-small-cell lung, lymphoid and cervical cancers, had shortened overall survival and time-to-tumor progression when dosed to target a hemoglobin of greater than 12 g/dL.

The FDA's initial black-box warning, imposed in March 2007, prompted the Centers for Medicare & Medicaid Services to institute payment restrictions on the use of ESAs in cancer patients.

CMS plans to hold its own public advisory committee meeting on March 24 to gain input on establishing a national coverage decision (NCD) for the use of ESAs in CKD patients. (See BioWorld Today, Aug. 24, 2009.)

Anemia is prevalent in CKD patients and is more common as the disease worsens. ESAs are used to raise hemoglobin and hematocrit levels in patients with anemia, including dialysis and nondialysis CKD patients.

About 95 percent of patients with end-stage renal disease (ESRD) receive ESAs, according to CMS. It is unclear, however, the number of pre-ESRD patients receiving ESAs for anemia.

Clinical trials of ESAs have raised "major concerns" about the use of the drugs to increase hemoglobin concentrations in patients with chronic kidney disease "above a level intended solely to avert the need for erythrocyte transfusions," Temple and his colleagues wrote.

Studies have shown that hemoglobin-concentration targets of 14 g/dL, 13.5 g/dL and 13 g/dL - and the ESA regimens used to achieve them - "are harmful," the officials said.

"It remains to be shown in a controlled trial that assignment to any higher target, as compared with any lower target, or to ESA dosing regimens necessary to attain these targets prevents cardiovascular events or indeed does not increase their likelihood," they contended. "It is time to establish, through randomized trials, the optimal hemoglobin target, dosing algorithm, and monitoring approach for patients with anemia from chronic kidney disease," the regulators wrote.

Although analysts already had reduced their Aranesp estimates following results reported last fall from Amgen's TREAT study, "We, and we think most investors, were not expecting this editorial nor another FDA advisory panel," said Credit Suisse analyst Michael Aberman. (See BioWorld Today, Aug. 27, 2009.)

But Baird & Co. analyst Christopher Raymond said the FDA's call for new trials and an advisory meeting "probably should have been expected."

Shares of Thousand Oaks, Calif.-based Amgen (NASDAQ:AMGN) dipped slightly Thursday, closing at $56.27, a loss of 52 cents.

Reviewers Give Thumbs Down for Forest CHF Drug

Drug reviewers Thursday recommended against approval of Forest Laboratories Inc.'s Bystolic (nebivolol) to treat chronic heart failure (CHF) in elderly patients.

Regulators said results from Forest's single randomized, double-blind, placebo-controlled, parallel-group, titrated-dose SENIORS trial lacked robustness.

In addition, drug reviewers noted that several "critical" changes were made late in the SENIORS study, which they said raised "concerns as to the interpretability of the findings.

"Given these results and late changes to the trial, the totality of the evidence is not convincing to support a claim for treatment of heart failure," the drug reviewers said.

The FDA's Cardiovascular and Renal Drugs Advisory Committee is meeting Monday to review Forest's application for Bystolic, an oral beta1-selective beta-adrenergic blocking agent with vasodilating activity.

The drug currently is approved in 79 countries, including the U.S., to treat hypertension. Bystolic also has gained approval in 71 countries for CHF, with the first approval in 1996.

In documents posted Thursday on the FDA's website, New York-based Forest argued that Bystolic "offers a new evidence-based treatment option with a favorable benefit risk profile for patients with CHF."

The drug's approval for heart failure, the company added, would provide an additional treatment option for patients, "which could result in more patients receiving the beneficial effects of beta blockade."

Guidance Encourages Crisis Contingency Plan

The FDA Thursday issued new draft guidelines for makers of so-called medically necessary drugs (MNDs) and firms that provide raw materials for those products about how to deal with manufacturing issues in the event of a large-scale crisis, which could result in high absenteeism of workers at production facilities.

The agency wants manufacturers to have contingency plans in place to avoid shortages of MNDs, which the FDA said could have a "negative impact on the national public health during such emergencies."

Firms that anticipate high absenteeism should give the highest priority to MNDs when scheduling manufacturing and making plans for reassigning or cross-training personnel, the FDA urged.

In addition, regulators said special attention should be given to MNDs for which a company is the sole source or supplies a significant share of the U.S. market. Drugmakers also should give priority to drugs vulnerable to shortages because of low levels of finished product likely to be in the supply chain at any given time.

Published  January 8, 2010