New Labeling Restrictions for ESAs: ODAC

June 1, 2007

The Food and Drug Administration (FDA) should require additional restrictions in product labeling and/or additional clinical trials before approving new erythropoiesis-stimulating agents (ESAs) or new indications for ESAs already on the market, the Oncologic Drugs Advisory Committee (ODAC) told the agency.

SILVER SPRING, Maryland—The Food and Drug Administration (FDA) should require additional restrictions in product labeling and/or additional clinical trials before approving new erythropoiesis-stimulating agents (ESAs) or new indications for ESAs already on the market, the Oncologic Drugs Advisory Committee (ODAC) told the agency.

The ODAC panel made other major recommendations that, if accepted, would more tightly restrict the use of ESAs (see box on page 7). Its votes on issues with significant implications for patients and ESA makers followed a day-long meeting on the safety and efficacy of the drugs.

In 2004, ODAC reviewed ESA-related safety issues raised by two studies, known as BEST and ENHANCE. Since then, several additional studies have led to greater concern about the off-label use of ESAs, such as for anemia unrelated to cancer treatments; the hemoglobin level at which physicians may try to maintain their patients; and the drug's safety. Two ESAs are currently FDA approved, Aranesp (darbepoetin alfa, Amgen) and Epogen and Procrit (epoetin alfa, Amgen and Ortho Biotech, respectively).

Among the newer studies that have generated concerns about ESAs are:

• The 103 study, which evaluated 989 patients with active malignant disease who were not getting chemotherapy or radiation treatments in a phase III, randomized, placebo-controlled study. Researchers observed no significant reduction in red blood cell transfusions but did find more deaths in patients randomized to darbepoetin than to placebo after 16 weeks of treatment, 26% vs 20%. At 4.3 months median follow-up, the absolute number of deaths was greater in the darbepoetin arm. [See ONI May 2007, page 2.]

• DAHANCA 10, which evaluated 522 patients with head and neck cancer undergoing radiation and randomized to either darbepoetin or placebo. An interim analysis of 484 patients showed the darbepoetin arm had a 10% increase in local-regional failure (P = .01), and at study termination, the ESA group had a trend toward poorer survival (P = .08).

In March, on the basis of these and other data, FDA issued a black box warning that ESAs increase the risk of death and serious cardiovascular events when administered to target a hemoglobin level higher than 12 g/dL, and it cautioned physicians to use the lowest dose necessary to avoid transfusions. [See page 42 for a report on Medicare's response to the black box warning.]

FDA's Concerns

FDA emphasized that ESAs are not indicated for cancer patients who are not receiving chemotherapy, and that the drugs "have not been shown to improve or relieve the symptoms of anemia, or to improve quality of life in patients with cancer."

Richard Pazdur, MD, director of FDA's Office of Oncology Drug Products, reminded committee members that ESAs are supportive care products, and that clinical studies aimed at demonstrating that the drugs improve overall survival or cancer tumor control have failed to do so. He added that FDA does not have access to all the data from some of the studies that have raised safety concerns about ESAs. "Nevertheless, these studies point to important risks that include increased thrombovascular events, survival, and increased tumor promotion, including decreased local and regional control and the possibility of decreased progression-free survival," Dr. Pazdur said.

The Companies Respond

In their presentations, officials from Amgen and Johnson & Johnson, Ortho Biotech's parent company, stressed the ESAs' safety and efficacy when used in accordance with the current labeling. Roger M. Perlmutter, MD, PhD, Amgen's executive vice president for research and development, noted that since 2004, cancer researchers have completed 36 randomized, controlled trials of ESAs, bringing the total number of such studies to 55. Of the 36 newer studies, only 3 raised additional concerns, he said.

He also argued that preclinical studies fail to show that the erythropoietin receptor (EPOR) plays any role in tumor progression. "The totality of data supports the view that ESAs have no demonstrable effect on overall survival or tumor progression when used according to the FDA-approved label," he added.

Amgen representatives also presented preliminary data from the 600-patient "145 study" showing that small-cell lung cancer patients on chemotherapy treated with darbepoetin required fewer transfusions than those on placebo with no difference in overall and progression-free survival (see ONI May 2007, page 20).

Clinician's Perspective

Approximately 90% of chemotherapy patients develop anemia, and up to 30% develop grade 3-4 anemia, said Jeffrey Crawford, MD, chief of medical oncology, Duke University, who gave a clinician's perspective on ESAs as part of the companies' presentations. Between 40% and 60% of anemic cancer patients who do not receive an ESA require transfusions, which carry the risk of infections, volume overload, acute and delayed reactions, alloimmunization, iron overload, and perhaps adverse cancer-related outcomes, he said. "The benefits of ESAs are clear to practicing clinicians," he added.

Roy Baynes, MD, PhD, Amgen's vice president for global development, oncology supportive care, discussed the results of an analysis that standardized and combined the six Amgen-sponsored, randomized, placebo-controlled studies in which 1,200 patients with chemotherapy-induced anemia (CIA) received darbepoetin and 912 received placebo.

The analysis found no significant difference in overall survival, investigator-determined progression-free survival, and most adverse events. However, darbepoetin did show a trend toward a higher rate of embolism and thrombosis. An analysis of 11 randomized, placebo-controlled studies of epoetin showed similar results. "ESAs are associated with a well-quantified and well-described increased risk of thromboembolism," Dr. Baynes acknowledged. The two analyses were questioned, however, by FDA medical reviewer Vinni Juneja, MD, who told ODAC that standardizing and combining the trial data limited the ability to detect adverse safety signals.

New Data on the Horizon

New data on ESAs will become available from ongoing pharmacovigilance programs during the next 12 months, and some open questions will be addressed in future studies, said Alex Zukiwski, MD, Johnson & Johnson's vice president of clinical development, oncology. "Benefits of ESA therapy in the CIA setting are substantial and unambiguous," Dr. Zukiwski concluded. "ESA risks in CIA are well characterized at the recommended dose and are supported by the totality of data. Amgen and J&J do not advocate targeting hemoglobin greater than 12 g/dL."