ODAC calls for more restrictions on ESAs

Panel recommends restricting use in patients with head and neck cancers and metastatic breast cancer.

The Oncologic Drugs Advisory Committee voted 13 to 1 yesterday that erythropoiesis-stimulating agents should continue to be marketed for treatment of chemotherapy-induced anemia.

The panel members also voted against restricting the drug’s use in patients with small cell lung cancer, but voted in favor of restricting the drug’s use in head and neck cancers and metastatic breast cancer. During the March 13 meeting, the panel also voted in favor of modifying the indication to exclude patients receiving curative treatment.

“Patients in a curative treatment group are at higher risk if affected by an adverse effect related to ESAs,” said panel member Wyndham Wilson, MD, PhD, a senior investigator in the Center for Cancer Research at the National Cancer Institute. “The patient could potentially be converted from a curative patient to a noncurative patient.”

The panel also voted to recommend the FDA implement an informed-consent procedure for patients to be treated with ESAs, but voted against recommending the FDA mandate a restricted distribution system of the drugs for these patients.

“To restrict access in this manner would be silly,” said panel member Michael Perry, MD, director of the division of hematology/medical oncology at the University of Missouri Ellis Fischel Cancer Center in Columbia, Mo. “All drugs have risks. If we require this process for each drug we give to patients, then we are trying to ‘over-mandate’ things.”

Four meetings, eight studies

The meeting was the fourth FDA advisory committee meeting to convene to evaluate the risks and benefits of ESAs. In May 2007, the ODAC panel called for tighter restrictions on the drugs. In September 2007, the Drug Safety & Risk Management Advisory Committee and the Cardiovascular & Renal Drugs Advisory Committee joint panel voted against lowering the target hemoglobin level from 12 g/dL for patients with anemia resulting from chronic kidney disease.

Since the May 2007 ODAC meeting, data from two studies have suggested trends toward decreased survival and/or tumor progression in patients with chemotherapy-induced anemia who were treated with ESAs. According to FDA briefing documents, data from eight oncology studies have also suggested these trends. Data from the two most recent studies, PREPARE and GOG-191, became available at the end of 2007.

The PREPARE study was a randomized, open-label, phase-3 trial in which 733 patients receiving neoadjuvant breast cancer treatment were assigned to darbepoetin alfa (Aranesp, Amgen) or transfusion. At a three-year interim analysis, the survival rate and the recurrence-free survival rate were lower in patients who received darbepoetin alfa.

Based on data from PREPARE and the Gynecologic Oncology Group’s cervical cancer study, the FDA approved updated safety information for darbepoetin alfa and epoetin alfa (Procrit, Johnson & Johnson) last week.

In the GOG-191 trial, patients with cervical cancer who were being treated with concurrent cisplatin and radiotherapy were randomly assigned to epoetin alfa or placebo for prevention of anemia. One-hundred fourteen patients of the planned 460 were enrolled when the trial was terminated due to an increase of thrombovascular events in the patients treated with epoetin alfa. Recurrence rates, progression-free survival and overall survival were also lower in the patients treated with epoetin alfa, compared with control.

Significance of trends

Although data from the eight studies have indicated trends toward decreased survival and/or increased rates of tumor progression, panel members questioned whether the data are conclusive. There has not been a statistically significant risk increase in a trial specifically designed to test on-label use.

“It’s a dangerous thing to cite that erythropoietin use causes tumor progression,” said panel member Bruce Redman, DO, associate professor of medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor, Mich. “The data are not there to support that.”

According to Samuel Silver, MD, PhD, section editor of Policy, Patient and Practice Issues for HemOnc Today, different interpretations of the same studies have led to these questions. Silver, director of the University Cancer Center Network at the University of Michigan in Ann Arbor, Mich., spoke during the public hearing at the meeting on behalf of the American Society of Hematology and ASCO.

“If all of these suggestions are taken by the FDA, there will be some major changes,” Silver told HemOnc Today. “ESAs won’t be given to patients receiving curative treatment, but what is considered curative, especially from a hematology point of view?”

If the recommendations are taken, with the current loss of ESA use, the new labeled restrictions would probably bring the market down another 25%, Silver said—and there will no doubt be changes to the current CMS National Coverage decision.

“Physicians have to wait for the recommendations to percolate through the FDA,” Silver said. “But without a doubt, they should expect change.” – by Emily Shafer