A meta-analysis of patient level data from over 10,000 clinical trial patients suggests that use of erythropoiesis-stimulating agents may have an adverse survival impact in the still-approved uses in supportive care for oncology.

A meta-analysis of patient-level data from 38 studies of ESA use in patients undergoing chemotherapy found a trend towards increased on-study deaths (hazard ratio=1.10 [95 percent confidence interval=0.98-1.24]) and decreased overall survival (HR: 1.06 [95 percent CI 1.00-1.12]) for ESA treated patients compared to controls, Amgen said Sept. 30.

"While neither of these results is statistically significant, they do not exclude the potential for adverse outcomes when ESAs are used according to current label," Amgen said.

Amgen disclosed the finding after receiving the executive summary of the Cochrane Collaboration's latest meta-analysis of ESA safety. The Cochrane Collaboration previously reviewed the data from 53 trials in almost 14,000 patients at the study level. The group's finding of an overall trend towards adverse mortality outcomes associated with the drugs (Amgen's Aranesp and Johnson & Johnson's Procrit) is already included in labeling.

That analysis, however, included data from unapproved uses. The new, patient-level analysis includes data limited to the still approved uses in chemotherapy.

Amgen says the results "emphasize the importance of adherence to the current ESA labeling," which includes a declaration that the drugs are not to be used in patients undergoing potentially curative therapy. FDA approved new labeling for Aranesp at the end of July, using its new authority to order safety labeling changes to end discussions on that topic (¹ Also see "FDA Flexes New FDAAA Muscle With ESA Safety Labeling - And May Help Tone Up Amgen’s Franchise" - Pink Sheet, 30 July, 2008.).

The next regulatory milestone in wrapping up the ESA safety issues is likely to be the adoption of a formal Risk Evaluation and Mitigation Strategy for the drugs. Amgen, J&J and FDA have been in discussions on a formal program for several months.

The sponsors are also continuing to discuss new post-marketing studies to resolve questions about outcomes in the remaining indications for the drug.

If the safety labeling model is any guide, it may be that FDA ultimately decides to impose the REMS and dictate follow-up studies on its own authority.

The new meta-analysis did not cause a ripple on Wall Street, where investors are focused almost exclusively on prospects for Amgen's osteoporosis therapy denosumab. However, there are concerns that Aranesp sales may be trending behind the downgraded expectations for the brand.

-Gregory Twachtman (g.twachtman@elsevier.com)

ESA Meta-Analysis Underscores Survival Risk

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