EPO Relabeling: Its Not the Black Box, Its What FDA Says About the Black Box

Whoever said actions speak louder than words hasn’t been paying attention to the regulatory response to drug safety issues involving the anemia therapies darbepoetin (Aranesp) and epoetin (Procrit, Epogen).

FDA unveiled strong new warnings on the EPO brands marketed by Amgen and Johnson & Johnson on November 8. The new warnings stress the dangers of using the agents too aggressively to elevate hemoglobin levels, and emphasize that there is no evidence that the drugs improve symptoms of anemia—they should only be used to reduce the risk of transfusion.

It is safe to assume that the new labeling will have absolutely no impact on how the drugs are actually used.

On the other hand, what FDA said about the new labeling will have an impact.

That’s because FDA used the relabeling to repeat its position that restrictive coverage rules implemented by the Centers for Medicare & Medicaid Services are “generally consistent” with the revised labeling.

FDA first made its position on the EPO drugs clear almost a month ago, in a letter to two powerful members of Congress. And in so doing, the agency ensured that the labeling change itself would be anti-climactic at best. That’s because it is CMS’ coverage policy—not FDA’s regulatory actions—that will drive use of the products going forward. (Although FDA still isn't done with EPO; what the agency does next probably won't make much of a difference to Amgen and J&J commercially, but will nevertheless be a key milestone in the implementation of the new drug safety law. You can read all about that in The RPM Report's November issue.)

The question of how the label matches the CMS coverage policy came up repeatedly during a media conference call hosted by FDA November 8. Office of Oncology Drug Products Director Richard Pazdur observed that the labeling says care should be taken that hemoglobin levels not exceed 12 g/dL. “This is not a target,” Pazdur stressed. “This is an upper boundary for safety.”

Office of New Drugs Director John Jenkins highlighted several elements of the labling, including the addition of a new chart summarizing results of six clinical trials showing an adverse impact on survival or tumor progression. The chart includes a column highlighting actual average hemoglobin levels achieved in the trial (data available for three of the six studies). Although the trials targeted hemoglobin levels above 12, actual measures achieved were below 12 in two of the three cases, including only 10.6 in one study that found an adverse survival outcome.

So, Jenkins observed, FDA has added to labeling a warning statement emphasizing that the available data cannot exclude a risk in patients whose hemoglobin levels are maintained below 12. In other words: FDA is saying the drugs are dangerous when used in patients with hemoglobin above 12, but the agency is not saying they are safe when used at levels below that.

Instead, Jenkins said, FDA's goal is to encourage conversations between doctors and patients about whether to use EPO “at all” and then to use “the lowest dose to prevent transfusion.”

Amgen and J&J, of course, see things a bit differently. In fact, they both formally asked CMS to reconsider the policy on November 8, the same day the new labeling was adopted.

Sharer responded to FDA's position that the CMS policy is consistent with the labeling. “I think the issue of consistency here is a bit of red herring," Amgen CEO Kevin Sharer said on an investor conference call to explain the new labeling. " I think the real issue is physician discretion. Clearly, the labeling gives physicians discretion here and the NCD does not. We see that as the point of policy that really needs to be focused on.”

Sharer, though, is not promising anything in terms of changes. "Our financial plan is to manage the company on the assumption that the NCD will stand.”

The reconsideration request certainly looks like a long shot. Sharer acknowledged that the submission does not have a lot of new data in the “literal use of the word data.” It does include a new study conducted in Germany showing now adverse outcomes in patients with Hodgkin’s lymphoma, and it includes some early data about signals of increased transfusions in the US resulting from the policy.

But what it mostly does is reargue the points addressed by CMS in the policy. “Over the course of this year, many different individuals, capable individuals and entities have looked at this data and come out in favor of giving the providers discretion,” Sharer said. “We think the weight of opinion of others looking at this data is very very important information.”