Editorial: The FDA and ESAs - "a case of wishing upon a star?"

I fear that the FDA’s change in the ESA label is a case of “Wishing Upon a Star”. Embodied in the “FDA Drug Safety Communication: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease” are the recommendations that:

For patients with CKD not on dialysis:

• Consider initiating ESA treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
• The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell transfusion; and
• Reducing the risk of alloimmunization and/or other red blood cell transfusion-related risks is a goal.
• If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of ESA and use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions.

For patients with CKD on dialysis:

• Initiate ESA treatment when the hemoglobin level is less than 10 g/dL.
• If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of ESA.

Presumably the FDA feels that this change in the ESA label is sufficient to address the safety signals emanating from the Normal Hematocrit, CHOIR and TREAT trials.

The problem is that it is not.

The study “Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes” published by Solomon and co-workers in the New England Journal of Medicine [I am a co-author] concluded: “A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels.” 

In other words, CKD patients who were hyporesponsive to ESA are at high risk of adverse effects. And, for stroke, the risk was increased with darbepoetin treatment regardless of response status.

Of course we can wish that reducing the target Hb levels, and perhaps reducing the ESA dose, will be sufficient to attenuate the risks of ESA treatment. But the point is that risk from ESAs is not uniform. Hyporesponsive patients seem to be at particularly high risk.

So the crux of the issue is this: we need to understand why hyporesponsive patients are at high risk; we need to identify these hyporesponsive patients before we initiate treatment; and, we need validated algorithms that minimize risk. To these points, in the NEJM paper Solomon et al write: “The ability to predict a poor initial response from a model incorporating 92 baseline characteristics was relatively limited." So, we don't have a good sense of who is at high risk and how to predict who will do badly. And, certainly, right now we have no treatment algorithms that have been validated. 

The other issue that resonates from the Solomon paper is a need to better understand why exposure to darbepoetin increases stroke risk regardless of response status. Even though the absolute risk of stroke in TREAT was low it was two-fold higher in the treated versus placebo patients. Why?

My sources at Amgen tell me that while a study on ESA hyporesponsive patients was being planned it hasn’t got going yet. Why? 

What we need from the FDA is a push to make sure that such a study - properly designed and powered and asking the right questions - gets started asap. And, please don't tell me that such a study is expensive. Of course it is, but the ESA business remains highly profitable, and key safety questions remain unanswered.

The bottom-line is that the FDA needs to stop “wishing on a star” that it’s job with regards to the safety of ESAs in CKD patients is done.