When Safe and Effective Means Neither Safe Nor Effective

We previously reported on a May 2007 Proposed Decision Memorandum issued by the Centers for Medicare and Medicaid Services (“CMS”) that would restrict the use of Erythropoiesis Stimulating Agents (“ESAs”) in cancer-related anemia and similar conditions.  The proposed memorandum was finalized in a July 30, 2007 National Coverage Determination (“NCD”).  The final NCD provides coverage, with restrictions, for treatment of chemotherapy-induced anemia in certain cancer types, such as solid tumors, multiple myeloma, lymphoma, and lymphocytic leukemia. ESAs are FDA-approved to stimulate red blood cell production, thereby preventing the need for blood transfusions.  Had this been the end of the matter, this might have posed an interesting administrative law hypothetical.  Recent inquires and proposed legislation from Congress on the ESA coverage issue, however, have raised interest in the issue.

On October 2, 2007, Representatives Henry Waxman (D-CA) and Pete Stark (D-CA) sent a letter to FDA asking for the Agency’s view on the NCD.  FDA responded in an October 12, 2007 letter in which the Agency essentially agreed with the CMS decision.  Specifically FDA’s response notes a number of health risks associated with the use of ESAs, including promotion of tumor growth and increased mortality and cardiovascular events.  ESAs are FDA-approved for hemoglobin levels of up to 12 g/dL; however, the July 30, 2007 NCD restricts ESA coverage to when hemoglobin is less than 10 g/dL.  FDA reconciled this difference by noting that the 12 g/dL level in FDA-approved labeling is “an upper safety limit for ESA dosing, not a target for the therapy.”  FDA further explained that ESAs are intended and approved to prevent the use of transfusions in patients with cancer and related diseases.  This is consistent with the CMS decision, because transfusions are rarely given to patients with a hemoglobin level of greater than 10g/dL.  FDA also noted that there was no corresponding higher quality of life in patients whose hemoglobin levels were higher than that needed to avoid blood transfusions. 

This decision certainly has monetary implications for drug manufacturers, as preliminary estimates on the cost of pending legislation (i.e., House Joint Resolution 54) that would overturn the July 30, 2007 NCD are estimated to cost Medicare $2.1 billion over the next 5 years.  But it also raises interesting questions about labeling.  FDA had previously issued a Black Box warning for ESAs expressing the same concerns about efficacy and advising that “the lowest dose necessary to avoid the need for blood transfusions” be used.  FDA has not, however, changed the 12 g/dL limit in the labeling itself.  This could therefore be considered a liberal interpretation of the requirement that the labeling set forth the conditions for which ESA use would be “safe and effective.”

UPDATE:

The American Society of Clinical Oncology (“ASCO”) and the American Society of Hematology (“ASH”) announced updated ESA Treatment Guidelines.  Among other things, the updated Treatment Guidelines recommend “the use of ESAs as a treatment option for cancer patients who become anemic as a result of chemotherapy when their hemoglobin approaches or falls below 10 g/dL, as well as patients with low-risk myelodysplasia.”  Additional information on the updated ASCO/ASH guidelines is available here and here.