Amgen, J&J Dodge a Bullet

A Food and Drug Administration advisory panel voted 14-5 today against lowering the red blood cell target in patients on dialysis or suffering from chronic kidney disease. The vote was a small victory for Amgen and Johnson & Johnson, which make Epogen, Aranesp and Procrit, the various versions of the same biotech drug that raises hemoglobin or red blood cell counts.

Clinical trials completed last year showed that raising hemoglobin to near normal levels through more extensive use of the drugs increases the risk of heart attacks, congestive heart failure and early death in patients with kidney disease. Last March, the FDA slapped a black box warning on the drugs. The FDA had requested that the advisers approve setting a target hemoglobin range on the drugs' labels of 11 grams per deciliter of blood, halfway between the range of 10 to 12 g/dL generally considered safe.

Including that target range on the label would have probably led some renal physicians to begin using less of the drugs, since half of all patients on dialysis in 2005 had hemoglobins higher than 12 g/dL. Indeed, nearly 20 percent had hemoglobin levels over 13 g/dL, which, the latest trials showed, was clearly dangerous.

But when Amgen and more importantly the FDA reviews the transcript of the meeting, they may find that the advisers didn't totally cave in to the promiscuous use of these drugs. The primary evidence introduced at the meeting showed that chronic kidney disease patients with red blood cell counts averaging 12.6 grams per deciliter of blood suffered 50 percent more deaths than patients at 11.3 g/dL. In the final vote of the afternoon, the panel recommended by a 14-3 margin with 2 abstentions that the FDA write dosing instructions on the drugs' labels that will result in hemoglobin levels similar to the lower (and safer) arm of that trial.

So, the votes were, in a sense, contradictory. Don't target 11. But dose to 11.

It remains to be seen how the FDA deals with the results of this meeting. The agency is currently negotiating changes in the Epogen and Aranesp labels with Amgen, one of the most powerful lobbying forces in Washington. Last week, Amgen, in league with the American Society of Clinical Oncologists, got the full Senate to approve a resolution calling on the Center for Medicare and Medicaid Services to roll back its latest payment policy that would restrict the use of erythropoietin in cancer patients. The latest trials in that field showed tumors growing faster and patients dying sooner when red blood cell counts rise to near normal levels.

FDA reviewer Ellis Unger told the panel that based on available clinical trial data, there is no justification for going over hemoglobins of 10 g/dL for dialysis patients and 11.3 g/dL for chronic kidney disease (pre-dialysis) patients. But in the end, the agency asked only for a target of 11 g/dL for both groups and didn't even get that.

"We don't have any evidence to say that 12 is worse than 11, so let's go with 12," responded one panelist who voted against the lower target. "If you set it too low, you'll have a large proportion of people fall to a level that will diminish their quality of life," said another.

That latter comment was odd, given that the review of the quality of life studies by Ann Marie Trentacosti of the FDA Office of New Drugs had concluded that the trials submitted by Amgen to the agency were poorly constructed and never established that the drugs actually improve patients' overall well-being. Of course, there is anecdotal evidence, some of it offered by patient advocates at the meeting. Dialysis or pre-dialysis patients in relatively good health who have red blood cell counts near the top of the allowable range no doubt have more energy and feel better than their counterparts with severe co-morbidities like poorly treated diabetes, hypertension and heart disease.

But Amgen and Johnson & Johnson, which markets erythropoietin as Procrit for the cancer, HIV/AIDS and pre-dialysis markets, have never conducted well-designed clinical trials to prove that. Nor have they conducted trials that prove that patients whose hemoglobin has been raised to, say, 12 g/dL, the target sought by Amgen and J&J, fare better than people at 11 or 10 g/dL.

"It is unconscionable that we've gotten to this point in time and still do not know the answers to these questions," fumed Judith Kramer, a researcher from Duke University who voted in favor of lowering the target range. "It is ultimately the responsibility of the sponsor to do those studies and they did not."

Representatives from the Renal Physicians Association, the National Kidney Foundation and both major dialysis chains showed up to argue against the lower target. Their representatives repeatedly raised the specter of a return to the bad old days of routine blood transfusions if the FDA lowered the target range to 11 g/dL.

Left unsaid was the fact that the number of patients in the higher hemoglobin arms of the clinical trials under review had nearly as many blood transfusions as patients randomized to the lower levels of 10 or 11 g/dL. Moreover, no one on the committee or from the FDA pointed out that the current target range of 11-12 g/dL pushes an estimated 20 percent of dialysis patients into the danger zone of greater than 13 g/dL, where there is a sharp increase in the annual death rate.

If I were on the panel, I would have asked the renal docs who showed up to argue Amgen's position this question: What do you think your patients would want, a lower risk of dying or a lower risk of a blood transfusion?

All in all, it was a curious meeting.

For more coverage, you can read the New York Times report and the Wall Street Journal report.

Posted by gooznews at September 11, 2007 08:24 PM