Endgame in the Pursuit of Normal

A Food and Drug Administration advisory committee this morning will consider the safety of the anti-anemia biotech wonderdrugs, Epogen, Procrit and Aranesp, which are made and marketed by Amgen and Johnson & Johnson. One question they have been asked to consider is whether there is any basis for targeting a specific red blood cell count to make patients in dialysis or approaching dialysis because of chronic kidney failure feel better. For over a decade, both companies have been attempting to prove that near normal hemoglobin levels (which requires using more drugs) gives dialysis, chronic kidney disease and chemotherapy patients more energy and improves their quality of life.

The answer, according to the FDA reviewers' presentation, posted on the agency website last Friday, is a flat-out no. Despite Amgen's 242-page submission, the agency concluded "overall, FDA has received no randomized, controlled clinical data establishing treatment benefits associated with the attainment of specific hemoglobin levels."

The language in parts of the review amounts to nothing less than a severe rebuke of Amgen's and J&J's research capacities. In describing the three clinical trials the companies submitted in pursuit of a targeted hemoglobin levels to achieve a better "quality of life" for dialysis patients, the agency said:

* Patients were not enrolled based upon a prespecified degree of anemia symptoms;

* All studies were not powered to detect changes in . . . "quality of life";

* None of the symptom efficacy claims instruments (i.e., patient surveys) were developed or validated to measure anemia symptoms in the target population; instead, post-hoc selection of specific items and subscales from various instruments were utilized to support symptom claims.

Here's what went on in one study. "Sometimes several questionnaires had to be provided with reminders that completing and returning each questionnaire promptly and on schedule was very important to the study. There were
still many questionnaires returned late or not returned at all," the reviewers noted. Of the 152 patients enrolled in that study, the researchers came up with information for just 77 patients (51%).

What did Amgen tell the FDA when they turned that study in, "The dog ate my homework"? There are 470,000 people on dialysis in this country and an estimated 8 million people with chronic kidney disease, who might end up there. They deserve better.

The other major focus of today's meeting will be the dangers that patients face when hemoglobin levels go too high. Amgen and J&J have been promoting "near normal" hemoglobin for years, claiming it would improve survival. Yet both studies that have tested that proposition in kidney disease patients -- one published in 1998; the other published last year, both funded by the companies -- came to the opposite conclusion. Hemoglobin levels above 13 grams per deciliter caused more heart attacks, strokes and premature death, not less.

Here's some data that won't be presented at the meeting. A study completed in 2003 (also funded by Amgen) that compared dialysis outcomes around the world found that the crude one-year mortality rates were 6.6 percent in Japan, 15.6 percent in Europe, and 21.7 percent in the US. Even after adjusting for age, gender, race, and 25 comorbid conditions, U.S. dialysis patients died at a rate that was more than 3 1/2 times greater than the Japanese and 33 percent higher than Europeans.

Another study published just last year (also supported by a grant from Amgen) found that Japanese dialysis patients had the lowest hemoglobin levels with a mean level of 10.1 g/dL -- about the level at which the U.S. begins dosing (or should we say overdosing) patients. The Europeans and U.S., meanwhile, had mean hemoglobin levels of 11.4, and 11.7 g/dl, respectively. The researchers said the difference could only partially be explained by the 30 percent higher burden of severe comorbidities of patients in the U.S.

One thing the advisory committee will hear is that when the mean hits 11 g/dL or higher, about 40 percent of patients are actually over 12 g/dL, which the FDA label now says you shouldn't go beyond. And about half of those are over 13 g/dL, the clinically proven danger point. Dennis Cotter of the Medical Technology Patterns and Practice Institute will also present data that shows that the sickest patients are the ones that get the highest doses of the EPO, and they are the ones that are most likely to suffer heart attacks and strokes.

The committee will have to wrestle with how to write a label that warns doctors against overdosing these non-responders, even if their hemoglobin levels are well below 11 or 12 g/dL. The sad thing is that neither Amgen and J&J, despite earning billions of dollars every year from selling these drugs, has ever conducted a clinical trial that will help the FDA or its advisers answer that question.

Posted by gooznews at September 11, 2007 12:02 AM