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"We also showed a very substantial reduction in quantity and quality of amputations, of gangrene and amputations," he says.
So, during the course of the study, XOMA convinced the FDA to change the end point of the study from mortality rate to a combination of possible benefits from the drug.
"During a trial, lots of things happen that are beyond people's control or expectations. Patients might not be as sick; the natural history of the disease may change. There are established procedures whereby people who are conducting the study can actually look at certain kinds of events," says Karen Weiss, director of the division of clinical trial design and analysis in the FDA's Center for Biologics Evaluation and Research. "This is a fairly unusual and extraordinary situation...We went to the effort and agreed with the company to discuss actually changing the end point."
When the study was over, the FDA agreed that it appeared Neuprex might have benefits. But, the agency said, the study (which took three years to include 400 patients) did not scientifically demonstrate what it needed to for approval.
"What happened was that on that agreed-upon end point, which was a composite of not only looking at survival but other morbidities, on that agreed-upon outcome, there still wasn't a difference. There wasn't evidence that it was effective based on that," Weiss says.
In 2000, the results of the study were made public. The report on Neuprex was far less glowing than it had been five years before when Tashica was number one. The disease itself seemed to have beaten the study's effort to succeed. The FDA's failure to approve the drug for any kind of use was devastating to XOMA and Giroir's team.
"Of course, we were very, very disappointed. We had done everything that we thought we could do, and I think the FDA didn't disagree with us," Scannon says. "They just felt that on top of everything we had done, that to convince them that the product was suitable for approval we needed more information."
Once death was eliminated as proof of the value of Neuprex, the stamp of approval had relied entirely on whether the secondary end point, the "composite," could show that Neuprex had a significant effect on meningococcal sepsis patients. Unfortunately, that composite was designed between the FDA and XOMA without Giroir's input or the input of any investigators. As a result, the composite secondary outcome was flawed and ultimately meant Neuprex would be rejected by the FDA.
The dramatic reduction in amputations among those treated with Neuprex was obvious to doctors looking at the research results, but final results were lumped with many minor effects. The huge reduction in amputations was so buried by irrelevant conditions that the important benefit ultimately became statistically insignificant, Giroir says.
"This is the essence of it. This is why the drug didn't get approved. Because the composite variable, the way they structured it, if you had knee pain and you had four extremity amputations, you were put in the same bucket, the same category," he says. "There was death, life and this intermediate category that lumped all kinds of things together.
"If you look at the whole trial, we had a 68 percent reduction in amputations," he says. "Four kids with four extremity amputations in the placebo group. No kids with four extremity amputations in the BPI group. That's pretty compelling."
"At first it was just at the tip of her toes, and then it started going on up, but after she got the medication, it stopped. I keep God first, but I really think it helped her."
Those involved in the failed efforts to get Neuprex to others who were in Tashica's position all similarly remain convinced the drug reduces amputations and that it could be proven to reduce death if it didn't take so long to get into doctors' hands.
"It's rather frustrating," says Elsbach, the researcher who is at the end of a career spent working on BPI. "I would agree with the FDA that they felt more information was necessary. But, you know, that is complicated by the fact that from what I could see looking at the data that if the agent had been available right on admission without delay, and I think Brett Giroir feels that way, that the results would have been quite convincing."
Scannon says he feels the same but concedes that launching a study that could get the drug to more patients is just too expensive to get funded. Even if it were funded, the speed of the disease competes with the time it takes to fill out paperwork to make the study valid.
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