Pulminiq Advisory Cmte. Splits On Survival Benefit In Lung Transplant

FDA committee members differ on whether Chiron should be required to conduct another trial prior to approval to confirm the suggested survival benefit seen in a lung transplant trial of aerosolized cyclosporine. Chiron points to difficulty in conducting a second placebo-controlled trial.

FDA's Pulmonary-Allergy Drugs Advisory Committee members split on whether Chiron's Pulminiq should be approved for increasing survival in lung transplant patients.

The 8-to-8 committee vote on June 6 reflected uncertainty about whether a survival difference seen in a 56-patient placebo-controlled study was due to the aerosolized cyclosporine agent.

[Editor's Note: To watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

"This is a very promising therapy," committee consultant Lawrence Hunsicker (University of Iowa) said. He called the survival results "hypothesis-generating."

Hunsicker voted against approval, commenting "I don't think we have gotten there."

Committee members voting for approval felt that the survival benefit may be real and that a confirmatory study could be conducted post-approval since there are no other approved drugs for lung transplant rejection.

"What is the competition that we are trying to beat right now? There are no drugs approved…You right now have a 50% mortality rate with the current treatments," committee consultant Jurgen Venitz (Virginia Commonwealth University) observed.

"I think the stakes are high and I'm willing to take a chance on the likelihood that this might be a study that doesn't prove beyond any reasonable doubt that the drug actually worked. In my final summary then, I would conclude even though I have this doubt about the likelihood this is real, the stakes to me favor saying that this is sufficient evidence."

Committee member David Schoenfeld (Massachusetts General Hospital Biostatistics Center) was the strongest supporter of the survival benefit seen with Pulminiq. "I thought that the survival analysis was robust," Schoenfeld said.

Schoenfeld took issue with FDA analyses that showed an imbalance in single and double transplant patients in the Pulminiq and placebo groups.

The imbalance, FDA argued, called into question whether the survival benefit was real since double transplant patients have a better prognosis than single transplant patients, who were more numerous in the placebo group (¹ (Also see "Pulminiq Survival Benefit May Be Due To Patient Imbalances, FDA Says" - Pink Sheet, 3 Jun, 2005.)).

There were other committee members who were troubled by the fact that while there may have been a difference in survival between Pulminiq and placebo, there were no statistical differences seen in other endpoints, including the primary study endpoint of prevention of acute rejection.

The "observed mortality difference may be due to treatment," committee consultant Allan Sampson (University of Pittsburgh) commented, but the mechanism of action is unexplained since the drug did not have an effect on other parameters.

"I don't see strong enough evidence at least in acute rejection," Samson said, noting that the acute rejection rate was actually higher, though not statistically, in the Pulminiq group.

One factor guiding those committee members who voted for approval was the possibility that Chiron would not be able to conduct another trial pre-approval. Chiron argued that institutional review boards would not approve another controlled trial with Pulminiq once they saw the survival data.

However, Hunsicker argued, "there are lots of ways in which this drug could be studied further. It's not this group's business to figure out what happens if we don't approve it. The question we have to deal with is whether it has reached an approvable status or not."

"I find myself worried about the idea that we would be chased into approval because if we didn't approve, nothing would ever happen again."

"I think that would be a very bad precedent because then all that the company would have to do coming to this group is to put you in the position where if you don't approve the drug, nothing is ever going to happen," Hunsicker said.

- Danielle Foullon, Andrew Shelton