Survival Benefit of Aerosolized Cyclosporine in Lung Transplant Patients may be due to Patient Imbalances
Jun 4, 2005 - 11:37:00 AM
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While [the imbalances] may not be a serious problem in a study originally intended to demonstrate a difference in rates of acute rejection episodes in allogeneic lung transplantation, it is a potential problem when evaluating patient survival.
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By FDA Advisory Committe,
[RxPG] A survival benefit for lung transplant patients seen with Chirons Pulminiq (aerosolized cyclosporine) may be due to patient imbalances across treatment groups in the drugs pivotal study, FDA said.
Randomization in the double-blind, placebo-controlled trial was not stratified by single versus double lung transplant, or other baseline donor/recipient characteristics known to influence long term survival, FDAs briefing document for the advisory committee review of the product states.
The Pulmonary-Allergy Drugs Advisory Committee will convene on June 6 to consider Chirons application for prevention of lung transplant rejection.
While [the imbalances] may not be a serious problem in a study originally intended to demonstrate a difference in rates of acute rejection episodes in allogeneic lung transplantation, it is a potential problem when evaluating patient survival.
In the study, 58% of Pulminiq patients had a single transplant versus 80% of patients on placebo. Forty-two percent of Pulminiq patients had a double transplant versus 20% on placebo.
These imbalances would be expected to predict worse patient long term survival in the placebo group, FDA said. Patients with single lung transplant have a worse prognosis than patients with double lung transplant one year after transplant and beyond.
The Pulminiq application contains one comparative study of 56 patients. The study failed to meet its primary objective of demonstrating a decrease in acute rejection in de novo lung transplant recipients, but an unexpected survival advantage for Pulminiq over placebo was reported, FDA said.
FDA said its Division of Pulmonary-Allergy Drug Products accepted the application because the study reported a statistically significant survival difference. In the two-year Phase II study, patients on Pulminiq had a mortality rate of 12% (3/26) versus 47% (14/30) for placebo.
However, due to the presence of baseline imbalances in factors that are considered to have an influence on long term survival, p-values obtained from any un-adjusted survival analysis (such as log-rank p-value) are not valid and not interpretable.
FDA said that one can examine the data on survival (it being most objective and the ultimate endpoint) in the spirit of data-mining.
However, this does not and should not lead to evidence based conclusions (positive or negative) about the treatment effects. It merely serves the purpose of evaluating the merit of possibility of future studies, the agency said.
FDA also pointed to results for Pulminiq in the endpoints of acute rejection, forced expiratory volume in the first second (FEV1) and bronchiolitis obliterans syndrome (BOS), which failed to corroborate the difference in survival.
While cyclosporine is a well characterized drug, FDA may have some questions for the committee about safety of the aerosolized agent.
FDA noted that the safety database for aerosolized cyclosporine is small in the lung transplant population and that the vehicle being proposed for the final product (propylene glycol) was not used in the studies. Preclinical studies with propylene glycol show that dogs given the vehicle over 28 days develop lung inflammation.
Overall, Pulminiq patients had more respiratory system adverse events than placebo patients in the trials.
The most common adverse events in the patients on drug were cough (50% vs. 27% in placebo), pharyngitis (39% vs. 17% in placebo), dyspnea exacerbated (31% vs. 13% in placebo) and lung consolidation (31% vs. 13% in placebo).
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Additional information about the news article
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This meeting will be held June 6, 2005 at the CDER advisory committee conference room in Rockville, Md. beginning at 8 a.m.
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