Safety Data Leads to Negative ODAC Vote on Prograf

GAITHERSBURG, Md—ODAC has declined to recommend that the FDA approve Prograf (tacrolimus, Fujisawa Healthcare) for the prophylaxis of graft-versus-host disease (GVHD) in patients receiving allogeneic bone marrow transplants (BMT).

Fujisawa presented data from two phase III randomized studies involving 509 patients who received either sibling-matched BMTs or transplants from unrelated donors: 255 received Prograf and 254 cyclosporine (Sandimmune). All patients received methotrexate.

The primary endpoint was reduction in acute moderate-to-severe GVHD at 100 days after transplant. The incidence of grade 2-4 GVHD (26% vs 41% and 51% vs 70%) favored Prograf in both studies. In the matched-sibling study, there were more advanced disease patients in the Prograf group, which accounted for a greater incidence of deaths at 6 months (42% vs 32%), the company said. In the unrelated donor study, there was no difference in the incidence of deaths between Prograf and cyclosporine (34% and 38%, respectively).

FDA reviewer Steven Hirschfeld, MD, noted that more Prograf patients went on to dialysis and more suffered a relapse than did patients on cyclosporine. “If we understood the relationship between the drugs and the deaths, I think we would feel more comfortable about making a recommendation,” said Richard M. Simon, DSc, of the NCI.