A difference in opinion apparently prompted the FDA to issue Guilford Pharmaceuticals Inc. a non-approvable letter rejecting a supplemental new drug application for use of the Gliadel Wafer in patients with newly diagnosed malignant glioma.
That letter caused the Baltimore-based company’s stock (NASDAQ:GLFD) to drop about 15.5 percent Wednesday to close at $8.14, down $1.49.
But in a conference call with analysts and reporters, company officials said they have requested a meeting with the FDA to discuss steps the company can take to gain approval. The Gliadel Wafer was approved in 1996 for use as an adjunct to surgery in patients with recurrent glioblastoma multiforme.
The issue at hand on the supplemental application appears to be a difference in interpretation of data from the 240-patient Phase III trial. The wafer’s safety was not questioned.
“Obviously, in the last three months [the FDA has] been deliberating,” Craig Smith, chairman and CEO of Guilford, said in the conference call. “During that time, the company has not had a chance to sit down with the review team. Now they are issuing their opinion and now we can sit down and try to define what, if anything, can be done to overcome some of their objections.”
Smith didn’t say whether Guilford would conduct another Phase III trial, instead, he suggested the solution may lie in existing supportive data or follow-up analysis of surviving trial participants.
“It would be premature for us to spell out what we plan to do or what the FDA would be receptive to,” Smith said. “We’ve enjoyed a good working relationship with this division and I think we would like to continue to work with them to try to satisfy their requirement for licensure.”
The primary endpoint in the trial was overall survival, and all participating patients were undergoing initial surgery for malignant glioma.
Guilford’s analysis indicated that, relative to the placebo group, the wafer group had a hazard ratio of 0.71, meaning a 29 percent reduction in the risk of dying during the trial. The p value was 0.03 for this treatment effect, determined using the log rank test, stratified by the country in which treatment was administered.
But the FDA said the wafer group had a hazard ratio of 0.77, meaning a 23 percent reduction in the risk of dying during the trial.
Smith released an excerpt from the FDA’s letter, which stated: “Trial T-301 [the Phase III] was a single, multicenter, randomized, placebo-controlled trial whose primary endpoint failed to reach statistical significance by the protocol-specified log rank test. The analysis of survival, which was the primary endpoint, showed no significant difference between study arms [log rank p=0.08].”
During the conference call, Smith was asked whether the FDA’s negative vote could be attributed to a lack of direction on the agency’s part due to President Bush’s failure to name a commissioner.
The response: “That’s a loaded question and I think I’ll pass,” Smith said. “But to be diplomatic, I would say many of us, and I would guess many people inside the agency, would like to see a commissioner appointed. What influence that would have on the direction of the agency is something I am very interested in, but I don’t have particular insight into it.”
In December, when Guilford argued its case before the FDA’s Oncologic Drugs Advisory Committee (ODAC), a few dissenters on the committee surfaced. In particular, Stacy Nerenstone, the panel’s chairman, called the wafer a placebo. (See BioWorld Today, Dec. 7, 2001.)
“I’m concerned that we have an intervention that has a borderline significance to prolong survival and we have no clinical statistics to show that it is meaningful. I’m concerned that we are going to approve a placebo,” Nerenstone, an associate clinical professor at the Helen & Harry Gray Cancer Center at the Hartford Hospital in Connecticut said at the time.
Nevertheless, the panel voted 8 to 5 in favor of the wafer, despite criticism from other panel members that the study was too small and showed only modest statistical significance.
At the end of the trial, 79 patients (78.2 percent) in the Gliadel group died and 85 patients (80.2 percent) in the placebo group died. The median survival for Gliadel patients was 13.9 months compared to 11.6 months for placebo patients. (See BioWorld Today, Dec. 7, 2001.)
The wafer works by delivering chemotherapy directly to the site of the tumor, minimizing drug exposure to other parts of the body. The product is a small, white, dime-sized wafer comprised of biodegradable polymer incorporating the chemotherapeutic agent BCNC (carmustine). Up to eight wafers can be implanted in the cavity created when a surgeon removes a brain tumor. There, the wafers slowly erode, releasing BCNU directly at the tumor site.
The wafer is approved in Canada for both first-line therapy and recurrent glioblastoma multiforme. Guilford filed for European approval on first-line therapy late last year. Aside from the U.S. and Canada, the wafer is approved for recurrent therapy in 23 other countries.
Last year, U.S. sales reached $20.4 million. Smith said Guilford has penetrated 50 percent of the market and has seen some off-label use.
As a result of the FDA’s decision against first-line therapy, Guilford has scaled back its projected 2002 sales from between $26 million to $29 million, down to between $19 million to $21 million.
In other business, Smith said Guilford is seeking a partner to replace Thousand Oaks, Calif.-based Amgen Inc. in development of a Parkinson’s disease drug. Amgen in September dropped the multimillion-dollar deal after a Phase II trial of neuroimmunophilin ligand missed all its endpoints. (See BioWorld Today, Aug. 22, 1997; July 27,2001; and Sept. 20, 2001.)