The FDA issued Guilford Pharmaceuticals Inc. approval to expand the use of the Gliadel Wafer as a first-line therapy for patients with high-grade malignant glioma.
Currently approved as an adjunct to surgery in patients with recurrent glioblastoma multiforme, the Gliadel Wafer delivers chemotherapy directly to the site of brain cancer, bypassing the blood-brain barrier and minimizing drug exposure to other areas of the body.
In the U.S. alone, approximately 3,000 patients each year undergo re-operation for recurrent malignant brain cancer and about 8,000 people undergo an initial surgery, Baltimore-based Guilford said.
"Most patients with high-grade malignant glioma live less than a year after diagnosis," Craig Smith, Guilford's chairman and CEO, told analysts and investors in a conference call Wednesday. "Gliadel, if used in conjunction with surgery, radiation and systemic chemotherapy, increases the chances of survival while offering a good quality of life."
The dime-sized wafer is comprised of a biodegradable polymer (polifeprosan 20) incorporating 7.7 mg of carmustine, a chemotherapeutic agent usually administered intravenously to treat a malignant glioma. Up to eight wafers can be implanted in the cavity created when a surgeon removes a brain tumor.
Worldwide sales in the recurrent indication totaled $14.2 million last year, and the company anticipates sales will reach $20 million to $25 million this year in both indications. Guilford expects to resubmit its European application for first-line therapy over the next few weeks. The company withdrew the application in November, but hopes the updated application will garner approval within three to six months.
Even though the wafer has been on the market since 1996, Guilford had some trouble winning FDA support of its supplemental application, which the agency rejected last March after the Oncologic Drugs Advisory Committee (ODAC) voted 8-5 in favor of it. (See BioWorld Today, March 21, 2002, and Dec. 7, 2001.)
"The analysis we did and presented to the ODAC panel showed a "p" value of 0.03, but the FDA looked at it slightly differently and came up with a "p" value of 0.07. They indicated to us that they did not feel that was a strong enough finding to approve the product," Smith told BioWorld Today.
Furthermore, Smith said, "when we went back and spoke to the FDA about concerns they had expressed in the non-approvable letter, it turned out that the principal issue, in fact the only issue, centered around the strength of evidence regarding the efficacy data. In other words, they did not have any problems or concerns about the safety of the product and they did not have any concerns with the manufacturing process."
The new drug application was based on a Phase III double-blind, placebo-controlled study of 240 patients at 38 centers in 14 countries. The primary endpoint was survival.
At the end of the two-year follow-up (July 2000), 58 patients were still alive.
"We were talking with the FDA in the spring of 2002, so we decided to go out and collect additional survival data on the 58 patients," he said. "Getting the follow-up data was not a trivial undertaking, considering the study was conducted at 38 centers in 14 countries around the world."
Nevertheless, the job paid off in the re-analysis.
"We were remarkably successful. In fact, we found all but one patient," he said. "With four years of follow-up instead of two, the "p" value is 0.017. In other words, the survival benefit was persistent and did not go away after two years."
Complete follow-up for as long as 48 months was obtained for 239 of the 240 patients. Of the 11 patients known to be alive on the date of the last follow-up, nine received the Gliadel Wafer and two received placebo. Survival was prolonged in the Gliadel Wafer treatment group, where the median survival increased to 13.9 months from 11.6 months (p<0.05), a statement from the company said.
Also, the company said the overall risk of dying during three to four years after treatment was reduced in the treatment group as reflected by a hazard ratio of 0.73.
Guilford's stock (NASDAQ:GLFD) closed Wednesday at $3.43, up 5 cents.