ODAC Sends Mixed Message on New Gliadel Wafer Indication

SILVER SPRING, Maryland—The Oncologic Drugs Advisory Committee (ODAC) sent the Food and Drug Administration a mixed message in its votes regarding a new indication for Gliadel Wafer (polifeprosan 20 with carmustine implant, Guilford Pharmaceuticals).

By a narrow vote, the panel found Gliadel to be safe and effective for patients with primary malignant glioma, but voted, again by a slim margin, that the pivotal study for the new indication was "not adequate."

The Gliadel Wafer is a dime-size disc made of a biodegradable polymer that contains and slowly releases carmustine (BCNU). Up to eight of the wafers are implanted in a tumor cavity after surgery for brain cancer. It is currently FDA approved as an adjunct to surgery to prolong survival in patients with recurrent glioblastoma multiforme for whom surgical resection is indicated.

The company is now seeking approval of Gliadel Wafer "as a treatment to significantly prolong survival and maintain overall function (as measured by preservation of Karnofsky performance status) and neurological function in patients with malignant glioma undergoing primary and/or recurrent surgical resection."

Federal law requires that studies used by the FDA in approving a medication must be adequate and well controlled. Guilford presented data from two phase III studies of Gliadel in support of the new indication.

After listening to and discussing presentations by the company and an FDA medical review team, committee members agreed unanimously that the pivotal study presented was well controlled, but voted 7 to 6 that the study was not adequate. Several members gave varying reasons for their nay votes.

Howard Fine, MD, of the National Cancer Institute and a voting consultant to ODAC, said that he felt the company presented insufficient histologic data. The absence of these data made it difficult to assess whether the study showed a benefit for Gliadel in the patients treated.

Panel member Stephen L. George, professor of biostatistics, Duke University, said that the issue of adequacy rests squarely on the question of whether the data analysis was reasonable. He also expressed the view that the study population was too small to provide sufficient statistical power.

Several other ODAC members expressed concern because a large majority of the research centers involved restricted enrollment to patients age 65 or younger, and they questioned whether the data would extrapolate to the United States, where patients over age 65 are commonly treated with Gliadel Wafers.

Then, in a series of split votes, the panel decided:

• 8 to 5 that the pivotal study provided "substantial evidence of a survival benefit of Gliadel in patients with newly diagnosed malignant glioma."

• 11 to 1, with one abstention, that the toxicity profile of Gliadel is "acceptable for patients with newly diagnosed malignant glioma."

• 8 to 5 "that Gliadel provides clinical benefit with an acceptable safety profile in patients with newly diagnosed malignant glioma."

"We have a thoroughly divided committee, so we are going to have to go back and look at what they said," said Robert Temple, MD, the senior FDA official at the meeting, after the votes.

The Pivotal Study

Guilford presented data from two trials—a 32-patient study conducted in Scandinavia and its pivotal phase III trial of 240 patients at 42 sites in 14 countries that included 12 patients accrued at five US sites.

The FDA medical review team focused its analysis on the pivotal study, designated T-301, which randomized 240 patients treated with surgery plus radiotherapy to receive either Gliadel Wafers or placebo wafers. The primary endpoint was the overall survival of all patients.

The Gliadel treated patients in T-301 survived a median of 13.9 months vs 11.6 months for those in the placebo group. "Gliadel Wafer administration produces a clinically significant increase in survival—a risk reduction equal to 29%—in malignant glioma patients undergoing primary surgery," said Dana C. Hilt, MD, Guilford’s vice president for clinical research.

Moreover, Gliadel patients had a statistically significant advantage in 10 of 11 neurological performance measurements, compared with the placebo group, Dr. Hilt told the panel. The one exception was visual status, where the trend favored Gliadel patients.

The FDA analysis of the primary endpoint agreed with the company’s figure of 13.9 months vs 11.6 months, but put the P value for the finding at .08. "There is no statistical difference between the two arms," Ning Li, MD, PhD, the FDA statistical reviewer said. "The evidence is insufficient to say there is a benefit."

Dr. Li also said that the FDA analysis found a statistically significant difference between the groups for only 1 of the 11 neurological performance measurements—speech.

The committee’s series of votes left senior FDA officials to ponder the ODAC hearing record and the data amassed by the company and its own medical reviewers.