sNDA # GLIADEL® WAFER (Polifeprosan 20 with Carmustine Implant) APPLICANT: GUILFORD PHARMACEUTICALS ODAC: December 6, 2001 Medical Reviewer: Alla Shapiro, M.D., Ph.D. Statistical Reviewer: Ning Li, M.D., Ph.D.

FDA Presentation Regulatory history Dr. Alison Martin Study T-301Dr. Alla Shapiro Dr. Ning Li Review IssuesDr. Alison Martin

Regulatory History Approved June 14, 1996 Indication: Adjunct to surgery to prolong survival in patients with recurrent GBM for whom surgical resection is indicated

Regulatory History Primary Basis of Approval –North American trial, #8802 –multicenter, randomized, placebo-controlled –22 pts with recurrent malignant glioma –subgroup analysis in GBM:  OS and 6 mo. survival Supportive: –Scandinavian trial, #CL-0190 –early closure (32/100); randomization imbalance –not sufficient to support a new indication

New Indication Meeting with FDA 1/30/97 Single trial can support a new indication if... –multicenter –results are robust Population of interest: GBM Placebo wafer accepted Standardization of subsequent treatments Prospective definition and collection of AEs

New Indication Sample size (90% power): based on 12 month survival rate for Gliadel of 70% vs. 50% FDA 8/22/97: –overly optimistic –if 62.5% vs. 50%, 53% power Amendment 3/18/99: –IDMC review of blinded data: overly optimistic –accrual  from 200 to 240 –preserve ability to distinguish 68% vs. 50%

Clinical Review Study T-301

GLIADEL Wafer Proposed Indication “GLIADEL Wafer is indicated for use 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”.

Study Objectives Primary - survival (ITT) Secondary - survival in the GBM subgroup -adjusted analyses for KPS, age and tumor type -1-year survival (ITT and GBM) - progression-free survival (ITT) - survival censoring patients with reoperation for disease progression (ITT) - KPS scores (ITT) - QoL (ITT) - neuroperformance measures (ITT)

Phase 3 Trial Study T-301 All patients randomized GliadelPlacebo Radiation therapy Histology ChemotherapyNo Chemotherapy AOD All others

Study Enrollment Patients – countries –48 patients in France –44 patients in Germany 38 centers –7 centers in France and 5 in Germany 5 centers in the US accrued 12 patients

Baseline Characteristics

Tumor Histology

Protocol-Specified Treatments Radiation Therapy Chemotherapy Other Treatment for Disease Progression

Chemotherapy GLIADEL Placebo N =120 (%) N=120 (%) Chemotherapy for PD 14 (11.7) 14 (11.7) Within 30 days AOD (0.8) 1 (0.8) AOA (1.7) 2 (1.7) TOTAL 17 (14.2) 17 (14.2)

Other Treatment for PD

Efficacy Results

Primary Efficacy Endpoint Overall Survival GLIADEL Placebo 88 (73.3%) 93 (77.5%) months % CI ( ) ( ) p = 0.08 log-rank (protocol-specified) p = 0.07 log-rank (stratified by center) p = 0.03 log-rank (stratified by country)

P rimary Efficacy Analysis: Statistical Issues

P rimary Efficacy Analysis Sponsor’s Protocol/SAP:  “Two groups will be compared with a log-rank test for the primary comparison” for overall survival(OS).  “A log-rank stratified on each prognostic covariate (KPS, AGE, GBM/non-GBM, and COUNTRY), will be performed” as “secondary efficacy analysis” and “is considered as supportive”.”.

Overall Survival Curves for Study T-301

Primary Efficacy Analysis (Protocol Specified OS ITT Analysis)

Secondary Analysis: Stratified Log-rank Tests (Protocol Specified OS ITT Analysis)

Survival Analysis: Cox Model Adjusting for Covariates

Survival Analysis Summary Results of the survival comparison between the two arms are not significant except the analysis stratified by COUNTRY Sponsor presented the log-rank test stratified by COUNTRY as the primary analysis and concluded a significant survival benefit Sponsor’s argument: stratified analysis is appropriate because “randomization list was stratified by country”, “over-stratification by Center”

Issues Stratified vs. non-stratified analysis: which one is more appropriate? FDA: Either one is acceptable; but need to pre-specify one in the protocol as the primary analysis. Retrospective selection will inflate the Type I error. The randomization was stratified by CENTER.

Randomization List for All U.S. Sites

Exploratory Analysis: Log-rank Stratified by CENTER

Primary Efficacy Analysis: Summary of Statistical Issues Protocol specified analysis for overall survival was not statistically significant (p=0.08). The log-rank test stratified by CENTER and all other stratified analyses demonstrated N.S. results. Log-rank test stratified by COUNTRY (p=0.03) is questionable as the primary analysis.

Secondary Endpoints

Secondary Endpoint: Survival in GBM GLIADEL Placebo 79 (78.2%) 85 (80.2%) months % CI ( ) ( ) p = 0.20 log-rank (protocol-specified) p = 0.16 log-rank stratified by center p = 0.09 log-rank stratified by country

Secondary Endpoint: 1-Yr Survival ITT population GLIADEL Placebo (%) % CI ( ) ( ) Not significant by log-rank, unstratified/stratified GBM subgroup GLIADEL Placebo (%) % CI ( ) ( ) Not significant by log-rank, unstratified/stratified

Secondary Endpoint: Progression-Free Survival Sponsor’s conclusion: median 5.9 months in both treatment groups p = 0.90 Log-rank, stratified by country FDA: Limitations of the endpoint

Secondary Endpoint: Time to KPS Deterioration GLIADEL Placebo months % CI ( ) ( ) p = 0.11 log-rank (protocol-specified) p = 0.27 log-rank (stratified by center) p = 0.05 log-rank (stratified by country)

Secondary Endpoint: Time to KPS Deterioration (Death not account as an event) GLIADEL Placebo Months % CI ( ) ( ) p = 0.61 log-rank p = 0.47 log-rank (stratified by center) p = 0.41 log-rank (stratified by country)

Secondary Endpoint: QoL QoL: EORTC and Brain Cancer Module –Global health questions #29 & 30 –Not powered to show significant differences

Time to Neuroperformance Deterioration (ITT Population)

Deaths within 30 days Local Complications Safety Results

Cause of Deaths in the First 30 Days of Randomization

Local Complications

Review Issues

Single Trials: Evidence of Effectiveness* Adequate and well-controlled –large, multicenter trial –consistent results across subsets –multiple endpoints involving different events –statistically persuasive Independent substantiation from related study data: –other phases of disease, populations –“strong prior” * FDA Guidance 1998

T-301: Single Trial Strengths multicenter placebo wafer (efficacy) blinded pathology review survival = 1 o endpoint point estimates of median survival prior approval Weaknesses placebo wafer (toxicity) 1 o endpoint: stat persuasive? –stratified logrank, multiple analyses, interim look? GBM - bridging population – not statistically persuasive prior approval: –malignant glioma NS

Can the trials presented in 1996 be considered confirmatory?

Primary Basis of Approval: North American Trial Recurrent malignant glioma 222 patients entered –145 (65%) with GBM –77 (35%) with other histologies - balanced

North American Trial

Overview of Median Survival in ITT Population

Supportive: Scandinavian Trial Newly diagnosed malignant glioma 32 patients of an intended 100 Overall survival (log-rank) Early closure due to lack of drug supply ODAC: Insufficient to support an indication

Scandinavian Trial

Summary of Review Issues T-301: Adequacy of single trial? –robustness of survival data –support from secondary endpoints –clinical meaning of an analyses significant only when stratified by country Are other trials confirmatory? –#CL-0190 –#8802 Favorable risk:benefit ratio?

Questions for the Committee 1. Is Study #T-301 an adequate and well-controlled trial? 2. Gliadel was considered to have a treatment effect only in patients with recurrent GBM and not in the overall population with recurrent malignant gliomas. If this was a true treatment effect, would this pattern be expected to be present in newly diagnosed patients? 3. Do the data from #T-301 provide substantial evidence of a survival benefit of Gliadel in patients with newly diagnosed malignant glioma?

Questions…. 4. If the answer to #3 is YES, do the North American and/or Scandinavian Trials together with T-301 provide convincing evidence of a survival benefit in patients with newly diagnosed malignant glioma? 5. Is the toxicity profile of Gliadel acceptable for patients with newly diagnosed malignant glioma? 6. Does the committee believe that Gliadel provides clinical benefit with an acceptable safety profile in patients with newly diagnosed malignant glioma?