# Presentation: 412026

## GLIADEL® WAFERsNDA 20-637s

**Guilford Pharmaceuticals Inc.**
**Baltimore, Maryland**

## GLIADEL® Wafer  Indication

**GLIADEL****® ****is indicated for use as an adjunct to surgery to prolong survival in patients with recurrent glioblastoma multiforme for whom surgical resection is indicated.**

## Clinical Trials:  Recurrent Malignant Glioma

## Clinical Trials:  Newly DiagnosedMalignant Glioma

## GLIADEL® Approvals (1996-2000)

**Newly Diagnosed and Recurrent:**
**Canada**
**Recurrent:**
**France****	****	****Argentina****	****   Austria****	****Brazil**
**Chile****	****	****Columbia****	****   Germany****	****Greece**
**Hong Kong****	****Israel****	****	****   Ireland****	****Luxembourg**
**Malaysia****	****The Netherlands****	****   New Zealand****	****Peru**
**Portugal****	****Singapore****	****   South Africa****	****South Korea**
**Spain****	****	****United Kingdom****	****   Uruguay**

## Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma

**0190 Trial: Interstitial Chemotherapy for Malignant Glioma:  A Phase III Placebo-controlled Study to Examine the Safety and Efficacy of GLIADEL****®**** Placed at the Time of First Surgery**
**T-301 Trial: A Phase III, Multicenter, Randomized Double-Blind, Placebo-Controlled Trial of Polifeprosan 20 with Carmustine 3.85% Implant in Patients Undergoing Initial Surgery for Newly-Diagnosed Malignant Glioma**

## 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.**

## Agenda

**Introductions**
**Louise Peltier, Senior Director, Regulatory Affairs, Guilford Pharmaceuticals Inc.**
**Overview of Primary Malignant Glioma: Clinical Features and Treatment**
**Allan Hamilton, M.D., Professor and Chairman, Department of Neurosurgery, University of Arizona School of Medicine**
**Phase III Trials (T-301and 0190) **
**Dana Hilt, M.D., Vice President of Clinical Research, Guilford Pharmaceuticals Inc.**
**Statistical Analytic Methods**
**Steven Piantadosi, M.D., Ph.D., Professor and Director, Oncology****Biostatistics, Johns Hopkins University School of Medicine**
**Phase III Trial (T-301) Efficacy and Safety Results **
**Dana Hilt, M.D., Vice President of Clinical Research, Guilford Pharmaceuticals Inc.**

## Guilford Invited Guests

**Henry Brem, M.D.****Harvey Cushing Professor of Neurosurgery and Oncology ****Chairman, Department of Neurosurgery ****Johns Hopkins School of Medicine**
**Henry Friedman, M.D.****Professor and Director, Neuro-oncology****Duke University School of Medicine**
**Janet Wittes, Ph.D.****President****Statistics Collaborative**

## Allan Hamilton, M.D. Professor and Chairman, Department of Neurosurgery, University of Arizona School of Medicine

**Overview of Primary Malignant Glioma:  Clinical Features and Treatment**

## Primary Malignant Glioma

**Incidence**
**Approximately 16,500 new cases annually**
**Glioblastoma multiforme accounts for  approximately 75% of patients**
**More than 13,000 deaths annually**

- Central Brain Tumor Registry US Statistical Report 1992-1997

**Notes:**
Malignant gliomas are the most common primary brain tumor, accounting for slightly more than half of the estimated 35,000 primary benign and malignant brain tumors diagnosed in 2000.  More than 80% of malignant gliomas are WHO Grade III (anaplastic astrocytoma) and Grade IV (glioblastoma multiforme) tumors.  The majority of the 13,000 deaths annually attributed to primary malignant brain tumors are due to malignant gliomas.

## Primary Malignant Glioma

**Presentation:  headache, seizure or new neurological deficit.  Average age at onset 55 – 60 years.**** **
**Imaging (CT or MRI) is key in provisional diagnosis.**** **
**During surgical resection a provisional or tentative diagnosis is made based on intra-operative pathology.**
**Final pathologic diagnosis requires fixed tissue examination.**

## Primary Malignant Glioma

**Treatment**
**Maximal surgical resection followed by radiation therapy +/- chemotherapy****1**
**  ****Complete surgical resection of high grade tumor difficult**
** ****Majority of tumors recur within 2 cm of original resection site****2**
**Carmustine (BCNU) is the most widely studied chemotherapeutic agent**

- 1Nat’l Comprehensive Cancer Network Guidelines 2000 (NCCN)
- 2Hochberg FH, et.al. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907-11

**Notes:**
The National Comprehensive Cancer Network Guidelines (2000) recommend maximal surgical resection followed by radiotherapy with or without chemotherapy as the current standard of care.  The most widely studied agent is carmustine (BCNU).  

## Glioblastoma:  Treatment Outcome

- St Louis, MO: Mosby-Wolfe; 1994: chap 26.

**Glioblastoma:  Treatment Outcome**

**Notes:**
The treatment  for this disease has evolved over time.  A great advance in median survival was made with the addition of radiotherapy to surgical resection.  The addition of intravenous BCNU, unfortunately, added less than a month to the median survival.  BCNU has been shown to have activity against these tumors in vitro; several reasons exist to explain why use of systemic BCNU has not resulted in greater gains.

## Natural History of High Grade Glioma: Effects of PCV Chemotherapy

**Randomized, prospective study of surgical resection and radiotherapy (RT) vs. surgical resection, radiotherapy, and PCV chemotherapy (RT-PCV) in high grade glioma patients**
**MRC, 15 centers in the UK **
**674 patients enrolled**
**RT (n=339)   **
**RT-PCV (n=335)**
**GBM Histology – 76%**

***  MRC Brain Tumour Working Party:  J Clin Oncol 19(2): 509-518 (2001).**

## Natural History of High Grade Glioma: Effects of PCV Chemotherapy

**MRC Brain Tumour Working Party:  J Clin Oncol 19(2): 509-518 (2001).**

**p = 0.50**

**Notes:**
The treatment  for this disease has evolved over time.  A great advance in median survival was made with the addition of radiotherapy to surgical resection.  The addition of intravenous BCNU, unfortunately, added less than a month to the median survival.  BCNU has been shown to have activity against these tumors in vitro; several reasons exist to explain why use of systemic BCNU has not resulted in greater gains.

## Prognostic Factors: Primary Malignant Glioma

**Prognostic Factors shown to influence survival**
**Age (**_**>**_**60 years)**
**Karnofsky Performance Score (**_**<**_**70)**
**Tumor histology**
**Proposed Prognostic Factors**
**Size of tumor**
**Extent of resection**

**Burger PC, et al., *****Cancer***** 59:1617-1625, 1987**
**Ammirati M, et al., *****Neurosurgery***** 21:201-206, 1987**

## Limitations of Systemic BCNU

**Rapidly cleared with t****1⁄2**** ~ 15 minutes****1**
**Limits exposure of tumor cells to BCNU**** **
**High doses required for adequate CNS levels**
**Achievable dose limited by systemic toxicity**** **

- 1Wang CH, et.al. The delivery of BCNU to brain tumors. J Control Release 1999;61:21-41

**Notes:**
Although BCNU has been shown to have activity against malignant gliomas in vitro, the survival benefit seen is, at most, one month.  The reasons for this are varied but are certainly related to the limitations of providing a systemic therapy for a predominantly local disease.  BCNU is rapidly cleared, thereby limiting tumor cell exposure to a cytotoxic agent.  Additionally, the levels needed systemically to allow adequate levels in the CNS are prohibitive, resulting in more significant myelosuppression, the primary toxicity of BCNU.  

These limitations led to development of a local drug delivery system incorporating BCNU, the GLIADEL® Wafer.  

## The GLIADEL® Wafer

**Biodegradable polyanhydride copolymer containing 7.7 mg BCNU/wafer**** **
**Circumvents limitations of systemic BCNU**
**Local delivery of BCNU over 2-3 weeks at high tissue levels**
**No detectable systemic BCNU levels**
**No systemic BCNU toxicity**
**N****o additional surgical intervention required**

**Notes:**
The GLIADEL® Wafer is a copolymer comprised of carboxyphenoxypropane and sebacic acid in a 20:80 ratio.  The polyanhydride bonds break down in an aqueous environment allowing controlled release of BCNU over a 2-3 week period.  Each wafer contains 7.7 mg of BCNU; up to 8 wafers are implanted into the resection cavity for a total dose of 61.6 mg of BCNU.  

Local delivery of BCNU avoids the systemic toxicity associated with BCNU while delivering high BCNU doses to the tumor cavity.  GLIADEL ® Wafer has been shown to be safe and effective in the setting of resection for recurrent glioblastoma multiforme.

## Phase III Trial of GLIADEL® Wafer in Newly Diagnosed Malignant Glioma

## 6 Month Survival Recurrent GBM (8802)

- Brem H, Plantations S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable
- polymers of chemotherapy for recurrent gliomas. *Lancet*. 1995;345:1008-1012.

**6 Month Survival ****Recurrent GBM (8802)**

- 90

- 80

- 70

- 60

- 50

- 40

- 30

- 20

- 10

- 0

- 0

- 1

- 2

- 3

- 4

- 5

- 6

**Months From Implant Surgery**

**Survival Rate (%)**

**GLIADEL****®**

- 100

**Placebo**

**Hazard Ratio:         .57**
**95% CI:****	****    0.36 – 0.89**
**Risk Reduction:   43%**
**P = 0.02**

**Notes:**
In the same trial, the 6-month survival benefit in the GBM subgroup was significant.  The product was well-tolerated in this trial and, based upon these data, the product was approved for use in the recurrent setting in 1996.

## Overall Survival (ITT) Primary Malignant Glioma (0190)

**Hazard Ratio:       0.37**
**95% CI:****	****    0.17– 0.82**
**Risk Reduction:   63%**
**P = 0.01**

## Clinical Experience To Date

**More than 6000 patients have been treated with GLIADEL****® ****Wafer to date**** **
**Well tolerated with attention to:**
**Post-operative management of cerebral edema**
**Water tight dural closure**
**Post-operative anticonvulsant medication**

**Notes:**
Given that malignant gliomas are a relatively uncommon disease, the clinical experience with GLIADEL® Wafer to date is significant.  Unlike other chemotherapeutic agents sometimes used in this disease, the clinical benefit of GLIADEL® Wafer is supported by more than one randomized, double-blind, placebo-controlled trial..  In the more than 6000 patients who have been treated with the wafer to date, and with attention to specific issues in the peri-operative period, adverse events are uncommon.

## Rationale for Phase III Study T-301

**Confirm safety & efficacy results of 0190 Study**
**Fully define safety profile in primary surgery**
**Determine extent of clinical benefit on:**
**Survival**
**Maintenance of KPS status and neuroperformance**
**Time-to-progression**

**Notes:**
Even though the Valtonen trial was a small study, the results of this 32 patient trial strongly suggested a survival benefit in patients undergoing initial surgical resection.  In order to confirm these results, and to respond to a request by the FDA, a larger trial was initiated.  This also provided an opportunity for the following: 1) to fully define the safety profile of the GLIADEL® Wafer, particularly as it relates to the use of external beam radiotherapy following implantation of the wafer; 2) to establish whether a survival benefit was accompanied by a slower deterioration in patients’ functional status as measured by KPS and neuroperformance measures; and 3) to determine time-to-progression.  

## Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma

**Dana C. Hilt, M.D.****Vice President of Clinical Research, Guilford Pharmaceuticals Inc.**

## Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma

**0190 Trial: Interstitial Chemotherapy for Malignant Glioma:  A Phase III Placebo-controlled Study to Examine the Safety and Efficacy of GLIADEL****®**** Placed at the Time of First Surgery**
**T-301 Trial: A Phase III, Multicenter, Randomized Double-Blind, Placebo-Controlled Trial of Polifeprosan 20 with Carmustine 3.85% Implant in Patients Undergoing Initial Surgery for Newly-Diagnosed Malignant Glioma**

## Study 0190:  Trial Design

**Primary malignant glioma patients**
**Surgery**
**Placebo or Gliadel****®**** Wafers**
**Radiotherapy**** **
**Study was conducted at four centers in Finland and Norway**
**Primary efficacy endpoints**** **
**12-Month survival**** **
**24-Month survival**

## Study 0190:  BaselinePatient Characteristics

## Overall Survival (ITT) Primary Malignant Glioma (0190)

**Hazard Ratio:      0.37**
**95% CI:****	****   0.17– 0.82**
**Risk Reduction:  63%**
**P = 0.01**

## Study 0190:  Overall Survival Adjusted for Prognostic Factors - GBM Patients1

| 
 | 
Hazard Ratio | 
                            95% CI | 
               P-Value |
| --- | --- | --- | --- |
| GLIADEL® vs. Placebo | 0. 27 | 0.10 - 0.71 | 0.008 |
| KPS | 0.96 | 0.93 – 0.99 | 0.02 |
| Age | 1.08 | 1.01 - 1.14 | 0.02 |

**1**** Valtonen et al., Neurosurgery 41(1): 44-49, 1997  **

## Study 0190:  Efficacy Conclusions1

**GLIADEL****®****, in conjunction with surgery and radiotherapy, decreases the risk of death by 63% in patients with newly diagnosed malignant glioma**
**Trial was positive in overall (ITT) population **
**Trial was positive in GBM patients when accounting for all major prognostic factors**

**1**** Valtonen et al., Neurosurgery 41(1): 44-49, 1997  **

## Study T-301:  Objectives

**To determine the efficacy and safety of **
**(GLIADEL****®**** Wafer) implants plus surgery and **
**limited field radiation therapy compared to **
**placebo implants plus surgery and limited **
**field radiation in patients undergoing initial **
**surgery for newly-diagnosed malignant glioma.**

## Study T-301:  Trial Design

**Randomized, double-blind, placebo- controlled study**
**Primary Efficacy Endpoint**
**Overall Survival - All Patients Randomized (ITT) by the Kaplan-Meier method 12 months after final patient was enrolled**
**FDA fully informed prospectively of study design and analysis**

## Study T-301:  Trial Design

**   ****Secondary Efficacy Endpoints**
**Overall Survival - GBM Patients**
**Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation**

## Study T-301: Clinical Sites

**Australia:**

**3 sites**

**Italy:**

**3 sites**

**Austria:**

**1 site**

**The Netherlands:**

**2 sites**

**Belgium:**

**2 sites**

**New Zealand:**

**1 site**

** **

**France:**

**7 sites**

**Spain:**

**3 sites**

**Germany:**

**5 sites**

**Switzerland:**

**2 sites**

**Greece:**

**1 site**

**United Kingdom:**

**4 sites**

**Israel:**

**3 sites**

**United States:**

**5 sites**

**Study T-301: Clinical Sites**

## Study T-301:  Inclusion Criteria

**1.  Male or female, aged between 18 and 65 years;**
**2.  Radiographic evidence on cranial MRI of a single contrast‐enhancing unilateral supratentorial cerebral tumor;**
**3.  Surgical treatment within two weeks of the baseline MRI scan indicated;**
**4.  Karnofsky Performance Score of 60 or higher;**
**5.  No previous treatment for suspected primary malignant glioma**

## Study T-301:  Baseline Characteristics

## Study T-301:  Baseline Characteristics

## Study T-301:  Tumor Size*

*** Comparability at baseline; p-value < 0.05 **

## Statistical Methodology

**Steven Piantadosi, M.D., Ph.D.**
**Professor and Director, Oncology Biostatistics**
**Johns Hopkins University School of Medicine**

## Outline

**Key design features to reduce bias**** **
**Pre-specification of analysis**** **
**Use of stratification**** **
**Control of prognostic factors**
**All the analyses are pre-specified per protocol**

## Features to Eliminate Bias in T-301 Study

**Placebo-controlled, double-masked**** **
**Stratified blocked randomization within center**
**Study also blocked by country because center is nested within country**
**Study not blocked by histological type, age, or Karnofsky Performance Score (FDA review Page 37)**
**Pre-specified analyses**

## Key Pre-specified Features in SAP

**Overall Survival estimated by Kaplan-Meier method**
**Treatment differences assessed by logrank test and proportional hazards model**
**Pre-specified covariates:**
**Age**
**Karnofsky performance score**
**Tumor type**
**Country of treatment**

## Approach to Analysis

**All analyses were performed by Steven Piantadosi, M.D., Ph.D.**
**Review of protocol and SAP before acquiring the data from the sponsor**
**No contact with sponsor before discussion of study results**
**Initial analysis used stratified (by country) log rank test and countries with small numbers of patients were pooled together**
**No post-hoc analyses conducted**

## Stratified Analysis

**The T-301 study was conducted using stratified blocked randomization by clinical center, as is typical with such trials.  This explicitly acknowledges center as a source of variation, and requires the use of a statistical test that accounts for the stratification, i.e, the stratified logrank test.**

## Stratification of Clinical Trials

**Treating known sources of variability as unknown sources of noise is to be avoided**
**Simon R (1980), Cancer Treat Rep 64: 405-410**
**Fleiss JL (1986), Controlled Clinical Trials 7:267-275**
**Localio AR (2001), Ann Int Med 135:112-123**
**Over stratification in the extreme becomes equivalent to no stratification at all**
**Simon R (1980), Cancer Treat Rep 64: 405-410**
**Simon R (1982), Br J Clin Pharm 14:473-482**
**Limited stratification is generally desirable to increase the sensitivity of the trial, over-stratification can be detrimental to a trial**
**Simon R (1982), Br J Clin Pharm 14:473-482**

## Stratification by Center vs. Country

**Stratified randomization within center also creates stratification by country**
**Treatment practices are likely to vary more between countries than within centers within a country**
**The protocol and SAP pre-defined country as an effect that might need to be controlled (covariate or stratification factor)**
**Stratification by 38 centers is almost equivalent to not controlling for center or country, because the sizes of the strata are too small**
**Stratification by country (pooling countries with a small number of patients) appropriately controls this extraneous variation**

## Effect of Country-of-Treatment on Survival:  Placebo-Group (T-301)

## Overall Survival

## Assessing the Influence of Prognostic Factors on Survival

**A priori identification of prognostic factors**
** ****Univariate regression was first used to identify the important prognostic factors (defined as p-value ******** 0.05)**
**In order to account for the effects of these significant prognostic factors on survival, a backward elimination method (stepdown method) of multiple regression using the proportional hazard model was used**
**FDA analysis on Page 39 is misleading**

## Univariable Prognostic Factors1

**1 ****Cox Model stratified by country with single covariates**

## Multivariable Proportional Hazards Analysis (ITT)

## Summary of Statistical Methodology

**T-301 provides, by design, unbiased, precise estimates of treatment effect.  It is adequate and well controlled **
**All of the analyses presented are rigorously prespecified**
**The use of stratification by the sponsor is correct and consistent with standard statistical practice**
**The GLIADEL****® ****treatment effect (risk reduction of 30%) is clinically significant and convincingly independent of prognostic factors**

## Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma

**Dana C. Hilt, M.D.****Vice President of Clinical Research, Guilford Pharmaceuticals Inc.**

## Study T-301: Overall Survival Analysis (ITT)

**	**
**Hazard Ratio:             0.71**
**95% CI:****	****         0.52 – 0.96**
**Risk Reduction:         29%**
**P  = 0.03****1**

**1****  Stratified by country**

## Overall Survival – Adjusted for Prognostic Factors1 – (ITT)

| 
 | 
Hazard Ratio | 
                          95% CI | 
              P-Value2 |
| --- | --- | --- | --- |
| GLIADEL® vs. Placebo | 0.72 | 0.53 - 0.98 | 0.03 |
| KPS <70 vs. KPS >70 | 1.93 | 1.37 - 2.72 | 0.0002 |
| Age >60 vs. <60 | 1.73 | 1.24 - 2.42 | 0.001 |

**1****  Adjusted for age, tumor type,  and Karnofsky Score**
**2****  Stratified by country**

## Study T-301:  Conclusion

**GLIADEL****®**** Wafer administration produces a clinically **
**significant increase in survival (risk reduction = 29%)**
**in malignant glioma patients undergoing primary **
**surgery.**
**Treatment effect is maintained after accounting for **
**the effect of prognostic factors (risk reduction = 28%)**

## Study T-301:  Reoperation for Disease Progression

**A higher percentage of patients had reoperation for disease progression than originally projected.**** **
**Reoperation may have confounded the primary endpoint of survival.**** **
**A prespecified sensitivity analysis was performed to account for the results of this event by censoring patients alive at the time of reoperation.**

## Study T-301: Overall Survival Analysis -   Reoperation for Disease Progression (ITT)

**1****  Stratified by country**

## Study T-301:  Secondary Efficacy Endpoints

**   ****Secondary Efficacy Endpoints**
**Overall Survival - GBM patients**
**Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation**

## Study T-301:  Overall Survival (GBM Patients)

**1****  Stratified by country**

## Study T-301:  Overall Survival Adjusted for Prognostic Factors1 (GBM Patients)

**1**** Adjusted for age and Karnofsky Score **
**2 ****Cox Proportional Hazard model stratified by country and **
**  ****number of wafers (<8,8) implanted**

| 
 | 
Hazard Ratio |  
95% CI |  | 
P-Value2 |
| --- | --- | --- | --- | --- |
| GLIADEL® vs. Placebo | 0.69 | 0.49 - 0.97 |  | 0.04 |
| KPS <70 vs. KPS >70 | 2.04 | 1.38 - 3.01 |  | <0.001 |
|  |  |  |  |  |

## Study T-301:  Karnofsky Performance Decline (ITT)

- 1.0

**1****  Stratified by country**

## Study T-301:  Neuroperformance  Decline (ITT)

**1**** Stratified by Country**

## Study T-301:  Neuroperformance Decline in Speech (ITT)

**1****  Stratified by country**

## Study T-301:  Neuroperformance Decline in Cranial Nerves III, IV, VI (ITT)

- 1.0

- 0.9

- 0.8

- 0.7

- 0.6

- 0.5

- 0.4

- 0.3

- 0.2

- 0.1

- 0.0

**Time to Deterioration (weeks)**

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 80

- 90

- 100

- 110

- 120

**GLIADEL****®**

**Placebo**

_**Median Deterioration (weeks)**_
**Gliadel****®****	****54.9**
**Placebo****	****49.1**

**Hazard Ratio:        0.68**
**95% CI:****	****    0.50 – 0.93**
**Risk Reduction:    32%**
**P = 0.02****1**

**Proportion Without Decline**

**1****  Stratified by country**

## Study T-301:  Neuroperformance Decline in Motor Status (ITT)

**1****  Stratified by country**

## Study T-301:  Neuroperformance Decline in Cerebellar Status (ITT)

**1****  Stratified by country**

## GLIADEL® Wafer Safety

**Review of safety in newly diagnosed malignant glioma**

## Safety Summary GLIADEL® Wafer in Primary Surgery

**Intracranial hypertension 9.2% vs. 1.7%. However, no difference in brain edema.**
**Intracranial hypertension was typically observed late, at the time of tumor recurrence, and was not likely associated with GLIADEL****®**** use.**
**CSF leak (5% vs. 0.8%) was more common in GLIADEL****®**** - treated patients. However, intracranial infections and other healing abnormalities were not increased.**
**Convulsions are not more common in GLIADEL****®**** -treated vs. placebo-treated patients.**

## Safety Summary GLIADEL® Wafer in Primary Surgery

**Careful monitoring of GLIADEL****®**** -treated patients for cerebral edema/intracranial hypertension with consequent steroid use is warranted.**** **
**CSF leak, though uncommon, may be more frequent in GLIADEL****®**** -treated patients.  Attention to a water tight dural closure and local wound care is indicated.**** **
**The safety profile of GLIADEL****®**** appears more benign in the primary surgery setting vs. recurrent disease.**

## Study T-301:  Neurologic Adverse Events Occurring in >5% of Patients

**Abnormal gait**

**Amnesia**

**Anxiety**

**Aphasia**

**Ataxia **

**Brain edema**

**Coma**

**Confusion**

**Convulsion**

**Depression**

**Dizziness **

**Facial paralysis **

**Grand mal convulsion**

**Hallucinations**

**Adverse Event**

## Study T-301:  Neurologic Adverse Events Occurring in >5% of Patients

## Convulsions  (T-301)

**Convulsions  (T-301)**

## Healing Abnormality:Fluid, CSF or Subdural Collections (T-301)

**Healing Abnormality:****Fluid, CSF or Subdural Collections (T-301)**

## Healing Abnormality:CSF Leak (T-301)

**Healing Abnormality:****CSF Leak (T-301)**

## Healing Abnormality: Wound Dehiscence, Breakdown or Poor Healing (T-301)

**Healing Abnormality: Wound Dehiscence, ****Breakdown or Poor Healing (T-301)**

## Healing Abnormality: Subgaleal or Wound Effusion (T-301)

**Healing Abnormality: Subgaleal or ****Wound Effusion (T-301)**

## Study T-301: Intracranial Infections

|  | 
GLIADEL®
n (%) | 
Placebo
n (%) |
| --- | --- | --- |
| Abscess | 4 (3) | 5 (4) |
| Meningitis | 2 (2) | 2 (2) |
| Total  | 6 (5) | 7 (6) |

## Post-operative Surgical Complications:Comparison of T-301 to Published Series

**The frequency of post-operative seizures, infections and hemorrhage/stroke are similar in the GLIADEL****® ****and placebo groups in the   T-301 study.**
**Is the placebo wafer group a benign control as it involves the implantation of a placebo wafer?**

## Comparison of Post-operative Surgical Infections

|            Author/Study | # of Patients |            Disease |        Infection |
| --- | --- | --- | --- |
| Brell et al1 | 200 | Glioma/
Metastasis | 5.5% |
| Sawaya et al2 | 327 | Glioma | 1.75% |
| Kourinek et al3 | 2944 | Craniotomy | 4% |
| Tenney et al4 | 251 | Tumor | 6% |
| T-301- GLIADEL | 120 | Glioma | 5% |
| T-301- Placebo | 120 | Glioma | 6% |

**1**** Brell et al., (2000) Acta Neurochir (Wien) 142:739-50**
**2 ****Sawaya et al., (1998) Neurosurgery 42:1044-56**
**3**** Kourinek et al., (1997) Neurosurgery 41:1073-81**
**4**** Tenney et al, (1985) J Neurosurg 62:243-7**

## Comparison of Post-operative Surgical Seizures

|            Author/Study | # of Patients |         Disease |    Seizures |
| --- | --- | --- | --- |
| Cabantog et al1 | 207 | GBM/AA | 1% |
| Brell et al2 | 200 | Glioma/
Metastasis | 4% |
| Sawaya et al3 | 327 | Glioma | 2.5% |
| Pace et al4 | 119 | Glioma | 36-83% |
| Tandon et al5 | 200 | Glioma | 51% |
| Moots et al6 | 65 | Glioma | 32% |
| T-301- GLIADEL | 120 | Glioma | 33% |
| T-301- Placebo | 120 | Glioma | 37% |
|  |  |  |  |

**1**** Cabantog et al., (1994) Can J Neurol Sci 32:213-18**
**2 ****Brell et al., (2000) Arta Neurochir 142:739-50**
**3**** Sawaya et al., (1998) Neurosurgery 42:1044-56**

**4**** Pace et al., (1998) J Exp Clin Canc Rsh 17:479-82**
**5 ****Tandon et al., (2001) Neurology India 49:55-9 **
**6**** Moots et al., (1995) Arch Neurol 52:717-24**

## Comparison of Post-operative Surgical Hemorrhage/Stroke

|       Author/Study | # of Patients |            Disease | Hemorrhage/Stroke |
| --- | --- | --- | --- |
| Cabantog et al1 | 207 | GBM/AA | 1% |
| Brell et al2 | 200 | Glioma/
Metastasis | 4.5% |
| Sawaya et al3 | 327 | Glioma | 2.0%
 |
| T-301- GLIADEL4 | 120 | Glioma | 7.5% |
| T-301- Placebo4 | 120 | Glioma | 4.8% |
|  |  |  |  |

**1**** Cabantog et al., (1994) Can J Neurol Sci 32:213-18**
**2 ****Brell et al., (2000) Acta Neurochir (Wien) 142:739-50**
**3 ****Sawaya et al., (1998) Neurosurgery 42:1044-56**
**4 ****Events reported within 30 days of surgery**

## Post-Operative Surgical Complications:  Conclusion

**The frequency of seizures, infections, and hemorrhage/**
**stroke after GLIADEL****® ****Wafer implantation is similar **
**to that observed after craniotomy for glioma**

## GLIADEL® Wafer in Primary Malignant Glioma:  Summary of Benefits and Risks

**No evidence of earlier onset of seizures or increased frequency of seizures in primary malignant glioma patients**
**CSF Leak was more common with GLIADEL****®**** treatment**
**No evidence for increase in intracranial infections or other healing abnormalities**

## GLIADEL® Wafer in Primary Malignant Glioma:  Summary of Benefits and Risks

**Gliadel****®**** Wafer studies expanded to newly diagnosed malignant glioma**** **
**Statistically significant and clinically meaningful increase in survival compared to placebo wafers**** **
**Delayed time to overall function (KPS) and neurological decline (10/11 measures)****S**

## Consistency of GLIADEL® Wafer Phase III Trial Results

**Consistent efficacy and safety profile between **
**two prospective randomized, placebo-controlled, **
**double-blind Phase III clinical studies in the **
**primary surgery for malignant glioma**

## Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (ITT)

## Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (GBM)

**1**** Hazard ratio adjusted for prognostic factors.**
**2**** Stratified by country**

## Summary of Benefits and Risks

**The benefit to risk ratio for **
**GLIADEL****®**** in patients with **
**primary malignant glioma **
**is favorable**

## 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.**