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1
GLIADEL® WAFERsNDA 20-637s
Guilford Pharmaceuticals Inc.
Baltimore, Maryland
2
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.
3
Clinical Trials: Recurrent Malignant Glioma
632TOTAL
Treatment Protocol349Study 9501
Multicenter, randomized, double-blind, placebo-controlled Phase III
222Study 8802
Multicenter, open-label Phase III40Study 9115
Multicenter, open-label, dose escalation Phase I/II
21Study 8701
Type of StudyPatients Enrolled
4
Clinical Trials: Newly DiagnosedMalignant Glioma
294TOTAL
Multicenter, randomized, double-blind, placebo-controlled Phase III
240Study T-301
Multicenter, randomized, double-blind, placebo-controlled Phase III
32Study 0190
Multicenter, open-label Phase I/II22Study 9003
Type of StudyPatients Enrolled
5
GLIADEL® Approvals (1996-2000)
Newly Diagnosed and Recurrent:
Canada
Recurrent:
France Argentina Austria BrazilChile Columbia Germany GreeceHong Kong Israel Ireland LuxembourgMalaysia The Netherlands New Zealand PeruPortugal Singapore South Africa South KoreaSpain United Kingdom Uruguay
6
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
7
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.
8
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.
9
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-oncologyDuke University School of Medicine
Janet Wittes, Ph.D.PresidentStatistics Collaborative
10
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
11
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
12
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.
13
Primary Malignant Glioma
Treatment
Maximal surgical resection followed by radiation therapy +/- chemotherapy1
Complete surgical resection of high grade tumor difficult
Majority of tumors recur within 2 cm of original resection site2
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
14
McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery. St Louis, MO: Mosby-Wolfe; 1994: chap 26.
0
2
4
6
8
10
12
Surgery Only Surgery + Radiotherapy
Surgery + Radiotherapy +Chemotherapy
9.25
4
10
Med
ian
Su
rviv
al (
Mo
nth
s)Glioblastoma: Treatment Outcome
15
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).
16
Natural History of High Grade Glioma: Effects of PCV Chemotherapy
0
2
4
6
8
10
12M
edia
n S
urv
ival
(M
on
ths)
Surgery +
Radiotherapy
9.5
Surgery +
Radiotherapy +
PCV Chemotherapy
10
MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509-518 (2001).
p = 0.50
17
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, 1987Ammirati M, et al., Neurosurgery 21:201-206, 1987
18
Limitations of Systemic BCNU
Rapidly cleared with t½ ~ 15 minutes1
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
19
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
No additional surgical intervention required
20
Phase III Trial of GLIADEL® Wafer in Newly Diagnosed Malignant Glioma
21Brem 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
00 1 2 3 4 5 6
Months From Implant Surgery
Su
rviv
al R
ate
(%)
GLIADEL®
100
PlaceboHazard Ratio: .57
95% CI: 0.36 – 0.89
Risk Reduction: 43%
P = 0.02
22
Overall Survival (ITT) Primary Malignant Glioma (0190)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24
Months from Implant Surgery
Su
rviv
al R
ate
(%)
GLIADEL®
Placebo
Median Survival (months)
Gliadel® 13.4Placebo 9.2
Hazard Ratio: 0.37
95% CI: 0.17– 0.82
Risk Reduction: 63%
P = 0.01
23
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
24
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
25
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.
26
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
27
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
28
Study 0190: BaselinePatient Characteristics
Characteristic
Median age (years)
Median Mini Mental score
Median Karnofsky Performance score
Median No. of wafers
GBM tumor histology
GLIADEL® Wafers(n=16)
56
24.5
75
8
11
PlaceboWafers(n=16)
54
24.5
90
8
16
29
Overall Survival (ITT) Primary Malignant Glioma (0190)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24
Months from Implant Surgery
Su
rviv
al R
ate
(%)
GLIADEL®
Placebo
Median Survival (months)
Gliadel® 13.4Placebo 9.2
Hazard Ratio: 0.37
95% CI: 0.17– 0.82
Risk Reduction: 63%
P = 0.01
30
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
31
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
32
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.
33
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
34
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
35
A total of 42 sites in 14 countries participated in the study
Australia: 3 sites Italy: 3 sitesAustria: 1 site The Netherlands: 2 sitesBelgium: 2 sites New Zealand: 1 site
France: 7 sites Spain: 3 sites
Germany: 5 sites Switzerland: 2 sitesGreece: 1 site United Kingdom: 4 sitesIsrael: 3 sites United States: 5 sites
Study T-301: Clinical Sites
36
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
37
Study T-301: Baseline Characteristics
CHARACTERISTIC
Age (years) MeanRange
Sex Male
Female
Tumor Type Anaplastic astrocytomaAnaplastic oligodendrogliomaAnaplastic oligoastrocytomaGlioblastoma multiformeMetastasis/Brain MetastasisOther
53.630-67
84
36
143
10615
52.621-72
76
44
157
10124
GLIADEL®
WAFER ( n = 120) (n = 120)
PLACEBO WAFER
38
Study T-301: Baseline Characteristics
PLACEBOWAFER (n=120)
GLIADEL®
WAFER
(n=120)
KARNOFSKYPerformance
Status
60
70
80
85
90
95
100
16
21
25
2
31
0
25
16
17
24
0
40
1
22
Karnofsky Score
39
Study T-301: Tumor Size*
34.060.0Median (cm3)
50.866.8Mean (cm3)
7683Number reported
Placebo Wafer (n=120)
GLIADEL® Wafer (n=120)
* Comparability at baseline; p-value < 0.05
40
Statistical Methodology
Steven Piantadosi, M.D., Ph.D.
Professor and Director, Oncology Biostatistics
Johns Hopkins University School of Medicine
41
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
42
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
43
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
44
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
45
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.
46
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
47
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
48
Effect of Country-of-Treatment on Survival: Placebo-Group (T-301)
Overall Survival
T-301
8802
0190
50
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
51
Univariable Prognostic Factors1
Prognostic Factor
Karnofsky Score<70 vs. KPS >70
Age >60 vs. <60
Number of Wafers implanted8 vs. <8
GBM Patients vs.Non-GBM Patients
Hazard Ratio
1.9
1.6
1.4
1.8
95% CI
1.4 – 2.6
1.2 – 2.2
1.0 – 1.9
1.1 – 2.9
P-value
<0.0001
0.03
0.02
0.02
1 Cox Model stratified by country with single covariates
52
Multivariable Proportional Hazards Analysis (ITT)
95% CIPrognostic Factor
Hazard Ratio1 Lower Upper P-Value
GLIADEL® vs. Placebo 0.72 0.53 0.98 0.03
1.93
1.37
2.72
0.0002
1.73 1.24 2.42 0.001
1.44
0.84
2.47
0.18
1 Proportional Hazard Model stratified by country
Karnofsky Score <70 vs. KPS >70
Age >60 vs. <60
GBM Patients vs Non-GBM Patients
53
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
54
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.
55
Study T-301: Overall Survival Analysis (ITT)
Hazard Ratio: 0.7195% CI: 0.52 – 0.96Risk Reduction: 29%P = 0.031
Months from Implant Surgery
Placebo
GLIADEL®
Su
rviv
al R
ate
(%)
100
90
80
70
60
50
40
30
20
0
0
2 4 6 8 10 12 14 16 18 20 22 24 26
10
Median Survival (months)
Gliadel® 13.9Placebo 11.6
1 Stratified by country
56
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
57
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%)
58
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.
59
Study T-301: Overall Survival Analysis - Reoperation for Disease Progression (ITT)
Months from Implant Surgery
Su
rviv
al R
ate
(%)
GLIADEL®
Placebo
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
10
20
30
40
50
60
70
80
100
90
Median Survival (months)
Gliadel® 14.8Placebo 11.4
Hazard Ratio: 0.6495% CI: 0.45 – 0.92Risk Reduction: 36%P = 0.011
1 Stratified by country
60
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
61
Study T-301: Overall Survival (GBM Patients)
GLIADEL®
Placebo
100
90
80
70
60
50
40
30
20
10
0
0 642 8 141210 16 222018 24
Su
rviv
al R
ate
(%)
Months from Implant Surgery
Median Survival (months)
Gliadel® 13.5Placebo 11.4
Hazard Ratio: 0.7695% CI: 0.55 – 1.05Risk Reduction: 24%P = 0.101
1 Stratified by country
62
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
63
Study T-301: Karnofsky Performance Decline (ITT)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 642 8 141210 16 222018 24 26
Months from Implant Surgery
Pro
po
rtio
n w
ith
ou
t D
ecli
ne
GLIADEL®
Placebo
Median Deterioration (months)
Gliadel® 11.9Placebo 10.4
Hazard Ratio: 0.7495% CI: 0.55 – 1.0Risk Reduction: 26%P = 0.051
1 Stratified by country
64
Study T-301: Neuroperformance Decline (ITT)
Neuroperformance Measure
Median Time without Deterioration (weeks) P Value1
Vital SignsLevel of ConsciousnessPersonalitySpeechVisual StatusFundusCranial Nerves III, IV, VICranial Nerves, OtherMotor StatusSensory StatusCerebellar Status
54.952.151.749.644.055.154.954.345.451.654.1
49.145.440.036.742.446.349.146.331.444.146.7
0.010.020.0080.0030.090.0070.020.0030.010.020.01
GLIADEL®
Wafer(n=120)Placebo
Wafer(n=120)
1 Stratified by Country
65
Study T-301: Neuroperformance Decline in Speech (ITT)
Pro
po
rtio
n W
ith
ou
t D
ecli
ne 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® 49.6Placebo 36.7
Hazard Ratio: 0.6495% CI: 0.48 – 0.86Risk Reduction: 36%P = 0.0031
1 Stratified by country
66
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® 54.9Placebo 49.1
Hazard Ratio: 0.6895% CI: 0.50 – 0.93Risk Reduction: 32%P = 0.021
Pro
po
rtio
n W
ith
ou
t D
ecli
ne
1 Stratified by country
67
Study T-301: Neuroperformance Decline in Motor Status (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® 45.4Placebo 31.4
Hazard Ratio: 0.6995% CI: 0.51 – 0.92Risk Reduction: 31%P = 0.011
Pro
po
rtio
n W
ith
ou
t D
ecli
ne
1 Stratified by country
68
Study T-301: Neuroperformance Decline in Cerebellar Status (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® 54.1Placebo 46.7
Hazard Ratio: 0.6795% CI: 0.49 – 0.91Risk Reduction: 33%P = 0.011
Pro
po
rtio
n W
ith
ou
t D
ecli
ne
1 Stratified by country
69
GLIADEL® Wafer Safety
Review of safety in newly diagnosed malignant glioma
70
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.
71
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.
72
Study T-301: Neurologic Adverse Events Occurring in >5% of Patients
Abnormal gaitAmnesiaAnxietyAphasiaAtaxia Brain edemaComaConfusionConvulsionDepressionDizziness Facial paralysis Grand mal convulsionHallucinations
6 (5.0)11 (9.2)8 (6.7)
21 (17.5)7 (5.8)
27 (22.5)5 (4.2)
28 (23.3)40 (33.3)19 (15.8)6 (5.0)8 (6.7)6 (5.0)6 (5.0)
6 (5.0)12 (10.0)5 (4.2)
22 (18.3)5 (4.2)
23 (19.2)6 (5.0)
25 (20.8)45 (37.5)12 (10.0)11 (9.2)5 (4.2)5 (4.2)4 (3.3)
Adverse Event
PLACEBO Wafer (n=120)n (%)
GLIADEL® Wafer (n=120)n (%)
73
Study T-301: Neurologic Adverse Events Occurring in >5% of Patients
Hemiplegia
Hypesthesia
Hypokinesia
Incoordination
Insomnia
Intracranial hypertension
Neuropathy
Paresthesia
Personality disorder
Somnolence
Speech disorder
Thinking abnormal
Tremor
49 (40.8)
7 (5.8)
2 (1.7)
3 (2.5)
6 (5.0)
11 (9.2)
8 (6.7)
7 (5.8)
10 (8.3)
13 (10.8)
13 (10.8)
7 (5.8)
6 (5.0)
53 (44.2)
6 (5.0)
8 (6.7)
8 (6.7)
7 (5.8)
2 (1.7)
12 (10.0)
10 (8.3)
9 (7.5)
18 (15.0)
10 (8.3)
10 (8.3)
8 (6.7)
Adverse Event
PLACEBO Wafer (n=120)n (%)
GLIADEL® Wafer (n=120)n (%)
74
Convulsions (T-301)
5 (4.2)6 (5.0)Grand Mal convulsions
24 (20)14 (11.7)Convulsions – severe
45 (37.5)40 (33.3)Number of patients (%)
Placebo Wafer (n=120)
GLIADEL® Wafer (n=120)
Time-to-First Seizure did not differ in the two treatment groups.
5 (4.2)3 (2.5)Convulsions (< 5 days)
75
1-6812-60Range for duration (days)
1015Median duration (days)
6 (5.0)5 (4.2)Number of patients (%)
Placebo Wafer (n=120)
GLIADEL® Wafer (n=120)
Healing Abnormality:Fluid, CSF or Subdural Collections (T-301)
76
32-211Range for duration (days)
39Median duration (days)
1 (0.8)6 (5.0)Number of patients (%)
Placebo Wafer (n=120)
GLIADEL® Wafer (n=120)
Healing Abnormality:CSF Leak (T-301)
77
2-1722-281Range for duration (days)
610Median duration (days)
6 (5.0)6 (5.0)Number of patients (%)
Placebo Wafer
(n=120)
GLIADEL® Wafer
(n=120)
Healing Abnormality: Wound Dehiscence, Breakdown or Poor Healing (T-301)
78
2-263-30Range for duration (days)
103Median duration (days)
5 (4.2)4 (3.3)Number of patients (%)
Placebo Wafer (n=120)
GLIADEL® Wafer (n=120)
Healing Abnormality: Subgaleal or Wound Effusion (T-301)
79
Study T-301: Intracranial Infections
GLIADEL®
n (%)
Placebo
n (%)
Abscess 4 (3) 5 (4)
Meningitis 2 (2) 2 (2)
Total 6 (5) 7 (6)
80
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?
81
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) 142:739-502 Sawaya et al., (1998) Neurosurgery 42:1044-563 Kourinek et al., (1997) Neurosurgery 41:1073-814 Tenney et al, (1985) J Neurosurg 62:243-7
82
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 32:213-182 Brell et al., (2000) Arta Neurochir 142:739-503 Sawaya et al., (1998) Neurosurgery 42:1044-56
4 Pace et al., (1998) J Exp Clin Canc Rsh 17:479-825 Tandon et al., (2001) Neurology India 49:55-9 6 Moots et al., (1995) Arch Neurol 52:717-24
83
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 32:213-182 Brell et al., (2000) Acta Neurochir (Wien) 142:739-503 Sawaya et al., (1998) Neurosurgery 42:1044-564 Events reported within 30 days of surgery
84
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
85
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
86
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
87
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
88
Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (ITT)
Study
8802
T-301
0190
Hazard Ratio
0.69
0.71
0.37
95% CI
0.47-1.02
0.52-0.96
0.17-0.82
P-value
0.06
0.031
0.01
1 Stratified by country
89
Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (GBM)
1 Hazard ratio adjusted for prognostic factors.2 Stratified by country
Study
8802
T-301
0190
Hazard Ratio1
0.57
0.72
0.21
95% CI
0.36-0.89
0.53-0.98
0.08-0.60
P-value
0.02
0.032
<0.01
90
Summary of Benefits and Risks
The benefit to risk ratio for
GLIADEL® in patients with
primary malignant glioma
is favorable
91
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.