RAFDR

> **NDA \# 20,637**
>
> **GLIADEL Wafer**

**(Polifeprosan 20 with Carmustine Implant)**

**Submission Date: April, 6, 2001**

**ODAC: December 6, 2001**

Medical Reviewer: Alla Shapiro, M.D.

Statistical Reviewer: Ning Li, M.D., Ph.D.

Applicant: Guilford Pharmaceuticals

#   {#section .unnumbered}

# 

**Table of Contents**

DRAFT [**Error! Bookmark not defined.**](#__RefHeading___Toc529707357)

Summary of Review Issues for sNDA 20-637
[4](#summary-of-review-issues-for-snda-20-637)

I Introduction and Background [6](#introduction-and-background)

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's
Proposed Indication(s), Dose, Regimens, Age Groups
[6](#drug-established-and-proposed-trade-name-drug-class-sponsors-proposed-indications-dose-regimens-age-groups)

B. State of Armamentarium for Indication(s)
[7](#state-of-armamentarium-for-indications)

C. Other Relevant Information [8](#other-relevant-information)

D. Important Issues with Pharmacologically Related Agents
[8](#important-issues-with-pharmacologically-related-agents)

II\. Clinically Relevant Findings From Chemistry, Animal Pharmacology
and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
Consultant Reviews
[8](#clinically-relevant-findings-from-chemistry-animal-pharmacology-and-toxicology-microbiology-biopharmaceutics-statistics-andor-other-consultant-reviews)

III\. Human Pharmacokinetics and Pharmacodynamics
[8](#human-pharmacokinetics-and-pharmacodynamics)

IV\. Description of Clinical Data and Sources
[9](#iv.-description-of-clinical-data-and-sources)

A. Overall Data [9](#overall-data)

B. Table of Clinical Trials [9](#table-of-clinical-trials)

C. Postmarketing Experience [11](#postmarketing-experience)

D. Literature Review [11](#literature-review)

V. Clinical Review Methods [11](#v.-clinical-review-methods)

A. How the Review was Conducted [11](#how-the-review-was-conducted)

B. Overview of Materials Consulted in Review
[12](#overview-of-materials-consulted-in-review)

C. Clinical Inspection Summary [12](#c.-clinical-inspection-summary)

D. Were Trials Conducted in Accordance with Accepted Ethical Standards
[12](#d.-were-trials-conducted-in-accordance-with-accepted-ethical-standards)

E. Evaluation of Financial Disclosure
[12](#e.-evaluation-of-financial-disclosure)

VI\. Phase III Trial T-301 [14](#phase-iii-trial-t-301)

A. Protocol Review \[Note19\] [14](#protocol-review-note19)

B. Trial Results [22](#b.-trial-results)

C. Efficacy Results [35](#c.-efficacy-results)

VII Review of Safety [42](#vii-review-of-safety)

VIII\. Conclusions and Recommendations
[56](#viii.-conclusions-and-recommendations)

APPENDIX I: Protocol T-301 Details
[57](#appendix-i-protocol-t-301-details)

APPENDIX II: Current Label for GLIADEL
[64](#appendix-ii-current-label-for-gliadel)

APPENDIX III: Excerpts from 1996 Review of CL‑0190 (Phase 3); #9003
(Phase 1); ODAC Questions and Vote
[79](#appendix-iii-excerpts-from-1996-review-of-cl0190-phase-3-9003-phase-1-odac-questions-and-vote)

**Table of Reviewer Tables**

Reviewer Table 1: Clinical Trials in Patients with Newly Diagnosed
Malignant Glioma [11](#__RefHeading___Toc529696348)

Reviewer Table 2: Protocol T-301 Milestones
[14](#__RefHeading___Toc529696349)

Reviewer Table 3: Eligibility Violations
[24](#__RefHeading___Toc529696350)

Reviewer Table 4: Age Distribution by Decades and Treatment Group
[26](#__RefHeading___Toc529696351)

Reviewer Table 5: Tumor Size and Extent of Resection
[28](#__RefHeading___Toc529696352)

Reviewer Table 6: Tumor Characteristics -- Histological Type
[29](#__RefHeading___Toc529696353)

Reviewer Table 7: Chemotherapy within 30 days of randomization.
[35](#__RefHeading___Toc529696354)

Reviewer Table 8: Sponsor's Analysis for Overall Survival (ITT analysis)
[36](#__RefHeading___Toc529696355)

Reviewer Table 9: FDA's Analysis for Overall Survival (ITT analysis)
[36](#__RefHeading___Toc529696356)

Reviewer Table 10: FDA Analysis of Overall Survival (ITT analysis) using
different stratification variables [37](#__RefHeading___Toc529696357)

Reviewer Table 11: FDA's Analysis for Overall Survival for GBM subgroup
[38](#__RefHeading___Toc529696358)

Reviewer Table 12: ITT Analyses for Survival Using Cox Model
[39](#__RefHeading___Toc529696359)

Reviewer Table 13: GBM Subgroup Analyses for Survival Using Cox Model
[39](#__RefHeading___Toc529696360)

Reviewer Table 14: One Year Survival [40](#__RefHeading___Toc529696361)

Reviewer Table 15: Reasons for Death in the First 30 days of
Randomization [43](#__RefHeading___Toc529696362)

Reviewer Table 16: Indication for Additional Surgeries during which
Wafers were Detected and Removed. [44](#__RefHeading___Toc529696363)

Reviewer Table 17: Convulsions in Patients in the ITT population
[51](#__RefHeading___Toc529696364)

Reviewer Table 18: Timeframe of Postoperative Seizures
[52](#__RefHeading___Toc529696365)

Reviewer Table 19: Additional Local Treatment-Emergent Adverse Events
[53](#__RefHeading___Toc529696366)

Reviewer Table 20: Surgical Complications in Selected Series
[55](#__RefHeading___Toc529696367)

Reviewer Table 21: Randomization List for US Sites
[57](#__RefHeading___Toc529696368)

## Summary of Review Issues for sNDA 20-637

GLIADEL, a sterile, biodegradable polymer wafer containing 7.7 mg of
compressed carmustine powder, is designed to deliver local chemotherapy
to the surgical cavity remaining after resection of a malignant glioma.
In 1996, GLIADEL was approved for "use as an adjunct to surgery to
prolong survival in patients with recurrent glioblastoma multiforme for
whom surgical resection is indicated." An sNDA is now submitted
requesting extension of the indication to treatment of patients
undergoing initial surgery.

The efficacy claims of this sNDA rest primarily upon data from protocol
T-301, a multicenter (38), international (14 countries), randomized,
double-blind placebo-controlled trial in 240 patients with newly
diagnosed glioma. After maximal resection of tumor, up to eight wafers
of either GLIADEL or placebo were placed against the resection surfaces.
All patients were to receive standard limited field radiation therapy
and patients with anaplastic oligodendroglioma were also to receive
systemic chemotherapy. The primary endpoint was overall survival, to be
performed 12 months after the last patient was enrolled.

At the protocol-specified cutoff date, 88 patients (73.3 %) in the
GLIADEL group and 93 patients (77.5 %) in the placebo group had died.
Median survival in the ITT population for patients treated with GLIADEL
was 13.9 months (12.1 -- 15.3) and 11.6 months (10.2 -- 12.6) for
patients receiving placebo.

-   Statistical significance is not reached by the protocol-specified
    logrank test (p=0.078).

-   Statistical significance is reached by the sponsor's analysis, a
    logrank test stratified by country (p=0.027). The sponsor's
    reasoning for stratifying the logrank test includes, but is not
    limited to, the following: (a) randomization was stratified by
    center, which is within a country; (b) use of center results in
    over-stratification; (c) analysis by country was a prespecified
    interest explicitly stated as a secondary endpoint.

The secondary endpoint of greatest interest was overall survival in
patients with GBM, the subgroup which supported approval in the relapsed
setting, the most frequent histology in adults, and the target
population during the protocol planning stage (except that histology is
not available prior to wafer implantation). Of the 240 patients
enrolled, 207 carried the diagnosis of GBM. Overall survival in this
population demonstrates a nonsignificant trend for improvement (p=0.2).

The usual regulatory requirement for evidence of drug efficacy is more
than one adequate and well-controlled trial \[Section 505(d) of the FDC
Act\]. However, this section has been amended by FDAMA, and guidance
published, to allow consideration of data from a single trial if
replicability is demonstrated by internal consistency especially from a
multicenter trial or by evidence of efficacy in another phase of the
disease. The guidance in oncology states "therapies that are effective
in one phase of a disease are often effective in other disease phases,
although the magnitude of the benefit and benefit-to-risk relationship
may differ...if a drug is known to be effective in patients with a
refractory stage of a particular cancer, a single adequate and
well-controlled study of the drug in an earlier stage of the same tumor
will generally be sufficient evidence of effectiveness to support the
new use."

The 1996 approval of GLIADEL was based on a survival benefit in patients
with GBM. Trial 8802 was a randomized, multicenter, placebo-controlled
trial enrolling patients with anaplastic astrocytoma, anaplastic
oligodendroglioma and oligodendroglioma (35%) as well as GBM (65%). The
FDA generally does not approve drugs based on subgroup analyses;
however, it was acknowledged that information on differences in the
natural history of histologic subtypes was not well known at the time
trial 8802 was designed. If trial 8802 is to be accepted as supportive,
consideration should be given to the fact that it was approved only for
patients with GBM; there was not convincing evidence of a survival
effect in the ITT population. (Further details of trial 8802 can be
found in the label in Appendix II and of the ODAC questions and vote in
Appendix III.)

Study CL-0190, a study in newly diagnosed patients with malignant
gliomas, was also submitted in 1996. A total of thirty two patients in
Norway and Finland were enrolled when lack of drug supply closed the
trial before protocol endpoints and/or target accrual were reached. A
statistically significant treatment effect on survival was seen in the
ITT population; however, the treatment arms were imbalanced in that all
5 patients with the more favorable histology (anaplastic astrocytoma,
oligodendroglioma, ependymoma) randomized to GLIADEL. The trend for
improvement in survival for patients with GBM was not statistically
significant. (Further details of trial CL-0190 and the ODAC questions
and vote can be found in Appendix III.)

ODAC will be asked to address whether data from trial T-301, which is
submitted in this sNDA, in conjunction with data from the prior
approval, provide sufficient evidence of clinical benefit in patients
with newly diagnosed malignant glioma to warrant approval.

## Introduction and Background

### Drug Established and Proposed Trade Name, Drug Class, Sponsor's Proposed Indication(s), Dose, Regimens, Age Groups

-   Name of drug:

> Established: Polifeprosan 20 with Carmustine Implant
>
> Proprietary: GLIADEL Wafer

• Applicant:

> Guilford Pharmaceuticals Inc.
>
> 6611Tributary Street
>
> Baltimore, MD 21224

-   Drug Class: Antineoplastic

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-   Indication:

Current: "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."

Proposed: "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."

-   Dosage and Administration

Excerpted from the label (no changes proposed): "Each GLIADEL wafer
contains 7.7 mg of carmustine, resulting in a dose of 61.6 mg when eight
wafers are implanted. It is recommended that eight wafers be placed in
the resection cavity if the size and shape of it allows. Should the size
and shape not accommodate eight wafers, the maximum number of wafers as
allowed should be placed. Since there is no clinical experience, no more
than eight wafers should be used per surgical procedure...

Once the tumor is resected, tumor pathology is confirmed, and hemostasis
is obtained, up to eight GLIADEL wafers ...may be placed to cover as
much of the resection cavity as possible. Slight overlapping of the
wafers is acceptable. Wafers broken in half may be used, but wafers
broken in more than two pieces should be discarded in a biohazard
container. Oxidized regenerated cellulose (Surgicel) may be placed over
the wafers to secure them against the cavity surface. After placement of
the wafers, the resection cavity should be irrigated and the dura closed
in a water tight fashion."

-   How Supplied

Excerpted from the label (final sentence is proposed addition): "GLIADEL
is available in a single dose treatment box containing eight
individually pouched wafers. Each wafer contains 7.7 mg of carmustine
and is packaged in two aluminum foil laminate pouches. The inner pouch
is sterile and is designed to maintain product sterility and protect the
product from moisture. The outer pouch is a peelable overwrap. The
outside surface of the outer pouch is not sterile."

### State of Armamentarium for Indication(s) 

The estimated annual incidence of newly diagnosed primary brain
neoplasms in adults is roughly 7 to 17 per 100,000 per year
(Smirniotopoulos, 1999). Gliomas are by far the largest category of
primary neoplasms: 50% are high grade. Glioblastoma multiforme accounts
for 80% of adult malignant gliomas and anaplastic astrocytoma for 20%
(Davis, 2000).

The revised World Health Organization (WHO) nomenclature classifies low
grade histologies tumors as anaplastic oligodendrogliomas (15%),
meningiomas (20%), ependymoma (3%), embryonal tumors, such as
medulloblastoma, PNET, and mixed glial tumors (11% )

(Cohen, 1999).

The standard treatment of newly diagnosed gliomas consists of surgery
followed by cranial radiation and, at times, adjuvant systemic
chemotherapy. The median survival after surgery alone in patients with
GBM is about 13 months (Shinoda, 2001).

Randomized trials of radiation therapy have consistently demonstrated
statistically significant improvement in survival of about 16 to 18
weeks over surgery alone (Walker, 1980). Randomized controlled trials of
systemic chemotherapy have not demonstrated a consistent improvement in
survival in GBM. Prospective randomized Brain Tumor Cooperative Group

BTCG trials comparing patients with high grade gliomas (anaplastic
astrocytoma and GBM) who received radiation therapy with and without
BCNU have mixed results. A 1993 meta-analysis of the major adjuvant
therapy trials showed that there was a 10% increase in survival at 1
year and an 8.6% increase at 2 years for patients treated with both
chemotherapy and radiation therapy as opposed to those treated with
radiation therapy alone (Fine, 1993). It has been argued that this
improvement is confined to the subgroup of patients with anaplastic
astrocytoma.

For patients with anaplastic oligodendroglioma, adjuvant therapy with
PCV (procarbazine, CCNU, vincristine) may be considered standard
adjuvant therapy (Prados, 1999). However, recent analysis by the
Radiation Therapy Oncology Group concluded that for newly diagnosed
anaplastic atrocytoma, the PCV regimen does not confer a survival
advantage over BCNU as adjuvant treatment of patients with anaplastic
astrocytomas (Prados, 1998).

### Other Relevant Information 

GLIADEL has received marketing approval for patients with *recurrent*
malignant gliomas or GBM in the following countries as of December 2000:
Canada, 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, U.K. and Uruguay. The sponsor states that "product is not
yet commercially available in all of these countries."

GLIADEL has received marketing approval for the treatment of *newly
diagnosed* malignant gliomas in Canada based on the data submitted to
the FDA in 1996. See Reviewer Table 1 in Section IVB and Appendix III.

### Important Issues with Pharmacologically Related Agents

The nitrosoureas (BCNU, carmustine), which is the active ingredient of
the GLIADEL wafer, have the same features as classic alkylating agents.
The major dose-limiting toxicity is pulmonary, predominantly fibrosis
(O'Driscol et al., 1990). The most consistently noted toxicity is
delayed myelosuppression, which reaches a nadir 4 to 6 weeks after
treatment and can prevent subsequent cycles of chemotherapy by 6 to 8
weeks (DeVita, 1993). High dose systemic BCNU is associated with hepatic
necrosis, encephalopathy, and cardiac necrosis (Phillips et al., 1983).

## Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

This document represents a collaborative review by the primary medical
and statistical reviewers. Independent medical or statistical reviews of
sNDA 20-637 were not produced. New data regarding chemistry, animal
pharmacology and toxicology, microbiology or biopharmaceutics were not
submitted by the Sponsor. For further information, the reader is
directed to the label for the marketed product (Appendix 1).

## Human Pharmacokinetics and Pharmacodynamics

The following is excerpted from the current label of the original
approval for GLIADEL.

"The absorption, distribution, metabolism and excretion of GLIADEL in
humans is unknown. A waiver was granted of the requirements for
information under Section 6, Human Pharmacokinetics and Bioavailability
in 1996. Classical bioequivalence studies are hampered by assay
insensitivity for uM or nM drug concentrations needed for radiolabeling
studies. Obtaining tissue (brain) samples for analysis is considered
inappropriate. Information on the biodegradability of the wafers in
humans is based on patients who have had a reoperation or autopsy.
Biodegradability of the wafers appears variable with a spectrum of
complete dissolution to remnants or complete wafers recovered months
later. In the few instances where BCNU content of the wafer remnants was
analyzed, it has not been found to be present in the wafer remnants.

Pharmacokinetic and/or pharmacodynamic information was not studied in
T-301 and no new information has been submitted with this sNDA.

## IV. Description of Clinical Data and Sources 

### Overall Data

Supplemental NDA 20-637 contains the primary (raw) data from the trial
T-301, conducted in 38 centers in 14 countries including the US.

### Table of Clinical Trials

Reviewer Table 1 presents the trials of GLIADEL conducted in newly
diagnosed patients with malignant glioma. Trial T-301 is new data not
previously reviewed by the FDA. Studies 9003 and CL-0190 were submitted
and reviewed in 1996 when study 8802 supported approval of GLIADEL for
patients with recurrent GBM for whom reoperation is indicated. In 1996,
ODAC did not considered the randomized trial CL-0190 sufficient to
extend the indication to newly diagnosed patients. Data from study 8802
in patients with recurrent GBM can be found in the label in Appendix II.
Excerpts from the 1996 review of CL-0190 and 9003 are located in
Appendix III.

[]{#__RefHeading___Toc529696348 .anchor}Reviewer Table 1: Clinical
Trials in Patients with Newly Diagnosed Malignant Glioma

+----------+---------+---+----------+-----------+--------+---+------------+
| **Pr     | **Enrol |   | **Tre    | **Pop     | *      |   | *          |
| otocol** | lment** |   | atment** | ulation** | *#Plan |   | *Primary** |
|          |         |   |          |           | ned/** |   |            |
|          | **      |   |          |           |        |   | **E        |
|          | Dates** |   |          |           | **Ent  |   | ndpoints** |
|          |         |   |          |           | ered** |   |            |
+----------+---------+---+----------+-----------+--------+---+------------+
| CO       |         |   |          |           |        |   |            |
| NTROLLED |         |   |          |           |        |   |            |
+----------+---------+---+----------+-----------+--------+---+------------+
| #T-301   | 1       |   | GLIADEL  | Newly-dx  | 2      | S |            |
|          | 2.19.97 |   | vs.      | Malignant | 40/240 | u |            |
|          | ⇒       |   |          |           |        | r |            |
|          |         |   | Placebo  | Glioma    |        | v |            |
|          | 0       |   |          |           |        | i |            |
|          | 6.30.99 |   |          |           |        | v |            |
|          |         |   |          |           |        | a |            |
|          |         |   |          |           |        | l |            |
+----------+---------+---+----------+-----------+--------+---+------------+
| #C       | 0       |   | GLIADEL  | Newly-dx  | 100/32 | D |            |
| L-0190\* | 3.23.92 |   | vs.      | Malignant |        | F |            |
|          | ⇒       |   |          |           |        | S |            |
|          |         |   | Placebo  | Glioma    |        | ; |            |
|          | 0       |   |          |           |        | S |            |
|          | 5.14.93 |   |          |           |        | u |            |
|          |         |   |          |           |        | r |            |
|          |         |   |          |           |        | v |            |
|          |         |   |          |           |        | i |            |
|          |         |   |          |           |        | v |            |
|          |         |   |          |           |        | a |            |
|          |         |   |          |           |        | l |            |
+----------+---------+---+----------+-----------+--------+---+------------+
| UNCO     |         |   |          |           |        |   |            |
| NTROLLED |         |   |          |           |        |   |            |
+----------+---------+---+----------+-----------+--------+---+------------+
| #9003\*  | 0       | G |          | Newly-dx  | 22     | S |            |
|          | 7.05.90 | L |          | Malignant |        | a |            |
|          | ⇒       | I |          |           |        | f |            |
|          |         | A |          | Glioma    |        | e |            |
|          | 0       | D |          |           |        | t |            |
|          | 8.14.91 | E |          |           |        | y |            |
|          |         | L |          |           |        | P |            |
|          |         |   |          |           |        | i |            |
|          |         |   |          |           |        | l |            |
|          |         |   |          |           |        | o |            |
|          |         |   |          |           |        | t |            |
|          |         |   |          |           |        |   |            |
|          |         |   |          |           |        | w |            |
|          |         |   |          |           |        | i |            |
|          |         |   |          |           |        | t |            |
|          |         |   |          |           |        | h |            |
|          |         |   |          |           |        | X |            |
|          |         |   |          |           |        | R |            |
|          |         |   |          |           |        | T |            |
+----------+---------+---+----------+-----------+--------+---+------------+

\*Previously reviewed; see Appendix III.

### Postmarketing Experience

Postmarketing data from the FDA's Adverse Event Reporting System (AERS),
contains reports of the adverse events from the US as well as foreign
reports. The most commonly reported toxicities were neurological
complications such as cerebral edema, convulsions, confusion, headache,
brain abscess and wound infection. Reported adverse events are
consistent with the GLIADEL labeling. The Sponsor did not submit
postmarketing events as part of the sNDA.

### Literature Review

Review of the published literature was conducted and did not identify
other randomized or single-arm efficacy trials with GLIADEL.

## V. Clinical Review Methods

### How the Review was Conducted

The efficacy review is primarily based on the data from the randomized
trial T-301, which was the only primary data submitted in this sNDA.
Additional data in patients with newly diagnosed malignant glioma
reviewed in 1996 was not considered sufficient to support an indication
in this population (see Reviewer Table 1 and Appendix III).

### Overview of Materials Consulted in Review

The following materials were reviewed by the medical and statistical
officers:

-   The regulatory history of the application;

-   The 1996 medical and statistical review of GLIADEL;

-   INDs 30,237 and 54,658;

-   Electronic submission of the sNDA, including Case Report Forms
    (CRFs), SAS and ACCESS datasets;

-   Relevant published literature.

### C. Clinical Inspection Summary

The Division of Scientific Investigations, CDER, FDA conducted an audit
of the centers with the largest accrual (two centers in France: 17 and
14 patients). Only 12 patients were accrued in the US.

The detailed report of the inspection concluded that "data related to
the primary endpoint (mortality) for this study are valid". Minor
deviations from the protocol were noticed in the methodology of
reporting of Serious Adverse Events (SAEs), possibly attributable to
differences in practice of reporting SAEs in France.

### D. Were Trials Conducted in Accordance with Accepted Ethical Standards

The sponsor states that study T-301 was conducted in accordance with the
Declaration of Helsinki and in compliance with local regulations and the
International Conference of Harmonization (ICH) Good Clinical Practice
guidelines. The protocol and its amendments were reviewed and approved
by Independent Ethics Committees and/or Institutional Review Boards.

Written informed consent was required prior to entering the study.

### E. Evaluation of Financial Disclosure

Louise Peltier, Senior Director, Regulatory Affairs, Guilford states,
"The sponsor of this clinical study (T-301), performed to support this
sNDA filing, was Aventis Pharma and was conducted under their IND
#54,654. Aventis was responsible for all financial arrangements with all
investigators who participated in this study.

Guilford Pharmaceuticals Inc. reacquired the rights to GLIADEL,
including Aventis's IND and NDA on October 24, 2000. It has not been
possible to date to obtain the financial information required to
complete item 2 of this Certificate. Guilford has and will continue to
make every effort to obtain this information from Aventis."

Reviewer comment:

Guilford Pharmaceuticals provided FDA with letters that reflect attempts
to obtain information on the financial disclosure from the investigators
and no responses were received.

## Phase III Trial T-301

**Phase III, Multicenter Randomized Double-Blind, Placebo-Controlled
trial of Polifeprosan 20 with Carmustine 3.85% Implant for Patients
Undergoing Initial Surgery for Newly Diagnosed Malignant Glioma**

### Protocol Review \[Note19\]

#### Principal Investigator: 

Professor M. Westphal

Department of Neurosurgery

University Hospital Eppendorf

Martinistrasse 52, Hamburg, Germany

[]{#__RefHeading___Toc529696349 .anchor}Reviewer Table 2: Protocol T-301
Milestones

  --------------- ---------- ------------ -----------------------------------
  **Milestone**   **Date**   **\# Pts     **Highlights/Comments**
                             Entered**    

  Amendment 1     6/10/97    0            Not submitted to FDA. Per sNDA: (1)
                                          change in total RT from 56-60 to
                                          55-60 Gy; (2) chemorx regimen for
                                          AO determined by investigator; (3)
                                          PD defined.

  Co-sponsor =    6/20/97    0            
  RPR                                     

  First Pt        12/19/97   1            
  Entered                                 

  Full sponsor =  3/12/99    Close to 200 
  RPR                                     

  Amendment 2     3/18/99    Close to 200 Sample size ↑ from 200 to 240.

  Last Pt Entered 6/30/99    240          

  Statistical     11/3/99                 
  Analysis Plan   revised?                
  submitted                               

  Last            6/30/00    \--          Per protocol, all pts followed for
  Observation                             a minimum of 1 year or until death.

  Data Cutoff     6/30/00                 
  Date                                    

  Data Lock       7/17/00                 Data unlocks after unblinding on
                                          8/12/00, 1/23/01, and 2/19/01

  Guilford        10/24/00                Financial disclosure not available.
  "reacquired                             AVENTIS was sponsor of trial;
  rights to                               Guildford is applicant.
  GLIADEL"                                

  SNDA submitted  4/6/01                  
  --------------- ---------- ------------ -----------------------------------

#### Study Design/Synopsis: 

Protocol T-301 was a multicenter, international, randomized,
double-blind, placebo-controlled phase 3 trial of GLIADEL wafer (7.7 mg
Carmustine per polifeprosan 20 copolymer implanted wafer) implanted at
the time of surgery in the resection cavity of patients with newly
diagnosed malignant glioma. After maximal resection, up to eight wafers
of either GLIADEL or placebo were placed against the resection surfaces.
Between postoperative days 14 and 28, patients on both arms were to
receive standard limited field radiation therapy (RT) described as 55-60
Gy delivered in 28 to 30 fractions over six weeks. Patients with
anaplastic oligodendroglioma were to receive systemic chemotherapy in
addition to GLIADEL and RT.

The primary endpoint was overall survival 12 months after the last
patient was enrolled. Secondary endpoints included overall survival in
the subgroup of patients with glioblastoma multiforme, progression-free
survival, 1-year survival, time to neurological deterioration, change in
baseline Karnofsky Performance Status (KPS), and Quality of Life (QoL)
measures.

#### Objective: 

"To determine the safety and efficacy of polifeprosan 20 with carmustine
3.85% implant plus surgery and limited field radiation therapy compared
to placebo implants plus surgery and limited field radiation therapy for
improving the survival in patients undergoing initial surgery for
newly-diagnosed malignant glioma."

Reviewer Comment: Secondary endpoints per statistical section include
adjusted analyses for survival, progression free survival, change in KPS
from baseline, and quality of life measures (EORTC QLQ -- C30 and Brain
Cancer Module-20).

#### Eligibility criteria:

-   18 to 65 years old

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-   Radiographic evidence on cranial magnetic resonance imaging (MRI) of
    a unilateral,

> unifocal, supratentorial cerebral tumor at the time of present surgery

\- KPS [\>]{.underline} 60

-   Intraoperative diagnosis of malignant glioma by frozen or squash
    preparation prior to wafer implantation (including patients with a
    prior proven biopsy)

\- Adequate organ function as defined by baseline laboratory parameters

**Exclusion criteria:**

\- Prior cytoreductive surgery (excluding diagnostic stereotactic
biopsy)

\- Previous and/or current use of chemotherapeutic agents

\- Prior radiotherapy to the brain

\- Concomitant life-threatening diseases with life expectancy less than
12 months

\- Known hypersensitivity to nitrosourea

\- Pregnancy

Reviewer comment: In a protocol planning meeting January 30, 1997, the
FDA expressed the preference for a trial population limited to GBM,
given the information on effect limited to patients with GBM in the
recurrent setting. However, it was conceded that definitive histology
can only be known after surgery and therefore it was not feasible to
enroll only patients with GBM. The FDA recommended that the primary
analysis be done in the intent-to-treat population as well as in the GBM
subgroup. Therefore, the analysis of the GBM subgroup was prespecified
in the protocol and statistical analysis plan. The Statistical Analysis
Plan states..."Because of its resistance to chemotherapy, the study
interest is mainly on GBM."

#### Randomization:

#### The protocol states that patients will be randomized to one of two groups: resection and limited field radiation plus either GLIADEL or placebo. "Treatment assignment will be determined by sequential enrollment in ascending order into randomized blocks." The Statistical Analysis Plan states that "the randomization list is equilibrated for each center by blocks."

Reviewer Comment: The sNDA states that randomization was stratified by
country (Final Study Report, section 5.3.2). Clarification of the
randomization codes and algorithm requested from the Sponsor identify
that stratification was by center. Block sizes of four were assigned to
a center. Treatment assignment within a center was carried out by
sequential enrollment in ascending order. Randomization was 1:1.

#### Treatment:

[Wafer]{.underline}. Following maximal tumor resection and the
intraoperative conformation of malignant glioma, up to eight wafers of
GLIADEL or placebo were to be positioned to cover the entire resected
surface.

[Radiation Therapy]{.underline}. Between study day 14 and 30, all
patients were to undergo a course of limited field radiation therapy to
the tumor site and surrounding margins. Patients would receive
fractionated radiation to a total of 55 to 60 Gy in 28 to 30 fractions
over a six week period. (For further details of the RT protocol, see
Appendix III). Patients with the diagnosis of pure anaplastic
oligodendroglioma may have radiation delayed or withdrawn, per
investigator.

[Chemotherapy]{.underline}. All patients with a pathologic diagnosis of
anaplastic oligodendrogloima (AO) as determined by the institution's
pathologist were to receive systemic chemotherapy "based on a regimen
which will be determined at the investigator's discretion." (Amendment
1)

Reviewer comment: The original protocol stated that the regimen for
patient's with AO should consist of six cycles of PCV (lomustine 110
mg/m^2^ d1; procarbazine 60 mg/m^2^ d 8-21; vincristine 1.4 mg/m^2^ d 8
and 29).

Patients with other histologic diagnoses were not to receive
chemotherapy for treatment of their initial tumor. At the time of
progressive disease, both systemic chemotherapy and reoperation were
allowed.

[Concomitant Medications]{.underline}. Supportive medication such as
steroids and anti-convulsant drugs were permitted at the investigator's
discretion.

#### Patient Evaluation and Schedule of Tests:

**Sponsor's Table 3 (Abridged): Schedule of Tests**

<table style="width:100%;">
<colgroup>
<col style="width: 25%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 4%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="5"><strong>Days</strong></td>
<td colspan="7"><strong>Months</strong></td>
</tr>
<tr class="even">
<td></td>
<td>Baseline</td>
<td>Surgery</td>
<td colspan="3"></td>
<td colspan="7"></td>
</tr>
<tr class="odd">
<td>Visit</td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>4</td>
<td>5</td>
<td>6</td>
<td>7</td>
<td>8</td>
<td>9</td>
<td>10</td>
<td>11</td>
<td>12</td>
</tr>
<tr class="even">
<td>Study Day<sup>2</sup></td>
<td>-14 – 0</td>
<td>1</td>
<td>3</td>
<td>7<sup>3</sup></td>
<td>14</td>
<td>28</td>
<td>3</td>
<td>6</td>
<td>12</td>
<td>18</td>
<td>24</td>
<td>30</td>
</tr>
<tr class="odd">
<td>Written informed consent</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Medical history</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Interim medical history</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Medication review</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Physical exam</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Neurological exam</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Focused physical exam</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>KPS</td>
<td>X</td>
<td>X<sup>4</sup></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>QoL</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Brain MRI</td>
<td>X</td>
<td>X<sup>5</sup></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Laboratory evaluations</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Urine pregnancy test<sup>6</sup></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Adverse event Reporting</td>
<td>X<sup>7</sup></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Begin radiation therapy</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X<sup>8</sup></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Begin systemic chemorx</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X<sup>9</sup></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Survival</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Wafer implantation</td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="13"><p><sup>1</sup> All timing was relative to the Day of
Study Surgery, which was defined as Study Day 1</p>
<p><sup>2</sup> <u>+</u>3 days for Visits 5-6, <u>+</u> 15 days for
Visits 7-12</p>
<p><sup>3</sup> Or Day of Discharge (the earlier of these dates was to
be Visit 4)</p>
<p><sup>4</sup> Neurological exam and KPS score were to be performed
pre-operatively</p>
<p><sup>5</sup> Post-operative MRI scan was to be performed within the
48 hours post-operatively</p>
<p><sup>6</sup> For women of child-bearing potential only</p>
<p><sup>7</sup> Adverse event reporting started after written informed
consent was obtained</p>
<p><sup>8</sup> Post-operative, limited field radiation therapy was to
begin between Study Days 14 and 30</p>
<p><sup>9</sup> Systemic chemotherapy was only for patients with
anaplastic oligodendroglioma</p></td>
</tr>
</tbody>
</table>

Reviewer comment: The neurologic examination was designed to rate 11
pre-specified parameters (vital signs, level of consciousness,
personality, speech, visual status, fundus, cranial nerves III, IV, VI,
cranial nerves other, sensory status, cerebellar status and other).

#### Definition of Endpoints

• **Survival**. Overall survival was defined "from the date of
randomization (study surgery) and the date of death from any cause, or
to the date of last contact for censored information."

• **Progression-free survival** was defined as the time between
randomization (day of surgery) and the first of two events, progression
or death. Progression is defined as clinical or radiologic
deterioration. Clinical deterioration is defined as new neurologic signs
or a decrease in the KPS of at least 10%. Radiologic progression is
defined as a 25% increase in tumor size based on the product of the 2
largest perpendicular diameters or appearance of a new lesion as
compared to the last previous post-operative MRI.

• **Quality of Life Measures.** Quality of Life Assessments were
measured by the EORTC QLQ -- C30 quality of life instrument as well as
the specially designed questionnaire for Brain Tumors (BCM-20; 20
items). The EORTC QLQ-C30 contains 5 functional scales (physical, role,
emotional, cognitive and social functioning), 3 symptom scales (fatigue,
nausea and vomiting, pain) 6 single items (dyspnea, insomnia, appetite
loss, constipation, diarrhea, financial difficulties) and one global
health status/QoL scale. The BCM-20 assesses 4 scales (future
uncertainty, visual disorder, motor dysfunction, communication deficit)
and 7 single symptoms. (See Appendix 1 for the questionnaires.)

• **Karnofsky Performance Status** was assessed according to the
schedule in Sponsor's Table 3 above.

#### Definition of Adverse Events 

An adverse event (AE) was defined as any symptom, sign, illness or
experience which develops or worsens in severity during the course of
the study. Serious Aes were an event that was fatal, life-threatening,
requires or prolongs hospitalization, results in persistent or
significant disability or incapacity, a congenital anomaly or birth
defect or an important medical event.

#### Statistical Considerations:

The primary endpoint was overall survival as assessed by the
Kaplan-Meier curve 12 months after enrollment of the last study patient.
The secondary endpoints were progression-free survival, overall survival
in a subgroup of patients with GBM, 1year survival, change in KPS
scores, change in neurologic evaluation and Quality of Life.

#### Statistical Analysis:

The following are excerpts from the protocol:

[Sample size]{.underline}. "Sample size estimation, based on the
following assumptions using the Log-rank test to compare two survival
curves, indicates that 200 patients are required for this study:

1.  50%-70% 12 month survival rates of the placebo and polifeprosan 20
    with carmustine implant treatment groups, respectively.

2.  15% patient loss rate.

3.  18 months accrual time.

4.  Minimum of 12 months follow-up after last patient is enrolled.

5.  Two-sided 5% significance level.

6.  90% power.

Data from prior studies indicate that approximately 70% of patients
meeting inclusion and exclusion criteria similar to the ones in this
protocol have a final pathological diagnosis of glioblastoma multiforme.
Thus, this study can be expected to enroll a total of 140 patients with
a final pathological diagnosis of glioblastoma multiforme. Using the
same assumptions mentioned above, a sample size of 140 glioblastoma
multiforme patients will yield 80% power to detect a difference between
the two survival curves using the logrank test.

The final tumor pathology based on the central neuropathological review
of all entered patients will be monitored throughout the study in a
blinded fashion. If after 200 patients are enrolled, the total number of
enrolled patients with glioblastoma multiforme is less than 140,
enrollment will continue until 140 patients with glioblastoma multiforme
have been enrolled.

Because the sample size calculations are based on the number of events
(deaths) over time, the number of deaths during the study will be
monitored in a blinded fashion, and cost free adjustments of the number
of patients enrolled and/or the length of follow-up may be made as
necessary.

[Analyses]{.underline}.

-   Primary: Survival will be estimated by the Kaplan-Meier method 12
    months after enrollment of the last study patient or after a
    sufficient number of deaths has been observed to reach the
    predetermined 90% power, whichever occurs first. The curves will be
    compared using the Wilcoxon test for the primary comparison (logrank
    test would be performed as a sensitivity test)."

> Reviewer Comment: FDA review from 8/22/97: (1) sample size may not be
> sufficient to provide power (falls from 90% to 53%) if the true 12
> month survival rate for GLIADEL is actually (not overly optimistic)
> 62.5% instead of 70%. (2) A logrank test is suggested as the primary
> analysis if a Cox regression analysis for covariate adjustment is the
> supporting analysis. Consistency in the direction of results across
> analyses is the goal in the regulatory setting. A Wilcoxon test is
> efficient when more deaths are expected at an early stage of a trial
> and eventually the total number of deaths will be similar at the end
> of the study, which would indicate that the proportional hazard
> assumption does not hold.
>
> Amendment 2 (3/18/99): RPR states that the IDMC had a second meeting
> 1/28/99 to review the blinded data collected up to 1/15/99. "The hope
> for surgical benefit of GLIADEL of 20% at one year is probably
> unrealistic." This amendment will increase accrual from 200 to 240 in
> order to detect a 1year survival for the GLIADEL group of 68% vs. 50%
> (from 70% vs. 50%) without changing the accrual period from 18 months.
> This would be expected to increase the number of patients with GBM
> from 140 to 168.

-   "The effect of center will be examined using a proportional hazards
    model."

```{=html}
<!-- -->
```
-   The effect of strong prognostic factors will be assessed in adjusted
    analyses using the proportional hazards regression model. Baseline
    KPS, age, and tumor type may be included depending on the validity
    of the proportional hazards assumptions.

```{=html}
<!-- -->
```
-   All survival analyses and proportional hazards regression analyses
    will also be performed for the subgroup of GBM patients.

-   The SAP states that the Cox model will include country. "Countries
    with a small number of patients included will be pooled together. If
    a country effect cannot be tested due to small number of patients in
    each country, countries will be pooled together in a geographical
    continent basis (Europe + Israel, USA, Australia...)....These
    analyses are considered as supportive..."

```{=html}
<!-- -->
```
-   Twelve-month survival rate will be estimated.

```{=html}
<!-- -->
```
-   PFS will be estimated by Kaplan-Meier and compared by a Wilcoxon
    test.

```{=html}
<!-- -->
```
-   KPS. Change from baseline will be computed for each of the treatment
    groups at each of the post-surgical timepoints.

QoL. "... summary of the main indicators and comparison of the evolution
over time of quality of life between the two treatment groups for each
subscale will be performed. Analytical methods will include general
linear model (repeated measures and survival techniques, time to QoL
deterioration)."

The Statistical Analysis Plan states that the Global Health status/QoL
scale based upon questions 29 and 30 of the EORTC QLQ-C30 will be the
primary QoL parameter of interest.

###  

### B. Trial Results

#### B.1. Conduct of the Study

-   **Informed Consent**

The study was conducted in accordance with the Declaration of Helsinki;
patients gave written informed consent.

-   **Randomization**

The sNDA provides the details of the randomization process.
Randomization was stratified by center.

-   **Blinding**

[Placebo]{.underline}. The placebo wafer was manufactured and packaged
by Guilford. The placebo was identical in composition to GLIADEL except
that the placebo did not contain the drug substance (BCNU). The physical
characteristics of the wafer differed in several regards from GLIADEL. A
chemistry amendment dated August 1, 1997 describes GLIADEL as off-white
to yellow and placebo as off-white to white.

[Unblinding]{.underline}. The study was to be unblinded after the last
patient enrolled was followed for 12 months. An individual investigator
could decide to unblind treatment for a patient after discussion with
the Clinical Project Director if this information was considered to be
important for management of an adverse event. The sNDA describes, "The
code information was part of the tear-off portion of the medication that
was attached to the randomization page of the CRF, once the implants
were used. The non-transparent layer covering the medication code on the
label could be erased to reveal the medication allocated to the
patient."

*Reviewer Comment: Theoretically, blinding could have been compromised
in two ways:*

1.  *Physical characteristics. Color was not identical, per chemistry
    amendment August 1, 1997 and confirmed upon inspection by reviewers
    at the FDA. Reviewers also noted increased friability. Sponsor Table
    42 below on page 88 presents frequency of broken wafers by treatment
    arm.*

2.  *Treatment code could be broken locally.*

In the protocol planning stage, the value of blinding was considered
important to control for supportive or treatment interventions. Balance
between the arms with regard to RT, chemotherapy and reoperation will be
addressed in the section, Trial Results.

-   **Central Refereed Pathology**

All diagnoses were to be reviewed locally by the institutional
pathologist and centrally by an independent neuropathologist blinded to
treatment. The initial histological diagnosis was determined by the
institutional (local) neuropathologist. The final histopathological
diagnosis was determined during the study by a centralized
neuropathological assessment. The central neuropathologist was Professor
C. Daumas --Duport in France. Differences between the local and central
pathology were to be sent to a referee neuropathologist whose
interpretation was final. The referee neuropathologist was Dr. G.
Reifenburger in Germany.

-   **Protocol Violations**

Sponsor Table 5 presents the number and type of protocol violation per
arm.

**Sponsor Table 5: Recorded Protocol Deviations (All Patients)**

+-----------------------------------+-----------------+---------------+
| **Protocol Deviation**            | **GLIADEL**     | **Placebo**   |
|                                   |                 |               |
|                                   | **N = 120**     | **N = 120**   |
+-----------------------------------+-----------------+---------------+
| RT outside schedule               | 35              | 27            |
+-----------------------------------+-----------------+---------------+
| Required RT not done              | 11              | 9             |
+-----------------------------------+-----------------+---------------+
| Anaplastic oligodendroglioma and  | 11              | 10            |
| no CT                             |                 |               |
+-----------------------------------+-----------------+---------------+
| RT outside schedule/CT for reason | 0               | 2             |
| other than progression            |                 |               |
+-----------------------------------+-----------------+---------------+
| CT for reason other than          | 1               | 1             |
| progression                       |                 |               |
+-----------------------------------+-----------------+---------------+
| Required RT not done/RT outside   | 0               | 1             |
| schedule                          |                 |               |
+-----------------------------------+-----------------+---------------+

RT = radiotherapy; CT = chemotherapy

Data extracted from Appendix II.F, Listing 1.03

Sponsor Table 5, Study Summary, p. 53

*Reviewer Comment*: *The* *most frequently occurring deviations were RT
outside of schedule, required radiotherapy not done, and a diagnosis of
anaplastic oligodendroglioma and no chemotherapy. We disagree with the
Sponsor's data on the number of patients listed as "Required RT not
done*"*. We identified 15 patients in the GLIADEL group and 11 patients
in the placebo group who did not receive radiation therapy by query of
the electronic database. Communication dated August 27, 2001 with
Sponsor indicates their agreement with FDA numbers.*

Eligibility violations are shown in Reviewer Table 3. There were 5
violations in the GLIADEL group and 6 in the placebo group.

[]{#__RefHeading___Toc529696350 .anchor}Reviewer Table 3: Eligibility
Violations

+--------------------------+------------------+------------------------+
| **Protocol Deviation**   | **GLIADEL**      | **Placebo**            |
|                          |                  |                        |
|                          | **N = 120**      | **N = 120**            |
+--------------------------+------------------+------------------------+
| Age \> 65                | 2                | 1                      |
+--------------------------+------------------+------------------------+
| Non-enhancing tumors     | 1                | 2                      |
+--------------------------+------------------+------------------------+
| Not supratentorial       | 0                | 1                      |
+--------------------------+------------------+------------------------+
| Multiple foci of tumor   | 0                | 2                      |
+--------------------------+------------------+------------------------+
| Tumor crossing midline   | 2                | 0                      |
+--------------------------+------------------+------------------------+

Ref: Final Study Report, p. 56 and 57

-   **Audits**

Site audits by the FDA's Division of Scientific Investigations was
conducted for the 2 largest accruing centers in France. Summary of the
results is presented on p.10, Section C of the review.

#### B.2. Enrollment, Demographics, Baseline Characteristics

-   **Enrollment by Study Center**

A total of 240 patients were enrolled at 38 centers in 14 countries. The
largest number of patients were accrued in two countries: a total of 48
patients were accrued in 7 centers in France; 44 patients were accrued
in 5 centers in Germany. Only 12 patients were accrued in 5 centers in
the U.S. Equal numbers of patients, 120, were randomized to the two
treatment arms.

Enrollment per country and center is displayed in Sponsor Table 1.02. on
he following page.

**Sponsor Table 1.02: Randomized Patients by Country and Center by
Treatment Group**

![](media/image1.png){width="5.311111111111111in"
height="2.654861111111111in"}

![](media/image2.png){width="5.320833333333334in"
height="2.736111111111111in"}![](media/image3.png){width="5.358333333333333in"
height="1.4243055555555555in"}

Ref: Appendix II.F

-   **Baseline Demographics:**

Sponsor Table 6 presents demographics by study arm. The majority of
patients were male, ranging from 63% to 70% in the ITT population and
64% to 69% in the GBM subgroup. All but 8 patients in the ITT and 6 in
the GBM population were caucasian. Age ranged from 21 to 72, with a mean
of 53 in the ITT population in the GLIADEL group and of 54 years in the
placebo group. In the GBM subgroup a mean age for both treatment group
was 54 years.

**Sponsor Table 6: Summary of Demography**

+-------------+-------------+-------------+-------------+-------------+
| **Chara     | **Overall   |             | **GBM       |             |
| cteristic** | (N = 240)** |             | Subgroup (N |             |
|             |             |             | = 207)**    |             |
+-------------+-------------+-------------+-------------+-------------+
|             | **GLIADEL\  | **Placebo\  | **GLIADEL\  | **Placebo** |
|             | (N = 120)** | (N = 120)** | (N = 101)** |             |
|             |             |             |             | **(N =      |
|             |             |             |             | 106)**      |
+-------------+-------------+-------------+-------------+-------------+
| **Sex**     | 76 (63.3)   | 84 (70.0)   | 65 (64.4)   | 73 (68.9)   |
|             |             |             |             |             |
| Male N (%)  | 44 (36.7)   | 36 (30.0)   | 36 (35.6)   | 33 (31.1)   |
|             |             |             |             |             |
| Female N    |             |             |             |             |
| (%)         |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Race**    | 116 (96.7)  | 116 (96.7)  | 97 (96.0)   | 103 (97.2)  |
|             |             |             |             |             |
| Caucasian N | 1 (0.8)     | 1 (0.8)     | 1 (1.0)     | 0           |
| (%)         |             |             |             |             |
|             | 1 (0.8)     | 1 (0.8)     | 1 (1.0)     | 1 (0.9)     |
| Black N (%) |             |             |             |             |
|             | 1 (0.8)     | 0           | 1 (1.0)     | 0           |
| Oriental N  |             |             |             |             |
| (%)         | 1 (0.8)     | 2 (1.7)     | 1 (1.0)     | 1 (1.9)     |
|             |             |             |             |             |
| Hispanic N  |             |             |             |             |
| (%)         |             |             |             |             |
|             |             |             |             |             |
| Other N (%) |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Age       | 52.6 (0.8)  | 53.6 (0.8)  | 53.5 (0.84) | 54.2 (0.78) |
| (years)**   |             |             |             |             |
|             | 21--72      | 30-67       | 28-72       | 30-65       |
| Mean (SEM)  |             |             |             |             |
|             |             |             |             |             |
| Range       |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

Ref: Final Study Report, p. 53

Age is also displayed by decade in Reviewer Table 4. No significant
imbalances between the treatment arms are noted in either the ITT
population or the GBM subgroup.

[]{#__RefHeading___Toc529696351 .anchor}Reviewer Table 4: Age
Distribution by Decades and Treatment Group

+-------------+------------+-------------+-------------+-------------+
|             | **Overall  |             | **GBM       |             |
|             | Po         |             | P           |             |
|             | pulation** |             | opulation** |             |
+-------------+------------+-------------+-------------+-------------+
| **Age       | *          | **Placebo** | **GLIADEL** | **Placebo** |
| Groups**    | *GLIADEL** |             |             |             |
|             |            | **N=120     | *           | **N=106**   |
|             | **N=120    | (%)**       | *N=101(%)** |             |
|             | (%)**      |             |             |             |
+-------------+------------+-------------+-------------+-------------+
| 21-39       | 12 (10)    | 8 (7)       | 7 (7)       | 5 (5)       |
+-------------+------------+-------------+-------------+-------------+
| 40-49       | 25 (21)    | 27 (22)     | 23 (23)     | 23 (22)     |
+-------------+------------+-------------+-------------+-------------+
| 50-59       | 49 (41)    | 49 (41)     | 40 (40)     | 43 (41)     |
+-------------+------------+-------------+-------------+-------------+
| 60-65       | 32 (27)    | 35 (29)     | 29 (29)     | 35 (33)     |
+-------------+------------+-------------+-------------+-------------+
| \>65        | 2 (2)      | 1 (1)       | 2 (2)       | 0           |
+-------------+------------+-------------+-------------+-------------+

-   **KPS:**

Sponsor Table 17 presents baseline KPS scores in the ITT population and
GBM subgroup by treatment arm. The KPS score was comparable between the
two treatment groups at baseline for the ITT. In the GBM subgroup,
slightly more patients in the placebo group (57 patients) compared to
the GLIADEL group (46 patients) had a KPS score of 90 or more.

![](media/image4.png){width="5.603472222222222in"
height="2.3020833333333335in"} Ref: Table 2.01, Appendix II.F

-   **Tumor Size and Extent of Resection**

Assessment of baseline tumor size is presented in two ways: (a)
pre-operative imaging studies (length and width; planar volume is not
presented because of 77% and 73% missing data on GLIADEL and placebo,
respectively); and (b) assessment at time of surgery. Extent of
resection is also presented in two ways: (a) type of surgery; and (b)
percent of tumor resected.

[]{#__RefHeading___Toc529696352 .anchor}Reviewer Table 5: Tumor Size and
Extent of Resection

+------------------+-----------+------------+------------+------------+
|                  | **Overall |            | **GBM      |            |
|                  | Pop       |            | Subgroup** |            |
|                  | ulation** |            |            |            |
+------------------+-----------+------------+------------+------------+
|                  | **        | *          | *          | *          |
|                  | GLIADEL** | *Placebo** | *GLIADEL** | *Placebo** |
|                  |           |            |            |            |
|                  | **N=120** | **N=120**  | **N=101**  | **N=106**  |
+------------------+-----------+------------+------------+------------+
| **IMAGING DATA** |           |            |            |            |
+------------------+-----------+------------+------------+------------+
| **Planar Size    | 114       | 111        | 97         | 97         |
| (Length)**       |           |            |            |            |
|                  | 6         | 9          | 4          | 9          |
| N                |           |            |            |            |
|                  | 4.73      | 4.47       | 4.68       | 4.42       |
| Missing          |           |            |            |            |
|                  | 0.126     | 0.143      | 0.136      | 0.152      |
| Mean             |           |            |            |            |
|                  | 4.70      | 4.00       | 4.70       | 4.00       |
| SEM              |           |            |            |            |
|                  | 1.8, 9.0  | 1.2, 9.0   | 1.8, 9.0   | 1.2, 9.0   |
| Median           |           |            |            |            |
|                  |           |            |            |            |
| Range            |           |            |            |            |
+------------------+-----------+------------+------------+------------+
| **Planar Size    | 114       | 111        | 97         | 97         |
| (Width)**        |           |            |            |            |
|                  | 6         | 9          | 4          | 9          |
| N                |           |            |            |            |
|                  | 4.12      | 4.04       | 4.14       | 4.00       |
| Missing          |           |            |            |            |
|                  | 0.109     | 0.121      | 0.117      | 0.124      |
| Mean             |           |            |            |            |
|                  | 4.00      | 4.00       | 4.00       | 4.00       |
| SEM              |           |            |            |            |
|                  | 1.7, 7.0  | 1.5, 7.5   | 1.7, 7.0   | 1.5, 7.2   |
| Median           |           |            |            |            |
|                  |           |            |            |            |
| Range            |           |            |            |            |
+------------------+-----------+------------+------------+------------+
| **SURGICAL       |           |            |            |            |
| DATA**           |           |            |            |            |
+------------------+-----------+------------+------------+------------+
| **Surgical       | 66.8      | 50.8 (5.3) | 67.2 (6.5) | 53.4 (5.9) |
| Estimate of      | (5.9)     |            |            |            |
| Tumor Volume     |           | 0.6-240.0  | 0.1-250.0  | 0.6-240.0  |
| (cm^3^)**        | 0.1-250.0 |            |            |            |
|                  |           |            |            |            |
| Mean (SEM)       |           |            |            |            |
|                  |           |            |            |            |
| Range            |           |            |            |            |
+------------------+-----------+------------+------------+------------+
| **Type           | 62 (51.7) | 66 (55.0)  | 51 (50.5)  | 56 (52.8)  |
| Resection**      |           |            |            |            |
|                  | 56 (46.7) | 49 (40.8)  | 48 (47.5)  | 46 (43.4)  |
| Subtotal         |           |            |            |            |
|                  | 2 (1.7)   | 4 (3.3)    | 2 (2.0)    | 4 (3.8)    |
| Total            |           |            |            |            |
|                  | 0         | 1 (0.8)    | 0          | 0          |
| Total +          |           |            |            |            |
| Lobectomy        |           |            |            |            |
|                  |           |            |            |            |
| Missing          |           |            |            |            |
+------------------+-----------+------------+------------+------------+
| **% Resected**   | 89.9      | 88.3 (1.6) | 90.1 (1.5) | 89.5 (1.5) |
|                  | (1.3)     |            |            |            |
| Mean (SEM)       |           | 14-100     | 21-100     | 14-100     |
|                  | 21-100    |            |            |            |
| Range            |           | 11 (9.2)   | 4 (4.0)    | 9 (8.5)    |
|                  | 5 (4.2)   |            |            |            |
| Missing          |           |            |            |            |
+------------------+-----------+------------+------------+------------+

Ref: Sponsor Tables 9, 12 and 2.05

*Reviewer Comment: If complete resection is redefined by pairing two
datasets, i.e., requiring extent of resection as total or total +
lobectomy and 100% resection, the absolute number of patients with a
complete resection falls to 45 (37.5%) on GLIADEL and 38 (31.6%) on
placebo. The relative difference between the arms, however, remains the
same with an approximate 4-6% advantage to the GLIADEL arm.*

-   **Tumor Histology:**

Institutional diagnoses were reviewed by a central pathologist blinded
to treatment. Disagreements were forwarded to a referee
neuropathologist, whose interpretation was final. Patients with a
diagnosis of giant cell glioblastoma and gliosarcoma were included in
the GBM subgroup. The most common tumor type was GBM:101 (84.2%)
patients in the GLIADEL arm and 106 (88.3%) patients in the placebo
group. The classification system is the World Health Organization
Grading System.

[]{#__RefHeading___Toc529696353 .anchor}Reviewer Table 6: Tumor
Characteristics -- Histological Type

+---------------------------------------+--------------+--------------+
|                                       | **Treatment  |              |
|                                       | group**      |              |
+=======================================+==============+==============+
|                                       | **GLIADEL®   | **Placebo**  |
|                                       | N=120**      |              |
|                                       |              | **N=120**    |
+---------------------------------------+--------------+--------------+
| **Glioblastoma multiforme**           | **101**      | **106**      |
+---------------------------------------+--------------+--------------+
| **Non-GBM**                           | **6**        | **5**        |
|                                       |              |              |
| **Anaplastic oligodendroglioma**      |              |              |
+---------------------------------------+--------------+--------------+
| **Anaplastic oligoastrocytoma**       | **8**        | **3**        |
+---------------------------------------+--------------+--------------+
| **Anaplastic astrocytoma**            | **1**        | **2**        |
+---------------------------------------+--------------+--------------+
| **Metastasis/Brain Metastasis**       | **2**        | **1**        |
+---------------------------------------+--------------+--------------+
| **Other**                             | **2**        | **3**        |
+---------------------------------------+--------------+--------------+
|                                       |              |              |
+---------------------------------------+--------------+--------------+
| **TOTAL**                             | **120**      | **120**      |
+---------------------------------------+--------------+--------------+

*Reviewer comment: Histology was verified by review of electronic
database UPAT -- description and disposition of patients, variables
L_DIAGH -- local histological diagnosis, C_DIAGN -- central histological
diagnosis, R_DIAGH -- referee histological diagnosis. This table differs
from Sponsor Table 11 in Sponsor's Briefing Document in one respect --
Sponsor agrees with FDA that one patient previously categorized as"
other" should be reclassified as anaplastic oligoastrocytoma.*

#### B.3. Protocol Treatment

-   **Wafer Implantation**

Patients could receive up to eight wafers following maximal resection of
tumor. Sponsor Table 41 presents the number of wafers implanted in the
ITT population and the GBM subgroup. Approximately a third of patients
received the maximum number of wafers.

**Sponsor Table 41: Number of Wafers Implanted**

+-----------------+-------------+------------+------------+-----------+
| **Number of     | **Overall   |            | **GBM      |           |
| wafers**        | (N=240)**   |            | subgroup   |           |
|                 |             |            | (N=207)**  |           |
| **Implanted**   |             |            |            |           |
+-----------------+-------------+------------+------------+-----------+
|                 | *           | **Placebo  | **         | **Placebo |
|                 | *GLIADEL^®^ | n=120**    | GLIADEL^®^ | n=106**   |
|                 | n=120**     |            | n=101**    |           |
|                 |             | **n (%)**  |            | **n (%)** |
|                 | **n (%)**   |            | **n (%)**  |           |
+-----------------+-------------+------------+------------+-----------+
| 8               | 44 (36.7)   | 47 (39.2)  | 35 (34.7)  | 42 (39.6) |
+-----------------+-------------+------------+------------+-----------+
| 7.5             | 2 (1.7)     | 0          | 1 (1.0)    | 0         |
+-----------------+-------------+------------+------------+-----------+
| 7               | 21 (17.5)   | 28 (23.3)  | 18 (17.8)  | 25 (23.6) |
+-----------------+-------------+------------+------------+-----------+
| 6.5             | 1 (0.8)     | 1 (0.8)    | 1 (1.0)    | 1 (0.9)   |
+-----------------+-------------+------------+------------+-----------+
| 6               | 26 (21.7)   | 16 (13.3)  | 24 (23.8)  | 14 (13.2) |
+-----------------+-------------+------------+------------+-----------+
| \<6             | 26 (21.7)   | 28 (23.3)  | 22 (21.8)  | 24 (22.6) |
+-----------------+-------------+------------+------------+-----------+
|                 |             |            |            |           |
+-----------------+-------------+------------+------------+-----------+

The protocol permitted the use of wafers that had broken in half (either
on opening the treatment box or during surgery), while those broken in
more than 2 pieces were to be discarded in a biohazard container. As
seen in Sponsor Table 42, GLIADEL wafers were broken at time of surgery
for 56 patients (46.6%). For 19.2% of patients, the wafers were broken
into more than 2 pieces and were to be discarded.

![](media/image5.png){width="5.415277777777778in"
height="2.754861111111111in"}

-   **Concomitant Medications**

Corticosteroids and anticonvulants were the most commonly prescribed
medication after wafer implantation. Sponsor Table 1.09 provides data on
the use of concomitant medications during the study.

**Sponsor Table 1.09: Summary of Patients with Concomittant
Corticosteroids or Anticonvulsants Overall and by Histological Subtype
and Treatment Group**

+---------------------+-----------+-----------+----------+-----------+
|                     | **        |           | **GBM**  |           |
|                     | Overall** |           |          |           |
+---------------------+-----------+-----------+----------+-----------+
|                     | **        | **        | **G      | **        |
|                     | GLIADEL** | Placebo** | LIADEL** | Placebo** |
|                     |           |           |          |           |
|                     | **N=120** | **N=120** | *        | **N=106** |
|                     |           |           | *N=101** |           |
+---------------------+-----------+-----------+----------+-----------+
| **No. of Patients** | 71        | 70        | 59       | 60        |
|                     | (59.2%)   | (58.3%)   | (58.4%)  | (56.6%)   |
| Without Concomitant |           |           |          |           |
| Rx                  | 49        | 50        | 42       | 46        |
|                     | (40.8%)   | (41.7%)   | (41.6%)  | (43.4%)   |
| With Concomitant Rx |           |           |          |           |
+---------------------+-----------+-----------+----------+-----------+
| **Concomitant       | 29        | 30        | 26       | 26        |
| Medication**        | (59.2%)   | (60.0%)   | (61.9%)  | (56.5%)   |
|                     |           |           |          |           |
| Corticosteroid      | 12        | 5 (10.0%) | 9        | 5 (10.9%) |
|                     | (24.5%)   |           | (21.4%)  |           |
| Anticonvulsant      |           |           |          |           |
+---------------------+-----------+-----------+----------+-----------+

There were no differences between the treatment arms with respect to
number of patients who received corticosteroids (59.2% in the GLIADEL
group and 60% in the placebo group); however patients in the GLIADEL
group were treated with anticonvulsants more frequently than patients
from the placebo group (24.5% and 10.0% respectively).

-   **Radiation Therapy**

Per protocol, patients were to receive radiation therapy between
postsurgical day 14 and 30 to a total dose between 55 and 60 Gy to the
tumor site and surrounding margins. See Appendix 1 for details of the
radiation protocol. Sponsor Table 20 presents actual radiotherapy
delivered.

**Sponsor Table 20: Summary of Patients Receiving Radiotherapy During
the Study**

+--------------------+------------+-----------+--------------+---------+
| **Radiotherapy     | **Overall  |           | **GBM        |         |
| Received**         | (N=240)**  |           | (N=207)**    |         |
+--------------------+------------+-----------+--------------+---------+
|                    | **GLIADEL  | **Placebo | **GLIADEL**  | **      |
|                    | (N=120)**  | (N=120)** |              | Placebo |
|                    |            |           | **(N=101)**  | (N      |
|                    | n (%)      | n (%)     |              | =106)** |
|                    |            |           | n (%)        |         |
|                    |            |           |              | n (%)   |
+--------------------+------------+-----------+--------------+---------+
| **No               | 11 (9.2)   | 9 (7.5)   | 10 (9.9)     | 7 (6.6) |
| Radiotherapy**     |            |           |              |         |
+--------------------+------------+-----------+--------------+---------+
| **Standard Course  | 93 (77.5)  | 98 (81.7) | 80 (79.2)    | 88      |
| of Radiotherapy**  |            |           |              | (83.0)  |
+--------------------+------------+-----------+--------------+---------+
| **Non-standard     | 13 (10.8)  | 8 (6.7)   | 8 (7.9)      | 6 (5.7) |
| Radiotherapy**     |            |           |              |         |
+--------------------+------------+-----------+--------------+---------+
| **Standard and     | 3 (2.5)    | 5 (4.2)   | 3 (3.0)      | 5 (4.7) |
| Non-standard       |            |           |              |         |
| Radiotherapy**     |            |           |              |         |
+--------------------+------------+-----------+--------------+---------+
| **TOTAL**          | 120        | 120       | 101          | 106     |
+--------------------+------------+-----------+--------------+---------+

*Reviewer comment: Review of the electronic database confirms the number
of patients who received standard XRT. However, the electronic database
indicate that 6 additional patients did not receive radiation therapy: 4
patients treated with GLIADEL and 2 patients on placebo. The Sponsor has
counted these patients in the category of "non-standard radiotherapy."
The total FDA count of patients who did not receive RT in the ITT
population is 15 (12.5%) treated with GLIADEL and 11(9.2%) treated with
placebo. Accordingly, the number of patients who received "non-standard"
radiotherapy by reviewer count is 9 and 6 patients for the GLIADEL and
placebo respectively, which differs from the sponsor's data (13 and 8).*

Non-standard radiotherapy is defined in Sponsor Table 21 below for all
29 patients (16 from the GLIADEL group and 13 from placebo).

Sponsor Table 21: Reasons for Patients Receiving Non-standard
Radiotherapy

  ---------------------------- --------------------- ---------------------
  **Reason for non-standard    **GLIADEL**           **Placebo**
  RT**                                               

  No reason given              4                     6

  **Not well                   4                     3
  enough/deterioration/PD**                          

  **Lack of specialized        2                     2
  equipment**                                        

  **RT outside timeframe/after 3                     0
  chemorx**                                          

  **Metastasis**               0                     1

  **RT at another              2                     1
  institution**                                      

  **Tumors located in multiple 1                     0
  sites**                                            

  **Pt also had spinat RT due  1                     0
  to dx of primitive                                 
  neuroectodermal tumor**                            

  **Tumor type dx anaplastic   1                     0
  oligodendroglioma**                                
  ---------------------------- --------------------- ---------------------

#### *Reviewer comment: Review of electronic database URAD -- radiotherapy, variables CM_RAD -- non-standard radiotherapy, RAD -- radiotherapy used, I_RADSR -- date start reveals that a total of 6 had more than one record in the database. This can explain the difference between the Sponsor and reviewer data (by reviewer count a total of 23 patients on this study received non-standard radiotherapy). The Sponsor data shows 29 patients who received non-standard RT.* 

#### B.4 Additional Treatment 

-   **Reoperation**

Post-study treatments that could potentially confound results were
examined. Treatment modalities for the patients in this study include:
reoperation, chemotherapy, gamma knife surgery, radiation therapy,
GLIADEL wafer re-implantation, or some combination of them.

Sponsor's Table 23 shows a summary of patients who had additional
surgical procedures for disease progression, as well as for the
postsurgical complications after initial wafer implantation.

![](media/image6.png)

Reviewer Comment: The number of patients who underwent additional
surgery for disease progression, as well as for the postsurgical
complication, was confirmed by analysis of the electronic database USURG
-- surgery, variable ASURGY -- additional surgery, CM_SURG -- reason.

-   **Chemotherapy**

The protocol states that patients with the pathological diagnosis of
anaplastic oligodendroglioma will receive chemotherapy after initial
surgery while others may receive chemotherapy at time of disease
progression. Sponsor Table 22 summarizes the number of patients who
received chemotherapy in the ITT population and GBM subgroup by
treatment arm.

**Sponsor Table 22: Summary of Patients Receiving Systemic
Chemotherapy**

**for Malignant Glioma**

+-------------+-------------+-------------+-------------+-------------+
| **Systemic  | **Overall   |             | **GBM       |             |
| Chemorx**   | (N=240)**   |             | subgroup    |             |
|             |             |             | (N=207)**   |             |
+-------------+-------------+-------------+-------------+-------------+
|             | **GLIADEL   | **Placebo   | **GLIADEL   | **Placebo   |
|             | N=120**     | N=120**     | N=101**     | N=106**     |
|             |             |             |             |             |
|             | **N(%)**    | **N(%)**    | **N(%)**    | **N(%)**    |
+-------------+-------------+-------------+-------------+-------------+
| **No**      | 103 (85.8)  | 108 (90.0)  | 91 (90.1)   | 99 (93.4)   |
+-------------+-------------+-------------+-------------+-------------+
| **Yes**     | 17 (14.2)   | 12 (10.0)   | 10 (9.9)    | 7 (6.6)     |
+-------------+-------------+-------------+-------------+-------------+

Reviewer Comment: Analysis of the electronic database UMND -- medication
and non-drug therapy, variables -- DRUGSY -- medication, CHEMO --
chemotherapy, as well as CRF's reveal that 13 patients in the GLIADEL
group and 11 in placebo were treated with chemotherapy at the time of
the disease progression.

Review of the electronic database UMND -- medication and non-drug
therapy, variables -- DRUGSY -- medication, CHEMO -- chemotherapy, as
well as CRF's, reveal patients who received chemotherapy within 30 days
of randomization. Details are presented in reviewer Table 7 below.

[]{#__RefHeading___Toc529696354 .anchor}Reviewer Table 7: Chemotherapy
within 30 days of randomization.

  ------------------------------------- ---------------- -----------------
                                        Treatment group  

                                        GLIADEL          PLACEBO

  Anaplastic oligodendroglioma          2/6              2/5

  Anaplastic oligoastrocytoma           3/8              1/3
  ------------------------------------- ---------------- -----------------

*Reviewer comment: It was noted that of the 6 patients in the GLIADEl
group with the final diagnosis of anaplastic oligodendroglioma only 2
patients received chemotherapy, and in the placebo group, only 2 of 5
patients were treated with chemotherapy. However, 4 patients (3 in the
GLIADEL and 1 in placebo) with pathological diagnosis of* anaplastic
oligoastrocytoma received systemic chemotherapy after the wafer
implantation.

-   **Other Treatments**

At the time of the disease progression, four patients, all in the
GLIADEL group, received treatments other than systemic chemotherapy.
They included tumor resection with GLIADEL wafer reimplantation in 2
patients, brachytherapy in 1 patient and stereotactic radiosurgery in 1
patient.

### C. Efficacy Results

#### Primary Efficacy Endpoint: Overall Survival (unadjusted) in the ITT.

The primary efficacy endpoint for this study was overall survival.
Survival time is defined in the protocol as time from the date of
randomization to the last day of follow up or the date of death. Per
protocol and SAP, "The survival curve will be estimated for each
treatment group using the Kaplan-Meier method." The survival curves were
to be compared by the logrank test. The Sponsor's results are summarized
in Reviewer

Table 8. The logrank analysis is stratified by **country.**

*Reviewer comment: FDA requested and reviewed randomization codes for
Study T-301. The FDA and the Sponsor reached an agreement that the
randomization was stratified by center.*

A total of 88 patients (73.3%) in the GLIADEL group and 93 patients
(77.5%) in the placebo group died before the study cut-off date.

[]{#__RefHeading___Toc529696355 .anchor}Reviewer Table 8: Sponsor's
Analysis for Overall Survival (ITT analysis)

+-------------+---------------+-----------------+------------+--------+
| **ITT       | **Median      | **Hazard        | **95% CI   | **Lo   |
| P           | (95%CI)**     | Ratio**         | for Hazard | g-rank |
| opulation** |               |                 | Ratio**    | P-v    |
|             | **(Month)**   |                 |            | alue** |
| **N=240**   |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+
| GLIADEL     | 13.9          | 0.711           | 0.53-0.96  |        |
|             | (12.1-15.3)   |                 |            |        |
| (88/120)    |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+
| Placebo     | 11.6          |                 |            | 0      |
|             | (10.2-12.6)   |                 |            | .027\* |
| (93/120)    |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+

> \*Based on Sponsor's logrank stratified by country.

[]{#__RefHeading___Toc529696356 .anchor}Reviewer Table 9: FDA's Analysis
for Overall Survival (ITT analysis)

+-------------+---------------+-----------------+------------+--------+
| **ITT       | **Median      | **Hazard        | **95% CI   | **P-v  |
| P           | (95%CI)**     | Ratio**         | for Hazard | alue** |
| opulation** |               |                 | Ratio**    |        |
|             | **(Month)**   |                 |            |        |
| **N=240**   |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+
| GLIADEL     | 13.9          | 0.77            | 0          | 0.     |
|             | (12.1-15.3)   |                 | .574-1.032 | 08\*\* |
| (88/120)    |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+
| Placebo     | 11.6          |                 |            | 0      |
|             | (10.2-12.6)   |                 |            | .078\* |
| (93/120)    |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+

> \*Based on non-stratified log-rank test.
>
> \*\* Wald test for HR.

*Reviewer comment: Median survival and hazard ratios favored the GLIADEL
arm, but did not reach significance in the* protocol*-specified
analysis.*

Reviewer Figure 1: Kaplan-Meier Survival Curves for Study T301

![](media/image7.wmf){width="5.5in" height="3.3125in"}

Reviewer Comment: The effect of stratifying for known and presecified
prognostic factors in this disease and by center is shown in Reviewer
Table 10 below. The statistical significance does not improve, in fact
moves in the opposite direction, when stratified by accepted prognostic
factors.

[]{#__RefHeading___Toc529696357 .anchor}Reviewer Table 10: FDA Analysis
of Overall Survival (ITT analysis) using different stratification
variables\*

+-----------+---------+----------+------------+-----------+---------+
| **ITT     | **p-    | *        | *          | **p-value | **      |
| Pop       | value** | *p-value | *p-value** | S         | p-value |
| ulation** |         | St       |            | tratified | Str     |
|           | **Str   | ratified | **         | by**      | atified |
| **N=240** | atified | by       | Stratified |           | by**    |
|           | by**    | Center** | by**       | **KPS**   |         |
|           |         |          |            |           | **Age** |
|           | **Co    |          | **G        |           |         |
|           | untry** |          | BM/Other** |           |         |
+-----------+---------+----------+------------+-----------+---------+
| **        | *       | **0.07** | **0.14**   | **0.67**  | **      |
| GLIADEL** | *0.03** |          |            |           | 0.103** |
|           |         |          |            |           |         |
| **(       |         |          |            |           |         |
| 88/120)** |         |          |            |           |         |
+-----------+---------+----------+------------+-----------+---------+
| **        |         |          |            |           |         |
| Placebo** |         |          |            |           |         |
|           |         |          |            |           |         |
| **(       |         |          |            |           |         |
| 93/120)** |         |          |            |           |         |
+-----------+---------+----------+------------+-----------+---------+

**\*The p-value for the overall survival without stratification is
0.078**

Reviewer Comment: The sample size was based upon a projected 68%
one-year survival in the treatment group. However, the observed one-year
survival for the treatment group is 59.2% (hazard rate of 0.044). The
current power is only about 46%. Even if the data provides 100% events,
the power would increase only to 57%.

-   **Subgroup Analysis: Survival in the GBM Group**

Although median survival was longer in the GLIADEL group (13.5 months)
than in placebo group (11.4 months), the Kaplan-Meier estimates compared
using a stratified logrank test did not reach statistical significance
(p=0.098).

Reviewer Table 11 summarizes the FDA's survival analysis for the
subgroup of patients with GBM. Figure 2 presents the K-M curves for the
same subpopulation. The sponsor provided an analysis that was based upon
an analysis stratified by country, which gave

a p-value of 0.10.

[]{#__RefHeading___Toc529696358 .anchor}Reviewer Table 11: FDA's
Analysis for Overall Survival for GBM subgroup\*

+-------------+---------------+-----------------+------------+--------+
| **ITT       | **Median      | **Hazard        | **95.6% CI | **P-v  |
| P           | (95%CI)**     | Ratio**         | for Hazard | alue** |
| opulation** |               |                 | Ratio**    |        |
|             | **(Month)**   |                 |            |        |
| **N=207**   |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+
| GLIADEL 78% | 13.5          | 0.82            | 0          |        |
|             | (11.4-14.8)   |                 | .601-1.113 |        |
| (79/101)    |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+
| Placebo 80% | 11.4          |                 |            | 0.20\* |
|             | (10.2-12.6)   |                 |            |        |
| (85/106)    |               |                 |            |        |
+-------------+---------------+-----------------+------------+--------+

> \*Based on protocol specified non-stratified log-rank test.
>
> **Figure 2. Kaplan-Meier Survival Curves for Study T301 GBM subgroup**

![](media/image8.wmf)

-   **Effect of Prognostic Factors on Survival**

The accepted prognostic factors in this disease are age, KPS and
histology, were prespecified, along with country, as being of interest
in exploratory analyses. Reviewer Table 12 presents the effect of these
factors on overall survival in the ITT population. Analyses are
performed for the factors individually and together. Age is analyzed as
a continuous variable; KPS as [\<]{.underline} 70 vs. \> 70; histology
as GBM vs. other. In a non-stratified test, none of the factors
individually or together reach statistical significance. KPS exerts the
strongest effect.

[]{#__RefHeading___Toc529696359 .anchor}Reviewer Table 12: ITT Analyses
for Survival Using Cox Model\*

+--------------------+----------------+---------------+---------------+
| **Covariates**     | **             | **Stratified  | **Stratified  |
|                    | Non-stratified | by            | by Country**  |
|                    | test**         | Center\*\***  |               |
+--------------------+----------------+---------------+---------------+
| **Treatment only** | 0.08           | 0.07          | 0.03          |
+--------------------+----------------+---------------+---------------+
| Trt+Age            | 0.20           | 0.17          | 0.12          |
+--------------------+----------------+---------------+---------------+
| Trt+KPS            | 0.06           | 0.05          | 0.02          |
+--------------------+----------------+---------------+---------------+
| Trt+GBM            | 0.12           | 0.14          | 0.05          |
+--------------------+----------------+---------------+---------------+
| Trt+Age+PSK        | 0.15           | 0.12          | 0.09          |
|                    |                |               |               |
| Trt+Age+GBM        | 0.23           | 0.23          | 0.14          |
|                    |                |               |               |
| Trt+PSK+GBM        | 0.08           | 0.08          | 0.03          |
+--------------------+----------------+---------------+---------------+
| Trt+Age+PSK+GBM    | 0.16           | 0.16          | 0.10          |
+--------------------+----------------+---------------+---------------+

I.  p-values for the treatment effect.

\*\*randomization was stratified by Center

Reviewer Table 13 presents the effect of prognostic factors on overall
survival in the GBM population. Again KPS exerts the strongest influence
([\<]{.underline} 70% vs. \>70%) but just reaches significance only if
the logrank is stratified by country.

[]{#__RefHeading___Toc529696360 .anchor}Reviewer Table 13: GBM Subgroup
Analyses for Survival Using Cox Model\*

  --------------------- ------------------ --------------- ---------------
  **Covariates**        **Non-stratified   **Stratified by **Stratified by
                        test**             Center\*\***    Country**

  **Treatment only**    0.20               0.16            0.10

  Trt +Age              0.32               0.24            0.18

  Trt+KPS               0.12               0.09            0.055

  Trt+Age+PSK           0.22               0.15            0.11
  --------------------- ------------------ --------------- ---------------

I.  p-values for the treatment effect.

\*\*randomization was stratified by Center

#### One-Year Survival

One-year survival was pre-specified as a secondary endpoint for both the
ITT and GBM populations. A 10% difference in one-year survival is noted
in both populations; however, confidence limits overlap. The difference
in 1 year survival between the treatment groups in the ITT population as
well as in the GBM subgroup does not show statistically significant
difference even using the stratified log-rank test (p= 0.108 and p=0.26)
for the ITT and GBM population, respectively.

[]{#__RefHeading___Toc529696361 .anchor}Reviewer Table 14: One Year
Survival

  ------------------------ ------------- ------------- ------------- -------------
  **One Year Survival**    **ITT**                     **GBM**       

                           **GLIADEL**   **Placebo**   **GLIADEL**   **Placebo**

  \%                       59.2%         49.6%         57.4%         48.6%

  95% CI                   50.4, 68.0    40.6, 58.6    47.8, 67.1    39.0, 58.1
  ------------------------ ------------- ------------- ------------- -------------

Ref: Sponsor Table 27 and 30

#### Progression-free survival

Sponsor's data does not show difference between the two treatment group
in the progression-free survival (p=0.901) in the stratified log-rank
test.

Reviewer Comment: Further analysis by the FDA was not undertaken. The
difficulty in assessing tumor size, and therefore progression, in the
setting of post-operative and post-radiation changes, further confounded
by edema and treatment with steroids is recognized.

-   **Karnofsky Performance Status**

The KPS score was comparable between the two treatment groups at
baseline for the ITT. In the GBM subgroup, slightly more patients in the
placebo group (57 patients -- 53.8%) compared to the GLIADEL group (46
patients -- 45.5%) had a KPS score of 90 or more.

The Sponsor states that the median time to performance status
deterioration in the ITT population was slightly longer in the GLIADEL
group compared to placebo: 11.9 months (95% CI 10.4-13.7) in the GLIADEL
group and 10.4 months (95% CI 9.5-11.9) in the placebo using a logrank
stratified by country (p=0.05).

The Sponsor states that median time to performance status deterioration
between the treatment arms in the GBM subgroup was not statisticaly
significant (p=0.189, stratified log-rank test).

*Reviewer comment: Karnofsky Performance Status deterioration was one of
three QoL measures prespecified in the protocol. The FDA analysis of KPS
shows that this prognostic factor did not reach statistical significance
in a non-stratified logrank test p=0.11). KPS deterioration becomes
statistically significant only if the logrank is stratified by country
(p=0.05), but not center (0.27).*

#### Quality of Life Assessment.

QoL was assessed by the Sponsor by EORTC and QoL Questionnaire-30 and
Brain Cancer Module, a validated 24-questions QoL instrument designed to
be used with QoL-30. The primary QoL parameter prespecified in the
protocol was the Global Health Status/QoL based upon Questions #29 and
#30.

The results of the analysis provided by the Sponsor did not show
significant differences between two treatment groups.

Reviewer comment: In the FDA analysis no significant differences was
shown between two treatment groups in this secondary endpoint in the
protocol prespecified unadjusted logrank test, as well as stratified by
country or by center.

#### Neurological Evaluation.

The Sponsor defined the time to neuroperfomance deterioration as time
from the date of randomization to the date of first neuroperfomance
measure. The Sponsor claims that in the ITT population as well as in the
GBM subgroup the time to neuroperfomance deterioration in the GLIADEL
group was longer and reached statistical significance

(p\< 0.05, stratified log-rank test) in both groups. The exception was
visual status that did not show statistical significance either for the
ITT population group (p=0.087) nor for the GBM subgroup (p=0.269).

Reviewer comment: The comparison for the 11 neuroperformance measures is
not adjusted for multiple comparisons and therefore prevents any
conclusion.

## VII Review of Safety

#### A. Extent of Exposure 

All 240 patients from T-301 are evaluable for safety, 120 patients in
each treatment group. Patients were evaluated on day 3, 7, and then
weekly for 1 month, and at 3, 6, 12, 18 and 24 months from the day of
randomization (initial surgery). Follow-up ranged from 12 months to 30
months. Forty-four patients (36.7%) in the GLIADEL group and 47 patients
(39.2%) in the placebo group received the maximum of eight wafers
implanted.

#### Deaths. 

By the study cut-off date, 88 patients (73.3%) in the GLIADEL group and
93 patients (77.5%) in the placebo group died.

Sponsor Table #52 presents a summary of reasons for death.

![](media/image9.png){width="5.697916666666667in"
height="3.8583333333333334in"}

The primary cause of death was disease progression in both groups. Ten
and 9 patients in the GLIADEL and placebo group, respectively, died of
causes listed by the investigator as "other". A detailed analysis of
this category is as follows. The most frequent cause of death was
pulmonary events: 5 patients in the GLIADEL group and 2 in the placebo
group died from pulmonary embolism, 2 patients in each group died from
pneumonia, and 1 patient in the GLIADEL group died of pneumothorax.
Acute cardiac events caused death in one patient from each group. In the
placebo group 2 patients died from the neurological complications (one
patients was listed as having "progressive neurological deficit" and the
other died of seizures). One patient in the placebo group committed
suicide and one died of sepsis. One patient in the GLIADEL died of tumor
progression (listed under "other", per investigator).

Reviewer comment: All causes of death listed as "other" were verified by
review of the CRFs.

#### Deaths in the first 30 days of randomization

Five patients (4.2%) in the GLIADEL group and two patients (1.7%) in the
placebo group died within 30 days of randomization.

*Reviewer comment: Review of database UPAT -- Description and
Disposition of Patients confirms the total number of deaths as well as
the number of patients of the listing who died in the first 30 days of
initial surgery (randomization).*

[]{#__RefHeading___Toc529696362 .anchor}Reviewer Table 15: Reasons for
Death in the First 30 days of Randomization

  -------------------------------- ------------------- -------------------
  **Cause of deaths**              **Total number of   
                                   patients**          

                                   **GLIADEL (N=120)** **Placebo (N=120)**

  Cerebral hematoma+/- edema       3                   0

  Pulmonary embolism               1                   0

  Acute abdominal or coron. Event  1                   0

  Sepsis                           0                   1

  Malignant disease                0                   1

  TOTAL                            5                   2
  -------------------------------- ------------------- -------------------

Ref: "Death Report Form" of CRF.

#### Discontinuation due to Adverse Events. 

One patient (ID 01056) was discontinued from the study due to an adverse
event, brain edema, on postoperative Day 5. Her condition improved on
Day 6, but subsequently the patient deteriorated, and was discontinued
from the study on Day 22 due to the severe confusion and aphasia.

#### Wafer Removal

In the study design section of the protocol, the sponsor states that
"the wafers begin to degrade following intracerebral implantation". The
clinical pharmacology section of the GLIADEL label states that "although
the rate of biodegradation varies from patient to patient, more than 70%
of the copolymer degrades by three weeks". Data obtained at the
re-operations and autopsies, from the randomized trial supporting the
approval in the recurrent GBM patients showed wafer remnants up to 232
days after GLIADEL implantation.

Reviewer Table 16 summarizes reasons for additional surgeries during
which wafers were detected and removed.

[]{#__RefHeading___Toc529696363 .anchor}Reviewer Table 16: Indication
for Additional Surgeries during which Wafers were Detected and Removed.

+-------------------------+---------------------+----------------------+
|                         | **GLIADEL (N=120)** | **Placebo (N=120)**  |
+-------------------------+---------------------+----------------------+
| **Complications**       | 4                   | 3                    |
|                         |                     |                      |
| first 30 days           | 2                   | 1                    |
|                         |                     |                      |
| 30 -- 80 days           |                     |                      |
+-------------------------+---------------------+----------------------+
| **Tumor progression**   | 11                  | 11                   |
+-------------------------+---------------------+----------------------+
| **TOTAL**               | **17 (14.4%)**      | **15 (12.5%)**       |
+-------------------------+---------------------+----------------------+

A total of 32 patients (17 in the GLIADEL arm and 15 in the placebo arm)
had wafer removed at the time of additional surgery. The majority of
patients (23 patients from both groups) underwent total wafer removal
while 9 patients had partial wafer removal.

Reviewer comment: The list of patients who underwent wafer removal due
to an early adverse event is presented below.

*[GLIADEL group]{.underline}:*

-   *Patients 01293 -- on post-operative Day 0 developed hematoma and
    underwent reopening craniotomy with subsequent wafer removal.*

```{=html}
<!-- -->
```
-   *Patient 02059 -- on post-operative Day 19, developed a brain
    abscess, had reopening craniotomy and wafer removal.*

```{=html}
<!-- -->
```
-   *Patient 01056 (the one patient --listed by the sponsor) -- had
    reoperation on Day 4 due to the brain edema.*

```{=html}
<!-- -->
```
-   *Patient 01138 -- underwent recraniotomy with wafer removal on Day
    22 for cyst formation.*

*[Placebo group]{.underline}:*

-   *Patients 01081 -- developed brain edema on Day 22 after the initial
    surgery, underwent reoperation and wafers were removed.*

```{=html}
<!-- -->
```
-   *Patient 01137 -- on the postoperative Day 13, developed abscess,
    underwent reoperation with* *wafer removal.*

```{=html}
<!-- -->
```
-   *Patient 01153 -- on the postoperative Day 4, underwent reoperation
    with wafer removal because of the ventricular obstruction by a
    cyst.*

Wafer remnants were present up to 392 days in the GLIADEL group (derived
from data base USURG --Surgery, variables ASURGNY -- additional surgery,
USMA -- Study Medication Administration, variable WAFREM -- wafer
removal, and NBD_WREM -- number of days from randomization to wafer
removal).

Reviewer comment: Since treatment is not ongoing, the category of
treatment withdrawal or discontinuation is open to interpretation. The
reviewer considered that reoperation for a complication during which the
surgeon also removed the wafers might qualify. Of the 32 cases (17 in
the GLIADEL group and 15 in the placebo) with an indication for surgery
that could be interpreted as for complication, 7 patients (4 from the
GLIADEL group and 3 from the placebo group), had additional surgeries in
the first 30 days of randomization, i.e., perioperatively.

#### F. Treatment-emergent adverse events (AE)

Treatment-emergent adverse events were identified by the sponsor as
"signs and symptoms that were not present at baseline, or that were
present at baseline but increased in severity during the course of the
study. Intercurrent illnesses or injuries should be regarded as adverse
events". In addition to an open ended form by any AE, specific Aes, as
described below, were also collected.

AE form AE7-12 requested details about the following 20 events: fever in
the absence of infection, pain body whole, infection, thrombophlebitis
deep, pulmonary embolus, nausea, vomiting, healing abnormality, aphasia,
edema brain, confusion, convulsions, headache, hemiplegia, meningitis,
intracranial abscess, hydrocephalus, anemia, leucopenia and
thrombocytopenia.

If "healing abnormality" was checked on form AE7-12, another checklist
was to be completed identifying type of abnormality: (a) fluid, CSF or
subdural collections; (b) CSF leaks; (c) wound dehiscence, breakdown or
poor healing; and (d) subgaleal or wound effusions.

Events defined as serious (fatal, life-threatening, requiring
prolongation of hospitalization or resulting in persistent or
significant disability) were reported on the Serious AE Query Form. All
convulsions were to be reported as serious events.

The incidence of common Aes defined as occurring in \>5% and
irrespective of causality is shown in Sponsor Table 46.

![](media/image10.png)

![](media/image11.png){width="5.329861111111111in"
height="7.236111111111111in"}The most common Aes are related to the
nervous system. Hematologic abnormalities, as seen with systemic BCNU,
occurred in \<5% of patients and therefore are not included. The overall
incidence of nausea and vomiting, also seen with systemic BCNU, appear
more common in patients treated with GLIADEL; however, similar numbers
(7 on GLIADEL and 6 on placebo) were considered severe or
life-threatening.

-   **Serious Adverse Events (SAEs)**

The incidence of common Serious Adverse Events by body system is
presented in sponsor Table 55 (excluding nervous system).

![](media/image12.png){width="4.6506944444444445in"
height="5.131944444444445in"}

![](media/image13.png){width="4.631944444444445in"
height="2.339583333333333in"}

Sponsor Table 56 summarizes SAEs involving the nervous system.

![](media/image14.png){width="4.829861111111111in"
height="4.065972222222222in"}

The most common serious adverse events noticed by the sponsor were
"aggravation reaction" which occurred in 85 patients (70.8%) in the
GLIADEL group and in 83 patients (69.2%) in the placebo group. This
term, not used in the U.S., is described in Sponsor Table 45.

![](media/image15.png){width="5.302083333333333in"
height="2.170138888888889in"}

Reviewer comment: "Aggravation reaction" is a term, used in collecting
data outside the US and is defined by the sponsor as "mainly
tumor/disease progression or general deterioration of condition".

**[Seizures]{.underline}**

In this study seizures were the most common serious treatment-emergent
adverse event involving nervous system. Reviewer Table 17 below presents
the total incidence of seizures.

[]{#__RefHeading___Toc529696364 .anchor}Reviewer Table 17: Convulsions
in Patients in the ITT population

+----------------------+-----------------------+-----------------------+
|                      | **Treatment Group**   |                       |
+----------------------+-----------------------+-----------------------+
|                      | **GLIADEL N=120 (%)** | **Placebo N=120 (%)** |
+----------------------+-----------------------+-----------------------+
| **New or worsening** | 40 (33.3)             | 45 (37.5)             |
|                      |                       |                       |
| **Convulsions**      | 6 (5)                 | 5 (4.2)               |
|                      |                       |                       |
| **Grand mal**        |                       |                       |
+----------------------+-----------------------+-----------------------+
| **TOTAL**            | 46 (38.3)             | 50 (41.7)             |
+----------------------+-----------------------+-----------------------+

*Reviewer Comment: The number of patients sited by the Sponsor with
seizures (grand mal and convulsions) were confirmed by the reviewer.
Each patient was counted only once (derived from database UAE -- adverse
events, variables -- D_AESR -- onset date, AESERNY -- serious, AECOSE --
COSTART term).*

In 10 patients in the GLIADEL group and 16 patients in the placebo
group, convulsions occurred within the first 30 days of randomization
(initial surgery).

##### [Frequency and Distribution of Postoperative Seizures.]{.underline}

The incidence and distribution of postoperative seizures in both groups
within the first 30 days of the wafer implantation, as well as at the
later periods for up to 120 days after the initial surgery is presented
in Reviewer Table 18.

[]{#__RefHeading___Toc529696365 .anchor}Reviewer Table 18: Timeframe of
Postoperative Seizures

+------------------------+----------------------+---------------------+
| ### Seizures           | **Treatment Group**  |                     |
+------------------------+----------------------+---------------------+
|                        | **GLIADEL**          | **Placebo**         |
|                        |                      |                     |
|                        | **N=120 (%)^\*^**    | **N=120 (%)^\*^**   |
+------------------------+----------------------+---------------------+
|                        |                      |                     |
+------------------------+----------------------+---------------------+
| **Reported at          | **30 (25.0)**        | **28 (23.3)**       |
| Baseline**             |                      |                     |
+------------------------+----------------------+---------------------+
| **First 30 Days**      | **11 ( 9.1 )**       | **16 ( 13.3 )**     |
|                        |                      |                     |
| **Patients**           | **24 ( 20.0 )**      | **45 ( 37.5 )**     |
|                        |                      |                     |
| **Events**             |                      |                     |
+------------------------+----------------------+---------------------+
| **31-90 Days**         | **12 ( 10 )**        | **7 ( 5.8 )**       |
|                        |                      |                     |
| **Patients**           | **15 ( 12.5 )**      | **8 ( 6.6 )**       |
|                        |                      |                     |
| **Events**             |                      |                     |
+------------------------+----------------------+---------------------+
| **91-120 Days**        | **8 ( 6.6 )**        | **8 ( 6.6)**        |
|                        |                      |                     |
| **Patients**           | **8 ( 6.6 )**        | **8 ( 6.6 )**       |
|                        |                      |                     |
| **Events**             |                      |                     |
+------------------------+----------------------+---------------------+

\* Each patient was counted only once.

Of the patients who developed seizures within the first 30 days, 6
patients in the GLIADEL group and 11 patients in the placebo group had
seizures at baseline. Among the patients who had baseline seizures and
postoperative seizures within the first 30 days, 5 of 6 in the GLIADEL
group and 6 of 11 in the placebo group had multiple events (from 2 to
10).

Reviewer comment: The incidence of seizures within the first month of
operation ranged from 9 to 13%. Although the frequency of postoperative
seizures is reasonably balanced between the arms, the control arm is a
placebo waver and may lead to underestimation of related seizures. A
literature search was conducted to assess this possibility -- see
Section I on page 55.

#### G. Healing Abnormalities Checklist 

The adverse events coded as "healing abnormalities" consisted of 4
categories: (1) fluid, CSF or subdural collection, (2) CSF leaks, (3)
wound dehiscence, breakdown or poor wound healing, and (4) subgaleal or
wound effusion.

Sponsor Table #50 summarizes the patients with healing abnormalities.

![](media/image16.png){width="4.603472222222222in"
height="3.283333333333333in"}A total of 33 patients (18 and 15 in the
GLIADEL and placebo group, respectively) had abnormal wound healing
recorded on their checklist. Sponsor notes that patients treated with
GLIADEL have an increased incidence of CSF leaks as well as a greater
duration of the complications of fluid collections, CSF leaks and
effusion at the wound site.

#### H. Additional Local Adverse Events.

Additional local adverse events from the database UPAT -- Description
and Disposition of Patients, UAE -- Adverse Events, and USURG --
Surgery) are presented in the Reviewer Table 19 below.

[]{#__RefHeading___Toc529696366 .anchor}Reviewer Table 19: Additional
Local Treatment-Emergent Adverse Events

+----------------------------+--------------------+--------------------+
| **Adverse Event**          | **Treatment        |                    |
|                            | Group**            |                    |
+============================+====================+====================+
|                            | **GLIADEL**        | **Placebo**        |
|                            |                    |                    |
|                            | **N=120 (%)**      | **N=120 (%)**      |
+----------------------------+--------------------+--------------------+
| Cerebral hemorrhage        | 8 (6)              | 5 (4)              |
+----------------------------+--------------------+--------------------+
| Brain cyst                 | 2 (1.7)            | 3 (2.5)            |
+----------------------------+--------------------+--------------------+
| Brain abscess              | 8( 6)              | 8 (6)              |
+----------------------------+--------------------+--------------------+
| Intracranial hypertension  | 11 (9)             | 2 (1.7)            |
+----------------------------+--------------------+--------------------+
| Cerebral edema             | 27 (22.5)          | 23 (19.2)          |
+----------------------------+--------------------+--------------------+

Reviewer comment: We confirmed the data presented by the Sponsor on the
number of patients with local complications such as cerebral
hemorrhages, intracranial hypertension and brain edema (by queries to
the electronic database UAE -- adverse events, variables AESERNY --
serious, D_AESR -- onset date; USURG -- surgery, variables ASURGNY --
additional surgical procedure). The number of patients with brain
abscess and cysts differs in Sponsors and reviewer assessment. These
differences are explained below.

\*One patient, ID 01209 from the placebo group, was included by the
sponsor only in the listing of patients who underwent an additional
surgical procedure (Table 1.06). However, this patient had additional
surgery on day 14 after the initial surgery due to the brain cyst
formation that caused midline shift, confusion and urinary incontinence.
Therefore this patient was included by the reviewer in the category of
treatment-emergent AE.

Brain abscess in 3 patients (2 from the GLIADEL and 1 from the placebo
group) were counted by the sponsor as "wound infection". Reviewer
included these patients in the category "brain abscess" because of the
information extracted from CRF's:

[GLIADEL group:]{.underline}

-   *Patient ID 01085 -- on postoperative day 14, patient developed a
    complication that was captured as "wound infection". On day 15,
    patient underwent exploratory craniotomy and was diagnosed with a
    brain abscess.*

-   *Patient ID 02059 -- on postoperative day 12, patient developed a
    complication that was captured as "wound infection". On day 19,
    patient underwent re-craniotomy and was diagnosed with a brain
    abscess.*

[Placebo group:]{.underline}

-   *Patient ID 01036 -- on postoperative day 36, the patient showed
    evidence of clinical deterioration and the next day underwent
    re-craniotomy with surgical resection of a brain abscess.*

*FDA requested information from the Sponsor regarding type of pathogens
isolated from patients who developed brain abscesses/wound infections.
Since the study protocol did not require the collection of information
on pathogens from patients with these AEs, this information was
collected at the discretion of the investigator and information is not
available for all patients. The following is a listing of the available
information.*

*[GLIADEL group:]{.underline} Propionobacterium acne was identified in 5
of 8 patients with brain abscesses or wound infection. For 3 patients in
this group, no bacterial culture information is available.*

*[Placebo group]{.underline}: Propionobacterium acne was identified in 1
of 8 patients. For the rest of the patients either no bacterial culture
information was available or "event was coded Not Serious by the
investigator, thus additional information was not collected."*

**I. Literature Search**

*Reviewer comment: Although local complications appear to be balanced
between both arms (exception of CSF leaks and duration of fluid
collections) the control arm is a placebo wafer, an attempt was made to
compare the results of local toxicity in T-301 with the data in the
literature. Parameters for the literature search included: years
searched: 1985 -- present, patients with initially diagnosed malignant
gliomas, and large studies (200 + patients) that included the
multiinstitutional as well as foreign studies. The Reviewer Table 20
below presents local complications from T-301 and published literature.*

[]{#__RefHeading___Toc529696367 .anchor}Reviewer Table 20: Surgical
Complications in Selected Series

+------------+-------+--------+------+--------+--------+------------+
| **\        | **\   | **\    | **\  | **P    | **\    | **He       |
| Aut        | D     | Pati   | Tum  | ostop. | Ab     | morrhage/\ |
| hor/Year** | esign | ents** | or** | Seiz   | scess\ | Stroke**   |
|            | ^1^** |        |      | ures** | (%)**  |            |
|            |       |        |      |        |        | **(%)**    |
|            |       |        |      | *      |        |            |
|            |       |        |      | *(%)** |        |            |
+------------+-------+--------+------+--------+--------+------------+
| **LEE**    | **R** | *      | *    | *      | **?**  | **?**      |
|            |       | *321** | *AA, | *1.8** |        |            |
| **1990**   |       |        | M,   |        |        |            |
|            |       |        | me   |        |        |            |
|            |       |        | ts** |        |        |            |
+------------+-------+--------+------+--------+--------+------------+
| **         | **R** | *      | **   | **1**  | *      | **1**      |
| CABANTOG** |       | *207** | GBM, |        | *1.9** |            |
|            |       |        | AA** |        |        |            |
| **1994**   |       |        |      |        |        |            |
+------------+-------+--------+------+--------+--------+------------+
| **SURI**   | **R** | *      | **   | *      | **?**  | **?**      |
|            |       | *551** | GBM, | *5.9** |        |            |
| **1996**   |       |        | AA** |        |        |            |
+------------+-------+--------+------+--------+--------+------------+
| **SAWAYA** | **P** | *      | **   | *      | *      | **0.5**    |
|            |       | *327** | GBM, | *2.5** | *1.5** |            |
| **1998**   |       |        | AA,  |        |        |            |
|            |       |        | L    |        |        |            |
|            |       |        | GG** |        |        |            |
+------------+-------+--------+------+--------+--------+------------+
| **BRELL**  | **R** | *      | *    | **4**  | *      | **3**      |
|            |       | *200** | *AA, |        | *1.5** |            |
| **2000**   |       |        | GBM, |        |        |            |
|            |       |        | M**  |        |        |            |
+------------+-------+--------+------+--------+--------+------------+
| *          | **P** | *      | *    | **2**  | **?**  | **?**      |
| *BUCKNER** |       | *275** | *AA, |        |        |            |
|            |       |        | G    |        |        |            |
| **2001**   |       |        | BM** |        |        |            |
+------------+-------+--------+------+--------+--------+------------+
| *          | **P** | *      | **   | **9.2/ | **3.3  | *          |
| *Sponsor** |       | *240** | GBM, | 13.3** | /1.7** | *5.0/2.5** |
|            |       |        | AA** |        |        |            |
| **         |       |        |      |        |        |            |
| GLIADEL/** |       |        |      |        |        |            |
|            |       |        |      |        |        |            |
| *          |       |        |      |        |        |            |
| *Placebo** |       |        |      |        |        |            |
|            |       |        |      |        |        |            |
| **(G/P)**  |       |        |      |        |        |            |
+------------+-------+--------+------+--------+--------+------------+

^1^ R = Retrospective; P = Prospective

Abbreviations: AA -- anaplastic astrocytoma; GBM -- glioblastoma
multiforme; LGG -- low grade glioma; M - medulloblastoma

Reviewer comment: The Table shows that the rate of local complications
such as seizures, intracranial abscesses, and cerebral hemorrhages
appear to be higher in patients in the current trial. However, the
difference can be attributed to the different methodology of the AEs
collecting in the presented selected series.

## VIII. Conclusions and Recommendations

Study T-301 met most of the criteria for an adequate and well controlled
study, e.g., statement of objectives, trial design, randomization, and
method of assessment of the endpoints. Median survival in the ITT
population for patients treated with GLIADEL was 13.9 months (12.1 --
15.3) and 11.6 months (10.2 -- 12.6) for patients receiving placebo.
Although median survival in the GBM subgroup was 13.5 months (11.4-14.8)
in the GLIADEl group and 11.4 months (10.2-12.6) in placebo a stratified
logrank test did not reach statistical significance.

The protocol identified the primary efficacy endpoint as survival in the
ITT population assessed by logrank test. The protocol identified country
as on of the potential covariates along with age, histological
diagnosis, and KPS, and stated that the treatment effect "will be
estimated using a model stratifying for this covariate." This analysis
was considered by the Sponsor as "supportive." The treatment effect on
survival in all patients with newly diagnosed malignant gliomas reached
statistical significance only when stratified by country**.** The FDA
and the Sponsor reached an agreement that the randomization was
stratified by center. The effect of stratifying for center was not
significant. We are concerned that bias was may be introduced with a
retrospectively chosen modification of the analysis.

Subgroup analysis for the GBM population did not reach statistical
significance in a

non-stratified or stratified logrank test. Other secondary endpoints
such as one-year survival, progression-free survival, and QoL did not
show significant differences. Only KPS deterioration becomes
statistically significant in the logrank test stratified by country, but
not by center. The strength of evidence lent by previous trials with
GLIADEL in malignant gliomas will be a topic of the discussion with the
Advisory Committee.

The toxicity profile of GLIADEL is consistent with a regional delivery
of the drug at the time of operation. The primary toxicities were
related to neurologic function (seizures, brain hemorrhages, brain
cysts) and wound infection/brain abscesses. Increased incidence of CSF
leaks and increased duration of fluid collection were noticed in the
GLIADEL and placebo group, respectively. Risk/benefit ration will also
be a topic of discussion for the Advisory Committee.

## APPENDIX I: Protocol T-301 Details

[]{#__RefHeading___Toc529696368 .anchor}Reviewer Table 21: Randomization
List for US Sites

  ----------------- ------------------- -------------------- ---------------------- ----------------------
  [Pat              [Arm]{.underline}   [Date]{.underline}   [Center]{.underline}   [Block#]{.underline}
  ID]{.underline}                                                                   

  2005\*            Placebo             2/12/98              US3096                 2

  2006              Gliadel             8/24/98              US3096                 2

  2013\*            Placebo             6/25/98              US4109                 4

  2014              Gliadel             10/28/98             US4109                 4

  2021\*            Placebo             2/20/98              US4110                 6

  2022              Gliadel             7/01/98              US4110                 6

  2023              Placebo             8/25/98              US4110                 6

  2024\*            Gliadel             1/30/98              US4110                 6

  2026              Placebo             8/13/98              US4288                 7

  2027              Gliadel             9/17/98              US4288                 7

  2028              Placebo             12/01/98             US4288                 7

  2029              Gliadel             2/01/99              US4400                 8
  ----------------- ------------------- -------------------- ---------------------- ----------------------

*Reviewer comment: We reviewed the randomization codes and come to an
agreement with the Sponsor that the randomization was stratified by
center (not country). We can tell this by checking US patients in all 5
US sites. A fixed block size of 4 was used. If the country was the
stratification factor, then the patients with similar randomization
dates should be clustering together. For example, 4 patients entered the
study in January and February: pt #2005, #2013, #2021, and #2024 should
share the same block number.*

Reviewer Table 22: Tumor Histology by Country

  ------------- ----------------- -------- --------- --------- ---------- ----------- ----------------- -------- --------- --------- ---------- -----------
  **Country**   **GLIADEL**                                                           **Placebo**                                               

                **Histology\***                                                       **Histology\***                                           

                **AA**            **AO**   **AOA**   **GBM**   **M/BM**   **Other**   **AA**            **AO**   **AOA**   **GBM**   **M/BM**   **Other**

  Austria                                            3                                                                     4                    

  Australia                                          7                    1                                      1         7                    1

  Belgium                                            7                                                  1                  6                    

  Switzerland                     2                  3                                                                     4                    

  Germany                         3                  18        1                                                           22                   

  Spain                                              2                                                                                          

  France                                   2         21                   1                             2        1         21                   

  U.K.                                     1         14                                                 1                  15                   1

  Greece                                             2                                                           1         1                    

  Israel                          1        2         13        1                                                           15                   

  Italy                                              1                                                                                          

  Netherlands   1                          1         5                                1                                    7                    

  N. Zealand                                         1                                                                     1         1          

  U.S.                                     2         4                                1                 1                  3                    1

  **Total**     1                 6        8         101       2          2           2                 5        3         106       1          3
  ------------- ----------------- -------- --------- --------- ---------- ----------- ----------------- -------- --------- --------- ---------- -----------

\*AA-Anaplastic astrocytoma AO-Anaplastic oligodendroglioma
AOA-Anaplastic oligoastrocytoma GBM-Glioblastoma multiforme
M/BM-Metastasis/Brain Metastasis

**RADIATION THERAPY PROTOCOL**

1\. General

> Patients should be treated with involved/limited field radiotherapy to
> the planning target volume (PTV) including the tumour \[gross tumour
> volume (GTV), clinical target volume (CTV)\] and a defined margin with
> localized radiotherapy technique.

2\. Patient positioning

> Patients should be immobilized in an immobilization device in use in
> the radiation therapy center.

3\. Volumes of treatment

3.1 Tumour volumes should be defined on the basis of preoperative
imaging.

3.2 GTV should be defined as the region of enhancement presumed to
represent tumour (on preoperative imaging --either CT or MRI). In
unenhancing tumours GTV should be defined by the region of low density
on CT of high signal intensity on T2 weighted MRI.

3.3 The definition of CTV is not mandatory and may include GTV plus 1 --
3 cm margin in 3 dimensions or the region of low signal intensity
(CT)/high signal intensity (T2W MRI) in enhancing tumour, or other
definition specific to the radiation therapy centre. Exception for the
margin definition can be made for bone and meningeal structures which
are considered anatomical barriers to tumour spread.

3.4 PTV definition may be related either to GTV or CTV.

> Overall it is recommended that PTV is defined as GTV/CTV plus 2 -- 5
> cm margin in 3 dimensions as used in the radiation therapy center.
> Exception for the margin definition can be made for bone and meningeal
> structures which are considered anatomical barriers to tumour spread.

3.5 The radiation therapy may be carried out to a single PTV throughout
or by a two phase technique reducing at 40 -- 45 Gy to a smaller PTV.

3.6 It is recommended that the planning volumes are defined by each
radiation therapy center prior to commencing the study.

4\. Treatment planning.

4.1 Treatment planning should be performed on a planning computer and
dose homogeneity within and coverage of the PTV should conform to the
ICRU 50 criteria.

4.2 The aim of treatment planning is to minimize the amount of normal
brain irradiated and minimize the dose to normal brain. Multiple field
arrangements are preferred. Parallel opposed lateral field arrangements
and whole brain radiotherapy should be avoided. The use of custom
blocking is optional.

5\. Dose fractionation

5.1 Dose should be prescribed according to the ICRU 50 criteria.

5.2 The total dose to the PTV should be 55 -- 60 Gy in 30 -- 33 daily
fractions. All fields should be treated daily, Monday to Friday.

**EORTC QLQ-C30**

We are interested in some things about you and your health. Please
answer all of the questions yourself by circling the number that best
applies to you. There are no "right" or "wrong" answers. The information
that you provide will remain strictly confidential.

Please fill in your initials : \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Your birthdate (Day, Month, Year) :
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Today's date (Day, Month, Year) :
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**No Yes**

1\. Do you have any trouble doing strenuous activities, like carrying 1
2

> a heavy shopping bag or a suitcase?

2\. Do you have any trouble taking a long walk? 1 2

3\. Do you have any trouble taking a short walk outside 1 2

of the house?

4\. Do you have to stay in a bed or a chair for most of the day? 1 2

5\. Do you need help with eating, dressing, washing yourself 1 2

or using the toilet?

6\. Are you limited in any way in doing either your work or 1 2

doing household jobs?

7\. Are you completely unable to work at a job or to do 1 2

household jobs?

**During the past week:**

**Not A Little Quite Very**

**At All A Bit Much**

8\. Were you short of breath? 1 2 3 4

9\. Have you had pain? 1 2 3 4

10\. Did you need to rest? 1 2 3 4

11\. Have you had trouble sleeping? 1 2 3 4

12\. Have you felt weak? 1 2 3 4

13\. Have you lacked appetite? 1 2 3 4

14\. Have you felt nauseated? 1 2 3 4

15\. Have you vomited? 1 2 3 4

16\. Have you been constipated? 1 2 3 4

17\. Have you had diarrhea? 1 2 3 4

18\. Were you tired? 1 2 3 4

19\. Did pain interfere with your daily 1 2 3 4

activities?

20\. Have you had difficulty in concen- 1 2 3 4

trating on things, like reading a

newspaper or watching television?

21\. Did you feel tense? 1 2 3 4

22\. Did you worry? 1 2 3 4

23\. Did you feel irritable? 1 2 3 4

24\. Did you feel depressed? 1 2 3 4

25\. Have you had difficulty 1 2 3 4

remembering things?

26\. Has your physical condition or 1 2 3 4

medical treatment interfered with

your family life?

27\. Has your physical condition or 1 2 3 4

medical treatment interfered with

your social activities?

28\. Has your physical condition or 1 2 3 4

medical treatment caused you

financial difficulties?

**For the following questions please circle the number between 1 and 7
that best applies to you**

29\. How would you rate your overall [physical condition]{.underline}
during the past week?

1 2 3 4 5 6 7

Very poor Excellent

30\. How would you rate your overall [quality of life]{.underline}
during the past week?

1 2 3 4 5 6 7

Very poor Excellent

**FINAL BRAIN CANCER MODULE (BCM 20) FOR USE IN COMBINATION WITH
QLQ-C30**

Please indicate how much you experienced the following during the past
week.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**During the past week : Not A Little Quite Very**

**At All A Bit Much**

1\. Did you feel uncertain about the future?

2\. Did you feel you had setbacks in your condition?

3\. Were you concerned about disruption of family life?

4\. Did you have headaches?

5\. Did your outlook on the future worsen?

6\. Did you have double vision?

7\. Was your vision blurred?

8\. Did you have difficulty reading because of your vision?

9\. Did you have seizures?

10\. Did you have weakness on one side of your body?

11\. Did you have trouble finding the right words to

express yourself?

12\. Did you have difficulty speaking?

13\. Did you have trouble communicating your

thoughts?

14\. Did you feel drowsy during the daytime?

15\. Did you have trouble with your coordination?

16\. Did hair loss bother you?

17\. Did itching of your skin bother you?

18\. Did you have weakness of both legs?

19\. Did you feel unsteady on your feet?

20\. Did you have trouble controlling your bladder?

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

## APPENDIX II: Current Label for GLIADEL

**Guilford Pharmaceuticals Inc.**

**6611 Tributary Street**

**Baltimore, Maryland 21224**

**GLIADEL^^ WAFER Rx only**

(polifeprosan 20 with carmustine implant)

**DESCRIPTION**

GLIADEL^^ Wafer (polifeprosan 20 with carmustine implant) is a sterile,
off-white to pale yellow wafer approximately 1.45 cm in diameter and 1
mm thick. Each wafer contains 192.3 mg of a biodegradable polyanhydride
copolymer and 7.7 mg of carmustine \[1,3-bis
(2-chloroethyl)-1-nitrosourea, or BCNU\]. Carmustine is a nitrosourea
oncolytic agent. The copolymer, polifeprosan 20, consists of
poly\[bis(p-carboxyphenoxy) propane: sebacic acid\] in a 20:80 molar
ratio and is used to control the local delivery of carmustine.
Carmustine is homogeneously distributed in the copolymer matrix.

The structural formula for polifeprosan 20 is:

The structural formula for carmustine is:

![](media/image19.wmf)

**CLINICAL PHARMACOLOGY**

GLIADEL is designed to deliver carmustine directly into the surgical
cavity created when a brain tumor is resected. On exposure to the
aqueous environment of the resection cavity, the anhydride bonds in the
copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane,
and sebacic acid. The carmustine released from GLIADEL diffuses into the
surrounding brain tissue and produces an antineoplastic effect by
alkylating DNA and RNA.

Carmustine has been shown to degrade both spontaneously and
metabolically. The production of an alkylating moiety, hypothesized to
be chloroethyl carbonium ion, leads to the formation of DNA cross-links.

The tumoricidal activity of GLIADEL is dependent on release of
carmustine to the tumor cavity in concentrations sufficient for
effective cytotoxicity.

More than 70% of the copolymer degrades by three weeks. The metabolic
disposition and excretion of the monomers differ. Carboxyphenoxypropane
is eliminated by the kidney and sebacic acid, an endogenous fatty acid,
is metabolized by the liver and expired as CO~2~ in animals.

The absorption, distribution, metabolism, and excretion of the copolymer
in humans is unknown. Carmustine concentrations delivered by GLIADEL in
human brain tissue have not been determined. Plasma levels of carmustine
after GLIADEL wafer implant were not determined. In rabbits implanted
with wafers containing 3.85% carmustine, no detectible levels of
carmustine were found in the plasma or cerebrospinal fluid.

Following an intravenous infusion of carmustine at doses ranging from 30
to 170 mg/m^2^, the average terminal half-life, clearance***,*** and
steady-state volume of distribution were 22 minutes, 56 mL/min/kg***,***
and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200
mg/m^2^ dose of ^14^C-carmustine was excreted in the urine over 96 hours
and 6% was expired as CO~2~.

GLIADEL wafers are biodegradable in human brain when implanted into the
cavity after tumor resection. The rate of biodegradation is variable
from patient to patient. During the biodegradation process, a wafer
remnant may be observed on brain imaging scans or at re-operation even
though extensive degradation of all components has occurred. Data
obtained from review of CT scans obtained 49 days after implantation of
GLIADEL demonstrated that images consistent with wafers were visible to
varying degrees in the scans of 11 of 18 patients. Data obtained at
re-operation and autopsies have demonstrated wafer remnants up to 232
days after GLIADEL implantation.

Wafer remnants removed at re-operation from two patients with recurrent
malignant glioma, one at 64 days and the second at 92 days after
implantation, were analyzed for content. The following table presents
the results of analyses completed on these remnants.

COMPOSITION OF WAFER REMNANTS REMOVED FROM

TWO PATIENTS ON RE-OPERATION

  ------------------------------------ ----------------- -----------------
  [Component]{.underline}              [Patient          [Patient
                                       A]{.underline}    B]{.underline}

  Days After GLIADEL Implantation      64                92

  Anhydride Bonds                      None detected     None detected

  Water Content (% of wafer remnant    95-97%            74-86%
  weight)                                                

  Carmustine Content (% of initial)    \<0.0004%         0.034%

  Carboxyphenoxypropane Content (% of  9%                14%
  initial)                                               

  Sebacic Acid Content (% of initial)  4%                3%
  ------------------------------------ ----------------- -----------------

The wafer remnants consisted mostly of water and monomeric components
with minimal detectable carmustine present.

**CLINICAL STUDIES**

In a randomized, double-blind, placebo-controlled clinical trial in
adults with recurrent malignant glioma, GLIADEL prolonged survival in in
patients with glioblastoma multiforme (GBM). Ninety-five percent of the
patients treated with GLIADEL had 7-8 wafers implanted.

In 222 patients with recurrent malignant glioma who had failed initial
surgery and radiation therapy, the six-month survival rate after surgery
increased from 47% (53/112) for patients receiving placebo to 60%
(66/110) for patients treated with GLIADEL. Median survival increased by
33%, from 24 weeks with placebo to 32 weeks with GLIADEL treatment. In
patients with GBM, the six-month survival rate increased from 36%
(26/73) with placebo to 56% (40/72) with GLIADEL treatment. Median
survival of GBM patients increased by 41% from 20 weeks with placebo to
28 weeks with GLIADEL treatment. In patients with pathologic diagnoses
other than GBM at the time of surgery for tumor recurrence, GLIADEL
produced no survival prolongation.

6-MONTH KAPLAN-MEIER SURVIVAL CURVES FOR PATIENTS

UNDERGOING SURGERY FOR RECURRENT GBM

![](media/image20.wmf)

OVERALL KAPLAN-MEIER SURVIVAL CURVES FOR PATIENTS

UNDERGOING SURGERY FOR RECURRENT GBM

![](media/image21.png){width="4.79375in" height="3.8055555555555554in"}

**INDICATIONS AND USAGE**

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.

**CONTRAINDICATIONS**

GLIADEL contains carmustine. GLIADEL should not be given to individuals
who have demonstrated a previous hypersensitivity to carmustine or any
of the components of GLIADEL.

**WARNINGS**

Patients undergoing craniotomy for malignant glioma and implantation of
GLIADEL should be monitored closely for known complications of
craniotomy, including seizures, intracranial infections, abnormal wound
healing, and brain edema. Cases of intracerebral mass effect
unresponsive to corticosteroids have been described in patients treated
with GLIADEL, including one case leading to brain herniation.

**Pregnancy:** There are no studies assessing the reproductive toxicity
of GLIADEL. Carmustine, the active component of GLIADEL, can cause fetal
harm when administered to a pregnant woman. Carmustine has been shown to
be embryotoxic and teratogenic in rats at i.p. doses of 0.5, 1, 2, 4, or
8 mg/kg/day when given on gestation days 6 through 15. Carmustine caused
fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0
mg/kg/day (about 1/6 the recommended human dose (eight wafers of 7.7 mg
carmustine/wafer) on a mg/m^2^ basis). Carmustine was embryotoxic in
rabbits at i.v. doses of 4.0 mg/kg/day (about 1.2 times the recommended
human dose on a mg/m^2^ basis). Embryotoxicity was characterized by
increased embryo-fetal deaths, reduced numbers of litters, and reduced
litter sizes.

There are no studies of GLIADEL in pregnant women. If GLIADEL is used
during pregnancy, or if the patient becomes pregnant after GLIADEL
implantation, the patient must be warned of the potential hazard to the
fetus.

**PRECAUTIONS**

**General:** Communication between the surgical resection cavity and the
ventricular system should be avoided to prevent the wafers from
migrating into the ventricular system and causing obstructive
hydrocephalus. If a communication **larger than the diameter of a
wafer** exists, it should be closed prior to wafer implantation.

**Imaging Studies:** Computed tomography and magnetic resonance imaging
of the head may demonstrate enhancement in the brain tissue surrounding
the resection cavity after implantation of GLIADEL wafers. This
enhancement may represent edema and inflammation caused by GLIADEL or
tumor progression.

**Therapeutic Interactions:** Interactions of GLIADEL with other drugs
or radiotherapy have not been formally evaluated. In clinical trials,
few patients have received systemic chemotherapy within 30 days of
GIADEL (6) or external beam radiation therapy (36**).**

Chemotherapy was withheld at least four weeks (six weeks for
nitrosoureas) prior to and two weeks after surgery in patients
undergoing re-operation for malignant glioma.

External beam radiation therapy was initiated no sooner than three weeks
after GLIADEL implantation. Of the 36 patients who received GLIADEL at
initial surgery for newly diagnosed, malignant glioma followed by
external beam radiation therapy, 3/15 (20%) in one study and 11/21 (52%)
in the other study experienced new or worsened seizures. Patients were
followed for a maximum of 24 months.

The short and long-term toxicity profiles of GLIADEL when given in
conjunction with radiation or chemotherapy have not been fully explored.

**Carcinogenesis, Mutagenesis, Impairment of Fertility:** No
carcinogenicity, mutagenicity or impairment of fertility studies have
been conducted with GLIADEL. Carcinogenicity, mutagenicity and
impairment of fertility studies have been conducted with carmustine, the
active component of GLIADEL. Carmustine was given three times a week for
six months, followed by 12 months observation, to Swiss mice at i.p.
doses of 2.5 and 5.0 mg/kg (about 1/5 and 1/3 the recommended human dose
(eight wafers of 7.7 mg carmustine/wafer) on a mg/m^2^ basis) and to SD
rats at i.p. dose of 1.5 mg/kg (about 1/4 the recommended human dose on
a mg/m^2^ basis). There were increases in tumor incidence in all treated
animals, predominantly subcutaneous and lung neoplasms. *Mutagenesis*:
Carmustine was mutagenic *in vitro* (Ames assay, human lymphoblast HGPRT
assay) and clastogenic both *in vitro* (V79 hamster cell micronucleus
assay) and *in vivo* (SCE assay in rodent brain tumors, mouse bone
marrow micronucleus assay). *Impairment of Fertility*: Carmustine caused
testicular degeneration at i.p. doses of 8 mg/kg/week for eight weeks
(about 1.3 times the recommended human dose on a mg/m^2^ basis) in male
rats.

**Pregnancy:** Pregnancy Category D: see **WARNINGS**.

**Nursing Mothers:** It is not known if either carmustine,
carboxyphenoxypropane, or sebacic acid is excreted in human milk.
Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions from carmustine in nursing
infants, it is recommended that patients receiving GLIADEL discontinue
nursing.

**Pediatric Use:** The safety and effectiveness of GLIADEL in pediatric
patients have not been established.

**ADVERSE REACTIONS**

Data in the following table are based on the experience of 222 patients
with recurrent malignant glioma randomized to GLIADEL or placebo (wafer
without carmustine).

The spectrum of adverse events observed in patients who received GLIADEL
or placebo in clinical studies was consistent with that encountered in
patients undergoing craniotomy for malignant gliomas.

GLIADEL was not reported to be the cause of death in any of the GLIADEL
clinical trials.

The following post-operative adverse events were observed in 4% or more
of the patients receiving GLIADEL surgery in the placebo-controlled
clinical trial. Except for nervous system effects, where there is a
possibility that the placebo wafers could have been responsible, only
events more common in the GLIADEL group are listed. These adverse events
were either not present pre-operatively or worsened post-operatively
during the follow-up period. The follow-up period in the randomized
trial was up to 71 months.

COMMON ADVERSE EVENTS OBSERVED IN [\>]{.underline}4% OF PATIENTS

IN THE RANDOMIZED TRIAL

+---------------------------------+----------------+------------------+
| **Body System**                 | GLIADEL        | PLACEBO          |
|                                 |                |                  |
| > Adverse Event                 | Wafer with     | Wafer without    |
|                                 | Carmustine     | Carmustine       |
|                                 |                |                  |
|                                 | \[N=110\]      | \[N=112\]        |
|                                 |                |                  |
|                                 | n (%)          | n (%)            |
+---------------------------------+----------------+------------------+
| **Body as a Whole**             | 13 (12)        | 9 (8)            |
|                                 |                |                  |
| > Fever                         | 8 (7)          | 1 (1)            |
| >                               |                |                  |
| > Pain\*                        |                |                  |
+---------------------------------+----------------+------------------+
| **Digestive System**            | 9 (8)          | 7 (6)            |
|                                 |                |                  |
| > Nausea and Vomiting           |                |                  |
+---------------------------------+----------------+------------------+
| **Metabolic and Nutritional     | 15 (14)        | 6 (5)            |
| Disorders**                     |                |                  |
|                                 |                |                  |
| > Healing Abnormal\*            |                |                  |
+---------------------------------+----------------+------------------+
| **Nervous System**              | 10 (9)         | 12 (11)          |
|                                 |                |                  |
| > Aphasia                       | 4 (4)          | 1 (1)            |
| >                               |                |                  |
| > Brain Edema                   | 11 (10)        | 9 (8)            |
| >                               |                |                  |
| > Confusion                     | 21 (19)        | 21 (19)          |
| >                               |                |                  |
| > Convulsion                    | 16 (15)        | 14 (13)          |
| >                               |                |                  |
| > Headache                      | 21 (19)        | 22 (20)          |
| >                               |                |                  |
| > Hemiplegia                    | 4 (4)          | 7 (6)            |
| >                               |                |                  |
| > Intracranial Hypertension     | 4 (4)          | 1 (1)            |
| >                               |                |                  |
| > Meningitis or Abscess         | 15 (14)        | 12 (11)          |
| >                               |                |                  |
| > Somnolence                    | 7 (6)          | 7 (6)            |
| >                               |                |                  |
| > Stupor                        |                |                  |
+---------------------------------+----------------+------------------+
| **Skin and Appendages**         | 6 (5)          | 4 (4)            |
|                                 |                |                  |
| > Rash                          |                |                  |
+---------------------------------+----------------+------------------+
| **Urogenital System**           | 23 (21)        | 19 (17)          |
|                                 |                |                  |
| > Urinary Tract Infection       |                |                  |
+---------------------------------+----------------+------------------+
| \*p \< 0.05 for comparison of   |                |                  |
| GLIADEL versus placebo groups   |                |                  |
| in the randomized trial         |                |                  |
| (two-sided Fisher's Exact Test) |                |                  |
+---------------------------------+----------------+------------------+

The following adverse events were also reported in 4-9% of GLIADEL
patients but were at least as frequent in the placebo group as in
GLIADEL-treated patients: infection, deep thrombophlebitis, pulmonary
embolism, nausea, oral moniliasis, anemia, hyponatremia, pneumonia.

The following four categories of adverse events are possibly related to
treatment with GLIADEL. The frequency with which they occurred in the
randomized trial along with descriptive detail are provided below.

**1. Seizures:** In the randomized study, the majority of seizures in
the placebo and GLIADEL groups were mild or moderate in severity. The
incidence of new or worsened seizures was 19% in patients treated with
GLIADEL and 19% in patients receiving placebo. Of the patients with new
or worsened seizures post-operatively, 12/22 (54%) of patients treated
with GLIADEL and 2/22 (9%) of placebo patients experienced the first new
or worsened seizure within the first five post-operative days. The
median time to onset of the first new or worsened post-operative seizure
was 3.5 days in patients treated with GLIADEL and 61 days in placebo
patients. The occurrence of seizures did not reduce the survival benefit
of GLIADEL.

**2. Brain Edema:** In the randomized trial, brain edema was noted in 4%
of patients treated with GLIADEL and in 1% of patients treated with
placebo. Development of brain edema with mass effect (due to tumor
recurrence, intracranial infection, or necrosis) may necessitate
re-operation and, in some cases, removal of wafer or its remnants.

**3. Healing Abnormalities:** The majority of these events were mild to
moderate in severity. Healing abnormalities occurred in 14% of
GLIADEL-treated patients compared to 5% of placebo recipients. These
events included cerebrospinal fluid leaks, subdural fluid collections,
subgaleal or wound effusions, and wound breakdown.

**4. Intracranial Infection:** In the randomized trial, intracranial
infection (meningitis or abscess) occurred in 4% of patients treated
with GLIADEL and in 1% of patients receiving placebo. In GLIADEL-treated
patients, there were two cases of bacterial meningitis, one case of
chemical meningitis, and one case of meningitis which was not further
specified. A brain abscess developed in one placebo-treated patient. The
rate of deep wound infection (infection of subgaleal space, bone,
meninges, or neural parenchyma) was 6% in both GLIADEL and placebo
treated patients.

The following adverse events, not listed in the table above, were
reported in less than 4% but at least 1% of patients treated with
GLIADEL in all studies (n=273). The events listed were either not
present pre-operatively or worsened post-operatively. Whether GLIADEL
caused these events cannot be determined.

**Body as a Whole:** peripheral edema (2%); neck pain (2%); accidental
injury (1%); back pain (1%); allergic reaction (1%); asthenia (1%);
chest pain (1%); sepsis (1%)

**Cardiovascular System:** hypertension (3%); hypotension (1%)

**Digestive System:** diarrhea (2%); constipation (2%); dysphagia (1%);
gastrointestinal hemorrhage (1%); fecal incontinence (1%)

**Hemic and Lymphatic System:** thrombocytopenia (1%); leukocytosis (1%)

**Metabolic and Nutritional Disorders:** hyponatremia (3%);
hyperglycemia (3%); hypokalemia (1%)

**Musculoskeletal System:** infection (1%)

**Nervous System:** hydrocephalus (3%); depression (3%); abnormal
thinking (2%); ataxia (2%); dizziness (2%); insomnia (2%); monoplegia
(2%); coma (1%); amnesia (1%); diplopia (1%); paranoid reaction (1%). In
addition, cerebral hemorrhage and cerebral infarct were each reported in
less than 1% of patients treated with GLIADEL.

**Respiratory System:** infection (2%); aspiration pneumonia (1%)

**Skin and Appendages:** rash (2%)

**Special Senses:** visual field defect (2%); eye pain (1%)

**Urogenital System:** urinary incontinence (2%)

**OVERDOSAGE**

There is no clinical experience with use of more than eight GLIADEL
wafers per surgical procedure.

**DOSAGE AND ADMINISTRATION**

Each GLIADEL wafer contains 7.7 mg of carmustine, resulting in a dose of
61.6 mg when eight wafers are implanted. It is recommended that eight
wafers be placed in the resection cavity if the size and shape of it
allows. Should the size and shape not accommodate eight wafers, the
maximum number of wafers as allowed should be placed. Since there is no
clinical experience, no more than eight wafers should be used per
surgical procedure.

**Handling and Disposal^1-7^:** Wafers should only be handled by
personnel wearing surgical gloves because exposure to carmustine can
cause severe burning and hyperpigmentation of the skin. Use of double
gloves is recommended and the outer gloves should be discarded into a
biohazard waste container after use. A surgical instrument dedicated to
the handling of the wafers should be used for wafer implantation. If
repeat neurosurgical intervention is indicated, any wafer or wafer
remnant should be handled as a potentially cytotoxic agent.

GLIADEL wafers should be handled with care. The aluminum foil laminate
pouches containing GLIADEL should be delivered to the operating room and
remain unopened until ready to implant the wafers. **The outside surface
of the outer foil pouch is not sterile.**

**Instructions for Opening Pouch Containing GLIADEL**

**Figure 1:** To remove the sterile inner pouch from the

outer pouch, locate the folded corner and slowly pull in

![](media/image22.wmf)an outward motion.

![](media/image23.png){width="2.1354166666666665in"
height="1.5104166666666667in"}

**Figure 2:** Do NOT pull in a downward motion rolling knuckles over the
pouch. This may exert pressure on the wafer and cause it to break.

![](media/image23.png){width="2.1354166666666665in"
height="1.5104166666666667in"}

![](media/image24.png){width="2.25in" height="1.6458333333333333in"}

**Figure 3:** Remove the inner pouch by grabbing hold of the **crimped**
edge and pulling upward.

![](media/image25.png){width="1.9583333333333333in"
height="1.4375in"}**Figure 4:** To open the inner pouch, gently hold the
crimped edge and cut in an arc-like fashion around the wafer.

![](media/image26.png){width="2.0104166666666665in" height="1.5625in"}

**Figure 5:** To remove the GLIADEL wafer, gently grasp the wafer with
the aid of forceps and place it onto a designated sterile field.

Once the tumor is resected, tumor pathology is confirmed, and hemostasis
is obtained, up to eight GLIADEL^^ Wafers (polifeprosan 20 with
carmustine implant) may be placed to cover as much of the resection
cavity as possible. Slight overlapping of the wafers is acceptable.
Wafers broken in half may be used, but wafers broken in more than two
pieces should be discarded in a biohazard container. Oxidized
regenerated cellulose (Surgicel^^) may be placed over the wafers to
secure them against the cavity surface. After placement of the wafers,
the resection cavity should be irrigated and the dura closed in a water
tight fashion.

Unopened foil pouches may be kept at ambient room temperature for a
maximum of six hours at a time.

**HOW SUPPLIED**

GLIADEL is available in a single dose treatment box containing eight
individually pouched wafers. Each wafer contains 7.7 mg of carmustine
and is packaged in two aluminum foil laminate pouches. The inner pouch
is sterile and is designed to maintain product sterility and protect the
product from moisture. The outer pouch is a peelable overwrap. **The
outside surface of the outer pouch is not sterile.**

GLIADEL must be stored at or below -20ºC (-4ºF).

**REFERENCES**

1\. Recommendations for the Safe Handling of Parenteral Antineoplastic
Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of
Documents, U.S. Government Printing Office, Washington, DC 20402.

2\. AMA Council Report, Guidelines for Handling Parenteral
Antineoplastics. JAMA, 1985; 253(11):1590-1592.

3\. National Study Commission on Cytotoxic Exposure \-- Recommendations
for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD.,
Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts
College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue,
Boston, Massachusetts 02115.

4\. Clinical Oncological Society of Australia, Guidelines and
Recommendations for Safe Handling of Antineoplastic Agents. Med J
Australia, 1983; 1:426-428.

5\. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report
from the Mount Sinai Medical Center. CA \-- A Cancer Journal for
Clinicians, 1983; (Sept/Oct) 258-263.

6\. American Society of Hospital Pharmacists Technical Assistance
Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp Pharm,
1990; 47:1033-1049.

7\. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic
(Antineoplastic) Drugs. Am J Hosp Pharm, 1986; 43:1193-1204.

NDC: 61379-0100-1

**CAUTION:** FEDERAL LAW PROHIBITS DISPENSING WITHOUT PRESCRIPTION.

U.S. Patent Nos. 4,789,724 and 5,179,189.

Manufactured by

Guilford Pharmaceuticals Inc.

Baltimore, MD 21224

## APPENDIX III: Excerpts from 1996 Review of CL‑0190 (Phase 3); #9003 (Phase 1); ODAC Questions and Vote

**Phase 3 Trial #CL-0190: Interstitial Chemotherapy for Malignant
Glioma: A Phase 3 Placebo Controlled Study to Examine the Safety and
Eficacy of GLIADEL Placed at the Time of First Surgery**

Protocol CL-0190 was conducted under a foreign IND and not identified
prospectively as a pivotal trial for submission with an NDA in the U.S.
The NDA's submitted protocol, statistical section, and amendments as
well as decisions made during the trial are not part of the Agency's
records and are presented below as per applicant.

1.  **Protocol Review**

-   *Review of Amendments*

Amendment #1, 11/15/91 \-- Sweden withdrew and was replaced with a
center in Norway.

\-- An upper age limit of 65 years was added.

\-- Imaging was rearranged to be on day of discharge.

Amendment #2, 2/5/92 \-- Randomization was changed from blocks of 10
patients per center (5 active + 5 placebo in random order) to blocks of
4 patients per center.

*Comment: All patients were enrolled after both amendments.*

-   *Objectives*

\"To determine the safety and efficacy of using GLIADEL® as adjunctive
treatment with surgery and external beam radiotherapy in newly diagnosed
malignant glioma patients.\"

Primary endpoint (per statistical section): \"The primary efficacy
analyses will be comparisons of survival and progression free time
between the two treatment groups.\"

-   *Study Design/Schema*

CL-0190 was a multicenter, randomized, double blind placebo-controlled
phase III trial, designed to compare the safety and efficacy of
interstitial BCNU chemotherapy in treatment-naive patients with
malignant glioma. Patients were enrolled after malignant glioma was
pathologically confirmed during surgery. After maximal tumor resection,
up to eight wafers, GLIADEL® or placebo, were placed against the
resection surface.

Eligibility Criteria:

\-- 18 to 65 years of age

\-- KPS [\>]{.underline} 60

\-- Witnessed informed consent

\-- Unilateral, unifocal tumor of [\>]{.underline} 1 cm diameter, by
brain imaging. Tumor must not cross midline

\-- Confirmation of high grade glioma by frozen or squash preparation
surgery

*Comment: High grade glioma was defined as a grade III glioma
(anaplastic astrocytoma) or IV glioma (glioblastoma multiforme) in the
CRF.*

Exclusion Criteria:

\-- Significant renal or hepatic disease, as determined by BUN,
creatinine, SGOT, SGPT, LDH or bilirubin levels exceeding 2 X ULN of the
center\'s normal range

\-- Concomitant life-threatening disease that would limit lifespan to
within 6 months of study entry

\-- Platelets \< 100,000/ml or leukocytes \< 4,000/ml

\-- Pregnancy

\-- Hypersensitivity to contrast material to the extent that
contrast-enhanced CT or MRI would not be obtained

-   *Procedure, Treatment, and Schedule of Tests*

[Randomization]{.underline}*.* Study centers received one block of 4
numbers (per amendment #2) to start and further blocks depending on
accrual. When drug and placebo wafers were received from the U.S.,
Orion-Farmos placed a non-peelable label over the Nova Pharmaceutical
label to blind the content. The labels were site-specific, and included
the patient number (randomization number) and principal investigator\'s
name.

[Treatment]{.underline}*.* Following maximal tumor resection, up to
eight wafers (GLIADEL® vs. polymer placebo) were to be placed in the
cavity. Once adequate hemostasis was obtained, the wafers were placed to
cover the entire resection surface, with overlapping permitted. Avitene,
gelfoam, or surgicel could be left along the brain surface. The
decompressed area could be filled with irrigation fluid prior to tight
closure of the dura. \"Standard methods and schedules (of radiotherapy)
will be used.\" No systemic chemotherapy was allowed.

[Schedule of Tests]{.underline}*.*

+---------------+----------+-----+-----+----------+-----+------------+
| **Visit \#**  | **\# 0** | **# | **# | **#3**   | **# | **#5,      |
|               |          | 1** | 2** |          | 4** | etc.**     |
| **Study Day** | **Base   |     |     | **       |     |            |
|               | line=B** | **D | **D | Discharg | **R | **D90,     |
|               |          | 1** | 3** | e=D^1^** | T** | etc. q 3   |
|               |          |     |     |          |     | mo.^2^**   |
+---------------+----------+-----+-----+----------+-----+------------+
| History/ P.E. | X        |     |     |          |     |            |
+---------------+----------+-----+-----+----------+-----+------------+
| Karnofsky PS  | X        |     |     | X        | X   | X          |
+---------------+----------+-----+-----+----------+-----+------------+
| Neurological  | X        |     |     | X        | X   | X          |
| Exam/         |          |     |     |          |     |            |
|               |          |     |     |          |     |            |
| MMSE          |          |     |     |          |     |            |
+---------------+----------+-----+-----+----------+-----+------------+
| CT or MRI     | X        | X   |     |          | X   | X          |
|               |          |     |     |          |     |            |
| (w & w/o      | (within  |     |     |          |     |            |
| contrast)     | 2 wks)   |     |     |          |     |            |
+---------------+----------+-----+-----+----------+-----+------------+
| CBC, SMA, U/A | X        |     | X   | X        | X   | X          |
+---------------+----------+-----+-----+----------+-----+------------+
| Surgery       |          | X   |     |          |     |            |
| /Implantation |          |     |     |          |     |            |
+---------------+----------+-----+-----+----------+-----+------------+
| Radiation     |          |     |     |          | X   |            |
| Therapy       |          |     |     |          |     |            |
+---------------+----------+-----+-----+----------+-----+------------+

^!^Visit \# is the date of discharge or day 10, whichever comes first.

^2^Followup in #8802 is q 2 months.

-   *Endpoints and Statistical Analysis*

Definitions of Endpoints*:*

> [Treatment failure]{.underline} was defined identically to #8802, by
> changes on contrast-enhanced CT or MRI scan and/or the Karnofsky
> performance status, see pages 6-7.

[(Survival]{.underline} was not specifically defined.)

Statistical Analysis:

> The protocol states\...\"The maximum number of 100 patients with
> histologically verified malignant, primary, supratentorial Grade
> III-IV glioma without any previous chemotherapeutic treatment will be
> enrolled in the study.
>
> The expected median survival time is 12 months after the first surgery
> and radiotherapy. GLIADEL is considered an effective treatment, if we
> shall obtain a 33% (4 months) longer median survival in comparison
> with placebo.
>
> Monitoring of the results is done after every tenth event using a
> sequential restricted triangular stopping rule. This rule will
> terminate the study early, with 80% power and 5% one-sided type error
> rate, if we find a 33% difference in the survival time.
>
> Primary analyses divide into three parts: assessment of demographics,
> efficacy and safety data. Evaluations on safety and efficacy will be
> based on neurological, Karnofsky, MMSE, medical events, concomitant
> medications, imaging results, time to treatment failure and survival
> data. **The primary efficacy analyses will be comparisons of survival
> and progression free time between the two treatment groups.**
>
> If there is no difference between the two treatment arms after the
> first 100 patients, the trial will be stopped due to ethical reasons
> and the analysis will be done with conventional survival analysis
> techniques. On the other hand, if the study stops because mortalities
> are different, sequential analysis of survivorship will be applied.\"

*Comment: Further details of the statistical analysis plan are not
prespecified.*

**9.2 Results**

9.2.1 [Conduct of the Study]{.underline}

-   *Early Termination.*

Patient accrual was terminated early by the sponsor, Orion-Farmos, after
enrollment of 32 patients due to inadequate drug supply. The applicant,
Guilford, references internal memoranda from Orion-Farmos and Nova
Pharmaceutical Corp. identifying two reasons. First, Orion-Farmos, after
noting three cases of infection, was concerned about the lack of
documentation that wafers from lot SR042-49-7 had not been retested at
intervals for sterility (subsequent testing by Orion-Farmos confirmed
sterility and the incidences of wound infection/meningitis were
attributed to a single center mistakenly placing the unsterile packet in
the sterile surgical field). The second reason is that lot SR042-49-10
did not pass a 6-month retest because of a \"slightly low BCNU
content\". There was no other drug supply; the last patient treated on
CL-0190 was the last patient treated with GLIADEL® on any trial until
Guilford assumed manufacture, opening a Treatment IND in the U.S. in
November 1995. An interim analysis of CL-0190 was performed in the
Spring of 1994 after data was collected on 16 patients (analysis not
provided with the NDA). On March 9, l994, Orion-Farmos notified the
Finnish regulatory authorities that the study was completed December 22,
l993.

-   *Randomization.*

Subject ID numbers (randomization numbers) were ranked from a low of
\"1\" to a maximum of \"12\" at any one center. Review of the order of
these numbers showed correlation with date of surgery/wafer implantation
with one exception. The Tondheim, Norway center entered the first
patient with a number of \"12\", although drug was shipped either in a
block of 10 (pre-amendment) or a block of four for the initial shipment
(2 blocks of 4 for subsequent shipments). Thereafter, the numbers were
consecutive and correlated in order with the date of surgery.
Information on patients registered but not entered is not available (not
collected).

-   *Eligibility.*

All patients were considered evaluable and are included in the final
analyses of safety and efficacy. The following were the protocol
eligibility violations:

**Reviewer Table 9**

  ---------------------- ----------------------- ------------------------
  Eligibility Criterion  GLIADEL®                Placebo

  Age 18 to 65           1 pt age 67             \--

  KPS [\>]{.underline}   \--                     1 pt with KPS 40
  60                                             

  LFTs \< 2X ULN         2 pts without baseline  1 pt without baseline
                         LFTs                    LFTs
  ---------------------- ----------------------- ------------------------

-   *Referee Neuropathologist.*

By protocol direction, samples of the tumors were sent to the sponsor,
and then forwarded to Dr. Hannu Kalimo at the University of Turku,
Finland. The referee pathologist was blinded to treatment. The local
pathologist and Dr. Kalimo agreed on the diagnoses in all but one case
in which an astrocytoma grade III was upgraded to GBM.

-   *Quality Assurance.*

Although CL-0190 was conducted by Orion-Farmos, Guilford \"has
independently assessed the integrity and accuracy of the clinical
data\...to assure their adequacy\...Audits have been conducted,
including comparison of case report forms to source documents, to assess
the validity of selected key data variables\...In addition, quality
assurance audits have been conducted at a number of participating
clinical sites\...to evaluate the conduct of the studies and the content
of the data at these sites.\"

9.2.2 [Enrollment, Demographics, Baseline Characteristics]{.underline}

-   *Study Dates:*

First Patient Randomized: 3/23/92

Last Patient Randomized: 5/14/93

Date of Last Observation: 5/14/95

-   *Study Centers:*

Enrollment and assignment to treatment arm per center is displayed in
Reviewer Table 10, derived from Applicant's Table 4.1.

**Reviewer Table 10**

+-------------------------+---------------------+----------------------+
| **SITE**                | **GLIADEL®**        | **PLACEBO**          |
|                         |                     |                      |
|                         | **N = 16**          | **N = 16**           |
+-------------------------+---------------------+----------------------+
| #1 Turku, Finland       | 4                   | 5                    |
+-------------------------+---------------------+----------------------+
| #2 Tampere, Finland     | 3                   | 2                    |
+-------------------------+---------------------+----------------------+
| #3 Helsinki, Finland    | 4                   | 5                    |
+-------------------------+---------------------+----------------------+
| #4 Tondheim, Norway     | 5                   | 4                    |
+-------------------------+---------------------+----------------------+

-   *Baseline Demographics and Clinical Characteristics*

Reviewer Table 11 is a composite of Applicant's Tables 4.2, 4.5, 4.6,
4.8, 4.11, and 4.12. The only statistically significant difference
between the treatment arms was tumor type. All patients randomized to
placebo carried the diagnosis of GBM; however, 11/16 (69%) treated with
GLIADEL® had GBM.

**Reviewer Table 11**: **Baseline Demographics and Clinical
Characteristics**

+--------------------------+--------------+-------------+------------+
|                          | **GLIADEL®** | **Placebo** | *          |
|                          |              |             | *P-value** |
|                          | **(n = 16)** | **(n =      |            |
|                          |              | 16)**       |            |
+--------------------------+--------------+-------------+------------+
| **[AGE                   | 53.5 (9.5)   | 53.9 (8.0)  | 0.905^1^   |
| (years)]{.underline}**   |              |             |            |
|                          | 56           | 54          |            |
| mean (S.D.)              |              |             |            |
|                          | 37-68        | 36-65       |            |
| median                   |              |             |            |
|                          |              |             |            |
| range                    |              |             |            |
+--------------------------+--------------+-------------+------------+
| **[GENDER]{.underline}** | 88           | 106         | 0.722^1^   |
|                          |              |             |            |
| male                     |              |             |            |
|                          |              |             |            |
| female                   |              |             |            |
+--------------------------+--------------+-------------+------------+
| **[RACE]{.underline}**\* |              |             |            |
+--------------------------+--------------+-------------+------------+
| **[KARNOFSKY             | 0            | 1           | 0.542^2^   |
| PS]{.underline}**        |              |             |            |
|                          | 3            | 1           | 0.402^3^   |
| 40                       |              |             |            |
|                          | 5            | 1           |            |
| 60                       |              |             |            |
|                          | 1            | 4           |            |
| 70                       |              |             |            |
|                          | 5            | 7           |            |
| 80                       |              |             |            |
|                          | 2            | 2           |            |
| 90                       |              |             |            |
|                          | 78.75        | 81.94       |            |
| 100                      | (14.08)      | (15.10)     |            |
|                          |              |             |            |
| Mean (S.D.)              | 75 (60-100)  | 90 (40-100) |            |
|                          |              |             |            |
| Median (range)           |              |             |            |
+--------------------------+--------------+-------------+------------+
| **[HISTOLOGY (referee    | 11 (69)      | 16 (100)    | 0.043^1^   |
| p                        |              |             |            |
| athology)]{.underline}** | 2 (13)       | 0           |            |
|                          |              |             |            |
| GBM                      | 2 (13)       | 0           |            |
|                          |              |             |            |
| AA                       | 1 (6)        | 0           |            |
|                          |              |             |            |
| Oligodendroglioma, gr 3  |              |             |            |
|                          |              |             |            |
| Ependymoma, gr 3         |              |             |            |
+--------------------------+--------------+-------------+------------+
| **[MMSE]{.underline}**   | 23.19 (4.59) | 22.88       | 0.839^2^   |
| **(total score)**        |              | (4.03)      |            |
|                          | 24.5         |             | 0.732^3^   |
| Mean (S.D.)              |              | 24.5        |            |
|                          |              |             |            |
| Median                   |              |             |            |
+--------------------------+--------------+-------------+------------+
| **[NEURO                 | 4.31 (3.48)  | 3.94 (3.45) | 0.762^2^   |
| EXAM]{.underline}**      |              |             |            |
| **(total score)**        | 4.00         | 4.00        | 0.675^3^   |
|                          |              |             |            |
| Mean (S.D.)              |              |             |            |
|                          |              |             |            |
| Median                   |              |             |            |
+--------------------------+--------------+-------------+------------+

\*Not collected on the CRF in this study

^1^Fisher\'s Exact Test for discrete variables; F-test from ANOVA for
the continuous variables

^2^Two sample t-test for comparing means between treatment groups

^3^Wilcoxon Rank Sum test for comparing means between two treatment
groups

-   *Tumor Size*

The mean tumor area was 22.4 ([+]{.underline} 8.6) cm^2^ in the GLIADEL®
arm vs. 19.2 ([+]{.underline}6.1) cm^2^ in the placebo group. Median
tumor areas were 20 cm^2^ in both arms. Tumor volume estimates were not
provided for this study because data was not available for one patient.

-   *Characteristics of Surgery*

In the GLIADEL® arm, 13 patients (81%) had eight wafers implanted; in
the placebo group, 10 patients (63%) received eight wafers. The least
number of wafers implanted was 5 in the GLIADEL® arm and 4 in the
placebo arm (Applicant\'s Table 4.15 which follows).

+---------------------------+---------------+-------------+-----------+
| **Applicant\'s Table      |               |             |           |
| 4.15: GLIADEL Dosage**    |               |             |           |
+---------------------------+---------------+-------------+-----------+
| Parameter                 | GLIADEL 3.85% | PLACEBO     | P         |
|                           |               |             | ‑value^a^ |
|                           | \[N = 16\]    | \[N = 16\]  |           |
+---------------------------+---------------+-------------+-----------+
| **Number of Wafers        | 7.6 (1.0)     | 6.9 (1.5)   | 0.176     |
| Implanted**               |               |             |           |
|                           | 8             | 8           |           |
| Mean (S.D.)               |               |             |           |
|                           | 4-8           | 4-8         |           |
| Median                    |               |             |           |
|                           |               |             |           |
| Range                     |               |             |           |
+---------------------------+---------------+-------------+-----------+
| **Number of Wafers        | 0 (0)         | 2 (13)      |           |
| Implanted** 4 wafers      |               |             |           |
|                           | 1 (6)         | 1 (6)       |           |
| 5 wafers                  |               |             |           |
|                           | 2 (13)        | 3 (19)      |           |
| 6 wafers                  |               |             |           |
|                           | 0 (0)         | 0 (0)       |           |
| 7 wafers                  |               |             |           |
|                           | 13 (81)       | 10 (63)     |           |
| 8 wafers                  |               |             |           |
+---------------------------+---------------+-------------+-----------+
| **Amount of BCNU (mg)**   | 58.23 (7.42)  | N/A         |           |
|                           |               |             |           |
| Mean (S.D.)               | 61.6          |             |           |
|                           |               |             |           |
| Median                    | 38.5 - 61.6   |             |           |
|                           |               |             |           |
| Range                     |               |             |           |
+---------------------------+---------------+-------------+-----------+
| \_\_^a^ Fisher's Exact    |               |             |           |
| test                      |               |             |           |
+---------------------------+---------------+-------------+-----------+

Excerpts from Applicant's Table 4 below comparing additional
characteristics of surgery are shown below. There were no statistically
significant differences between the arms.

+-----------------------------+---------------+--------------+--------+
| **Applicant\'s Table 4.12:  |               |              |        |
| Characteristics of Wafer    |               |              |        |
| Implantation Surgery**      |               |              |        |
+-----------------------------+---------------+--------------+--------+
|                             | GLIADEL 3.85% | PLACEBO      | P‑va   |
|                             |               |              | lue^a^ |
|                             | \[N = 16\]    | \[N = 16\]   |        |
+-----------------------------+---------------+--------------+--------+
| **Hemisphere**              |               |              | 1.000  |
+-----------------------------+---------------+--------------+--------+
| Left                        | 6 (38)        | 6 (38)       |        |
|                             |               |              |        |
| Right                       | 10 (63)       | 10 (63)      |        |
+-----------------------------+---------------+--------------+--------+
| **Tumor Location by Lobe**  |               |              | 0.752  |
+-----------------------------+---------------+--------------+--------+
| Frontal                     | 6 (38)        | 6 (38)       |        |
|                             |               |              |        |
| Temporal                    | 7 (44)        | 5 (31)       |        |
|                             |               |              |        |
| Parietal                    | 2 (13)        | 1 (6)        |        |
|                             |               |              |        |
| Occipital                   | 1 (6)         | 3 (19)       |        |
|                             |               |              |        |
| Temporal / Occipital        | 0 (0)         | 1 (6)        |        |
+-----------------------------+---------------+--------------+--------+
| **Duration of Anesthesia    |               |              | 0.675  |
| (Hours)**                   |               |              |        |
+-----------------------------+---------------+--------------+--------+
| Mean (S.D.)                 | 4.4 (1.3)     | 4.2 (1.1)    |        |
|                             |               |              |        |
| Median                      | 4.6           | 4.2          |        |
|                             |               |              |        |
| Range                       | 2.7 - 6.5     | 2.2 - 5.7    |        |
+-----------------------------+---------------+--------------+--------+
| **Surgical Resection**      |               |              | 1.000  |
+-----------------------------+---------------+--------------+--------+
| Subtotal                    | 14 (88)       | 15 (94)      |        |
|                             |               |              |        |
| Total                       | 1 (6)         | 1 (6)        |        |
|                             |               |              |        |
| Total with Lobectomy        | 1 (6)         | 0 (0)        |        |
+-----------------------------+---------------+--------------+--------+
| **Tumor Volume (cm^3^)**    |               |              | 0.640  |
+-----------------------------+---------------+--------------+--------+
| N                           | 15            | 16           |        |
|                             |               |              |        |
| Mean (S.D.)                 | 103.9 (92.7)  | 91.5 (47.8)  |        |
|                             |               |              |        |
| Median                      | 80            | 82           |        |
|                             |               |              |        |
| Range                       | 1.5 - 336     | 18.8 - 181   |        |
+-----------------------------+---------------+--------------+--------+
| **% of Resection**          |               |              | 0.756  |
+-----------------------------+---------------+--------------+--------+
| Mean (S.D.)                 | 79.3 (16.3)   | 77.4 (18.6)  |        |
|                             |               |              |        |
| Median                      | 80            | 85           |        |
|                             |               |              |        |
| Range                       | 40 - 100      | 40 - 98      |        |
+-----------------------------+---------------+--------------+--------+

^a^ P-value from Fisher\'s Exact Test for categorical variables, F-test
for continuous variables

-   *Treatment After Wafer Implantation Surgery*

[Radiation Therapy]{.underline}. All but one patient, who died on study
day 35 of a rapidly growing tumor, received post-operative radiation
therapy. Applicant's Table 4 presents the mean and median doses of
radiation delivered.

+-------------------------+---------------+-------------+-------------+
| **Applicant\'s Table    |               |             |             |
| 4.14: Radiotherapy      |               |             |             |
| Treatment Regimen       |               |             |             |
| Summary**               |               |             |             |
+-------------------------+---------------+-------------+-------------+
|                         | GLIADEL 3.85% | PLACEBO     | P‑value^a^  |
|                         |               |             |             |
|                         | \[N = 16\]    | \[N = 16\]  |             |
+-------------------------+---------------+-------------+-------------+
|                         | Number        |             |             |
|                         | (Percentage)  |             |             |
|                         | of Patients   |             |             |
+-------------------------+---------------+-------------+-------------+
| **Cumulative            |               |             |             |
| Radiotherapy (cGy)**    |               |             |             |
+-------------------------+---------------+-------------+-------------+
| N                       | 15            | 16          |             |
+-------------------------+---------------+-------------+-------------+
| Mean (SD)               | 5649.5        | 5362.9      | 0.2454      |
|                         | (333.0)       | (878.1)     |             |
+-------------------------+---------------+-------------+-------------+
| Median                  | 5575          | 5403        |             |
+-------------------------+---------------+-------------+-------------+
| Range                   | 5040 - 6000   | 2895 - 6400 |             |
+-------------------------+---------------+-------------+-------------+
| ^a^ Fisher's Exact Test |               |             |             |
+-------------------------+---------------+-------------+-------------+

[Systemic Chemotherapy]{.underline}. Only one patient on the placebo arm
received systemic chemotherapy, two courses of procarbazine, lomustine,
and vincristine.

-   *Concomitant Medications*

Dexamethasone was the most commonly prescribed medication after wafer
implantation. All patients received dexamethasone, methylprednisolone or
betamethasone. There were no statistically significant differences
between the treatment arms with respect to mean daily dose and total
dose per patients for each medication.

Anticonvulsants were not commonly prescribed; 3 patients on GLIADEL® and
1 on placebo were prescribed carbamazepine.

9.2.3 [Efficacy Results]{.underline}

Orion-Farmos, the sponsor, performed an interim analysis after the first
16 patients, the results of which have not been provided. The NDA states
that\...\"the analysis was blinded and consisted of a few tabulations
and a non-parametric analysis of survival. The treatment code for the
study was unblinded on June 28, l995.\"

*Comment: The p-values provided by Guilford for the final reported
survival analysis are unadjusted for this first look. However, since the
p values are not borderline, this should not have a significant impact
on the results*

Guilford has assessed the primary endpoint of survival by survival rate
at 12 months as well as Kaplan-Meier techniques at two timepoints, 12
and 24 months post wafer implantation. Guilford states, \"The 12-month
timepoint for the analyses was chosen because 12 months was given in the
protocol as the expected median survival in the placebo treatment group,
and was used as the basis for the protocol\'s power calculation\....The
24-month timepoint for the analyses was chosen because the maximum
duration of follow-up for all patients was 24 months.\" In addition to
survival, the protocol identified a second primary endpoint as the
progression-free interval.

-   *Twelve-Month Outcomes*

[Mortality Rate]{.underline}. Six patients on GLIADEL® and 13 on placebo
died by 12 months after wafer implantation (p = 0.029, Fisher\'s exact
test), leaving 10 alive on GLIADEL® and 3 alive on placebo.

[Survival]{.underline}. The twelve-month Kaplan-Meier survival curve by
treatment arm is shown in Applicant\'s Figure 2.

![](media/image27.png){width="6.496527777777778in"
height="4.252083333333333in"}

Cumulative mortality through 12 months shows a highly significantly
difference between the arms, with a lower mortality for the GLIADEL® arm
with a logrank p = 0.0087 and a Gehan\'s generalized Wilcoxon p =
0.0105.

[Twelve-Month Survival Adjusted for Prognostic Factors]{.underline}.
Eight variables were selected as being of potential clinical importance.
Of the eight factors evaluated by univariate regression, three were
identified as statistically significant as defined by a P \< 0.15
(Applicant\'s Table 4.20, p.34).

**Applicant\'s Table 4.19: Potential Prognostic Factors for Overall
Patient Survival**

**(Univariate Cox Regression) \-- All Patients**

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**95% Confidence Limits**

**[Prognostic Factor Risk Ratio Lower Upper P‑value\*]{.underline}**

GBM Patients vs. Non-GBM Patients 4.715 1.092 20.35 **0.0377**

Karnofsky Score \>70 vs. 70 0.723 0.327 1.597 0.4226

75% Resection vs. \<75% Resection 0.941 0.419 2.113 0.8824

Age (per Decade) 1.826 1.131 2.950 **0.0138**

Male vs. Female Patients 1.370 0.629 2.987 0.4280

MMSE Scores Median 0.377 0.170 0.833 **0.0159**

Prior Seizures vs. None 0.774 0.309 1.938 0.5845

Number of Wafers 6 vs. \>6 1.037 0.449 2.395 0.9328

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\*Wald Chi-Square test; P‑values 0.15 appear in bold-face type

*Comment: The NDA lacks a discussion of choice of 8 factors for the
Finnish study vs. 15 for the North American Study or for 8 vs. generally
accepted prognostic factors in newly diagnosed patients. No new factors
are added; some deletions apply to the relapsed setting only, e.g.,
radiation, prior chemotherapy, years from first surgery, resection vs.
biopsy at first surgery, and prior brachytherapy vs. none; information
on race was not collected; the remaining two deletions were prior
convulsions vs. none and prior steroid use vs. none. KPS, generally
accepted as an important prognostic factor in newly diagnoses patients,
was not seen to be statistically significant in the applicant\'s
analysis. However, it was found to be significant in analyses performed
by the FDA\'s Statistical Reviewer.*

After adjustment for prognostic factors, GLIADEL® produced a
statistically significant reduction in mortality compared to placebo.
For all patients, the risk ratio was 0.154 (p=0.0010) and 0.179 for all
patients stratified by tumor type (p=0.0038). See Applicant\'s Table
4.20.

  ------------------------------- ----------- ------------ -------- ------------
  Applicant Table 4.20: 12-Month                                    
  Treatment Effect Adjusted for                                     
  Prognostic Factors \-- All                                        
  Patients                                                          

  Prognostic Factor               Risk Ratio  95%                   
                                              Confidence            
                                              Limits                

                                              Lower        Upper    P‑value^a^

  **All Patients**                                                  

  GLIADEL 3.85% vs. PLACEBO       0.154       0.051        0.467    0.0010

  Age (per decade)                2.302       1.089        4.864    0.0290

  Mini-Mental Scores Median       0.207       0.070        0.613    0.0044

  **All Patients Stratified by                                      
  Tumor Type**                                                      

  GLIADEL 3.85% vs. PLACEBO       0.179       0.056        0.574    0.0038

  Age (per decade)                2.266       1.075        4.777    0.0315

  Mini-Mental Scores Median       0.218       0.074        0.645    0.0059

  ^a^ Wald Chi-Square test                                          

                                                                    
  ------------------------------- ----------- ------------ -------- ------------

-   *Overall Survival*

As of the data cutoff date of 5/14/95 (observation period up to 24
months), six patients were alive: 5 of 16 (31%) who had received
GLIADEL® and 1 of 16 (6%) who had received placebo (p = 0.172, Fisher\'s
exact test). The median duration of survival was 13.37 months (95% CI:
9.66 - inestimable maximum) and 9.17 months (95% CI: 8.64 - 10.33) in
the GLIADEL® and placebo groups, respectively.

The Kaplan-Meier curve for 24 months is shown below in Applicant\'s Fig.
3.

![](media/image28.png){width="5.728472222222222in"
height="6.913888888888889in"}

[Overall Survival Adjusted for Prognostic Factors]{.underline}. After
adjustment for prognostic factors, GLIADEL® produced significant
reductions in overall survival. The risk ratios were 0.177 for all
patients (p=0.0005) and 0.214 for all patients stratified by tumor type
(p=0.0029), as shown in Applicant\'s Table 4.21.

+--------------------------+-------------+--------+---------+--------+
| **Applicant Table 4.21:  |             |        |         |        |
| Overall Treatment Effect |             |        |         |        |
| Adjusted for Prognostic  |             |        |         |        |
| Factors \--**            |             |        |         |        |
|                          |             |        |         |        |
| **All Patients All       |             |        |         |        |
| Patients**               |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
| Prognostic Factor        | Risk Ratio  | 95%    |         |        |
|                          |             | Conf   |         |        |
|                          |             | idence |         |        |
|                          |             | Limits |         |        |
+--------------------------+-------------+--------+---------+--------+
|                          |             | Lower  | Upper   | P‑va   |
|                          |             |        |         | lue^a^ |
+--------------------------+-------------+--------+---------+--------+
|                          |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
| GLIADEL 3.85% vs.        | 0.177       | 0.067  | 0.468   | 0.0005 |
| PLACEBO                  |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
| Age (per decade)         | 2.248       | 1.208  | 4.182   | 0.0106 |
+--------------------------+-------------+--------+---------+--------+
| Mini-Mental Scores       | 0.250       | 0.100  | 0.626   | 0.0031 |
| Median                   |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
| **All Patients           |             |        |         |        |
| Stratified by Tumor      |             |        |         |        |
| Type**                   |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
| GLIADEL 3.85% vs.        | 0.214       | 0.078  | 0.590   | 0.0029 |
| PLACEBO                  |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
| Age (per decade)         | 2.219       | 1.193  | 4.131   | 0.0119 |
+--------------------------+-------------+--------+---------+--------+
| Mini-Mental Scores       | 0.241       | 0.094  | 0.619   | 0.0031 |
| Median                   |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
| ^a^ Wald Chi-square test |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+
|                          |             |        |         |        |
+--------------------------+-------------+--------+---------+--------+

-   *Subgroup Analysis: GBM Patients*

Twenty-seven of 32 patients carried the diagnosis of GBM: 11/16 (69%) in
the GLIADEL® arm and 16/16 (100%) in the placebo arm. Twelve and
24-month survival for all patients and for GBM vs. non-GBM patients is
shown in Reviewer Table 12.

**Reviewer Table 12: Survival Rates for All Patients and by Tumor Type**

+----------------+--------------+------------+------------+------------+
|                | 12-Month     |            | Overall    |            |
|                |              |            | (up to 24  |            |
|                |              |            | months)    |            |
+----------------+--------------+------------+------------+------------+
|                | GLIADEL®     | Placebo    | GLIADEL®   | Placebo    |
+----------------+--------------+------------+------------+------------+
| **All Patients | n = 16       | n = 16     | n = 16     | n = 16     |
| (n = 32)**     |              |            |            |            |
|                | 6            | 13         | 11         | 15         |
| Dead           |              |            |            |            |
|                | 10           | 3          | 5          | 1          |
| Alive          |              |            |            |            |
+----------------+--------------+------------+------------+------------+
| Fisher\'s      | p = 0.029    |            |            | p = 0.172  |
| Exact Test     |              |            |            |            |
+----------------+--------------+------------+------------+------------+
| **GBM (n =     | n = 11       | n = 16     | n = 11     | n = 16     |
| 27)**          |              |            |            |            |
|                | 5            | 13         | 9          | 15         |
| Dead           |              |            |            |            |
|                | 6            | 3          | 2          | 1          |
| Alive          |              |            |            |            |
+----------------+--------------+------------+------------+------------+
| Fisher\'s      | p = 0.097    |            |            | p = 0.5487 |
| Exact Test     |              |            |            |            |
+----------------+--------------+------------+------------+------------+
| **Non-GBM (n = | n = 5        | n = 0      | n = 5      | n = 0      |
| 5)**           |              |            |            |            |
|                | 1            |            | 2          |            |
| Dead           |              |            |            |            |
|                | 4            |            | 3          |            |
| Alive          |              |            |            |            |
+----------------+--------------+------------+------------+------------+

Applicant\'s Fig. 5 shows an overall Kaplan-Meier survival curve for GBM
patients only. The median survival duration was 12.3 months (95% CI:
9.23 - 17.87 mo.) for patients treated with GLIADEL® and 9.2 months (95%
CI: 8.64 - 10.35 mo.) for patients on placebo. The difference in
12-month and 24-month survival is shown in below.

![](media/image29.png){width="5.324305555555555in"
height="5.772222222222222in"}

-   *Time to Treatment Failure (All Patients)*

Time to treatment failure was measured from the time of wafer
implantation surgery to the earliest point that treatment failure was
declared, using protocol specified criteria. Twelve patients (75%) in
the GLIADEL® arm and 14 (88%) in the placebo arm were considered to have
failure of treatment. The median time to treatment failure for patients
on GLIADEL® was 7.79 months (95% CI: 3.22 - 9.66 mo.) vs. 6.67 months
(95% CI: 3.02 - 9.86 mo.), p = 0.4668 (logrank) or p = 0.9635
(Wilcoxon).

-   *Secondary Efficacy Analyses*

The applicant found no significant differences between the treatment
arms with regard to change in mean KPS or mini-mental status exam from
baseline. See Statistical Review for further details.

-   *Drug-Demographic Interactions*

The applicant did not provide analyses for a significant treatment by
age or gender interaction for this study. Information on race was not
collected on the CRF. See the Statistical Review for these analyses; an
interaction with gender is seen, with survival in women greater than in
men; however, these data should be interpreted cautiously given the
small numbers of patients available for analysis.

9.2.4 [Safety Results]{.underline}

Adverse events were collected on the CRF by asking the investigator to
(1) list the AE; (2) judge severity on a four point scale of mild,
moderate, severe, life-threatening; (3) judge its relationiship to
treatment as not assessable, none, remote, possible, or probable (i.e.,
no \"definite\" category); (4) provide start and end dates; and (5)
describe outcome. Specific A.E.s were not solicited.

The NDA states\...\"Pre-existing medical conditions that did not worsen
in severity during the study period were not considered
treatment-emergent adverse events. Multiple events with the same term,
reported by one patient during the study period but having different
severities, were treated as a single event of the worst recorded
severity\...\"

-   *Deaths*

+-----------------------------+-------------+-------------+----------+
| Applicant Table 4.34:       |             |             |          |
| Summary of Cause of Death   |             |             |          |
| and Relationship of Death   |             |             |          |
| to Study Medication         |             |             |          |
+-----------------------------+-------------+-------------+----------+
|                             | GLIADEL     | PLACEBO     | P‑value  |
|                             | 3.85%       |             |          |
|                             |             | \[N = 15\]  |          |
|                             | \[N = 11\]  |             |          |
+-----------------------------+-------------+-------------+----------+
|                             | Number      |             |          |
|                             | (           |             |          |
|                             | Percentage) |             |          |
|                             | of Patients |             |          |
+-----------------------------+-------------+-------------+----------+
| **Cause of Death**          | 10 (91)     | 13 (87)     | 0.213    |
|                             |             |             |          |
| Brain Tumor                 | 0 (0)       | 1 (7)\*     |          |
|                             |             |             |          |
| Other                       | 1 (9)       | 1 (7)       |          |
|                             |             |             |          |
| Not Assessable              |             |             |          |
+-----------------------------+-------------+-------------+----------+
| **Relationship of Death to  | 0 (0)       | 0 (0)       | 0.083    |
| Study Medication**^a^       |             |             |          |
|                             | 0 (0)       | 0 (0)       |          |
| Probable                    |             |             |          |
|                             | 0 (0)       | 1 (7)       |          |
| Possible                    |             |             |          |
|                             | 10 (91)     | 14 (93)     |          |
| Remote                      |             |             |          |
|                             |             |             |          |
| None                        |             |             |          |
+-----------------------------+-------------+-------------+----------+

\*Death due to pulmonary embolus

*Comment: Deaths were not clustered in the perioperative period, see K-M
curves above.*

-   *Treatment Withdrawal Due to Toxicity*

There were no reports of wafer removal in this study.

-   *All Treatment-Emergent A.E.s by Body System*

Due to the limited number of patients on this trial, all
treatment-emergent A.E.s (rather than A.E.s with [\>]{.underline} 5%
incidence) are presented (Applicant\'s Table 4.35 on the following
page). Twice as many events (31 vs. 16) were reported in the GLIADEL®
arm compared to the placebo arm. The body system that had the most
number of A.E.s was the nervous system, with 19 reported in patients
treated with GLIADEL® and 9 in patients who received placebo. The
difference in the number of patients with A.E.s (vs. number of A.E.s)
between the arms was not statistically significant.

+---------------+-------+-------------+---------+-------------+------+
| Applicant     |       |             |         |             |      |
| Table 4.35:   |       |             |         |             |      |
| All           |       |             |         |             |      |
| Treat         |       |             |         |             |      |
| ment-Emergent |       |             |         |             |      |
| Adverse       |       |             |         |             |      |
| Events        |       |             |         |             |      |
| Summarized by |       |             |         |             |      |
| Body System   |       |             |         |             |      |
+---------------+-------+-------------+---------+-------------+------+
|               | GL    |             | PLACEBO |             | P‑   |
|               | IADEL |             |         |             | valu |
|               | 3.85% |             | \[N =   |             | e^a^ |
|               |       |             | 16\]    |             |      |
|               | \[N = |             |         |             |      |
|               | 16\]  |             |         |             |      |
+---------------+-------+-------------+---------+-------------+------+
| Body          | N     | Number      | Number  | Number      |      |
| System^b^     | umber | (           | of      | (           |      |
|               | of    | Percentage) | Occu    | Percentage) |      |
|               | O     | of Patients | rrences |             |      |
|               | ccurr |             |         | of Patients |      |
|               | ences |             |         |             |      |
+---------------+-------+-------------+---------+-------------+------+
| Body as a     | 2     | 2 (13)      | 2       | 2 (13)      | 1    |
| Whole         |       |             |         |             | .000 |
+---------------+-------+-------------+---------+-------------+------+
| C             | 4     | 3 (19)      | 2       | 1 (6)       | 0    |
| ardiovascular |       |             |         |             | .600 |
+---------------+-------+-------------+---------+-------------+------+
| Endocrine     | 1     | 1 (6)       | 0       | 0 (0)       | 1    |
|               |       |             |         |             | .000 |
+---------------+-------+-------------+---------+-------------+------+
| Hemic and     | 0     | 0 (0)       | 2       | 2 (13)      | 0    |
| Lymphatic     |       |             |         |             | .484 |
+---------------+-------+-------------+---------+-------------+------+
| Metabolic and | 1     | 1 (6)       | 0       | 0 (0)       | 1    |
| Nutritional   |       |             |         |             | .000 |
+---------------+-------+-------------+---------+-------------+------+
| Mu            | 1     | 1 (6)       | 0       | 0 (0)       | 1    |
| sculoskeletal |       |             |         |             | .000 |
+---------------+-------+-------------+---------+-------------+------+
| Nervous       | 19    | 10 (63)     | 9       | 6 (38)      | 0    |
|               |       |             |         |             | .289 |
+---------------+-------+-------------+---------+-------------+------+
| Respiratory   | 0     | 0 (0)       | 1       | 1 (6)       | 1    |
|               |       |             |         |             | .000 |
+---------------+-------+-------------+---------+-------------+------+
| Special       | 2     | 2 (13)      | 0       | 0 (0)       | 0    |
| Senses        |       |             |         |             | .484 |
+---------------+-------+-------------+---------+-------------+------+
| Uncertain     | 1     | 1 (6)       | 0       | 0 (0)       | 1    |
|               |       |             |         |             | .000 |
+---------------+-------+-------------+---------+-------------+------+
| Total         | 31    |             |         | 16 events   |      |
|               | e     |             |         | were        |      |
|               | vents |             |         | reported    |      |
|               | were  |             |         |             |      |
|               | rep   |             |         | by 9        |      |
|               | orted |             |         | patients    |      |
|               |       |             |         |             |      |
|               | by 12 |             |         |             |      |
|               | pat   |             |         |             |      |
|               | ients |             |         |             |      |
+---------------+-------+-------------+---------+-------------+------+
| ^a^ Fisher    |       |             |         |             |      |
| Exact test    |       |             |         |             |      |
|               |       |             |         |             |      |
| ^b^ The       |       |             |         |             |      |
| investigator  |       |             |         |             |      |
| verbatim      |       |             |         |             |      |
| term\* was    |       |             |         |             |      |
| used in place |       |             |         |             |      |
| of a COSTART  |       |             |         |             |      |
| preferred     |       |             |         |             |      |
| term when the |       |             |         |             |      |
| verbatim term |       |             |         |             |      |
| was judged to |       |             |         |             |      |
| be so         |       |             |         |             |      |
| nonspecific   |       |             |         |             |      |
| that          |       |             |         |             |      |
| assignment to |       |             |         |             |      |
| an            |       |             |         |             |      |
| appropriate   |       |             |         |             |      |
| COSTART       |       |             |         |             |      |
| preferred     |       |             |         |             |      |
| term could    |       |             |         |             |      |
| not be made   |       |             |         |             |      |
| u             |       |             |         |             |      |
| nambiguously, |       |             |         |             |      |
| or when the   |       |             |         |             |      |
| most          |       |             |         |             |      |
| appropriate   |       |             |         |             |      |
| COSTART       |       |             |         |             |      |
| preferred     |       |             |         |             |      |
| term was      |       |             |         |             |      |
| either        |       |             |         |             |      |
| misleading,   |       |             |         |             |      |
| so general as |       |             |         |             |      |
| to be         |       |             |         |             |      |
| u             |       |             |         |             |      |
| ninformative, |       |             |         |             |      |
| or too        |       |             |         |             |      |
| specific to   |       |             |         |             |      |
| be accurate.  |       |             |         |             |      |
| If a patient  |       |             |         |             |      |
| had more than |       |             |         |             |      |
| one instance  |       |             |         |             |      |
| within a      |       |             |         |             |      |
| category,     |       |             |         |             |      |
| only the      |       |             |         |             |      |
| instance with |       |             |         |             |      |
| the greatest  |       |             |         |             |      |
| severity is   |       |             |         |             |      |
| listed.       |       |             |         |             |      |
+---------------+-------+-------------+---------+-------------+------+

-   *Frequently Reported Treatment-Emergent A.E.s*

A.E.s reported in [\>]{.underline} 2 patients are displayed in Applicant
Table 4.36 below.

+--------------------+-----------------+----------------+--------------+
| Applicant Table    |                 |                |              |
| 4.36:              |                 |                |              |
| Treatment-Emergent |                 |                |              |
| Adverse Events     |                 |                |              |
| Occurring in Two   |                 |                |              |
| or More Patients   |                 |                |              |
| in Either          |                 |                |              |
| Treatment Group by |                 |                |              |
| Body System and    |                 |                |              |
| COSTART Term       |                 |                |              |
+--------------------+-----------------+----------------+--------------+
|                    | GLIADEL 3.85%   | PLACEBO        | P‑value^a^   |
|                    |                 |                |              |
|                    | \[N = 16\]      | \[N = 16\]     |              |
+--------------------+-----------------+----------------+--------------+
| Body               | Number          |                |              |
| System/Adverse     | (Percentage) of |                |              |
| Event^b^           | Patients        |                |              |
+--------------------+-----------------+----------------+--------------+
| **Nervous**        | 2 (13)          | 1 (6)          | 1.000        |
|                    |                 |                |              |
| Aphasia            | 3 (19)          | 2 (13)         | 1.000        |
|                    |                 |                |              |
| Convulsion         | 6 (38)          | 4 (25)         | 0.704        |
|                    |                 |                |              |
| Hemiplegia         |                 |                |              |
+--------------------+-----------------+----------------+--------------+
| **Special Senses** | 2 (13)          | 0 (0)          | 0.484        |
|                    |                 |                |              |
| Visual Field       |                 |                |              |
| Defect             |                 |                |              |
+--------------------+-----------------+----------------+--------------+
| ^a^ Fisher's Exact |                 |                |              |
|                    |                 |                |              |
| ^b^ The            |                 |                |              |
| investigator       |                 |                |              |
| verbatim term\*    |                 |                |              |
| was used in place  |                 |                |              |
| of a COSTART       |                 |                |              |
| preferred term     |                 |                |              |
| when the verbatim  |                 |                |              |
| term was judged to |                 |                |              |
| be so nonspecific  |                 |                |              |
| that assignment to |                 |                |              |
| an appropriate     |                 |                |              |
| COSTART preferred  |                 |                |              |
| term could not be  |                 |                |              |
| made               |                 |                |              |
| unambiguously, or  |                 |                |              |
| when the most      |                 |                |              |
| appropriate        |                 |                |              |
| COSTART preferred  |                 |                |              |
| term was either    |                 |                |              |
| misleading, so     |                 |                |              |
| general as to be   |                 |                |              |
| uninformative, or  |                 |                |              |
| too specific to be |                 |                |              |
| accurate.          |                 |                |              |
+--------------------+-----------------+----------------+--------------+

-   *Severity of Treatment-Emergent A.E.s*

In the GLIADEL® arm, 2 A.E.s (P.E. and stupor) were rated by the
investigator as life-threatening and 17 severe compared to no
life-threatening and 7 severe A.E.s in the placebo arm. Applicant\'s
Table 4.38 tabulates these A.E.s by patient.

+-------------------------------+-----------------+--------------------+
| > Applicant Table 4.38:       |                 |                    |
| > Life-threatening and Severe |                 |                    |
| > Treatment Emergent Adverse  |                 |                    |
| > Events                      |                 |                    |
| >                             |                 |                    |
| > by Treatment Group and by   |                 |                    |
| > Body System and COSTART     |                 |                    |
| > Term                        |                 |                    |
+-------------------------------+-----------------+--------------------+
|                               | GLIADEL 3.85%   | PLACEBO            |
|                               |                 |                    |
|                               | \[N = 16\]      | \[N = 16\]         |
+-------------------------------+-----------------+--------------------+
| Body System/                  | Number          |                    |
|                               | (Percentage) of |                    |
| Adverse Event^a^              | Patients        |                    |
+-------------------------------+-----------------+--------------------+
| **Cardiovascular**            | 1^b^            | 1                  |
|                               |                 |                    |
| Pulmonary Embolus             | 1               | 1^c^               |
|                               |                 |                    |
| Thrombophlebitis              |                 |                    |
+-------------------------------+-----------------+--------------------+
| **Metabolic and Nutritional** | 1               | 0                  |
|                               |                 |                    |
| Diabetes Mellitus             |                 |                    |
+-------------------------------+-----------------+--------------------+
| **Musculoskeletal**           | 1               | 0                  |
|                               |                 |                    |
| Spondylitis VIII-IX\*         |                 |                    |
+-------------------------------+-----------------+--------------------+
| **Nervous**                   | 2               | 0                  |
|                               |                 |                    |
| Aphasia                       | 1               | 0                  |
|                               |                 |                    |
| Brain Edema                   | 1               | 0                  |
|                               |                 |                    |
| Convulsion                    | 1               | 0                  |
|                               |                 |                    |
| Depression                    | 5               | 4                  |
|                               |                 |                    |
| Hemiplegia                    | 1               | 0                  |
|                               |                 |                    |
| Hydrocephalus                 | 1               | 1                  |
|                               |                 |                    |
| Meningitis                    | 1^b^            | 0                  |
|                               |                 |                    |
| Stupor                        |                 |                    |
+-------------------------------+-----------------+--------------------+
| **Special Senses**            | 1               | 0                  |
|                               |                 |                    |
| Visual Field Defect           |                 |                    |
+-------------------------------+-----------------+--------------------+
| **Uncertain**                 | 1               | 0                  |
|                               |                 |                    |
| Rapid Deterioration\*         |                 |                    |
+-------------------------------+-----------------+--------------------+
| ^a^ The investigator verbatim |                 |                    |
| term\* was used in place of a |                 |                    |
| COSTART preferred term when   |                 |                    |
| the verbatim term was judged  |                 |                    |
| to be so nonspecific that     |                 |                    |
| assignment to an appropriate  |                 |                    |
| COSTART preferred term could  |                 |                    |
| not be made unambiguously, or |                 |                    |
| when the most appropriate     |                 |                    |
| COSTART preferred term was    |                 |                    |
| either misleading, so general |                 |                    |
| as to be uninformative, or    |                 |                    |
| too specific to be accurate.  |                 |                    |
| If a patient had more than 1  |                 |                    |
| instance within a category,   |                 |                    |
| only the instance with the    |                 |                    |
| greatest severity is listed.  |                 |                    |
|                               |                 |                    |
| ^b^ Life-threatening          |                 |                    |
| treatment-emergent adverse    |                 |                    |
| event; all other events were  |                 |                    |
| severe.                       |                 |                    |
|                               |                 |                    |
| ^c^FDA reviewer addition to   |                 |                    |
| applicant table to correct    |                 |                    |
| typographical error           |                 |                    |
+-------------------------------+-----------------+--------------------+
|                               |                 |                    |
+-------------------------------+-----------------+--------------------+

-   *Treatment-Related, Treatment-Emergent A.E.s*

There were no A.E.s that the investigator rated as definitely (not
listed as an option on the CRF) or probably related to treatment. The
four that were listed as possibly related were infection, fever and
headache in 3 patients on GLIADEL® and infection in one patient who
received placebo wafer.

-   *Clinically Significant A.E.s with Possible Causal Relationship*

[Convulsion]{.underline}. There were no statistically signiciant
differences in convulsions between the treatment arms. Three patients in
the GLIADEL® arm and 2 patients who received placebo had
treatment-emergent convulsions. The median time to onset of
treatment-emergent convulsions was 207 days in the GLIADEL® group and 61
days in the placebo group.

[Healing Abnormality]{.underline}. One patient who received placebo
wafer had a CSF leak from the nose, judged to be of mild severity by the
investigator.

[Infection]{.underline}. Four serious infections occurred, 2 on GLIADEL®
(wound infection and meningitis) and 2 on placebo (wound infection and
CSF leak/meningitis).

[Hydrocephalus/cerebral edema]{.underline}. One patient treated with
GLIADEL® had meningitis diagnosed on day 6 and subsequently developed
hydrocephalus by day 36. Another patient who received GLIADEL®
experienced severe postoperative cerebral edema on day 1.

**10.2 #9003: Interstitial Chemotherapy for Malignant Glioma: A Pilot
Study to Examine the Safety of GLIADEL® Placed at the Time of First
Surgery**

#9003 was a multicenter, open-label safety pilot in a maximum of 30
patients in whom GLIADEL® would be implanted during initial resection,
followed by standard external beam radiation therapy.

10.2.1 [Protocol Review]{.underline}

*Objective*: \"To determine the safety of GLIADEL® as an adjunctive
treatment with surgery and external beam radiotherapy in newly diagnosed
malignant glioma patients.\"

*Eligibility/Exclusion Criteria*: Patients with unifocal, unilateral
malignant glioma at least 1.0 cm diameter, at least 18 years of age and
with a KPS of [\>]{.underline} 60. *(Criteria matched the other study
enrolling initially diagnosed patients, #CL-0190, with the exception
that #9003 did not have an upper age limit.)*

*Procedure*: Up to eight wafers of GLIADEL® were to be placed in the
resection cavity. Sample slides were to be sent to the referee
pathologist, Dr. Peter Burger at Duke University. XRT was required to be
consistent with \"standard methods and schedules,\" starting three weeks
post surgery.

*Baseline and Followup Examinations*: Physical examination and KPS,
MMSE, CT or MRI, and laboratory tests. *(This matched #CL-0190 with the
exception that followup was every 2 months starting with the date of
surgery.)*

*Statistical section*: The protocol states that \"in order to have a
sufficient number of evaluable patients entered to make reasonable
conclusions regarding safety, the study will be initiated at three
centers. Each center will have the potential to enroll ten patients;
however, when any one center reaches ten patients, study entry will be
terminated at the remaining centers.\" All patients were to be evaluated
for safety 6 months after radiation therapy for a final study evaluation
but followed for a maximum of 2 years postop. Time to treatment failure
was defined identically to the controlled studies although this was not
a protocol objective. Adverse events were described by severity (mild,
moderate or severe), relation to GLIADEL®, whether intervention was
required, and information on the outcome (recovered, ongoing, died, lost
to followup).

*Amendments*: **Amendment #1** dated August 6, 1990 prohibited adjuvant
systemic BCNU and provided criteria for early cessation of the study
based on toxicity. Entry onto the study would cease until a thorough
investigation had been completed in the following circumstances: (1) if
two patients exhibit a decrement in the neurological examination score
of [\>]{.underline} 2 points (scale 0-4) in [\>]{.underline} 5 of the 11
categories within two weeks of initiation of XRT that is not
attributable to tumor progression; or, (2) death of two patients within
one month of initiation of XRT not attributable to progressive disease.
**Amendment #2** dated October 3, l990 expanded the critical timeframe
for noting changes in the neurological evaluation from within two weeks
of XRT initiation to during XRT and within two weeks from the conclusion
of XRT.

10.2.2 [Results]{.underline}

Twenty two patients were enrolled at three institutions (JHOC 10,
Columbia Presbyterian Medical Center 6, Charlotte Memorial Hospital 6)
from July 5, l990 to August 14, l991. Seven patients were female (32%)
and 15 male (68%) with a median age of 60 (range 40-86). Referee and
institutional pathologists agreed that 20 patients had a glioblastoma
multiforme and one had anaplastic astrocytoma (the diagnosis of one
patient is missing). The median KPS was 85 (range 40-100).Eighteen
patients had 8 wafers implanted; four had 7. Three patients (14%) had
total resections, 5 patients (23%) had total resection by lobectomy, and
14 patients (64%) had subtotal resections. Twenty-one of the 22 patients
received XRT (median dose 5816 cGy, range 4500-8280); followup on the
remaining patient is unclear.

-   *Deaths.* As of last followup November 10, 1995, 19/22 (86%) of
    patients had died, with a median survival of 41.7 weeks (95% CI 31.9
    to 54.0 weeks). The earliest death occurred 132 days after surgery.
    The 6-, 12-, and 24-month survival rates were 82%, 36% and 14%,
    respectively. Deaths were secondary to brain tumor recurrence with
    the exception of one patient who died of a concurrent
    intra-abdominal malignant lymphoma, for which treatment was refused.
    None of the deaths occurred within 2 weeks of the conclusion of XRT.

```{=html}
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```
-   *Adverse Events.* Treatment emergent A.E.s experienced by
    [\>]{.underline} 2 patients were convulsion, penumonia, necrosis,
    and UTI; see Reviewer Table 15 derived from the data listings. The
    most frequent and serious treatment-emergent A.E.s were related to
    the nervous system. Sixteen patients (73%) experienced one or more
    A.E.s related to the nervous system and 7 (32%) experienced one or
    more events elsewhere in the body. Seventeen patients (29%) had an
    A.E. rated as severe; however, only the events in the central
    nervous system had more than one patient with a severe A.E. There
    were no A.E.s considered by the investigator to be
    definitely-related to study drug.

**Reviewer Table** **15**

+-------------+---------+-----------+----------+----------+----------+
| **Body      | **\#    | **\#      | **Tre    |          |          |
| System**    | P       | Patients  | atment-R |          |          |
|             | atients | (%) with  | elated** |          |          |
|             | (%)**   | Severe    |          |          |          |
|             |         | A.D.**    | **       |          |          |
|             | **with  |           | Probable |          |          |
|             | A.E.**  |           | Possible |          |          |
|             |         |           | Unr      |          |          |
|             |         |           | elated** |          |          |
+-------------+---------+-----------+----------+----------+----------+
| Nervous     | 12 (54) | 3 (14)    | 0 (0)    | 2 (9)    | 9 (41)   |
|             |         |           |          |          |          |
| Convulsion  | 3 (14)  | 1 (5)     | 1 (5)    | 2 (9)    | 0 (0)    |
|             |         |           |          |          |          |
| Necrosis    | 2 (9)   | 1 (5)     | 0 (0)    | 2 (9)    | 0 (0)    |
|             |         |           |          |          |          |
| Edema       | 4 (18)  | 4 (18)    | 0 (0)    | 1 (5)    | 3 (14)   |
|             |         |           |          |          |          |
| Confusion,  | 1 (4)   | 0 (0)     | 0 (0)    | 1 (5)    | 0 (0)    |
| Coma, Neuro |         |           |          |          |          |
+-------------+---------+-----------+----------+----------+----------+
| Infection   | 4 (18)  | 1 (5)     | \-       | \-       | 4 (18)   |
|             |         |           |          |          |          |
| Pneumonia   | 3 (14)  | 0 (0)     |          |          | 3 (14)   |
|             |         |           |          |          |          |
| UTI         | 1 (5)   | 1 (5)     |          |          | 1 (5)    |
|             |         |           |          |          |          |
| Sepsis      | 1 (5)   |           |          |          | 1 (5)    |
|             |         |           |          |          |          |
| Healing     |         |           |          |          |          |
| Abnormality |         |           |          |          |          |
+-------------+---------+-----------+----------+----------+----------+
| DVT         | 2 (9)   | 1 (5)     | \-       | \-       | 2 (9)    |
+-------------+---------+-----------+----------+----------+----------+
| Metabolic   | 1 (5)   | 1 (5)     | \-       | \-       | 1 (5)    |
|             |         |           |          |          |          |
| Dehydration |         |           |          |          |          |
+-------------+---------+-----------+----------+----------+----------+
| Digestive   | 1 (5)   | 1 (5)     | \-       | \-       | 1 (5)    |
|             |         |           |          |          |          |
| GI          | 1 (5)   | 1 (5)     |          |          | 1 (5)    |
| hemorrhage  |         |           |          |          |          |
|             |         |           |          |          |          |
| Vomiting    |         |           |          |          |          |
+-------------+---------+-----------+----------+----------+----------+
| Other       | 2 (9)   | 1 (5)     | \-       | \-       | 2 (9)    |
|             |         |           |          |          |          |
| Dilantin    | 1 (5)   | 1 (5)     |          |          | 1 (5)    |
| Toxicity    |         |           |          |          |          |
|             |         |           |          |          |          |
| 2nd         |         |           |          |          |          |
| malignancy  |         |           |          |          |          |
+-------------+---------+-----------+----------+----------+----------+

Of the 11 patients with convulsions, the outcomes of six were considered
\"recovered\" and of 5 to be \"ongoing.\" Two patients had convulsion
within the first month of surgery; one had a convulsion 10 days postop
requiring intubation. The average time from surgery to convulsion was
2.7 months. Two of the 11 patients had convulsion listed as a baseline
medical condition.

-   *Reoperation.* Nine of 19 patients underwent reoperation. All
    patients had completed a course of EBRT.

*Comment: In study CL-0190 in which initially diagnosed patients
underwent wafer plus XRT, no patient underwent second operation, perhaps
due to patterns of practice between the countries.*

3.  Conclusion

Toxicity was considered acceptable in this patient population. No
dose-limiting toxicities as defined in the protocol were seen.

**Reviewer Summary from 1996 NDA 20,637 (Gliadel)**

Trial 8802 appears to be an adequate and well-controlled study. The
treatment effect on overall survival for patients with high grade
gliomas does not reach statistical significance. The largest treatment
difference is seen at six months, which does not appear to be a
surrogate for overall survival in a population with a median survival of
less than a year. The robustness of such a six-month endpoint is
weakened by lack of a correlation with improvement in QoL parameters,
e.g., KPS, MMSE, and wide variability of results depending on adjustment
for prognostic factors, which are not generally accepted in this
recurrent patient population. However, the robustness improves for the
subgroup of patients with glioblastoma multiforme, where the survival
advantage for patients treated with Gliadel® is seen not only at
six-months, but is reflected in overall survival in an unadjusted
analysis (Gehan\'s generalized Wilcoxon test), both specified in the
protocol.

Study CL-0190, which had not been discussed with the FDA prior to NDA
submission, meets many of the criteria for an adequate and
well-controlled study; however, the early closure of the trial and
limited patient numbers are serious flaws. Even accepting the early
closure as unbiased, i.e., no further study drug, only 32 patients were
entered thereby possibly inflating any proposed treatment effect.
Although a statistically significant treatment effect on survival is
seen when all patients are analyzed, clinical trials in malignant glioma
are typically conducted separately for AA vs GBM or the trial provides
for stratification on the basis of histology due to inherent differences
in outcomes. In CL-0190, the 5 patients with the more favorable
histology all randomized to Gliadel®. When these patients are excluded
in a subgroup analysis for GBM, the statistically significant difference
between the treatment groups is lost.

An argument could be made that it would be biologically plausable for a
treatment effect in relapsed patients to convey to newly diagnosed
patients. However, the results from #8802 might not be considered
robust, with variable results depending on the type of analysis and the
statistical signficance depending on conducting subgroup analysis or a
Cox Regression based on prognostic factors not accepted in the relapsed
population. Furthermore, it is not certain that relapsed GBM is more
resistant than newly diagnosed GBM, i.e., since the tumor presents as
resistant initially, results may not be more dramatic in patients who
have not yet received chemotherapy. Other concerns raised at the ODAC
meeting were lack of knowledge of chronic toxicity, e.g., dementia which
has resulted from other local treatment such as intraarterial
chemotherapy to the brain or any effect related to nonbiodegradable
wafers, both of which may be more relevant issues for the newly
diagnosed patient. Lastly, intravenous BCNU is an available alternative
while definitive trials with Gliadel® in the newly diagnosed patient are
being conducted.

The toxicity profile of Gliadel® in relapsed patients is consistent with
a regional delivery system at the time of operation. The primary
toxicities in relapsed patients were related to neurologic function and
wound healing/infection. The toxicities could be considered acceptable
given the clinical setting; however, it should be noted that the
incidence may be underestimated since the control arm was a foreign
body. The biodegradability of the wafers appears to be variable, the
clinical significance of which is not yet known.

**1996** **Oncology Drugs Advisory Committee Questions and Votes**

Dr. Paul Bunn chaired the ODAC meeting held June 14, 1996.

Questions re. Study #8802:

1\. **Is Study #8802 an adequate and well-controlled study?** 8/8 Yes.

2.  **Do the survival data provide convincing evidence of efficacy of
    Gliadel® wafers?**

4/8 Yes; 4/8 No.

3\. **Is the toxicity profile of Gliadel® acceptable for patients with
recurrent malignant gliomas?** 7/8 Yes; 1/8 abstention.

4\. **Is Gliadel® approvable in conjunction with surgical resection for
treatment of recurrent malignant gliomas?** The committee commented that
the labeling should be clear that Gliadel® is an adjunct for patients in
whom surgical resection is indicated, i.e., a surgical procedure is not
recommended for the sole purpose of implanting Gliadel®. 6/8 Yes; 2/8
No.

5\. **If so, should approval be limited to glioblastoma multiforme or be
for all types of malignant gliomas?** 7/8 Yes; 1/8 abstention.

Questions re. Study #CL-0190:

l\. **Is CL-0190 an adequate and well-controlled study?** The question
was amended to be answered in two parts: (a) to provide supportive data
for #8802, and (b) to provide efficacy data for Gliadel® in newly
diagnosed patients. (a) 6/8 Yes; 2/8 No. (b) 8/8 No.