# Presentation: 453359

## sNDA # 20-637GLIADEL® WAFER(Polifeprosan 20 with Carmustine Implant)APPLICANT:  GUILFORD PHARMACEUTICALS

- ODAC:  December 6, 2001
-      Medical Reviewer:   Alla Shapiro, M.D., Ph.D.
- Statistical Reviewer:  Ning Li, M.D., Ph.D.

## FDA Presentation

- Regulatory history    	Dr. Alison  Martin
- Study T-301		Dr. Alla Shapiro					Dr. Ning  Li
- Review Issues		Dr. Alison Martin

## Regulatory History 

- <date/time>

- Regulatory History

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

## Regulatory History

- <date/time>

- Regulatory History

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

## New Indication

- <date/time>

- New Indication

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

## New Indication

- <date/time>

- New Indication

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

## Clinical ReviewStudy T-301

**Notes:**
Thank you.

## GLIADEL Wafer Proposed Indication

-     “GLIADEL Wafer is indicated for use as a treatment to significantly prolong survival and maintain overall function (as measured by preservation of Karnofsky Performance Status)* *and neurological function in patients with malignant glioma undergoing primary and/or recurrent surgical resection”.

**Notes:**
Current indication is different from the previous Gliadel approval in terms of the stage of the disease (newly diagnosed malignant glioma vs. recurrent), and patient population (ITT for this study and GBM subgroup for the previous application).

## Study Objectives

- _Primary_
- 		- survival (ITT)
- _Secondary_
- _	__	_- survival in the GBM subgroup
- 		-adjusted analyses for KPS, age and tumor type
-    		-1-year survival (ITT and GBM)
- 		- progression-free survival (ITT)
- 		- survival censoring patients with reoperation for
-              disease progression (ITT)
- 		- KPS scores (ITT)
- 		- QoL (ITT)
- 		- neuroperformance measures (ITT)

**Notes:**
Survival in the ITT population was the primary efficacy endpoint for the study.
Secondary endpoints are listed on the slide.
It was stated in the SAP GBM population was defined as population of interest for the treatment effect.
The protocol did not rank the secondary endpoints and there were no adjustments in the SAP for multiplicity.

## Phase 3 Trial  Study T-301

**Notes:**
TRIAL DESIGN:
All patients were randomized to Gliadel or placebo group.  Randomization was STRATIFIED by CENTER.
After maximal surgical resection all patients were to receive limited field radiation therapy.  Subsequently, all patients with the histological diagnosis of AOD were to receive 6 cycles of chemotherapy .  No systemic chemotherapy was permitted for treatment of initial tumor for patients with other histological diagnoses.

## Study Enrollment

- Patients
- 240
- 14 countries
- 48 patients in France
- 44 patients in Germany
- 38 centers
- 7 centers in France and 5 in Germany
- 5 centers in the US accrued 12 patients

**Notes:**
A total of 240 patients were enrolled at 38 centers in 14 countries.  The largest number of patients were accrued in 7 centers in France and in 5 centers in Germany.  In the US only 12 patients were accrued in 5 centers.

## Baseline Characteristics

**Notes:**
The next  2 slides show the distribution of 3 known and accepted prognostic factors in newly diagnosed glioma.  Patients age and baseline KPS appear reasonably balanced in both groups.

## Tumor Histology

**Notes:**
We agree with the Sponsor data that Glioblastoma multiforme  comprises the majority of histological diagnoses in both groups.
 We also agree on the number of patients with non-GBM histology with the exception of 3 patients.  We carried further the determination of diagnoses termed as “other” for this 3 patients,  because we believe that it is more informative in the data analysis.
Overall, there were slightly more patients with a favorable histology in the Gliadel than in the placebo (17 and 13 patients, respectively).  
We agree with the Sponsor that one  patient with the diagnosis of ASTROCYTOMA, GEMISTOCYTIC that we included into the AA group, should be termed as “other”. 
To assess the effect of slight imbalances in the most important prognostic factors such as age, KPS, and tumor histology, we performed an exploratory Cox- regression analysis adjusting for these 3 covariates. This analysis will be presented by Dr. Li. 

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

**Notes:**
Protocol-specified treatments included:
Standard XRT was delivered to 78% of patients on the Gliadel group and 80% on placebo.  The remaining of the patients received either “non-standard” or “no radiation”.

## Chemotherapy

-                                           GLIADEL 	  Placebo
-        		                           N =120 (%)        N=120 (%)
- 						   		       Chemotherapy for PD        14 (11.7)	    14 (11.7)
-      Within 30 days
-                AOD - 11	                  1 (0.8)	       1 (0.8)
- 	    AOA -  11		 2 (1.7)           2 (1.7)
-         TOTAL		                17 (14.2)          17 (14.2)

**Notes:**
This table summarizes all patients who received chemotherapy, both for disease progression as well as for the histological diagnoses of AOD and AOA.  There were 11 patients with AOD and AOA.  Although all patients did not receive chemotherapy as per protocol, the number of patients who did is balanced across the arms.

## Other Treatment for PD

**Notes:**
This slide presents additional treatments that could potentially impact survival.  They are reoperation, with or without Gliadel re-implantation, and radiation.
Overall, there was only a difference of 2 patients receiving additional therapy between the arms.

## Efficacy Results

## Primary Efficacy Endpoint Overall Survival

- 		           _GLIADEL_		     _Placebo_
- _	__	_           88 (73.3%)	              93 (77.5%)
-  months              13.9		                  11.6
-  95 % CI        (12.1 -15.3)                      (10.2-12.6)
- p = 0.08         log-rank  (protocol-specified)
- p = 0.07         log-rank  (stratified by center)
- p = 0.03         log-rank  (stratified by country)

**Notes:**
Primary analysis for survival was to be conducted 12 months after the last patient was entered.  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.
In the Gliadel group median survival was increased by 2 months compared to the placebo.
The protocol and SAP specified a log-rank test for the primary analysis, which did not reach statistical significance.  
The Sponsor presents the primary analysis by a LR stratified by country which has a “p”value of 0.03. 
THIS IS ONE OF OUR REVIEW ISSUES AND WILL NOW BE DISCUSSED BY Dr. LI IN GREATER DETAIL.

## Primary Efficacy Analysis:Statistical Issues

## Primary Efficacy Analysis

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

**Notes:**
 The primary analysis proposed in the sponsor’s protocol as well as in the Statistical analysis plan was to “compare the overall survival in the  two treatment groups with a log-rank test.
And the log-rank test stratified on each of the Four prognostic covariates, I. E. Kronosky Performance Score, Age, tumor type (GBM/or non-GBM), and COUNTRY,  would be performed  as secondary analysis and is considered as supportive to the primary efficacy analysis.
Supportive analysis usually used to strengthen the primary analysis results when the primary wins.

## Overall Survival Curves for Study T-301

**Notes:**
This is the resulting overall K-M survival curves for Study T-301. The  doted curve is Gliadel arm and the solid line is the placebo arm .

##  Primary Efficacy Analysis(Protocol Specified OS ITT Analysis) 

- <date/time>

-  Primary Efficacy Analysis(Protocol Specified OS ITT Analysis)

**Notes:**
The protocol specified primary analysis result is summarized in this slide.
There were  88 events in Gliadel group and 93 events in the placebo control group.
The estimated median survival difference is about 2.3 month with a hazard ratio of .77 in favor of the Gliadel group. But there is no statistically significant difference (log-rank p-value is 0.08) between the two arms.The sponsor claimed a 23% (or 29%) risk reduction based upon the Hazard ratio point estimate. But since the CI upper bound can not exclude 1, statistically speaking, there is no evidence that the risk in the trt arm is lower than the placebo arm even we want to take 5% chance to make a wrong decision. 

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

- <date/time>

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

**Notes:**

As mentioned earlier, the supportive secondary analysis using a log-rank test stratified by the four pre-specified prognostic covariats were performed. This slide shows the results. 
The log-rank test stratified by Kronosky score has a p-value of 0.07.
And the log-rank test stratified by age has a p-value of 0.10 and by GBM has a p-value of 0.14.
the stratified analysis by Center results in a p-value of 0.07. But Center was not a pre-specified stratification variable.
The only significant difference is the log-rank test stratified by  COUNTRY, which has a p-value of 0.03.

## Survival Analysis: Cox Model Adjusting for Covariates

**Notes:**

The analyses adjusting all pre-specified prognostic variables were performed as secondary analyses. Entries are p-values for the treatment effect.  When adjusting all of these three covariates,  no statistically significant treatment effect can be detected in three types of analyses. These analyses are supportive analyses. Supportive analysis usually used to strengthen the primary analysis results when the primary wins.

## Survival Analysis Summary 

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

**Notes:**
To summarize the survival analysis, all results of survival comparisons between the two arms are not statistically significant except the analysis stratified by COUNTRY.

The sponsor presented the stratified by country analysis as the primary analysis and concluded significant survival benefit. The sponsor ‘s argument is that stratified analysis is appropriate because randomization list was stratified by COUNTRY and “using center may cause over-stratification” 

## Issues

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

**Notes:**
Now we have two statistical related issues.  
The first issue is: Should one use a stratified or non-stratified analysis? Which one is more appropriate? 
Our position is: either one is acceptable as long as you pre-specify one in the protocol.
Retrospective selection is problematic because it will inflate Type I error.
The second issue about stratified factor has been resolved after discussing with the sponsor and came to an  agreement that the randomization was stratified by CENTER Not Country.

## 	Randomization List for All U.S. Sites

**Notes:**

We can tell this by checking all 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 pts entered the study in Jan and FEB:  pt number with asteroids and italics #2005, #2013, #2021, and #2024 should share  the same block number.  

##  Exploratory Analysis: Log-rank Stratified by CENTER

- <date/time>

-  Exploratory Analysis: Log-rank Stratified by CENTER

**Notes:**
If we believe a stratified analysis should be used, then according to the sponsor’s argument, the CENTER should be the stratification factor. The result is similar to non-stratified log-rank test with a p-value of 0.073.  

## Primary Efficacy Analysis:Summary of Statistical Issues

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

**Notes:**
To  conclude, 
Protocol specified analysis for overall survival was not statistically significant with a  p-value of 0.08.
The log-rank test stratified by center and all other stratified analysis,
which includes stratified by Age, stratified by Perfomance score, stratified by tumor type, or adjusted all three covariates, are not statistically significant.
Sponsor's analysis, log-rank test stratified by COUNTRY, is  questionable as the primary analysis because:
  (1). It is not pre-specified as the primary. 
  (2). The result is not supported by secondary adjusted analyses.
  (3). If both stratified and non-stratified analyses had been pre-specified, then multiple analyses would be an issue and certain alpha adjustment will be needed.
Dr. Shapiro will present the results for secondary endpoints.

## Secondary Endpoints

**Notes:**
Thank you.

## Secondary Endpoint:Survival in GBM

- 		_	__	__	_
- 		_	__ __GLIADEL_		    _Placebo__	__	_	79 (78.2%)       	  85 (80.2%)
-  months   	     13.5	                    11.4
-  95 % CI          (11.4 -14.8)             	   (10.2-12.6)
- p =  0.20          log-rank (protocol-specified)
- p =  0.16          log-rank stratified by center
- p =  0.09          log-rank stratified by country

**Notes:**
In the SAP GBM subgroup was chosen as a population of main interest for the treatment effect. 
Of the 240 patients enrolled, 207 ( 86%) carried the diagnosis of GBM.  A total of 79 patients (78.2%) in the Gliadel group and 85 patients (80.2%) in the placebo group died before the study cut-off date.
Overall survival in this population demonstrates a nonsignificant trend favoring the Gliadel group. 
The difference in the point estimate of median survival is 2 months. 
Statistical significance between the treatment arms was not shown by either non-stratified or stratified log-rank analyses.

## Secondary Endpoint: 1-Yr Survival

-  ITT population
- 		  	  	_GLIADEL_	        	  _Placebo_
- 		(%)	      	      59.2 		    49.6
-      	95 % CI       (50.4 - 68.0)	        (40.6 - 58.6)
- Not significant by log-rank, unstratified/stratified
- GBM subgroup
- _	_	           		 _GLIADEL_                         _Placebo_
- 		(%)	                57.4		                     48.6
- 		95 % CI	  (47.8 - 67.1)	                  (39.0 - 58.1)
-  Not significant by log-rank, unstratified/stratified

**Notes:**
Comparison of one year survival rate in both the ITT and GBM subgroup appear to favor Gliadel but they are not significant by Log-rank non-stratified or stratified. 

## Secondary Endpoint: Progression-Free Survival 

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

**Notes:**
The Sponsor’s analysis of PFS showed no difference between the treatment groups. FDA did not analyze this secondary endpoint.  We consider PFS difficult to assess in this patient population previously treated with surgery, radiation therapy, or steroids.

## Secondary Endpoint:Time to KPS Deterioration

- 		    	          _GLIADEL_         		 _Placebo_
-   months                      11.9	                             10.4
-  95% CI	       (10.4 - 13.7)		 (9.5 - 11.9)
-  p = 0.11        log-rank (protocol-specified)
** **p = 0.27        log-rank (stratified by center)
-  p = 0.05        log-rank (stratified by country)

**Notes:**
Time to Karnofsky Performance Status deterioration was one of 3 QOL measures prespecified in the protocol. 

In assessing time to KPS deterioration, 
the sponsor counted death as an event. This slide shows the result.
In a non - stratified log-rank test this prognostic factor did not reach statistical significance.  Time to KPS deterioration becomes statistically significant if the log-rank is stratified by country, but not center.  

## Secondary Endpoint: Time to KPS Deterioration (Death not account as an event)

- 		    	          _GLIADEL_         		 _Placebo_
-   Months                      18.3	                             17.9
-  95% CI	       (14.3 - 24.0)		 (17.2- 24.0)
-  p = 0.61        log-rank
** **p = 0.47        log-rank (stratified by center)
-  p = 0.41        log-rank (stratified by country)

**Notes:**
However, we believe death should not be counted as an event for this analysis because death is an confounding variable. 
The log-rank tests did not reach statistical significance in any of the analysis.

## Secondary Endpoint: QoL

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

**Notes:**
QoL was also assessed by EORTC Quality of Life Questionnaire-30 and Brain Cancer Module, a validated 24-question QoL instrument designed to be used with QoL-30.  The primary QoL parameter prespescified in the protocol was a measure of Global Health Status based upon  Questions # 29 and #30.
No significant differences were shown between the two groups in both sponsor and FDA analyses.
Not powered to show significant differences Not powered to show significant differences Not p#29:  How would you rate your overall physical condition during the past week?
#30:     --------------- your QoL during the past week?
owered to show nificant differences Not powered to show significant differences Not powered to show significant differences Not powered to sw significant differences Not powered to show significant differences Not powered toow significant differences Not powered to show significant differences Not powered to show significant differences Not powered to show significant differences Not powered to show significant differences 

## Time to Neuroperformance Deterioration (ITT Population)

**Notes:**
Sponsor has presented a summary of data collected for the eleven pre-specified neuroperformance measures.

Although consistency in outcome appears across most of these measures, conclusions about significance are questionable.  The protocol did not pre- specify for multiple testing in either in secondary analyses or analysis as a whole in this population.  Furthermore, these findings are not supported by the analyses of time to KPS deterioration or patient-report QoL.

## Time to Neuroperformance Deterioration (ITT Population)

**Notes:**
Sponsor has presented a summary of data collected for the eleven pre-specified neuroperformance measures.

Although consistency in outcome appears across most of these measures, conclusions about significance are questionable.  The protocol did not pre- specify for multiple testing in either in secondary analyses or analysis as a whole in this population.  Furthermore, these findings are not supported by the analyses of time to KPS deterioration or patient-report QoL.

## Deaths within 30 days

Local Complications

- Local Complications

- Safety Results

**Notes:**
In assessing Safety Results we will be focusing on death within first 30 days after surgery as well as local complications.

## Cause of Deaths in the First 30 Days of Randomization

**Notes:**
The Agency looks at deaths within 30 days of therapy as possibly related to therapy.
The groups are balanced for systemic causes of deaths within 30 days - 2 in each arm.  Only the Gliadel arm had deaths due to local complications such as cerebral hemorrhages.

##    Local Complications

**Notes:**
Local complications are presented on this slide. 
We agree with Sponsor’s assessment of occurrence of the most common local complications after wafer implantation.  
There are a numerical differences in incidence of ICH, CSF leak and post-operative mortality in the Gliadel group.
It is also possible that assessment of risk may be underestimated since the control group is placebo wafer.
We will ask the committee to weigh the (significance?) acceptability of these findings against any benefit when we conclude with the questions.
And now I’d like to turn the ...... “The review issues”.  Thank you.

## Review Issues

## Single Trials:   Evidence of Effectiveness*

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

## T-301: Single Trial

- Strengths
- multicenter
- placebo wafer (efficacy)
- blinded pathology review
- survival = 1o endpoint
- point estimates of median survival
- prior approval

- Weaknesses
- placebo wafer (toxicity)
- 1o endpoint: stat persuasive?
- stratified logrank,  multiple analyses,  interim look?
- GBM - bridging population
-  not statistically persuasive
- prior approval:
- malignant glioma NS

## Can the trials presented in 1996 be considered confirmatory?

## Primary Basis of Approval: North American Trial

- Recurrent malignant glioma
- 222 patients entered
- 145 (65%) with GBM
- 77 (35%) with other histologies - balanced

## North American Trial

## Overview of Median Survival in ITT Population

**Notes:**
The previous approval was based on a survival effect in GBM in the recurrent setting.  One might expect if histology is an important factor for treatment effect, that this subgroup would show more of an effect in the first line setting when the disease could be more sensitive.  However, survival did not reach significance in the newly diagnosed GBM.  The p value appears to be driven by the other histologic subgroup in newly diagnosed patients.  

Prior approval considered histology important.  Not borne out in first line setting by subgroup analysis of Cox regression.  Does this make sense?

## Supportive:  Scandinavian Trial

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

## Scandinavian Trial

## Summary of Review Issues

- <date/time>

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

**Notes:**

covariates

## Questions for the Committee

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

## Questions....

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

## Slide 54