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FDA Review :
Cisplatin / Epinephrine Gel (CEG) in the Treatment of
Head and Neck Cancer
Outline of FDA Presentation
• Regulatory overview
• Medical review findings
• Statistical review findings
• Summary and introduction of questions
FDA Cisplatin-Gel NDA Review Team
Project Managers Dianne SpillmanDotti Pease
Medical Gregory K. Frykman, M.D.Grant Williams, M.D.
Statistics Rajeshwari Sridhara, Ph.D./Jasmine Choi, M.S.Gang Chen, Ph.D.
Chemistry& Haripada, Sarker, Ph.D.Manufacturing Eric Duffy, Ph.D./Hasmukh Patel, Ph.D.
Pharmacology& Doo Y. Lee Ham, Ph.D.Toxicology David Morse, Ph.D.
Clinical Sophia Abraham, Ph.D.Pharmacology Atiqur Rahman, Ph.D.
D. Scientific Khin U, M.D.Investigations
Requirements for New Drug Approval
• 1962 efficacy amendment to Federal Food, Drug and Cosmetic Act– Adequate and well controlled trials– Clinical benefit
Basis of Oncology Drug Approvals
• Prior to mid-1980s, approvals based on RR
• Mid 1980s: Requirement for survival or improvement in symptoms
• Subsequently, RR or other tumor endpoints sometimes accepted on case-by-case basis
Full Approval Based on RR or other Tumor Endpoints
• Disease free survival• Complete responses• Consideration of response rate should
include response duration and treatment toxicity
• Legitimacy of RR is enhanced by correlation with improvement in tumor-related symptoms
Oncology Drug Approvals Supported by RR or TTP
• Cutaneous lesions of Kaposi’s Sarcoma or Cutaneous T cell lymphoma
Approvals Based Primarily on Tumor-Related Symptoms
• Photofrin for obstructing esophageal cancer (1995)
• Photofrin for obstructing lung cancer (1998)
• Mitoxantrone (1996)
FDA meetings with Applicant
• 1994: RR not accepted as clinical benefit
• Clinical trials :– Randomized, blinded assessment of
improvement in individual problems.
FDA Reservations about Protocol
• Preventive goals– questions about legitimacy of goals– advantage for Cisplatin Gel based on
differential dropout, not on a difference in event rate
– FDA analyses exclude preventive goals
• 1-point change on palliative scale
FDA Clinical Review
Study DesignMain Objectives
• Compare the effect on tumor volume
• Assess achievement of primary treatment goal
Key Design Features
» Stratified
» Randomized
» Double-blind
» Placebo-controlled
» Powered to Detect ORR Difference
Study DesignStratification
Stratum 1 0.5 - 5.0 cm3
Stratum 2 >5.0 - 20.0 cm3
Stratum 3 20.0+ cm3
Submitted Clinical Data
414-94-2 III 110 US, Canada HNSCC
514-94-2 III 115 Europe/Israel HNSCC
516-99-PK 16 US, Europe HNSCC
39-92-2 I 45 US Solid Tumors
403-93-2 II 67 US Solid Tumors
503-93-2 II 59 Eur./S. Africa Solid Tumors
Correspondence with Applicant• “Symptomatic response” strongly recommended as primary efficacy endpoint (12/97)
• Agreed that Primary analysis will be symptom improvement; tumor responses to be supportive. (12/97)
• Agency will require a strong correlation between patient benefit and tumor shrinkage in individuals. (5/00)
• Improvement in one point may not be sufficient evidence of clinical benefit. (5/00)
Clinical Endpoints
Dosing RegimenPre-Amendment V
• 0.5 mL gel/cm3 of tumor volume
• Injection volume based on initial tumor
dimensions
• Single injection technique
• 62 patients enrolled
Dosing RegimenPost-Amendment V
• 0.25 mL gel/cm3 of tumor volume
• Tumor volume recalculated each visit
• Injection by “fanning” or “grid” technique
• 163 patients enrolled
Study Design Key Eligibility Criteria
• Recurrent or Refractory SCC of the Head & Neck
• At least one course of therapy:–chemotherapy, radiotherapy, surgery or biological
response modifier therapy
• Primary or metastatic lesions allowed
• Exclude systemic disease, arrhythmias
Study DesignStudy Phases
TreatmentPhase
Follow-upPhase
ExtendedFollow-up
Phase10-12 weeks 5 months Not specified
TreatmentPeriod
Eval.Period
6-8 weeks 4 weeks
Study 414 ResultsNumber of Centers, Location, Duration
44 Centers
US and Canada
15 Jun. 1995 - 22 Mar. 2000
Study 514 ResultsNumber of Centers, Location, Duration
28 Centers
Europe and Israel
21 Jun. 1995 - 22 Mar. 2000
Study 414 & 514 ResultsDemographics
Patients enrolled on to each study appeared reasonably equally distributed between the arms and strata for:
Age
KPS
Histological Grade
Prior therapy
Ethnicity
Study 414 ResultsTreatment Delivered
No. ofTreatmentsReceived
Active CEGn = 62
Placebo Geln = 24
1 62 100.0% 100.0% 242 56 90.3% 95.8% 233 42 67.7% 70.8% 174 28 45.2% 25.0% 65 15 24.2% 4.2% 16 10 16.1% 0.0% 0
Study 514 ResultsTreatment Delivered
No. ofTreatmentsReceived
Active CEGn = 57
Placebo Geln = 35
1 57 (100.0%) 35 (100.0%)2 55 (96.5%) 30 (85.7%)3 49 (86.0%) 24 (68.6%)4 34 (59.6%) 15 (42.9%)5 24 (42.1%) 8 (22.9%)6 24 (42.1%) 6 (17.1%)
Study 414 ResultsReason for Termination
Reason for Termination Number (%)Systemic disease progression 28 (25.6)Progressive disease of the target tumor 22 (20.0)Patient request, not otherwise specified 18 (16.3)Unacceptable AE’s/local toxicity 15 (13.6)Death on study 12 (10.9)Need for other therapy not per protocol 5 (4.5)Completed study 1 (0.9)Other 9 (8.2) Total 110 (100.0 %)
Study 514 ResultsReason for Termination
Reason for Termination Number (%)Systemic disease progression 22 (19.1)Progressive disease of the target tumor 44 (38.2)Patient request, not otherwise specified 9 (7.8)Unacceptable AE’s/local toxicity 9 (7.8)Death on study 13 (11.3)Need for other therapy not per protocol 2 (1.7)Completed study 6 (5.2)Other 10 (8.7) Total 115 (100.0 %)
Study 414 ResultsEfficacy Analysis - Active Arm
OR 20/62 (32.3%)*
CB 3/51 (5.9%)
CB+OR 2/51 (4.0%)
* Only 3/20 ORs were treated with the protocol-
specified dose and schedule
Study 514 ResultsEfficacy Analysis - Active Arm
OR 13/57 (22.8%)*
CB 10/54 (18.5%)
CB+OR 5/54 (9.3%)
*Only 6/13 ORs were treated with the protocol-
specified dose and schedule
Study 414 & 514 ResultsBlinding Adequacy Questions
» Differential toxicity
» Differential dropout
» Local Hair loss
» Yellow-colored Eschar
» Reflux
» Possibility of Direct Observation
» Sleeve Removal Potential
Study 414 & 514 ResultsCauses of Dosing Errors
Measurement Error
Inherent error
Small Lesions Amplify Uncertainty
Local Tissue Disruption
Calculation Error
Dose Calculation
Missing Data
Injection in the Absence of Tumor Size
Administration Error
Incorrect Dosing (reflux, PI discretion)
Study 414 ResultsActual Dose vs. Planned Dose
0
20
40
60
80
100
120
-90 ~ -100
-50 ~ -89.9
-25 ~49.9
-10 ~ -24.9
-0.01 ~-9.9
0.01 ~9.9
10 ~24.9
25 ~49.9
50 ~89.9
90 ~100
100 ~more
Dosing Errors in Percent
Study 514 ResultsActual Dose vs. Planned Dose
0
2
4
6
8
10
12
14
16
18
-90 ~ -100
-50 ~ -89.9
-25 ~49.9
-10 ~ -24.9
-0.01~ -9.9
0.01 ~9.9
10 ~24.9
25 ~49.9
50 ~89.9
90 ~100
100 ~more
# o
f T
reat
me
nts
Study 414 & 514 ResultsInternal Consistency Concerns» Missing Data
» Patient and PI Palliative Benefit Score
Inconsistent
» Palliative Benefit Inconsistent with
Local Toxicity
» Palliative Benefit Inconsistent with Tumor
Size
Study 414 & 514 ResultsLocal Toxicity Parameters
» Bleeding/Hemorrhage
» Erythema
» Erosion
» Eschar formation
» Necrosis
» Swelling
» Ulceration
Study 414 & 514 Safety
• Six cases of stroke
• One case of complete blindness
• Inadvertant direct injection into vital organs
cannot be excluded.
Study 414 & 514 Summary
• Concerns about Study Conduct
• Concerns about Blinding
• Concerns about Internal Consistency
• Modest ORR
• Minimal Benefit with OR
• Smaller Lesions Respond Better
Study 414 & 514 Summary
• Local Toxicity Greater than Placebo
• Stroke and Blindness were Observed to be
Associated with IntraDose and Placebo
Administration
• Clinical Value of Local Treatment in the
Presence of Regional or Systemic Progression
FDA Statistical Review
Areas of Major Statistical Problems
• Two co-primary efficacy endpoints: objective tumor response and patient benefit, in both randomized studies (Studies 414 and 514)
• Association between objective tumor response and patient benefit
Objective MTT Response
Objective MTT Response - Study 414
% ResponseIntraDose
(N= 62)Placebo(N = 24)
P-value
SponsorAnalysis
34% 0% 0.001
FDAAnalysis
32% 0% 0.001
Objective MTT Response -Study 514
% ResponseIntraDose
(N= 57)Placebo(N = 35)
P-value
SponsorAnalysis
25% 3% 0.007
FDAAnalysis
23% 3% 0.014
Graph of Survival Data
Clinical Patient Benefit
Patient Benefit
• Sponsor / Per Protocol Analysis: Palliative and Preventive Treatment Goals selected by investigators, not patients
• Patient Benefit Algorithm• Palliative Goals measured on a scale of 1-4• Decrease in score by 1 point ( 1) is benefit• Preventive Goals measured as met or not met• Different Goals for each patient
Patient Benefit Algorithm
Clinical Benefit - Study 414 and Study 514: Sponsor Analyses
% Clinical BenefitIntraDose Placebo
P-value
Study 414 34%N = 62
17%N = 24
0.18
Study 514 19%N = 57
9%N = 35
0.24
Study 414 +Study 514
27%N = 119
12%N = 59
0.046
Pooled Analysis Not Acceptable• When both studies have failed to demonstrate
clinical benefit• Inflates type I error• Causes Imbalance in Randomization• The patient population differs between the
two studies• Selection pattern of treatment goals differs
between the two studies• Can only be used as supportive evidence and
not primary evidence
Treatment Received - Study 414
0
20
40
60
80
100
1 2 3 4 5 6
Number of Treatments Received
Pe
rce
nta
ge
IntraDose
Placebo
Treatment Received - Study 514
0
20
40
60
80
100
1 2 3 4 5 6
Number of Treatments Received
Pe
rce
nta
ge
IntraDose
Placebo
Preventive Goals - Investigator Assessment
TotalN
Met Same NotMet
N.E.
Study 414 IntraDose 31 71% 13% 13% 3% Placebo 13 31% 46% 0% 23%Study 514 IntraDose 11 36% 27% 9% 27% Placebo 10 20% 40% 10% 30%
Patient preventive Benefit
• The preventive Benefit was discredited by the FDA, because:
* Differential pattern in number of treatments administered between IntraDose and Placebo arms– Potential for bias in assessment– Potential for unblinding– Not interpretable– Incidence within 8 - 12 weeks period not established
* Almost all the benefitters that the sponsor has claimed in the US Study are based on achievement of preventive goal
Investigator Assessment of Change in Palliative Treatment Goal Score
Study 414
Change inScore
IntraDose Placebo
-2 0 0-1 1
3%0
0 23 74% 11 100%+1 6 0+2 0
19%0
N.E. 1 0
Investigator Assessment of Change in Palliative Treatment Goal Score
Study 514
Change inScore
IntraDose Placebo
-2 2 0-1 5
15%1
4%
0 31 67% 20 80%+1 5 2+2 2 0+3 1
17%
0
8%
N.E. 0 2
Patient or Investigator Palliative Benefit Assessment - Study 414 FDA Analyses
IntraDoseN = 51
PlaceboN = 20
P-value1
P-value2
1Better 3 (6%) 1 (5%) 0.26 1.00Worse 13 (25%) 2 (10%)No Change 34 (67%) 16 (80%) 2Better 2 (4%) 0 (0%)Worse 1 (2%) 0 (0%)1 = Wilcoxon-rank-sum test; 2 = Binary outcome -Fisher's exact testJonckhere Terpstra Test: P-value = 0.15
Patient or Investigator Palliative Benefit Assessment - Study 514 FDA Analyses
IntraDoseN = 54
PlaceboN = 33
P-value1
P-value2
1Better 10 (19%) 1 (3%) 0.69 0.05Worse 12 (22%) 4 (12%)No Change 31 (57%) 25 (76%) 2Better 2 (4%) 0 (0%)Worse 3 (6%) 0 (0%)1 = Wilcoxon-rank-sum test; 2 = Binary outcome -Fisher's exact testJonckhere Terpstra Test: P-value = 0.84
Clinical Patient Benefit - FDA Analyses
6 5
19
3
25
1022
12
6780
57
76
0
20
40
60
80
100
IntraDose Placebo IntraDose Placebo
Pe
rce
nta
ge
Better
Worse
No Change
Study 414 Study 514
Clinical Patient Benefit• Both the randomized studies failed to demonstrate clinical
patient benefit of IntraDose versus Placebo by Sponsor’s Analyses and FDA Analyses.
• Validity of a one-point change as a clinically meaningful patient benefit is debatable. If one-point change is excluded, then both studies demonstrated < 5% palliative benefit. If one-point change is included then only 6% appear to have palliative benefit versus 25% who got worse in the US Study 414 and 19% appear to have palliative benefit versus 22% who got worse in the Europe Study.
• Per Sponsor 6/119 (5%) of IntraDose treated versus 1/59 (2%) of placebo treated patients attained investigator and patient
specified primary treatment goals.
Association Between Tumor Response and Patient Benefit - Study 414
Sponsor AnalysisMTT Response
PatientBenefit
Responder Non-responder
Benefitter10 11
Non-benefitter
11 30
p-value 0.16Sensitivity = 10/21 = 0.48
Association Between Tumor Response and Patient Benefit - Study 514
Sponsor Analysis
MTT ResponsePatientBenefit
Responder Non-responder
Benefitter6 5
Non-benefitter
8 38
p-value 0.02Sensitivity = 6/14 = 0.43
Association Between Tumor Response and Patient Benefit - Study 414
FDA Analysis
MTT ResponsePatientBenefit
Responder Non-responder
Benefitter2 1
Non-benefitter
14 34
Sensitivity = 2/16 = 0.13
Association Between Tumor Response and Patient Benefit - Study 514
FDA Analysis
MTT ResponsePatientBenefit
Responder Non-responder
Benefitter5 5
Non-benefitter
7 37
Sensitivity = 5/12 = 0.42
Association Between Tumor Response and Patient Benefit
• P-values of association between tumor response and patient benefit should be interpreted cautiously.
• The association is predominantly because of large
number of patients classified as non-responders and non-benefitters
• Preferred measure of association between patient
benefit and tumor response is sensitivity, and this was < 50% in each of the studies and in the
combined study data.
Summary
• Both the randomized studies failed to demonstrate clinical patient benefit (primary endpoint) of IntraDose
• It is not evident that the objective tumor response translates into clinical benefit
Summary of FDA Findings
Objective Response Rate
Cis Gel PlaceboStudy 414 32% (20/62) 0% (0/24)Study 514 23% (13/57) 3% (1/35)
CEG Placebo
Better 6% (3/51) 5% (1/20)
Worse 25% (13/51) 10% (2/20)
Primary palliative goalStudy 414
Study 514CEG Placebo
Better 19% (10/54) 3% (1/33)
Worse 22% (12/54) 12% (4/33)
Issues to consider• Evaluate primary palliative goals, tumor
response, and association between the two
• What is the clinical importance of other data:– the objective response data – other data on clinical benefit
• Accelerated Approval not a viable option
