FDA Review : Cisplatin / Epinephrine Gel (CEG) in the Treatment of Head and Neck Cancer

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