FDA Review : Cisplatin Epinephrine Gel CEG in the Treatment of Head and Neck Cancer - PowerPoint PPT Presentation

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

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Sponsor / Per Protocol Analysis: Palliative and Preventive Treatment Goals ... Evaluate primary palliative goals, tumor response, and association between the two ... – PowerPoint PPT presentation

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Title: FDA Review : Cisplatin Epinephrine Gel CEG in the Treatment of Head and Neck Cancer


1
FDA Review Cisplatin / Epinephrine Gel (CEG)
in the Treatment of Head and Neck Cancer
2
Outline of FDA Presentation
  • Regulatory overview
  • Medical review findings
  • Statistical review findings
  • Summary and introduction of questions

3
FDA Cisplatin-Gel NDA Review Team
Project Managers Dianne Spillman Dotti
Pease Medical Gregory K. Frykman,
M.D. Grant Williams, M.D. Statistics Rajeshwa
ri 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
4
Requirements for New Drug Approval
  • 1962 efficacy amendment to Federal Food, Drug and
    Cosmetic Act
  • Adequate and well controlled trials
  • Clinical benefit

5
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

6
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

7
Oncology Drug Approvals Supported by RR or TTP
  • Cutaneous lesions of Kaposis Sarcoma or
    Cutaneous T cell lymphoma

8
Approvals Based Primarily on Tumor-Related
Symptoms
  • Photofrin for obstructing esophageal cancer
    (1995)
  • Photofrin for obstructing lung cancer (1998)
  • Mitoxantrone (1996)

9
FDA meetings with Applicant
  • 1994 RR not accepted as clinical benefit
  • Clinical trials
  • Randomized, blinded assessment of improvement in
    individual problems.

10
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

11
FDA Clinical Review
12
Study Design
  • Main Objectives
  • Compare the effect on tumor volume
  • Assess achievement of primary treatment goal

13
Key Design Features
  • Stratified
  • Randomized
  • Double-blind
  • Placebo-controlled
  • Powered to Detect ORR Difference

14
Study Design
  • Stratification
  • Stratum 1 0.5 - 5.0 cm3
  • Stratum 2 gt5.0 - 20.0 cm3
  • Stratum 3 20.0 cm3


15
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

16
Clinical Endpoints
  • 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)

17
Dosing Regimen
  • Pre-Amendment V
  • 0.5 mL gel/cm3 of tumor volume
  • Injection volume based on initial tumor
  • dimensions
  • Single injection technique
  • 62 patients enrolled


18
Dosing Regimen
  • Post-Amendment V
  • 0.25 mL gel/cm3 of tumor volume
  • Tumor volume recalculated each visit
  • Injection by fanning or grid technique
  • 163 patients enrolled


19
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

20
Study Design
  • Study Phases


21
Study 414 Results
  • Number of Centers, Location, Duration
  • 44 Centers
  • US and Canada
  • 15 Jun. 1995 - 22 Mar. 2000


22
Study 514 Results
  • Number of Centers, Location, Duration
  • 28 Centers
  • Europe and Israel
  • 21 Jun. 1995 - 22 Mar. 2000


23
Study 414 514 Results
  • Demographics
  • Patients enrolled on to each study appeared
    reasonably equally distributed between the arms
    and strata for
  • Age
  • KPS
  • Histological Grade
  • Prior therapy
  • Ethnicity


24
Study 414 Results
  • Treatment Delivered


25
Study 514 Results
  • Treatment Delivered


26
Study 414 Results Reason for Termination
27
Study 514 Results Reason for Termination
28
Study 414 Results
  • Efficacy Analysis - Active Arm
  • OR 20/62 (32.3)
  • CB 3/51 (5.9)
  • CBOR 2/51 (4.0)
  • Only 3/20 ORs were treated with the protocol-
  • specified dose and schedule


29
Study 514 Results
  • Efficacy Analysis - Active Arm
  • OR 13/57 (22.8)
  • CB 10/54 (18.5)
  • CBOR 5/54 (9.3)
  • Only 6/13 ORs were treated with the protocol-
  • specified dose and schedule


30
Study 414 514 Results
  • Blinding Adequacy Questions
  • Differential toxicity
  • Differential dropout
  • Local Hair loss
  • Yellow-colored Eschar
  • Reflux
  • Possibility of Direct Observation
  • Sleeve Removal Potential


31
Study 414 514 Results Causes 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)

32
Study 414 Results Actual Dose vs. Planned
Dose

33
Study 514 Results Actual Dose vs. Planned Dose

34
Study 414 514 Results Internal Consistency
Concerns
  • Missing Data
  • Patient and PI Palliative Benefit Score
  • Inconsistent
  • Palliative Benefit Inconsistent with
  • Local Toxicity
  • Palliative Benefit Inconsistent with Tumor
  • Size

35
Study 414 514 Results Local Toxicity
Parameters
  • Bleeding/Hemorrhage
  • Erythema
  • Erosion
  • Eschar formation
  • Necrosis
  • Swelling
  • Ulceration

36
Study 414 514 Safety
  • Six cases of stroke
  • One case of complete blindness
  • Inadvertant direct injection into vital organs
  • cannot be excluded.


37
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


38
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


39
FDA Statistical Review
40
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

41
Objective MTT Response
42
Objective MTT Response - Study 414
43
Objective MTT Response -Study 514
44
Graph of Survival Data
45
Clinical Patient Benefit
46
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

47
Patient Benefit Algorithm
48
Clinical Benefit - Study 414 and Study 514
Sponsor Analyses
49
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

50
Treatment Received - Study 414
51
Treatment Received - Study 514
52
Preventive Goals - Investigator Assessment
53
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

54
Investigator Assessment of Change in Palliative
Treatment Goal Score Study 414
55
Investigator Assessment of Change in Palliative
Treatment Goal Score Study 514
56
Patient or Investigator Palliative Benefit
Assessment - Study 414 FDA Analyses
57
Patient or Investigator Palliative Benefit
Assessment - Study 514 FDA Analyses
58
Clinical Patient Benefit - FDA Analyses
Study 414
Study 514
59
Clinical Patient Benefit
  • Both the randomized studies failed to demonstrate
    clinical patient benefit of IntraDose versus
    Placebo by Sponsors 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 lt 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.

60
Association Between Tumor Response and Patient
Benefit - Study 414 Sponsor Analysis
61
Association Between Tumor Response and Patient
Benefit - Study 514 Sponsor Analysis
62
Association Between Tumor Response and Patient
Benefit - Study 414 FDA Analysis
63
Association Between Tumor Response and Patient
Benefit - Study 514 FDA Analysis
64
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 lt 50 in each of the studies and in the
    combined study data.

65
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

66
Summary of FDA Findings
67
Objective Response Rate
68
Primary palliative goal
Study 414
Study 514
69
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
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