Efficacy and Safety of Combidex (NDA 21-115)

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Efficacy and Safety of Combidex (NDA 21-115)

• FDA Oncology Advisory Committee
• March 3, 2005

Zili Li, MD, MPH Division of Medical Imaging and
Radiopharmaceutical Drug Products, FDA
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FDA Reviewers

• Chemistry David Place and Eldon Leutzinger
• Pharmacology Tushar Kokate and Adebayo Laniyonu
• Clinical Pharmacology Alfredo Sancho and
  Young-Moon Choi
• Statistical Mahboob Sobhan and Mike Welch
• Medical Robert Yaes, Melanie Blank, Barbara
  Stinson and Zili Li
• Project Management James Moore, Thuy Nguyen and
  Pat Stewart
• Internal Consultants Charles Lee, Ann Corken
  Mackey, Janos Bacsanyi
• and Kathy
  Robie-Suh

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Combidex

• Drug Class An Iron-based MR Contrast Agent
• Proposed Clinical Dose 2.6 mg Fe/Kg
• Methods of Administration
• Diluted in 100 ml/slow infusion
• Diluted in 50 ml/slow infusion
• Undiluted/direct bolus injection

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Sponsor Proposed Indication
Combidex can assist in the differentiation of
metastatic and non-metastatic lymph nodes in
patients with confirmed primary cancer who are at
risk for lymph node metastases.
Is this an MR contrast agent for all cancers?
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Efficacy and Safety Studies

• Efficacy
• US Phase 3 study (n152)
• Three European Phase 3 studies (n181)
• New England Journal Of Medicine (NEJM) study
  (n80)

• Safety
• Multiple Phase 1, 2 3 clinical studies (n2061)

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NEJM Study A pooled subgroup analysis of
prostate cancer patients from two ongoing
clinical studies
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Efficacy and Safety Conclusions (FDA vs. Sponsor)

• Efficacy
• Sponsor Combidex offers high sensitivity AND
  high specificity
• FDA Generalizibility and validity of study
  findings are still issues

• Safety
• Sponsor No death or life-threatening AEs were
  associated with dilution and slow infusion
• FDA Dilution and slow infusion are not entirely
  risk free

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Issues to Be Discussed

• Efficacy Issues
• Study sample size
• Representation of different tumor types
• Study inclusion/exclusion criteria
• Development and use of Combidex Imaging
  Guidelines
• Safety Issues
• Hypersensitivity reactions
• Comparison with iodinated contrast agents
• Risk/Benefit Ratio
• Sponsors risk management program
• Need to define the conditions of use

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Issue 1 Small Number of Patients Included In
the Primary Analysis
US Study European Studies (N181) European Studies (N181) European Studies (N181)
38804-10 (Multiple Cancer types) 3-2-A (Head neck) 3-7-A (Pelvis) 3-10-A (Breast)
Number of Patients Received Combidex 152 90 56 35
Included in Primary Analysis (n) () Blinded Reader 1 Blinded Reader 2 97 (64) 99 (65) 37 (41) 36 (40) 11 (20) 9 (16) -- --
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Issue 2 Inadequate Representation of Tumor
Types
Top 10 Tumor Types In the US Distribution of New Cancer Cases in the US Total Number of Patients in Primary Analysis Total Number of Patients in Primary Analysis
Top 10 Tumor Types In the US Distribution of New Cancer Cases in the US US Study European Studies
1. Prostate Cancer 232,090 (17) 5 5
2. Breast Cancer 212,930 (16) 20 --
3. Lung Cancer 172,570 (13) 25 --
4. Colon Rectal Cancer 145,290 (11) 2 --
5. Bladder Cancer 63,210 (5) 4 6
6. Melanoma 59,580 (4) 0 --
7. Uterus/Cervix 51,250 (4) 6 --
8. Head Neck 39,250 (3) 27 37
9. Kidney Cancer 36,160 (3) 2 --
10. Pancreatic Cancer 32,180 (2) 1 --
All other sites 328,400 (25) 7 --
Total 1,372,910 (100) 99 48
Source Data American Cancer Society. Cancer
Facts and Figures 2005. Atlanta American Cancer
Society 2005.
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Why Many Cancer Patients Were Not Included in the
Primary Analysis
Visualized by blinded readers
Matched to Pathology
Nodes Included in Primary Analysis
All lymph nodes visualized by the site
investigators
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Number of Lymph Nodes Included in the Primary
Analysis
(N number of patients) US Study European Studies (N181) European Studies (N181) European Studies (N181)
(N number of patients) 38804-10 (N152) 3-2-A (N90) 3-7-A (N56) 3-10-A (N35)
Nodes Visualized by Site Investigators on MR images (n) 371 834 333 234
Nodes Matched to Pathology Results (n) () 276 (74) 86 (10) 65 (20) 144 (62)
Nodes Included in the Primary Analysis (n) () Reader 1 Reader 2 167 (45) 154 (42) 47 (6) 46 (6) 11 (3) 11 (3) -- --
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Variation in Sensitivity of Combidex by Tumor Type
Primary Tumor Sites US Study US Study US Study European Studies European Studies European Studies
Primary Tumor Sites NO. of Cancer Positive Nodes Point Estimate Lower Bound of 95 CI NO. of Cancer Positive Nodes Point Estimate Lower Bound of 95 CI
Head Neck 29 86 67 39 95 82
Lung 9 100 66 -- -- --
Breast 25 76 55 -- -- --
Abdomen Pelvis 21 81 58 6 100 55
Total 84 83 73 45 89 76
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Variation in Specificity of Combidex by Tumor Type
Primary Tumor Sites US Study US Study US Study European Studies European Studies European Studies
Primary Tumor Sites NO. of Cancer Negative Nodes Point Estimate Lower Bound of 95 CI NO. of Cancer Negative Nodes Point Estimate Lower Bound of 95 CI
Head Neck 34 91 75 7 86 42
Lung 18 44 21 -- -- --
Breast 34 71 52 -- -- --
Abdomen Pelvis 13 62 32 6 100 55
Total 99 72 62 13 92 64
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Issue 3 Impact of Study Inclusion/Exclusion
Criteria

• Excluded if received
• chemotherapy in the past 6 months
• radiation treatment in the past 6 months

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Issue 4 Independence of Combidex Imaging
Guidelines Development

• Original Statement
• To finalize the Guidelines, the Sponsor looked
  at the histology results for the images that
  consultant had reviewed to correlate her
  descriptions and drawings to diagnoses of
  metastatic and non-metastatic nodes
• Revised Statements (February 14, 2005)
• The guidelines and visual diagrams were
  developed with the Phase II images
• Images from 16 patients in the Phase III study
  were reviewed by consultant
• No pathologic information regarding the nodes
  was provided to consultant

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Correlation Between European Guidelines and
Combidex Imaging Guidelines

• European Guidelines

Combidex Imaging Guidelines
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Combidex-Induced Hypersensitivity Reactions

• Hypersensitivity-Related Death
• 70 year-old male with history of allergy to
  contrast
• Received undiluted bolus injection
• Reaction began 1-2 minutes post injection
• 911 was called
• Patient was pronounced dead in ER 35 minutes
  post-dosing
• Autopsy revealed no evidence of MI or PE
• Cause of Death Combidex-induced anaphylactic
  shock

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The Size of Safety Database Patient Exposure by
Dose and Administration
Dose (mg Fe/kg) Method of Administration Method of Administration Method of Administration Total
Dose (mg Fe/kg) Direct Bolus Injection 50 mL dilution/ slow infusion 100 mL dilution/ slow infusion Total
0.3 1.7 129 38 324 491
2.6 2 326 1236 1564
3.4 -- -- 6 6
Total 131 364 1566 2061
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Risk and Severity of Hypersensitivity Reactions
Type of Hypersensitivity Reactions Risk of Hypersensitivity Reactions by Method of Administration Risk of Hypersensitivity Reactions by Method of Administration Risk of Hypersensitivity Reactions by Method of Administration
Type of Hypersensitivity Reactions At all doses and methods of administration (N2061) At proposed dose and administration (N1236) At direct bolus injection (n131)
All Hypersensitivity Reactions 111 (5.4) 66 (5.3) 8 (6.1)
Death 1 (0.04) 0 1 (0.7)
Serious non-fatal adverse event 6 (0.3) 2 (0.16) 3 (2.3)
Hypersensitivity reaction involving at least two body systems 20 (1.0) 13 (1.1) 3 (2.3)
Treated with antihistamine 48 (2.8) 27 (2.4) 3 (2.3)
Treated with steroids 21 (1.0) 19 (1.5) 0
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Presenting Symptoms of Hypersensitivity Reactions
Presenting Symptoms (not mutually exclusive) Distribution of Presenting Symptoms by Method of Administration Distribution of Presenting Symptoms by Method of Administration Distribution of Presenting Symptoms by Method of Administration
Presenting Symptoms (not mutually exclusive) At all doses and methods of administration (N111) At proposed dose and administration (N66) At direct bolus injection (N8)
Rash, urticaria or pruritus 95 (86) 56 (85) 5 (63)
Dyspnea with vasodilation, hypotension or syncope 14 (13) 10 (15) 2 (25)
Facial, laryngeal or generalized edema 9 (8) 5 (8) 2 (25)
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Comparison with Iodinated Contrast Agents
Hypersensitivity Reactions in the Clinical Trials Three Iodinated Contrast Agents Combidex
Death 0/4545 1/2061 (All) 0/1236 (Infusion)
Serious non-fatal 0/4545 6/2061 (All) 2/1236 (Infusion)
Uriticaria Rash Pruritus 0.3 to 0.8 0.6 0.1 to 1.6 2.2 2.8 2.4
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Improving the Risk/Benefit Ratio
Risk Benefit
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Sponsors Risk Management Program

• Use of Dilution and Slow Infusion
• Labeling (Warnings Precautions)
• Physician Education
• Target launch to academic centers and monitor
  first 1,000 patients

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FDA To Enhance the Benefit to the Patients

• Need to better understand Combidex performance by
  tumor type and nodal size
• Need to define the conditions of use

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Sensitivity and Specificity by Size (US Study
Only)
Size of Lymph Nodes Readers Sensitivity Specificity
lt 10 mm Reader 1 Reader 2 69 66 81 78
gt 10 mm Reader 1 Reader 2 93 98 56 71
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Prevalence of Histologically Positive Nodes by
Nodal Size
Nodal Size from Pathology US Study 38804-10 European Studies European Studies European Studies
Nodal Size from Pathology US Study 38804-10 3-2-A 3-7-A 3-10-A
lt 10 mm 33/329 (10) -- 46/696 (7) 99/466 (21)
gt 10 mm 56/167 (34) 85/129 (66) 17/87 (20) 26/50 (52)
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Predictive Values of a Positive or Negative
Combidex Test
Lymph Nodes Size lt 10 mm Sensitivity 68, Specificity 80 Lymph Nodes Size lt 10 mm Sensitivity 68, Specificity 80 Lymph Nodes Size lt 10 mm Sensitivity 68, Specificity 80 Lymph Nodes Size gt 10 mm Sensitivity 95, Specificity 64 Lymph Nodes Size gt 10 mm Sensitivity 95, Specificity 64 Lymph Nodes Size gt 10 mm Sensitivity 95, Specificity 64
Prevalence PPV NPV Prevalence PPV NPV
1 3 99 25 47 98
10 27 96 50 73 93
25 53 88 75 89 81
50 77 71 90 96 59
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To Define the Conditions of Use

• Uses that may not be helpful
• Patient with a low risk for metastasis
• Patients with a lymph node (gt 10 mm) visualized
  from non-contrast MR imaging
• Substitute for pathology confirmation
• Surveillance for tumor recurrences in treated
  patients

• Key question How will Combidex results be
  benefit to patients ?
• Prostate Cancer
• Bladder Cancer
• Breast Cancer
• Head Neck Cancer