Transcript Efficacy and Safety of Combidex (NDA 21-115) FDA Oncology Advisory Committee

FDA Oncology Advisory Committee
March 3, 2005
Efficacy and Safety of Combidex
(NDA 21-115)
Zili Li, MD, MPH
Division of Medical Imaging and
Radiopharmaceutical Drug Products, FDA
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 (n=152)
 Three European Phase 3
studies (n=181)
Safety:
 Multiple Phase 1, 2 & 3
clinical studies (n=2061)
 New England Journal Of
Medicine (NEJM) study
(n=80)
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NEJM Study – A pooled subgroup analysis of prostate
cancer patients from two ongoing clinical studies
US
IND Study
N=158
(single site)
NEJM
N=40
Study
N=80
N=40
European
Non-IND
Study
N=306
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Efficacy and Safety Conclusions (FDA vs. Sponsor)
Efficacy:
Safety:

Sponsor: Combidex offers
high sensitivity AND high
specificity

Sponsor: No death or lifethreatening AEs were
associated with dilution
and slow infusion

FDA: Generalizibility and
validity of study findings
are still issues

FDA: Dilution and slow
infusion are not entirely
risk free
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Issues to Be Discussed

Efficacy Issues





Safety Issues



Study sample size
Representation of different tumor types
Study inclusion/exclusion criteria
Development and use of Combidex Imaging Guidelines
Hypersensitivity reactions
Comparison with iodinated contrast agents
Risk/Benefit Ratio


Sponsor’s 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
Number of Patients
Received Combidex
Included in Primary
Analysis (n) (%)
Blinded Reader #1
Blinded Reader #2
European Studies (N=181)
38804-10
(Multiple
Cancer types)
3-2-A
(Head &
neck)
3-7-A
(Pelvis)
3-10-A
(Breast)
152
90
56
35
97 (64%)
99 (65%)
37 (41%) 11 (20%)
36 (40%) 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
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
--
328,400 (25%)
7
--
1,372,910 (100%)
99
48
All other sites
Total
* 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)
Nodes Visualized by Site
Investigators on MR
images (n)
Nodes Matched to Pathology
Results (n) (%)
Nodes Included in the
Primary Analysis (n) (%)
Reader 1
Reader 2
US Study
European Studies (N=181)
38804-10
(N=152)
3-2-A
(N=90)
3-7-A
(N=56)
3-10-A
(N=35)
371
834
333
234
276 (74%)
86 (10%)
65 (20%)
144 (62%)
167 (45%)
154 (42%)
47 (6%)
46 (6%)
11 (3%)
11 (3%)
--12
Variation in Sensitivity of Combidex by Tumor Type
Primary Tumor
Sites
US Study
European Studies
NO. of
Cancer
Positive
Nodes
Point
Estimate
Lower
Bound of
95% CI
NO. of
Cancer
Positive
Nodes
Point
Estimate
Lower
Bound of
95% CI
29
86%
67%
39
95%
82%
9
100%
66%
--
--
--
Breast
25
76%
55%
--
--
--
Abdomen &
Pelvis
21
81%
58%
6
100%
55%
Total
84
83%
73%
45
89%
76%
Head & Neck
Lung
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Variation in Specificity of Combidex by Tumor Type
Primary Tumor
Sites
US Study
European Studies
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]” 16
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
Total
Direct Bolus
Injection
50 mL
dilution/
slow
infusion
100 mL
dilution/
slow
infusion
129
38
324
491
2.6
2
326
1236
1564
3.4
--
--
6
6
131
364
1566
2061
0.3 – 1.7
Total
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Risk and Severity of Hypersensitivity Reactions
Type of
Hypersensitivity
Reactions
Risk of Hypersensitivity Reactions by Method of Administration
At all doses and
methods of
administration
(N=2061)
At proposed dose and
administration
(N=1236)
At direct bolus
injection
(n=131)
111 (5.4%)
66 (5.3%)
8 (6.1%)
1 (0.04%)
0
1 (0.7%)
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
All Hypersensitivity
Reactions
Death
Serious non-fatal
adverse event
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Presenting Symptoms of Hypersensitivity Reactions
Presenting Symptoms
(not mutually
exclusive)
Distribution of Presenting Symptoms by Method of Administration
At all doses and
methods of
administration
(N=111)
At proposed dose and
administration
(N=66)
At direct bolus
injection
(N=8)
Rash, urticaria or
pruritus
95 (86%)
56 (85%)
5 (63%)
Dyspnea with
vasodilation,
hypotension or
syncope
14 (13%)
10 (15%)
2 (25%)
9 (8%)
5 (8%)
2 (25%)
Facial, laryngeal or
generalized edema
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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
0/1236
(All)
(Infusion)
Serious non-fatal
0/4545
6/2061
2/1236
(All)
(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
23
Sponsor’s 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
25
Sensitivity and Specificity by Size (US Study Only)
Size of Lymph
Nodes
Readers
Sensitivity
Specificity
< 10 mm
Reader 1
Reader 2
69%
66%
81%
78%
> 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
3-2-A
3-7-A
3-10-A
< 10 mm
33/329
(10%)
--
46/696
(7%)
99/466
(21%)
> 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 < 10 mm
Sensitivity 68%, Specificity 80%
Lymph Nodes: Size > 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
(> 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
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