Efficacy and Safety of Combidex Efficacy and Safety of Combidex

(NDA 21-115)(NDA 21-115)

FDA Oncology Advisory CommitteeFDA Oncology Advisory Committee

March 3, 2005March 3, 2005

Zili Li, MD, MPHZili Li, MD, MPH

Division of Medical Imaging and Division of Medical Imaging and Radiopharmaceutical Drug Products, FDARadiopharmaceutical Drug Products, FDA

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FDA ReviewersFDA Reviewers

Chemistry:Chemistry: David Place and Eldon Leutzinger David Place and Eldon Leutzinger

Pharmacology:Pharmacology: Tushar Kokate and Adebayo Laniyonu Tushar Kokate and Adebayo Laniyonu

Clinical Pharmacology:Clinical Pharmacology: Alfredo Sancho and Young-Moon Choi Alfredo Sancho and Young-Moon Choi

Statistical:Statistical: Mahboob Sobhan and Mike Welch Mahboob Sobhan and Mike Welch

Medical:Medical: Robert Yaes, Melanie Blank, Barbara Stinson and Zili Li Robert Yaes, Melanie Blank, Barbara Stinson and Zili Li

Project Management:Project Management: James Moore, Thuy Nguyen and Pat Stewart James Moore, Thuy Nguyen and Pat Stewart

Internal Consultants:Internal Consultants: Charles Lee, Ann Corken Mackey, Janos Bacsanyi Charles Lee, Ann Corken Mackey, Janos Bacsanyi

and Kathy Robie-Suhand Kathy Robie-Suh

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CombidexCombidex

Drug Class:Drug Class: An Iron-based MR Contrast Agent An Iron-based MR Contrast Agent

Proposed Clinical Dose:Proposed Clinical Dose: 2.6 mg Fe/Kg 2.6 mg Fe/Kg

Methods of Administration:Methods of Administration: Diluted in 100 ml/slow infusionDiluted in 100 ml/slow infusion Diluted in 50 ml/slow infusion Diluted in 50 ml/slow infusion Undiluted/direct bolus injectionUndiluted/direct bolus injection

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Sponsor Proposed IndicationSponsor 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 StudiesEfficacy and Safety Studies

Efficacy:Efficacy:

US Phase 3 study (n=152)US Phase 3 study (n=152)

Three European Phase 3 studies (n=181)Three European Phase 3 studies (n=181)

New England Journal Of Medicine New England Journal Of Medicine (NEJM) study (n=80)(NEJM) study (n=80)

Safety:Safety:

Multiple Phase 1, 2 & 3 Multiple Phase 1, 2 & 3 clinical studies (n=2061)clinical studies (n=2061)

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NEJM Study – A pooled subgroup analysis of prostate NEJM Study – A pooled subgroup analysis of prostate cancer patients from two ongoing clinical studiescancer patients from two ongoing clinical studies

US

IND Study

N=158

(single site)

European

Non-IND Study

N=306

NEJM

Study

N=80

N=40 N=40

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Efficacy and Safety Conclusions (FDA vs. Sponsor)Efficacy and Safety Conclusions (FDA vs. Sponsor)

Efficacy:Efficacy:

Sponsor:Sponsor: Combidex offers high Combidex offers high sensitivity AND high specificitysensitivity AND high specificity

FDA: FDA: Generalizibility and validity of Generalizibility and validity of study findings are still issuesstudy findings are still issues

Safety:Safety:

Sponsor:Sponsor: No death or life-threatening No death or life-threatening AEs were associated with dilution and AEs were associated with dilution and slow infusionslow infusion

FDA:FDA: Dilution and slow infusion are not Dilution and slow infusion are not entirely risk freeentirely risk free

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Issues to Be DiscussedIssues to Be Discussed Efficacy IssuesEfficacy Issues

Study sample sizeStudy sample size Representation of different tumor typesRepresentation of different tumor types Study inclusion/exclusion criteriaStudy inclusion/exclusion criteria Development and use of Combidex Imaging GuidelinesDevelopment and use of Combidex Imaging Guidelines

Safety IssuesSafety Issues Hypersensitivity reactionsHypersensitivity reactions Comparison with iodinated contrast agentsComparison with iodinated contrast agents

Risk/Benefit RatioRisk/Benefit Ratio Sponsor’s risk management programSponsor’s risk management program Need to define the conditions of useNeed to define the conditions of use

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Issue #1: Small Number of Patients Included In the Issue #1: Small Number of Patients Included In the Primary AnalysisPrimary Analysis

US Study European Studies (N=181)

38804-10(Multiple

Cancer types)

3-2-A(Head &

neck)

3-7-A(Pelvis)

3-10-A(Breast)

Number of Patients Received Combidex

152152 9090 5656 3535

Included in Primary Analysis (n) (%)

Blinded Reader #1 Blinded Reader #2

97 (64%)97 (64%)99 (65%)99 (65%)

37 (41%)37 (41%)36 (40%)36 (40%)

11 (20%)11 (20%)9 (16%)9 (16%)

--------

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Issue #2: Inadequate Representation of Tumor Types 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 55

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 66

6. Melanoma 59,580 (4%) 0 ----

7. Uterus/Cervix 51,250 (4%) 6 ----

8. Head & Neck 39,250 (3%) 27 3737

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 4848* 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 Why Many Cancer Patients Were Not Included in the Primary AnalysisPrimary Analysis

All lymph nodes visualized by the site investigators

Matched to Pathology

Nodes Included in Nodes Included in Primary AnalysisPrimary Analysis

Visualized by blinded readers

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Number of Lymph Nodes Included in the Primary AnalysisNumber of Lymph Nodes Included in the Primary Analysis

(N = number of patients) 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)

Nodes Visualized by Site Investigators on MR images (n)

371371 834834 333333 234234

Nodes Matched to Pathology Results (n) (%)

276 (74%)276 (74%) 86 (10%)86 (10%) 65 (20%)65 (20%) 144 (62%)144 (62%)

Nodes Included in the Primary Analysis (n) (%)

Reader 1 Reader 2

167 (45%)167 (45%)154 (42%)154 (42%)

47 (6%)47 (6%)46 (6%)46 (6%)

11 (3%)11 (3%)11 (3%)11 (3%)

--------

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Variation in Sensitivity of Combidex by Tumor TypeVariation in Sensitivity of Combidex by Tumor Type

Primary Tumor Sites

US Study European Studies

NO. ofCancer PositiveNodes

Point Estimate

Lower Bound of 95% CI

NO. ofCancer PositiveNodes

Point Estimate

Lower Bound of 95% CI

Head & Neck 2929 86%86% 67%67% 3939 95%95% 82%82%

Lung 99 100%100% 66%66% ---- ---- ----

Breast 2525 76%76% 55%55% ---- ---- ----

Abdomen & Pelvis

2121 81%81% 58%58% 66 100%100% 55%55%

Total 8484 83%83% 73%73% 4545 89%89% 76%76%

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Variation in Specificity of Combidex by Tumor TypeVariation 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 3434 91%91% 75%75% 77 86%86% 42%42%

Lung 1818 44%44% 21%21% ---- ---- ----

Breast 3434 71%71% 52%52% ---- ---- ----

Abdomen & Pelvis

1313 62%62% 32%32% 66 100%100% 55%55%

Total 9999 72%72% 62%62% 1313 92%92% 64%64%

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Issue #3: Impact of Study Inclusion/Exclusion CriteriaIssue #3: Impact of Study Inclusion/Exclusion Criteria

Excluded if received Excluded if received chemotherapy in the past 6 monthschemotherapy in the past 6 months radiation treatment in the past 6 monthsradiation treatment in the past 6 months

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Issue #4: Independence of Combidex Imaging Issue #4: Independence of Combidex Imaging Guidelines DevelopmentGuidelines Development

Original Statement:Original Statement:

““To finalize the Guidelines, the Sponsor To finalize the Guidelines, the Sponsor looked at the histology results for the images looked at the histology results for the images that [consultant] had reviewed to correlate that [consultant] had reviewed to correlate her descriptions and drawings to diagnoses her descriptions and drawings to diagnoses of metastatic and non-metastatic nodes”of metastatic and non-metastatic nodes”

Revised Statements (February 14, 2005): Revised Statements (February 14, 2005):

““The guidelines and visual diagrams were The guidelines and visual diagrams were developed with the Phase II images”developed with the Phase II images”

““Images from 16 patients in the Phase III Images from 16 patients in the Phase III study were reviewed by [consultant]”study were reviewed by [consultant]”

““No pathologic information regarding the No pathologic information regarding the nodes was provided to [consultant]”nodes was provided to [consultant]”

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Correlation Between European Guidelines and Correlation Between European Guidelines and Combidex Imaging GuidelinesCombidex Imaging Guidelines

European Guidelines: European Guidelines: Combidex Imaging Guidelines Combidex Imaging Guidelines

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Combidex-Induced Hypersensitivity ReactionsCombidex-Induced Hypersensitivity Reactions

Hypersensitivity-Related DeathHypersensitivity-Related Death

70 year-old male with history of allergy to contrast70 year-old male with history of allergy to contrast

Received undiluted bolus injectionReceived undiluted bolus injection

Reaction began 1-2 minutes post injectionReaction began 1-2 minutes post injection

911 was called911 was called

Patient was pronounced dead in ER 35 minutes post-dosingPatient was pronounced dead in ER 35 minutes post-dosing

Autopsy revealed no evidence of MI or PEAutopsy revealed no evidence of MI or PE

Cause of Death: Combidex-induced anaphylactic shockCause of Death: Combidex-induced anaphylactic shock

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The Size of Safety Database: Patient Exposure by Dose and The Size of Safety Database: Patient Exposure by Dose and AdministrationAdministration

Dose (mg Fe/kg) Method of Administration Total

Direct Bolus Injection

50 mL dilution/

slow infusion

100 mL dilution/

slow infusion

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 ReactionsRisk 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)

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 ReactionsPresenting 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%)95 (86%) 56 (85%)56 (85%) 5 (63%)

Dyspnea with Dyspnea with vasodilation, vasodilation, hypotension or hypotension or syncopesyncope

14 (13%) 10 (15%) 2 (25%)

Facial, laryngeal or Facial, laryngeal or generalized edemageneralized edema

9 (8%) 5 (8%) 2 (25%)

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Comparison with Iodinated Contrast Agents Comparison with Iodinated Contrast Agents

Hypersensitivity Reactions in the Clinical Trials

Three Iodinated Contrast Agents

Combidex

Death 0/45450/4545 1/2061 (All)0/1236 (Infusion)

Serious non-fatal 0/4545 6/2061 (All)2/1236 (Infusion)

UriticariaRashPruritus

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 RatioImproving the Risk/Benefit Ratio

Risk

Benefit

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Sponsor’s Risk Management ProgramSponsor’s Risk Management Program

Use of Dilution and Slow InfusionUse of Dilution and Slow Infusion

Labeling (Warnings & Precautions)Labeling (Warnings & Precautions)

Physician EducationPhysician Education

Target launch to academic centers and monitor first 1,000 Target launch to academic centers and monitor first 1,000 patientspatients

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FDA: To Enhance the Benefit to the PatientsFDA: To Enhance the Benefit to the Patients

Need to better understand Combidex performance by Need to better understand Combidex performance by tumor type and nodal sizetumor type and nodal size

Need to define the conditions of useNeed to define the conditions of use

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Sensitivity and Specificity by Size (US Study Only) Sensitivity and Specificity by Size (US Study Only)

Size of Lymph Nodes

Readers Sensitivity Specificity

< 10 mm Reader 1 Reader 2

69%69%

66%66%81%78%

> 10 mm Reader 1 Reader 2

93%93%

98%98%56%71%

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Prevalence of Histologically Positive Nodes by Nodal SizePrevalence of Histologically Positive Nodes by Nodal Size

Nodal Size from Pathology

US Study38804-10

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 TestPredictive Values of a Positive or Negative Combidex Test

Lymph Nodes: Size < 10 mmSensitivity 68%, Specificity 80%

Lymph Nodes: Size > 10 mmSensitivity 95%, Specificity 64%

Prevalence PPV NPV Prevalence PPV NPV

1% 3%3% 99%99% 25% 47%47% 98%98%

10% 27%27% 96%96% 50% 73%73% 93%93%

25% 53%53% 88%88% 75% 89%89% 81%81%

50% 77%77% 71%71% 90% 96%96% 59%59%

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To Define the Conditions of UseTo Define the Conditions of Use

Uses that may not be helpfulUses that may not be helpful

Patient with a low risk for metastasisPatient with a low risk for metastasis

Patients with a lymph node (> 10 Patients with a lymph node (> 10 mm) visualized from non-contrast MR mm) visualized from non-contrast MR imagingimaging

Substitute for pathology confirmationSubstitute for pathology confirmation

Surveillance for tumor recurrences in Surveillance for tumor recurrences in treated patientstreated patients

Key question: How will Key question: How will Combidex results be benefit to Combidex results be benefit to patients ?patients ?

Prostate CancerProstate Cancer

Bladder CancerBladder Cancer

Breast CancerBreast Cancer

Head & Neck CancerHead & Neck Cancer