1. 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

2. 2 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 and Kathy Robie-Suh

3. 3 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

4. 4 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?

5. 5 Efficacy and Safety Studies Efficacy: Efficacy:  US Phase 3 study (n=152)  Three European Phase 3 studies (n=181)  New England Journal Of Medicine (NEJM) study (n=80) Safety: Safety:  Multiple Phase 1, 2 & 3 clinical studies (n=2061)

6. 6 NEJM Study – A pooled subgroup analysis of prostate cancer 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

7. 7 Efficacy and Safety Conclusions (FDA vs. Sponsor) Efficacy: Efficacy:  Sponsor: Combidex offers high sensitivity AND high specificity  FDA: Generalizibility and validity of study findings are still issues Safety: 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

8. 8 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  Sponsor’s risk management program  Need to define the conditions of use

9. 9 Issue #1: Small Number of Patients Included In the Primary Analysis US StudyEuropean 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 Combidex152905635 Included in Primary Analysis (n) (%) Blinded Reader #1 Blinded Reader #2 97 (64%) 99 (65%) 37 (41%) 36 (40%) 11 (20%) 9 (16%) ----

10. 10 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 StudyEuropean Studies 1. Prostate Cancer232,090 (17%)55 2. Breast Cancer212,930 (16%)20-- 3. Lung Cancer172,570 (13%)25-- 4. Colon & Rectal Cancer145,290 (11%)2-- 5. Bladder Cancer63,210 (5%)46 6. Melanoma59,580 (4%)0-- 7. Uterus/Cervix51,250 (4%)6-- 8. Head & Neck39,250 (3%)2737 9. Kidney Cancer36,160 (3%)2-- 10. Pancreatic Cancer32,180 (2%)1-- All other sites328,400 (25%)7-- Total1,372,910 (100%)9948 * Source Data: American Cancer Society. Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005.

11. 11 Why Many Cancer Patients Were Not Included in the Primary Analysis All lymph nodes visualized by the site investigators Matched to Pathology Nodes Included in Primary Analysis Visualized by blinded readers

12. 12 Number of Lymph Nodes Included in the Primary Analysis (N = number of patients)US StudyEuropean 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)371834333234 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%) ----

13. 13 Variation in Sensitivity of Combidex by Tumor Type Primary Tumor Sites US StudyEuropean 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 Head & Neck2986%67%3995%82% Lung9100%66%------ Breast2576%55%------ Abdomen & Pelvis2181%58%6100%55% Total8483%73%4589%76%

14. 14 Variation in Specificity of Combidex by Tumor Type Primary Tumor Sites US StudyEuropean 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 & Neck3491%75%786%42% Lung1844%21%------ Breast3471%52%------ Abdomen & Pelvis1362%32%6100%55% Total9972%62%1392%64%

15. 15 Issue #3: Impact of Study Inclusion/Exclusion Criteria Excluded if received  chemotherapy in the past 6 months  radiation treatment in the past 6 months

16. 16 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]”

17. 17 Correlation Between European Guidelines and Combidex Imaging Guidelines European Guidelines: European Guidelines: Combidex Imaging Guidelines Combidex Imaging Guidelines

18. 18 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

19. 19 The Size of Safety Database: Patient Exposure by Dose and Administration Dose (mg Fe/kg)Method of AdministrationTotal Direct Bolus Injection 50 mL dilution/ slow infusion 100 mL dilution/ slow infusion 0.3 – 1.712938324491 2.6232612361564 3.4-- 66 Total13136415662061

20. 20 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) All Hypersensitivity Reactions 111 (5.4%)66 (5.3%)8 (6.1%) Death1 (0.04%)01 (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 steroids21 (1.0%)19 (1.5%)0

21. 21 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%) Facial, laryngeal or generalized edema 9 (8%)5 (8%)2 (25%)

22. 22 Comparison with Iodinated Contrast Agents Hypersensitivity Reactions in the Clinical Trials Three Iodinated Contrast Agents Combidex Death0/45451/2061 (All) 0/1236 (Infusion) Serious non-fatal0/45456/2061 (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%

23. 23 Improving the Risk/Benefit Ratio Risk Benefit

24. 24 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

25. 25 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

26. 26 Sensitivity and Specificity by Size (US Study Only) Size of Lymph Nodes ReadersSensitivitySpecificity < 10 mmReader 1 Reader 269%66% 81% 78% > 10 mmReader 1 Reader 293%98% 56% 71%

27. 27 Prevalence of Histologically Positive Nodes by Nodal Size Nodal Size from Pathology US Study 38804-10 European Studies 3-2-A3-7-A3-10-A < 10 mm33/329 (10%) --46/696 (7%) 99/466 (21%) > 10 mm56/167 (34%) 85/129 (66%) 17/87 (20%) 26/50 (52%)

28. 28 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% PrevalencePPVNPVPrevalencePPVNPV 1%3%99%25%47%98% 10%27%96%50%73%93% 25%53%88%75%89%81% 50%77%71%90%96%59%

29. 29 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 ? Key question: How will Combidex results be benefit to patients ?  Prostate Cancer  Bladder Cancer  Breast Cancer  Head & Neck Cancer