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 ManagersDianne Spillman Dotti Pease MedicalGregory K. Frykman, M.D. Grant Williams, M.D. StatisticsRajeshwari 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 Kaposi’s 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 10.5 - 5.0 cm3 Stratum 2>5.0 - 20.0 cm3 Stratum 320.0+ cm3

15. Submitted Clinical Data 414-94-2 III110US, CanadaHNSCC 514-94-2 III115Europe/IsraelHNSCC 516-99-PK 16US, EuropeHNSCC 39-92-2 I 45USSolid Tumors 403-93-2 II 67USSolid Tumors 503-93-2 II 59Eur./S. AfricaSolid Tumors

16. 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) Clinical Endpoints

17. Dosing Regimen Pre-Amendment V 0.5 mL gel/cm 3 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%) CB+OR 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%) CB+OR 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 414Study 514

59. Clinical Patient Benefit Both the randomized studies failed to demonstrate clinical patient benefit of IntraDose versus Placebo by Sponsor’s 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 < 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 < 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