1. 1 Voriconazole NDAs 21-266 and 21-267 Empiric Antifungal Therapy of Febrile Neutropenic Patients Study 603 John H. Powers, M.D. Medical Officer Division of Special Pathogen and Immunologic Drug Products Center for Drug Evaluation and Research

2. 2 Introduction  Scientific and regulatory background in indication of Empiric Antifungal Therapy in Febrile Neutropenic Patients (ETFN)  Discussion of primary composite endpoint and statistical definition of non-inferiority  Discussion of selected issues with secondary endpoints  breakthrough infections within 7 days of EOT  survival at 7 days after end of therapy  discontinuations due to lack of efficacy or toxicity  defervescence prior to recovery from neutropenia  baseline fungal infections  Summary

3. 3 Background fungal infections in neutropenic hosts  Neutropenia one of major risk factors for invasive fungal infections  risk varies with depth and duration of neutropenia  Candida and Aspergillus species most common  Autopsy studies show 12% to 43% incidence of invasive fungal infections  Difficulty in pre-mortem diagnosis with occult infections may occur in as many as 50%  High mortality of 48% to 80% in various studies

4. 4 Background basis for treatment  Idea of empiric therapy  treat occult infections which would not be diagnosed by conventional means  prevent infections in patients at risk  Two randomized trials address question  Pizzo et al. Am J Med 1982;72:101-110  EORTC trial Am J Med 1989;86:668-672  Empiric therapy has become standard of practice

5. 5 Background prior discussion of study design  Two public meetings in 1994 and 1995 to discuss issues of study design in antifungal drugs  non-inferiority study design recommended  amphotericin B deoxycholate (AMB-D) suggested as comparator  not FDA approved for this indication but approval was in 1956  for approval need at least one study showing efficacy in another fungal indication plus one study in ETFN  prove efficacy in documented infections

6. 6 Background important points from workshops Points from 1994 and 1995 workshops  certainty of efficacy since resolution of fever rather than proven infection is determinant of sample size  lower bound of 95% CI to determine non- inferiority suggested as -10%  composite endpoint recommended as trials with primary endpoint of BT infections may have prohibitively large sample size  considered important to detect:  differences in proven fungal infections  differences in mortality  differences in fever within a 10% CI  differences in safety

7. 7 Background  Dr. Alan Sugar at 4/14/97 Advisory Committee “Empiric therapy is given to patients because some will actually need it. However, others will not, that is, they are treated unnecessarily. At issue is the diagnosis of invasive fungal infections and the difficulties associated with it…….Also at issue is the degree of neutropenia. What places the patient at higher risk? Overall consensus is that patients with an ANC of <100 are at highest risk. The duration of neutropenia also contributes to risk.”

8. 8 Trial Design and Analysis  Non-inferiority trial with non-inferiority margin of -10%  primary analysis population MITT  Stratified by risk of fungal infections and prophylaxis  Open label study design  no oral systemically active form of L-AMB  ethics of two IV infusions in seriously ill pts.  Data Review Committee blinded assessments of fungal infections and outcomes

9. 9 Background previous approvals in ETFN  Two agents approved for ETFN using composite endpoint similar to Study 603  Ambisome (liposomal amphotericin B, L-AMB)  “empirical therapy for presumed fungal infections in febrile, neutropenic patients”  Sporanox (itraconazole injection, oral solution)  “empiric therapy of febrile neutropenic patients with suspected fungal infections.”  overall response greater for itraconazole than AMB-D but more D/C due to lack of efficacy with itraconazole, more D/C due to toxicity with AMB-D

10. 10 Overall Response Rate in Study 603  Primary analysis was stratified overall response rate of composite (5 component) endpoint  Lower bound of CI to select sample size and define statistical non-inferiority defined as -10% based on 50% overall response rate in MSG 32 study with Ambisome vs. AMB-D  Stratified response rates in Study 603  voriconazole 23.7%  L-AMB 30.1%  difference -6.1% (-12.0%, -0.1%)  FDA weighted 95% CI (-11.6%, 0.1%)  Note: lower bound of 95% CI falls below -10%

11. 11 Overall Response Rate in Study 603  Statistical points about defining non-inferiority  Lower bound of 95% CI below (more negative) pre-specified limit implies that drug may not be non-inferior to control drug  Defining non-inferiority implies knowledge of efficacy of control drug over placebo/no treatment in superiority trial  Lower bound of 95% CI used to define non- inferiority margin in non-inferiority trial cannot be greater than difference in control drug over placebo/no treatment

12. 12 Overall Response Rate in Study 603  Hypothetical example:  lower bound of 95% CI in a randomized, placebo (or no treatment) controlled trial shows an absolute benefit of control drug over no treatment of at least 7%  in subsequent non-inferiority trial, test drug with lower bound of 95% CI of -11% compared to control is potentially no better than placebo

13. 13 Overall Response Rate in Study 603  Clear that neutropenic patients develop invasive fungal infections  At issue in selecting non-inferiority margin in ETFN:  Do antifungal drugs prevent breakthrough infections in neutropenic patients?  If so, what is the magnitude of this benefit relative to no treatment?  How does this impact the selection of a non- inferiority margin in clinical trials using a composite endpoint rather than BT infections as primary endpoint?

14. 14 Previous Trials in ETFN  Two previous trials in ETFN comparing AMB-D to no treatment  not adequately powered to determine difference in breakthrough infections  EORTC trial used resolution of fever as primary endpoint  included mucosal as well as invasive disease in breakthrough infections  did not include deaths and discontinuations as failures in analysis of BT infections

15. 15 Previous Trials in ETFN  True difference of AMB vs. no treatment in prevention of BT infections may be from 60% better to 8% worse than no treatment  How does this impact studies using the current composite endpoint?  What is clinical relevance of non-inferiority margin of -10% in ETFN  Can we extrapolate from studies 20 years ago to current rate of emergent fungal infections?

16. 16 Secondary Endpoints and Subset Analyses  When primary endpoint not met, can attempt to explain failure by looking at secondary and subset analyses  secondary and subset analyses considered hypothesis generating in this situation  Subset analyses of patients stratified according to risk of fungal infections and/or receipt of prophylaxis  Secondary endpoints are 5 individual components of composite endpoint

17. 17 Secondary Endpoints and Subset Analyses  In attempt to adjust for multiple comparisons for the 5 secondary endpoints, 99% confidence intervals are presented  Not primary endpoint of trial so study not adequately powered to determine true difference in secondary endpoints and subsets  Secondary and subset analyses may have small numbers of patients in each group  Look for consistency in outcomes of secondary endpoints as sensitivity analysis

18. 18 Overall Response Rate in Study 603 subset analysis by risk of fungal infection * allogeneic BMTs and relapsed leukemia patients

19. 19 Secondary Endpoints *all subsequent 99% CI based on these rates, so that focus is on lower bound

20. 20 Breakthrough Infections  Fewer BT infections in voriconazole arm compared to L-AMB  voriconazole1.9% (8/415)  L-AMB5.0% (21/422)  Difference of 3.1% in favor of voriconazole with 99% CI (-0.37%, 6.5%)  difference greatest in Aspergillus BT infections with 4 in voriconazole vs. 13 in L-AMB  BT infections included proven and probable disease  6/8 patients proven disease in voriconazole arm  20/21 patients proven disease in L-AMB arm

21. 21 Breakthrough Infections sensitivity analysis  Sensitivity analysis considering BT infections as primary endpoint may consider patients who die as failures  voriconazole9.2% (38/415)  L-AMB9.2% (39/422)  difference of 0% with 95% CI (- 4.2%, 4.2%)

22. 22 Breakthrough Infections subset analysis by risk of infection and prophylaxis

23. 23 Survival at 7 days after EOT  More deaths in voriconazole arm vs. L-AMB  voriconazole 8.0% (33/415)  L-AMB 5.9% (25/422)  difference of 2.1% in favor of L-AMB with 99% CI (-6.9%, 2.7%)  difficulty of attribution of death in seriously ill patients  attribution of death not blinded or reviewed by DRC

24. 24 Discontinuations  More discontinuations due to lack of efficacy or toxicity in voriconazole arm  voriconazole9.9% (41/415)  L-AMB6.6% (28/422)  difference of 3.3% in favor of L-AMB with 99% CI (-8.4%, 1.8%)  Composite endpoint combines discontinuations due to lack of efficacy with those due to toxicity  combines efficacy and safety endpoint  can obscure important differences in outcomes  Look at various reasons for discontinuations

25. 25 Discontinuations lack of efficacy and toxicity  More discontinuations due to lack of efficacy in voriconazole arm compared to L-AMB  voriconazole5.3% (22/415)  L-AMB1.2% (5/422)  difference 4.1% in favor of L-AMB  Fewer discontinuations due to toxicity in voriconazole arm compared to L-AMB  voriconazole4.6% (19/415)  L-AMB5.5% (23/422)  difference 0.9% in favor of voriconazole  open label trial and potential for bias

26. 26 Discontinuations lack of efficacy  More discontinuations with persistent fever as reason for lack of efficacy in voriconazole arm  voriconazole n = 14 out of 22  L-AMBn = 2 out of 5  Failure to become afebrile in neutropenic patients may indicate presence of occult fungal infections

27. 27 Defervescence Prior to RFN  Fewer patients in voriconazole arm meet definition of defervescence prior to recovery from neutropenia  voriconazole32.5% (135/415)  L-AMB36.5% (154/422)  difference 4.0% in favor of L-AMB with 99% CI (-12.7%, 4.7%)  results highly dependent on definition of defervescence  previous trials required defervescence at any time prior to RFN  Study 603 required 48 hours without fever prior to RFN

28. 28 Defervescence Prior to RFN rates of fever resolution prior to recovery from neutropenia in ETFN trials

29. 29 Defervescence Prior to RFN  Sensitivity analysis for overall response changing definition of defervescence in Study 603  defervescence within 24 hours prior to RFN  voriconazole 35.9%  L-AMB 40.8%  difference -4.9% with 95% CI (-11.7%, 1.9%)  defervescence any time prior to RFN  voriconazole50.1%  L-AMB56.2%  difference -6.1% with 95% CI (-13.1%, 0.9%)  results of sensitivity analyses are supportive of primary analysis

30. 30 Baseline Infections

31. 31 Baseline Infections  Small numbers of patients with BL infections expected given exclusion criteria  Difficult to compare efficacy in treatment of BL infections with small numbers  Two of 6 voriconazole successes developed invasive Candida infections 2-4 months after EOT

32. 32 Summary  Drugs in ETFN should have proven efficacy vs. documented Candida and Aspergillus infections  Aspergillosis global study  Candida esophagitis data and ongoing candidemia study  Since therapy is empiric, patients in ETFN may receive treatment without having fungal infections  safety profile of drug

33. 33 Summary  Voriconazole fails to meet definition of statistical non-inferiority in Study 603  Subset analysis of overall composite endpoint showed numerical advantage of voriconazole in high risk patients but advantage of L-AMB in moderate risk patients  Secondary analyses of BT infections showed numerical advantage of voriconazole especially in prevention of Aspergillus infections  sensitivity analysis including deaths as failures showed no difference between drugs  Secondary analysis of other 4 components of composite endpoint in favor of L-AMB

34. 34 Considerations for the Committee  Clinical relevance of non-inferiority margin of -10% in ETFN trials with composite endpoint  Secondary analyses in study which did not meet primary endpoint  Need to consider safety of drug in empiric therapy where patients may receive drug who do not have infections