Expanded Indications and Claims for Guidant CRT-D Devices

1. Expanded Indications and Claims for Guidant CRT-D Devices Owen P. Faris, Ph.D. Scientific Reviewer U.S. Food and Drug Administration July 28, 2004

2. FDA Review Team Lead: Owen Faris, Ph.D. Statistical: Barbara Krasnicka, Ph.D. Clinical: Scott Proestel, M.D. Ileana Piña, M.D. Bioresearch Monitoring: Rachel Solomon MHS, FAHA

3. Regulatory Background • September 8, 1999: Agreement letter for COMPANION clinical trial sent to sponsor from FDA • January 20, 2000: First patient enrolled in COMPANION • May 2, 2002: Guidant CONTAK CD (CRT-D) approved by FDA • November 30, 2002: COMPANION trial stopped • January 26, 2004: Guidant CONTAK TR/RENEWAL TR (CRT-P) approved by FDA • March 26, 2004: Request for expanded indications and new claims for Guidant’s CRT-D devices based on results from COMPANION submitted to FDA

4. COMPANION Agreements • Inclusion and exclusion criteria • Primary and secondary hypotheses • Statistical analysis plan • Statistical plan would not support CRT-D vs. CRT-P comparisons • To address multiplicity, consistency across primary and secondary endpoints was required to evaluate any one endpoint

5. Changes from Current Indication The sponsor’s proposed indication requests the following changes based upon results from the COMPANION clinical trial: • Expanded indication to include the entire population described in COMPANION • New Claims • Primary composite endpoint benefit • Mortality benefit

6. Proposed Indication • Guidant Cardiac Resynchronization Therapy Defibrillators (CRT-Ds) are indicated for patients with moderate to severe heart failure (NYHA III/IV) who remain symptomatic despite stable, optimal heart failure drug therapy, and have left ventricular dysfunction (EF </= 35%) and QRS duration >/= 120 ms. • Guidant Cardiac Resynchronization Therapy Defibrillators (CRT-Ds) have demonstrated the following outcomes in the indicated population specified above: • Reduction in risk of all-cause mortality or first all-cause hospitalization • Note: Hospitalization is defined as administration of IV inotropes or vasoactive drugs > 4 hours (outpatient or inpatient), or admission to a hospital that includes or extends beyond a calendar date change. • Reduction in risk of all-cause mortality • Reduction of heart failure symptoms

7. Scope of FDA’s Review • COMPANION primary and secondary endpoint results • COMPANION hospitalizations and adverse events • Consistency with pre-specified clinical and statistical plans • Presentation of data in device labeling

8. FDA Statistical Review of COMPANION Barbara Krasnicka, Ph.D. FDA, CDRH Division of Biostatistics

9. Study Design • Objective of the COMPANION study was a comparison of: • OPT (Optimal Pharmacologic Therapy) • CRT-P (OPT plus Cardiac Resynchronization Therapy) • CRT-D (OPT plus CRT + Defibrillator therapy )

10. Study Design • Prospective • Three arms • Multi-center (128) • Randomized • Group sequential design • Trial was planned to stop after 1000 primary endpoint events (mortality or hospitalization) would be identified

11. Study Design • It was expected that, compared to OPT alone, CRT-D could reduce • combined all-cause mortality and all-cause hospitalization (primary effectiveness endpoint) • all-cause mortality and cardiac morbidity (secondary effectiveness endpoints) • Safety Endpoint: None

12. Data Collection and Quality • Primary effectiveness endpoint was modified three times • All-cause hospitalization • Original definition admission to a hospital for any reason and endpoint would include emergency room visits (or unscheduled office visits) that result in treatment with IV therapy • Last version of the definition hospitalization for which the discharge date was different from the admission date or hospitalization longer than 4 hours during which patient received IV therapy

13. Data Collection and Quality • Hospitalization Case Report Form included data on the admission and discharge dates not taking into account exact time • Capture of the hospitalization events longer than 4 hours during which patient received IV therapy was based on the duration of the IV therapy • Case Report Forms missing for some hospitalizations

14. Data Quality • Study stopped in December, 2002 • 941 “potential” primary endpoint events had been submitted • Many withdrawals from the study • Withdrawal rates at 12 months were different for the two groups: • OPT group - 21% (64 patients) • CRT-D group - 4% (25 patients) • FDA is concerned that worsening of patients’ health status was probably the reason for withdrawals

15. Data Quality • Withdrawn patients re-consented to collect endpoints data and vital status • FDA is concerned that post-withdrawal information regarding hospitalizations may be unreliable

16. Statistical Analyses • Combined all-cause mortality or all-cause hospitalization and all-cause mortality • Kaplan-Meier method, Log-rank test or Wilcoxon test • Cox model • Cardiac morbidity, adverse events • Exploratory analyses

17. All-cause mortality and all-cause hospitalizationKaplan-Meier estimates of the event-free functions

18. All-cause mortality and all-cause hospitalization • Tentative assumptions: • Quality of Data set was good • The primary endpoint (all-cause hospitalization) was not changed • Censoring was non-informative, i.e., the censoring was independent of occurrence of an event

19. All-cause mortality and all-cause hospitalization • For combined all-cause mortality and all-cause hospitalization endpoint: • The event-free time of some patients could be censored as a result of a worsening of their health status, i.e., censoring may be informative • Fundamental assumption for the survival analyses may not be satisfied.

20. All-cause mortality and all-cause hospitalization Kaplan-Meier estimates of the failure rates

21. All-cause mortality and all-cause hospitalization • Survival functions for the CRT-D and OPT groups are different • P value = 0.025 (Wilcoxon test) • Under assumption of proportionality, Cox model supplied for the CRT-D vs. OPT hazard ratio • Point estimate: 0.81 (i.e., 19% reduction in the relative risk) • 95 % confidence interval (0.68,0.96) • P value = 0.015 • Proportional hazards assumption may not be satisfied in this case

22. All-cause mortality and all-cause hospitalization • Results of the statistical analysis may be problematic because: • The primary effectiveness endpoint definition was changed during the study

23. All-cause mortality and all-cause hospitalization • The assumptions underlying the statistical methods used may not be satisfied • Censoring may be informative The censoring may not be independent on the occurrence of the event because some patients withdrew from the study due to worsening of their health status • The hazard functions and the Schoenfeld residuals indicate that the proportionality assumption may not be valid

24. All-cause mortality • Statistical analyses for all-cause mortality secondary endpoint raises similar statistical concerns as the primary effectiveness endpoint analyses

25. Kaplan-Meier estimates of the survivor functions for all-cause mortality

26. Kaplan-Meier estimates of the survivor functions and their confidence limits for all-cause mortality

27. Death rates (Kaplan-Meier estimates) for the CRT-D and OPT groups

28. All-cause mortality • Survival functions for the CRT-D and OPT groups are different • P value = 0.003 • CRT-D vs. OPT hazard ratio (Cox model) • Point estimate: 0.64 (i.e., 36% reduction in the relative risk) • 95 % confidence interval (0.48,0.86) • P value = 0.003

29. All-cause mortality • The statistical results may be problematic because: • The assumptions underlying the statistical methods used may not be satisfied Hazard functions and the Schoenfeld residuals do not reasonably support the proportionality assumption

30. Secondary Endpoint - Cardiac Morbidity • Sponsor considered only cardiac morbidity events that occurred in hospitals • However, cardiac morbidity events may occur out of hospital Cardiac death during the first 30 days after randomization

31. Adverse Events • Sponsor’s definition: “undesirable clinical outcomes and included device-related events as well as events related to the patients' general condition”

32. Adverse Events during 6 Months after Randomization

33. Adverse Events • Adverse Events rates at 6 months after randomization • For the approach assuming that each lost-to-follow-up patient before the 6-months was event-free CRT-D group - 3.21 (1909 events/595 patients) OPT group - 2.05 (632 events/308 patients) • For the worst –case (upper limit) approach CRT-D group - 3.73 (1909 events/512 patients) OPT group - 2.80 (632 events/226 patients)

34. Adverse Events • OPT patients experienced fewer adverse events during the 6 months after randomization • Validity of sponsor’s statistical analyses is of concern since: • Correlation between multi events within a patient was not taking into account • Time of an adverse event occurrence was not taken into account • Many lost-to-follow-up patients were excluded • All exploratory analyses should be interpreted with caution

35. Statistical Review Conclusions • Treatment comparisons for the primary effectiveness and mortality endpoints should be interpreted with caution • Definition of all-cause hospitalization changed • Withdrawals not clearly independent of outcome • Open label design

36. Statistical Review Conclusions • For the cardiac morbidity and adverse events • All cardiac morbidity events that occurred outside hospitals were not taken into account • Lost-to-follow-ups patients, correlation within a patient and times of the events occurrence were not taken into account

37. FDA CLINICAL REVIEW of COMPANION Scott E. Proestel, M.D. Medical Officer U.S. Food and Drug Administration July 28, 2004

38. Presentation • Summarize COMPANION Design • Primary Endpoint • Secondary Endpoints • Additional FDA Efficacy Analyses • Safety Analysis

39. COMPANION Summary Intended to enroll up to 2200 patients with moderate to severe heart failure, and randomize 1:2:2 • OPT • CRT-P • CRT-D

40. Inclusion Criteria • NYHA Class III/IV • EF ≤ 35% • QRS ≥ 120 ms • PR > 150 ms • LVEDD ≥ 60 mm or > 3.0 cm/m2 • Optimal medical therapy

41. Inclusion Criteria (cont) At least one of the following events during previous 12 months: • Hospitalization for heart failure • Outpatient visit in which IV inotropes or vasoactive infusion were administered for ≥ 4 hours • ED visit of at least 12 hours duration in which IV HF medications were administered

42. Exclusion Criteria • Indicated for an ICD • Indicated for antibradycardia pacing • Expected to receive a heart transplant within 6 months • Chronic, medically refractory atrial tachyarrhythmias • Unexplained syncope • MI within 60 days

43. Exclusion Criteria (cont) • Unstable angina • Uncontrolled HTN • CAD with surgical or PCI correction within 60 days • Hypertrophic obstructive cardiomyopathy • Amyloid disease • Hospitalization for heart failure or IV inotropic or vasoactive therapy in excess of 4 hours within 30 days • Life expectancy < 6 months due to any other medical conditions

44. Endpoints Primary • Time to all-cause mortality plus all-cause hospitalization Secondary • Total survival • Cardiac morbidity • Change in maximal oxygen consumption (exercise substudy)

45. Results 1638 patients enrolled 1520 (92.8%) randomized January 2000 - November 2002 Enrollment terminated on December 1, 2002 (Based on DSMB recommendation) • 595 CRT-D • 617 CRT-P • 308 OPT

46. Baseline Characteristics

47. Baseline Characteristics (cont)

48. Pre-Specified Primary Endpoint • “…a combination of all-cause mortality and all-cause hospitalization, where all-cause mortality is defined as death from all causes and all-cause hospitalization is defined as admission to a hospital for any reason.” • “In addition, this endpoint will include emergency room visits (or unscheduled office visits) that result in treatment with intravenous (IV) inotropes or vasoactive drugs.”

49. Primary Endpoint Modifications Definition changed 3 times: • Hospitalizations > 24 hours • Hospitalizations for which the discharge date differed from the admission date • Inotrope or vasoactive infusion duration > 4 hours Data to calculate the pre-specified primary endpoint does not exist

50. Ultimate Definition of Primary Endpoint • All hospitalizations associated with a calendar date change, without regard to whether the hospitalization was considered elective or related to heart failure, with the following exceptions: • Index hospitalizations • Reimplant attempt hospitalizations • Hospitalizations that were considered elective and associated with the device • All outpatient infusions of inotropic or vasoactive therapy for > 4 hours for worsening heart failure • All-cause mortality