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

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

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

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

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

Proposed IndicationGuidant 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 hospitalizationNote: 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

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

FDA Statistical Review of COMPANION

Barbara Krasnicka, Ph.D.

FDA, CDRH

Division of Biostatistics

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 )

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

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

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 definitionhospitalization for which the discharge date was different from the admission date or hospitalization longer than 4 hours during which patient received IV therapy

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

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

Withdrawn patients re-consented to collect endpoints data and vital status

FDA is concerned that post-withdrawal information regarding hospitalizations may be unreliable

Data Quality

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

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

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

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.

All-cause mortality and all-cause hospitalization

All-cause mortality and all-cause hospitalization

Time CRT-D (N=595) OPT (N=308)

Failure# of

Available Failure# of

Available

Rate Patients Rate Patients

30 days 0.12 516 0.17 241

60 days 0.22 458 0.26 212

200 days 0.45 307 0.47 126

400 days 0.59 184 0.69 56

Kaplan-Meier estimates of the failure rates

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 theCRT-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

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

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

All-cause mortality and all-cause hospitalization

All-cause mortality

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

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

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

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

Time CRT-D OPT

 Death

Rate# of Active

Pts.Death

rate# of Active

Pts.

10 days 0.008 590 0.00 306

30 days 0.012 581 0.0098 301

60 days 0.019 573 0.033 291

200 days 0.074 510 0.0976 250

400 days 0.125 387 0.2164 167

600 days 0.197 169 0.3104 63

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

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

Secondary Endpoint - Cardiac Morbidity

  CRT-D OPT

Hospital 0 2

Out of hospital 5 1

Total 5 3

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

Adverse Events

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

Adverse Events during 6 Months after Randomization

 CRT-D (N=595) OPT (N=308)

Time Interval# of # of Pts. # of Pts. # of # of Pts. # of Pts.

  Events with Events Observed Events with Events Observed

0 Day - 30 Days 742 367 576 190 119 288

0 Day - 60 Days 1039 426 568 284 155 276

0 Day - 180 Days 1909 509 512 632 204 226

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)

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

Adverse Events

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

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

FDA CLINICAL REVIEW of COMPANION

Scott E. Proestel, M.D.Medical Officer

U.S. Food and Drug Administration

July 28, 2004

Presentation

• Summarize COMPANION Design• Primary Endpoint• Secondary Endpoints• Additional FDA Efficacy

Analyses• Safety Analysis

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

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

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

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

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

Endpoints

Primary

– Time to all-cause mortality plus all-cause hospitalization

Secondary

– Total survival– Cardiac morbidity– Change in maximal oxygen

consumption (exercise substudy)

Results

1638 patients enrolled1520 (92.8%) randomizedJanuary 2000 - November 2002Enrollment terminated on December 1, 2002(Based on DSMB recommendation)

– 595 CRT-D– 617 CRT-P– 308 OPT

Baseline Characteristics

CRT-D CRT-P OPT

Age (years) 65.6 65.3 66.7

Male 67.4% 67.3% 68.5%

Female 32.6% 32.7% 31.5%

Class III 86.1% 87.0% 82.1%

Class IV 13.9% 13.0% 17.9%

Ischemic 54.6% 53.7% 58.8%

Non-Ischemic 45.4% 46.3% 41.2%

Baseline Characteristics (cont)

CRT-D CRT-P OPT

EF 22.5% 22.0% 22.8%

LBBB 72.9% 69.2% 69.8%

RBBB 10.3% 12.3% 8.8%

IVCD 16.8% 18.5% 21.4%

QRS 159 159 156

PR Interval 206 203 202

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.”

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

Ultimate Definition of Primary Endpoint

1. 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

2. All outpatient infusions of inotropic or vasoactive therapy for > 4 hours for worsening heart failure

3. All-cause mortality

Impact of Modifications to thePrimary Endpoint

• Is the new primary endpoint clinically important?

• Do the changes that occurred in the primary endpoint undermine our belief in the observed effect?

FDA Analysis of Mortality(Secondary Endpoint)

CRT-D CRT-P OPT

Total Patients 595 617 308

Cumulative Follow-up (yrs) 777.2 812.9 374.8

Deaths/100 Pt-Yrs 13.5 16.1 20.5

Cardiac Deaths/100 Pt-Yrs 9.8 13.4 15.5

Pump Failure Dths/100 Pt-Yrs 6.7 6.5 9.1

SCD/100 Pt-Yrs 2.2 5.9 4.8

Cardiac Morbidity (Secondary Endpoint)

Defined as the occurrence of the following events:

– Worsening heart failure resulting in use of IV vasoactive or inotropic therapy > 4 hours

– Mechanical respiratory or cardiac support

– Any cardiac surgery, including heart transplant

– Resuscitated cardiac arrest or sustained VT requiring intervention

Cardiac Morbidity (continued)

– Hospitalization for acute decompensation of heart failure

– Hospitalization that results in death from cardiac causes

– Significant device-related events resulting in:

• Permanent disability• Hospitalization for pending death or

permanent disability

FDA Analysis of Cardiac Morbidity

However, the definition of a cardiac morbid event ultimately used was any hospitalization during which one or more of the specified “cardiac morbid” events occurred.

CRT-D 368 cardiac hospitalizations(0.5 events / year)

OPT 312 cardiac hospitalizations(1.0 events / year)

Additional Analysesfor Labeling

CRT-D 2.0 hospitalizations / yearOPT 1.6 hospitalizations / year

CRT-D 11.0 days / yearOPT 10.7 days / year

FDA Analysis of All-Cause HospitalizationFDA Analysis of All-Cause Hospitalization(includes implant hospitalizations)(includes implant hospitalizations)

FDA Analysis of Implant Hospitalizations

• Of the 595 CRT-D patients, 541 underwent a successful implant, 47 had unsuccessful attempts, and 7 were intents

• 588 CRT-D patients underwent 641 implant hospitalizations

• Mean hospitalization was 2.9 +/- 4.9 days

FDA Analysis of Safety

FDA reviewed all adverse events, defined in the protocol as undesirable clinical outcomes including device-related events as well as events related to a patient’s general condition.

CRT-D 3,732 AEs (4.9 AEs/year)

OPT 1,230 AEs (3.9 AEs/year)

FDA Analysis of Safety

Adverse Events:

CRT-D 14.5% Complications

85.5% Observations

OPT 19.6% Complications

80.4% Observations

Summary

Summary: Scope of 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

Summary: Primary Endpoint

• Modifications were made to the hospitalization definition, part of the primary endpoint, during the course of the COMPANION trial.

• Fundamental statistical assumptions underlying some analyses may not have been met.

• Whether COMPANION demonstrated a benefit for the primary endpoint as originally defined is unknown.

• FDA requests guidance from the panel in interpreting the modified primary endpoint.

Summary: Mortality• The CRT-D device was associated with a

decrease in all-cause mortality compared to OPT.

• Fundamental statistical assumptions underlying parts of the analysis may not have been met.

• Since the pre-specified statistical plan required consistency between primary and secondary endpoints, FDA requests guidance from the panel in assessing the impact of modifications to the primary endpoint on interpretation of a mortality benefit.

Summary: Additional Analyses

• The sponsor’s analyses included data obtained from patients after withdrawal.

• When implant hospitalizations were included, the CRT-D device was associated with an increase in all-cause hospitalizations compared to OPT.

• The CRT-D device was associated with an increase in adverse events compared to OPT.

• FDA requests guidance from the panel in determining the how these considerations should impact the sponsor’s CRT-D labeling.