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FDA Perspectives on Erythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure: Hemoglobin Target and Dose Optimization. Joint Meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Ellis F. Unger, M.D.

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slide1

FDA Perspectives onErythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure:Hemoglobin Target and Dose Optimization

Joint Meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee

Ellis F. Unger, M.D.

Deputy Director for Science (Acting)

Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

September 11, 2007

outline
Outline
  • What is the correct hemoglobin target for ESAs for anemia of chronic renal failure?
    • Randomized controlled clinical trials
    • Observational data
  • ESA responsiveness
  • Dose optimization challenges
  • Potential path forward
approved erythropoiesis stimulating agents esas for anemia of chronic renal failure
Approved Erythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure:
  • Epoetin alfa (Epogen® /Procrit®): 1989
  • Darbepoetin alfa (Aranesp®): 2001
randomized controlled clinical trials of discrete hemoglobin targets
Randomized Controlled Clinical Trials of Discrete Hemoglobin Targets:
  • “Normal Hematocrit”
  • CHOIR
  • CREATE
normal hematocrit study
Normal Hematocrit Study

Goal:

Assess risks and benefits of achieving a “normal” hematocrit in hemodialysis patients with clinically evident CHF or ischemic heart disease

Conducted:

1993 to 1996, with follow-up through 7/1997

normal hematocrit study design
Normal Hematocrit Study: Design
  • Open label
  • All subjects received Epoetin alfa
  • 1:1 randomization to:
    • low hematocrit = 30±3% (Hgb ~10±1 g/dL); or
    • “normal” hematocrit = 42±3% (Hgb ~14±1 g/dL)
  • At entry, patients:
    • clinically evident ischemic heart disease or CHF
    • on hemodialysis
    • clinically stable on Epoetin alfa
  • 1°endpoint: Time to death or non-fatal MI
normal hematocrit study results
Normal Hematocrit Study Results:
  • Randomization:

n = 634 to “normal” hematocrit (42 ± 3%)

n = 631 to low hematocrit (30 ± 3%)

  • Terminated early

“Our study was halted when differences in mortality between the groups were recognized as sufficient to make it very unlikely that continuation of the study would reveal a benefit for the normal-hematocrit group and the results were nearing the statistical boundary of a higher mortality rate in the normal hematocrit group.”

NEJM, 1998

normal hematocrit study results9
Normal Hematocrit Study Results:

Hematocrit (%)

Time (months)

Mean (95% CI) Hematocrit by Study Month (NEJM, 1998)

normal hematocrit study results10

Normal hematocrit group

Low hematocrit group

Normal Hematocrit Study Results:

final log rank p = 0.01

Probability of death or non-fatal MI (%)

Time (months)

Death or Non-Fatal MI by Study Month (NEJM, 1998)

normal hematocrit study results11
Normal Hematocrit Study Results:

Components of Primary Endpoint

normal hematocrit study12
Normal Hematocrit Study:
  • Negative Association Between Mean Hemoglobin (throughout study) and Mortality:

Lower target

Higher target

n=

FDA analysis of data collected through 7/5/97

normal hematocrit study summary
Normal Hematocrit Study Summary:
  • Hemodialysis patients with clinically evident CHF or ischemic HD
  • Targeting a hematocrit of 42 ± 3% versus 30 ± 3% (Hgb ~14 ± 1 versus ~10 ± 1 g/dL) associated with increased mortality and cardiovascular morbidity.
  • Somewhat paradoxically, higher mean hemoglobin concentrations were associatedwith survival in both treatment arms.
choir study design
CHOIR Study Design
  • Open label, Epoetin alfa
  • Patients
    • no Epoetin alfa in past 3 months
    • not on dialysis
    • hemoglobin < 11 g/dL
  • 1:1 randomization to hemoglobin 11.3 or 13.5 g/dL
  • Primary endpoint: composite of mortality, CHF hospitalization, non-fatal stroke, non-fatal MI
choir study results
CHOIR Study Results
  • Randomization:

715 to hemoglobin of 13.5 g/dL

717 to hemoglobin of 11.3 g/dL

  • Terminated early

“The DSMB recommended that the study be terminated in May 2005 at the time of the second interim analysis…because the conditional power for demonstrating a benefit for the high-hemoglobin group was less than 5% for all plausible values of the true effect for the remaining data.” NEJM, 2006

choir study results16
CHOIR Study Results

mean hemoglobin (g/dL)

time (months)

Mean (95% CI) Hemoglobin by Study Month (NEJM, 2006)

choir study results17
CHOIR Study Results

Primary Composite Endpoint

High hemoglobin group

Probability of composite event

Low hemoglobin group

Time (months)

choir study results19
CHOIR Study Results
  • Negative Association Between Mean Hemoglobin (throughout study) and Mortality:

Lower target

Higher target

n=

FDA exploratory analysis

choir summary
CHOIR Summary
  • For pre-dialysis patients, administration of Epoetin alfa to target a Hgb of ~13.5 versus 11.3 g/dL is associated with increased mortality and CHF hospitalization.
  • Paradoxically, higher mean hemoglobin concentrations were associatedwith survival in both treatment arms.
create study design
CREATE Study Design
  • Open label, Epoetin beta
  • Patients
    • mild anemia (hemoglobin 11 to 12.5 g/dL)
    • not on dialysis
    • no prior ESAs
  • 1:1 randomization to normal hemoglobin (13 – 15 g/dL) or subnormal hemoglobin (11 – 12.5 g/dL)
  • Epoetin beta begun in subnormal group once hemoglobin < 10.5 g/dL
create study design results
CREATE Study Design & Results
  • Primary composite endpoint: sudden death, MI, acute heart failure, stroke, TIA, angina requiring hospitalization, peripheral vascular disease complication or cardiac arrhythmia requiring hospitalization
  • Randomization:

301 to normal hemoglobin (13–15 g/dL)

302 to subnormal hemoglobin (11–12.5 g/dL)

create study results
CREATE Study Results

Median (SD) Hemoglobin by Study Month

NEJM, 2006

create study results24
CREATE Study Results
  • Primary endpoint events (NEJM, 2006):

- 58/301 in normal hemoglobin group

- 47/302 in sub-normal hemoglobin group

    • HR 0.78 (95% CI 0.53 – 1.12)
  • Few endpoint events despite broad composite endpoint
  • Results directionally support lower hemoglobin target
observational data 58 058 u s hd patients
Observational Data – 58,058 U.S. HD Patients:

Database from DaVita, Inc.

Regidor DL, Kopple JD, Kovesdy CP, et al. J Am Soc Nephrol. 2006;17:1181.

nkf k doqi guidelines 2006
NKF K/DOQI Guidelines (2006)

“Cohort-based observational trials and cross-sectional analyses of large medical databases…consistently show that higher achieved hemoglobin values (including ≥ 12 g/dL) are associated with improved patient outcomes …. The failure of observational associations to be confirmed by interventional trials renders use of observational evidence unsuitable to support the development of an intervention guideline statement.”

www.kidney.org/professionals/KDOQI/guidelines_anemia/cpr21.htm

data to support ideal hemoglobin target 1
Data to Support Ideal Hemoglobin Target (1):

↓ morbidity/mortality

↑ morbidity/mortality

Normal hematocrit

(hemodialysis)

10

14

?

↓ morbidity/mortality

↑ morbidity/mortality

11.3

CHOIR

(pre-dialysis)

13.5

Observational data, by association only

data to support ideal hemoglobin target 2
Data to Support Ideal Hemoglobin Target (2):
  • Observational data from HD patients
  • Exploratory analyses of NHCT and CHOIR
    • associations between higher mean hemoglobin concentration achieved and survival
  • Association does not prove causality
  • Achieved hemoglobin ≠ hemoglobin target.
  • J-shape relation suggests that there is some Hgb concentration that is excessive in the CRF population.
data to support ideal hemoglobin target 3
Data to Support Ideal Hemoglobin Target (3)
  • Perhaps patients who achieve higher hemoglobin concentrations have less advanced renal disease and lower CV disease burden  better outcomes.
  • We are not aware of a RCT that demonstrates, in a convincing way, that a higher hemoglobin target is associated with less cardiovascular morbidity and mortality than a lower target.
slide31

1. Could we prospectively identify hypo-responders, at higher risk of cardiovascular events?2. If hypo-responders could be identified, how should they be treated?

Dose Optimization Challenges;

ESA Responsiveness

survival by hemoglobin normal hct study
Survival by Hemoglobin (Normal HCT Study)

Less responsive to ESAs

Lower target

Higher target

n=

FDA analysis of data collected through 7/5/97

survival by mean weight adjusted epoetin alfa dose normal hct study
Survival by Mean Weight-Adjusted Epoetin Alfa Dose (Normal HCT Study)

Dose and responsiveness are inversely rated

Fraction surviving

Highest dose; less responsive to ESAs

FDA exploratory analysis

time (months)

prospective evaluation of esa responsiveness normal hct study 1
Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (1)
  • FDA exploratory analysis
  • NHCT study provided unique opportunity to assess ESA-responsiveness.
  • Stable HD patients, maintained on Epoetin alfa; hematocrit 27 to 33% for 4 weeks
  • Subjects randomized to “normal” hemoglobin target group had standard protocol-mandated ESA “challenge”
  • Epoetin alfa dose increased by factor of 1.5 on study entry
prospective evaluation of esa responsiveness normal hct study 2
Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (2)
  • Epoetin alfa-responsiveness calculated for patients who received constant weekly Epoetin alfa dosing for 2 to 6 weeks following study entry.
  • Responsiveness ºslope of hemoglobin-time relation throughout the 2- to 6-week period (linear regression).
prospective evaluation of esa responsiveness normal hct study 3
Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (3)
  • 618 patients randomized to “normal” hemoglobin target
    • EPO-responsiveness could be calculated for 414:
      • 117 patients experienced a decrease in hemoglobin, despite a 50% increase in Epoetin alfa dose
      • 297 patients experienced no change or an increase in hemoglobin: divided in quintiles
prospective evaluation of esa responsiveness normal hct study 4
Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (4)

Assessments:

  • Survival by initial Epoetin alfa-responsiveness
  • Overall Epoetin alfa responsiveness (mean hemoglobin concentration throughout study) by initial Epoetin alfa response
initial epoetin alfa responsiveness does not predict subsequent mortality in the nhct study
Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study

FDA exploratory analysis

initial epoetin alfa responsiveness does not predict subsequent mortality in the nhct study39
Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study

FDA exploratory analysis

initial epoetin alfa responsiveness does not predict overall hgb response in the nhct study
Initial Epoetin Alfa Responsiveness Does Not Predict Overall Hgb Response in the NHCT Study

less initial response more initial response

Mean Hgb throughout study (g/dL)

0

Hgb rate of change with initial 50% increase in EPO dose (g/dL/week)

FDA exploratory analysis

slide41

Could we prospectively identify hypo-responders, at higher risk of cardiovascular events?In the NHCT Study, where patients had protocol-mandated 50% increase in EPO dose on study entry:Initial Hgb response did not predict subsequent mortality, and did not predict overall Hgb response.* ESA responsiveness may need to be assessed on ongoing basis.

slide43

Conclusions: Dose Optimization Challenges; ESA Responsiveness (1)- Prospective identification of hypo-responders may be difficult (i.e., erythropoietic response to an ESA challenge)- Identification of hypo-responders is feasiblein practice

slide44

Conclusions: Dose Optimization Challenges; ESA Responsiveness (2)For hypo-responsive patients, the labeling suggests a search for causative factors, but does not explicitly state a maximum ESA dose, or what constitutes an adequate attempt to raise hemoglobin.KeyUnansweredQuestion: whether less responsive patients or those with specific risk factors would experience fewer cardiovascular events if attempts were not made to raise their hemoglobin to some “ideal” target.

dose optimization challenges46
Dose Optimization Challenges
  • ESA labeling warns against excessive rate of rise of Hgb (> 1 g/dL per 2 weeks)
  • Is risk related to hemoglobin response?
dose optimization challenges cycling in a subject from the normal hematocrit study49
Dose Optimization Challenges: Cycling in a Subject from the Normal Hematocrit Study

Week 50, hemoglobin 9.9, rate of change 0.6 g/dL/week

Week 49, hemoglobin 9.3

slide50

Normal Hematocrit Study:“Dynamic” Analysis of Relations Between Serious Cardiovascular Events, Prevailing Hemoglobin, and Preceding Hemoglobin Rate of Change

serious CV events/ patient-yr

[Hemoglobin] (g/dL)

Hemoglobin rate of change (g/dL/wk)

FDA Analysis

dose optimization challenges51
Dose Optimization Challenges
  • ESA labeling warns against excessive rate of rise of Hgb (> 1 g/dL per 2 weeks)
  • Hemoglobin oscillations are associated with serious cardiovascular events
    • Due to underlying patient characteristics?
    • Worth trying to prevent?
dose optimization challenges development of esa dosing algorithms
Dose Optimization Challenges: Development of ESA Dosing Algorithms

Limit hemoglobin oscillations

Prevent excessive hemoglobin rates of change

Prevent overshoot

Provide appropriate means to identify and treat hypo-responders

summary
Summary:
  • Best RCT data available: “Ideal” hemoglobin target is 10 g/dL for HD patients; 11.3 g/dL for pre-dialysis patients
  • Data to support a hemoglobin target as high as 12 g/dL are observational in nature and of limited utility:
    • association ≠ causality
    • achieved hemoglobin ≠ target hemoglobin
  • Unknown if ESA-hyporesponsive and/or high-risk patients should be treated differently
  • Little data to show that current labeling addresses how best to reduce hemoglobin overshoot and cycling
potential path forward
Potential Path Forward
  • Hemoglobin target: conduct prospective, randomized, controlled cardiovascular outcome study(ies) to determine optimum hemoglobin target(s)
    • Consider, a priori, disparate targets based on risk factor(s)
  • Develop new dosing paradigm(s):
    • Special dosing strategies might be considered for hypo-responsive patients and those at higher risk of CV events
    • Strategy could consider “futility”
  • Test prospectively in RCT(s)

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