Transcript FDA Perspectives on Erythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure:

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.
Deputy Director for Science (Acting)
Office of Surveillance and Epidemiology (OSE)
Center for Drug Evaluation and Research (CDER)
September 11, 2007
1
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
2
Approved Erythropoiesis-Stimulating Agents
(ESAs) for Anemia of Chronic Renal Failure:
Epoetin alfa (Epogen® /Procrit®): 1989
Darbepoetin alfa (Aranesp®): 2001
3
What is the Correct Hemoglobin
Target (or Range) for ESAs in
Anemia of Chronic Renal Failure?
4
Randomized Controlled Clinical Trials
of Discrete Hemoglobin Targets:
“Normal Hematocrit”
CHOIR
CREATE
5
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
6
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
7
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
8
Hematocrit (%)
Normal Hematocrit Study Results:
Time (months)
Mean (95% CI) Hematocrit by Study Month (NEJM, 1998)
9
Normal Hematocrit Study Results:
final log rank
p = 0.01
Normal hematocrit group
Probability
of death or
non-fatal MI
(%)
Low hematocrit group
Time (months)
Death or Non-Fatal MI by Study Month (NEJM, 1998)
10
Normal Hematocrit Study Results:
Components of Primary Endpoint
Target
42%
(Normal Hct)
N = 634
Death
Nonfatal MI
Either
RR
95% CI
30%
(Low Hct)
N = 631
221 (35%)
185 (29%) 1.19 1.01 to 1.40
20 (3.2%)
16 (2.5%)
241 (38%)
201 (32%) 1.19 1.03 to 1.39
1.24 0.65 to 2.38
11
Normal Hematocrit Study:
Negative Association Between Mean
Hemoglobin (throughout study) and Mortality:
80
70
Lower target
Higher target
mortality (%)
60
50
40
30
20
10
n=
206 218 172
3
29
48
33
79
222
249
>1 2 .
8
.8
to 12
11.6
.6
to 11
10.6
.6
to 10
10.2
<1 0 .
2
.
>1 2 .
8
.8
to 12
11.6
.6
to 11
10.6
.6
to 10
10.2
<1 0 .
2
0
Hgb quintile (g/dL)
FDA analysis of data collected through 7/5/97
12
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 associated
with survival in both treatment arms.
13
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
14
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
15
mean hemoglobin (g/dL)
CHOIR Study Results
time (months)
Mean (95% CI) Hemoglobin by Study Month (NEJM, 2006)
16
CHOIR Study Results
Primary Composite Endpoint
High hemoglobin group
Probability
of
composite
event
Low hemoglobin group
Time (months)
17
CHOIR Study Results: 1° Endpoint Components
13.5 Hgb
N = 715
Any
component
Death
CHF
hospitalization
Non-fatal MI
Non-fatal
stroke
11.3 Hgb
N = 717
RR
(95% CI)
125 (17.5%) 97 (13.5%) 1.29 (1.01,
1.65)
39 (5.5%)
26 (3.6%) 1.50 (0.93,
2.44)
59 (8.3%)
42 (5.9%) 1.41 (0.96,
2.06)
12 (1.7%)
13 (1.8%) 0.93 (0.43,
2.01)
12 (1.7%)
11 (1.5%) 1.09 (0.49,
2.46)
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CHOIR Study Results
Negative Association Between Mean
Hemoglobin (throughout study) and Mortality:
15
mortality (%)
Lower target
Higher target
10
5
n=
184
247
209
14
48
97
72
34
233 267
>1 3 .
0
.0
to 13
12.1
.1
to 12
11.5
.5
to 11
11.1
<1 1 .
1
.
>1 3 .
0
.0
to 13
12.1
.1
to 12
11.5
.5
to 11
11.1
<1 1 .
1
0
Hgb quintile (g/dL)
FDA exploratory analysis
19
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 associated with
survival in both treatment arms.
20
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
21
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)
22
CREATE Study Results
Median (SD) Hemoglobin by Study Month
NEJM, 2006
23
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
24
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.
25
NKF K/DOQI Guidelines (2006)
“Cohort-based observational trials and crosssectional 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
26
Data to Support Ideal Hemoglobin Target (1):
↓ morbidity/mortality
Normal
hematocrit
10
(hemodialysis)
↑ morbidity/mortality
14
?
↓ morbidity/mortality
11.3
CHOIR
(pre-dialysis)
↑ morbidity/mortality
13.5
8
9
10
11
12
13
14
15
16
Observational data,
by association only
hemoglobin concentration (g/dL)
27
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.
28
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.
29
Dose Optimization Challenges;
ESA Responsiveness
30
Dose Optimization Challenges;
ESA Responsiveness
1. Could we prospectively identify hyporesponders, at higher risk of cardiovascular
events?
2. If hypo-responders could be identified,
how should they be treated?
31
Survival by Hemoglobin (Normal HCT Study)
Less responsive to ESAs
80
70
Lower target
Higher target
mortality (%)
60
50
40
30
20
10
n=
206 218 172
3
29
48
33
79
222
249
>1 2 .
8
.8
to 12
11.6
.6
to 11
10.6
.6
to 10
10.2
<1 0 .
2
.
>1 2 .
8
.8
to 12
11.6
.6
to 11
10.6
.6
to 10
10.2
<1 0 .
2
0
Hgb quintile (g/dL)
FDA analysis of data collected through 7/5/97
32
Survival by Mean Weight-Adjusted Epoetin Alfa Dose
(Normal HCT Study)
1.0
Dose and
responsiveness
are inversely
rated
Fraction surviving
0.8
0.6
<83.5 U/k g/wk (n=252)
83.5 to 155 U/k g/wk (n=252)
0.4
Highest dose;
less responsive
to ESAs
155 to 252 U/k g/wk (n=251)
252 to 423 U/k g/wk (n=252)
0.2
> 423 U/k g/wk (n=252)
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
FDA exploratory analysis
time (months)
33
Prospective Evaluation of ESAResponsiveness (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
34
Prospective Evaluation of ESAResponsiveness (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  slope of hemoglobintime relation throughout the 2- to 6-week
period (linear regression).
35
Prospective Evaluation of ESAResponsiveness (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
36
Prospective Evaluation of ESAResponsiveness (Normal HCT Study) (4)
Assessments:
Survival by initial Epoetin alfaresponsiveness
Overall Epoetin alfa responsiveness
(mean hemoglobin concentration
throughout study) by initial Epoetin alfa
response
37
Initial Epoetin Alfa Responsiveness Does Not
Predict Subsequent Mortality in the NHCT Study
1.0
fraction survi ving
0.8
0.6
Hgb decreased (n=117)
Q1: less responsive (n=60)
0.4
Q2 (n=58)
Q3 (n=63)
0.2
Q4 (n=56)
Q5: more responsive (n=60)
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
time (m onths)
FDA exploratory analysis
38
Initial Epoetin Alfa Responsiveness Does Not
Predict Subsequent Mortality in the NHCT Study
1.0
fraction survi ving
0.8
0.6
Hgb decreased (n=117)
Q1: less responsive (n=60)
0.4
Q2 (n=58)
Q3 (n=63)
0.2
Q4 (n=56)
Q5: more responsive (n=60)
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
time (m onths)
FDA exploratory analysis
39
Initial Epoetin Alfa Responsiveness Does Not
Predict Overall Hgb Response in the NHCT Study
less initial response
more initial response
(g/dL)
study
HgbHthroughout
Mean
Mean
gb throughout
study
(g/dL)
14
13
12
11
10
9
8
-0.40
-0.24
-0.08
0
0.08
0.24
gb rof
atechange
of change
initial
50%
incr ease
in E po
dose
(g/dL/week)
HgbHrate
withwith
initial
50%
increase
in EPO
dose
(g/dL/week)
FDA exploratory analysis
40
Could we prospectively identify hypo-responders,
at higher risk of cardiovascular events?
In the NHCT Study, where patients had protocolmandated 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.
41
ESA-Hyporesponsiveness in a Single Patient:
150
18
120
14
12
90
10
8
60
6
[h e m og lo b in ] g /d L
4
30
e p o e tin a lfa d o s e
2
0
(Thousands)
[hemoglobin] (g/dL)
16
epoetin alfa dose (units/week)
20
0
0
16
32
48
64
80
tim e (weeks)
42
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 feasible
in practice
43
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.
Key Unanswered Question: 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.
44
Dose Optimization Challenges
45
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?
46
Dose Optimization Challenges:
Cycling in a Subject from the Normal Hematocrit Study
47
Dose Optimization Challenges:
Cycling in a Subject from the Normal Hematocrit Study
48
Dose Optimization Challenges:
Cycling in a Subject from the Normal Hematocrit Study
Week 49,
hemoglobin
9.3
Week 50,
hemoglobin
9.9, rate of
change 0.6
g/dL/week
49
Normal Hematocrit Study:
“Dynamic” Analysis of Relations Between Serious
Cardiovascular Events, Prevailing Hemoglobin, and
Preceding Hemoglobin Rate of Change
2.5
2
<9.9
serious
CV
events/
patient-yr
9.9 to 10.8
1.5
10.8 to 11.7
11.7 to 13.4
1
>13.4
0.5
0
< - 0.5
-0.5
to - -0.33
0.33 to - -0.15
0.15 to <0
FDA Analysis
<9.9
9.9 to 10.8
10.8 to 11.7
0 to
0.1
0.1 to
0.25
11.7 to 13.4
0.25
to
0.35
>13.4
0.35
to
0.55
>0.55
50
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?
51
Dose Optimization Challenges:
Development of ESA Dosing Algorithms
Rate of change/ week
most recent Hgb
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
<9
+50%
+50%
+50%
+50%
+50%
+50%
no change
no change
hold
9.0 - 9.5
+50%
+50%
+50%
+50%
+50%
+25%
no change
no change
hold
9.6 - 10.0
+50%
+50%
+50%
+50%
+25%
+25%
no change
no change
hold
10.1 - 10.5
+25%
+25%
+25%
+25%
+25%
+25%
no change
no change
hold
10.6 - 11.0
+25%
+25%
+25%
+25%
no change
no change
no change
-25%
hold
11.1 - 11.5
+25%
no change
no change
no change
no change
no change
-25%
hold
hold
11.6 - 12.0
no change
no change
no change
no change
no change
no change
hold
hold
hold
>12.0
hold
hold
hold
hold
hold
hold
hold
hold
hold
Limit hemoglobin oscillations
Prevent excessive hemoglobin rates of
change
Prevent overshoot
Provide appropriate means to identify and
treat hypo-responders
52
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
53
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)
Return to Unger
54