Transcript LECTURE 10-97

Endpoints
(also Outcomes, Major Response
Variables)
How do you determine whether the
treatment is effective?
Randomization (√)
Blinding (√)
Well-defined target population (√)
Appropriate control (√)
Excellent follow-up (√)
Adequate sample size (√)
Appropriate interim monitoring (√)
Endpoints (?)
Outline
• General endpoint considerations
• Surrogate endpoints
• Composite endpoints and recurrent events
• Safety outcomes (adverse events)
Major Problems that Limit
Interpretation of Randomized Trials
• Inappropriate controls
• Endpoints which are not clinically relevant
• Inadequately powered studies
• Poor follow-up
• Improper interim analyses
Protocol and Trial Report - 1
• Endpoints should be pre-specified:
– Written down in the protocol before trial begins
– Defines the trial objectives (in part)
– Basis for sample size
• Example: Herpes Zoster Vaccine Protocol
– Hypotheses and Objectives: “The primary objective of
this study is to determine whether immunization with live-attenuated
varicella-zoster vaccine (OKA/Merck Strain) can reduce the
incidence and/or severity of herpes zoster (HZ) and its
complications, primarily postherpetic neuralgia (PHN) in persons 60
years of age and older. This will be accomplished by comparing a
measure of the burden of illness due to HZ and PHN in vaccine and
placebo recipients.
Protocol and Trial Report - 2
• Example: Herpes Zoster Vaccine Trial
Report (N Engl J Med 2005)
– “The Shingles and Prevention Study (Department of
Veterans Affairs [VA] Cooperative Study No. 403) was
conducted to determine whether vaccination with a live
attenuated VZV vaccine would decrease the incidence,
severity, or both of herpes zoster and post-herpetic
neuralgia in adults 60 years of age or older.”
– “The primary endpoint was the burden of illness due to
herpes zoster, a severity-by-duration measure of the
total pain and discomfort associated with herpes zoster
in the population of study subjects.”
Primary Endpoint
– Usually one outcome is specified as most important (primary
endpoint)
– Key variable in design (follows from objective)
– Basis for sample size
– A focus of interim monitoring and QA
– Response variable given major attention in trial report
– Usually, but not always, e.g., Cox-2 trials on GI bleeding, relates to
efficacy. In some studies the primary endpoint encompasses
efficacy and safety, e.g., mortality in CHF study, lipid study, HIV
treatment study
– “A clinical endpoint that provides evidence sufficient to fully
characterize the effect of a treatment in a manner that would
support a regulatory claim for treatment” (O’Neill RT, Cont Clinical
Trials, 1997;18:550-556)
Secondary Endpoints
• There are usually several efficacy endpoints and
these are commonly referred to as secondary
endpoints or secondary efficacy endpoints.
• Safety endpoints must also be specified and are
usually consider secondary
–
–
–
–
Discontinuation of study treatment
Side effects/adverse events
Serious adverse events
O’Neill (FDA) defines a secondary endpoint as one that
“provides additional characterization of treatment effect
but that is not sufficient to characterize fully the benefit
or to support a claim for a treatment effect”.
Characteristics Desired for
Endpoint
• Relevant; easy to interpret
• Easy to diagnose
• Can be ascertained and classified in an unbiased
manner
• Sensitive to treatment differences
• Measurable within a reasonable period of time
General Considerations - 1
More commonly occurring endpoints (high incidence) will
result in smaller sample sizes than less frequent events (low
incidence) as long as expected relative difference between
treatment groups is similar
• CHD + non-fatal MI vs. CHD death for lipid-lowering trial
• Progression-free survival vs survival for cancer trial
Continuous response variables usually result in smaller
sample sizes than binary or time to event
• BP change vs. % with normal BP
• HIV RNA change vs. % < 50 copies/mL
• Weight change vs. % who lose > 5% of baseline weight
General Considerations - 2
More serious events should be considered along with less serious
ones
• Count CHD deaths along with non-fatal MIs
Related to this, some events may have to be included to avoid
misinterpretation due to informative censoring (this could result in a
loss of power)
•
•
•
Non-arrhythmic deaths along with arrhythmic deaths
(DEFINITE, NEJM 2004)
Death and missing data along with change in exercise duration
(PICO, Heart 1996)
Progression to AIDS or death from any cause (SMART, NEJM
2006)
Endpoint Examples - 1
MRFIT (JAMA 1982 and Amer J Cardiol 1986)
Primary:
CHD Death
Secondary: CHD Death or non-fatal MI
CVD mortality
All-cause mortality
NuCombo HIV Study (N Engl J Med 1996)
Primary:
Progression to AIDS or death from any cause
Secondary: Death
AMIS (JAMA 1982)
Primary:
All deaths
Secondary: CHD death or non-fatal MI
Endpoint Examples - 2
• New BP-lowering drug – Systolic BP change
• CHF device – change in NYHA class; 6minute walk
• New antiretroviral drug – HIV RNA
suppression at 24 and 48 weeks
Special considerations: longitudinal measurements; informative
missing data; left censoring
Choice of Endpoint in TOMHS
[Antihypertensive Drugs]
BP, Side Effects, Quality of Life
Echocardiographic and Electrocardiographic
Changes (Asymptomatic CVD)
Non-fatal MI, Stroke, Angina, Peripheral Artery
Disease (Symptomatic CVD)
CVD Death
• CHD
• Stroke
Total Mortality
Choice of Endpoint in Antiretroviral
Trials
CD4+ count; viral load
Genotypic/phenotypic resistance;
Loss of drug options
Clinical disease progression (AIDS)
Serious AIDS and non-AIDS events
Survival
Choice of Endpoint in HIV Vaccine Trials
HIV Infection
Durable control of viremia post-infection (viral
load set point)
CD4+ decline/ART
AIDS or death
Endpoints Used to Approve Cancer
Drugs and Biologics
• Survival
• Symptom endpoints (patient reported
outcomes)
• Disease-free survival (e.g., time to tumor
recurrence or death)
• Objective response rate (e.g., proportion of
patients with tumor size reduction of a predefined amount for a minimum time period)
Guidance for Industry. Clinical Trial Endpoints for the
Approval of Cancer Drugs and Biologics. May 2007.
Requirements for FDA Approval Vary
• Antiretroviral drugs for HIV – viral load
(regimen failure)
• Antihypertensive drug – BP
• CHF drug – morbidity and mortality
• Device for CHF – functional status
• Osteoporosis drugs – bone density
For Other Areas There is Uncertainty
• Treatments for community acquired bacterial
pneumonia (CABP)
– Should focus be on clinical endpoints that
capture how a patient feels or should outcomes
incorporate clinical signs (e.g., fever) and
laboratory tests (e.g., WBC count)?
– FDA position in November 2011: “improvement
in at least 2 symptoms attributable to CABP… at
a minimum cough, sputum production, chest
pain, and shortness of breath at an early time
point (i.e., day 3 or 5 after enrolment).
Anti-Infective Drugs Advisory Committee Briefing Document
November 2011
Choice of Endpoint: General
Hierarchical Categorization
• Clinical outcome (morbidity and mortality)
• Surrogate for clinical outcome (may be hard to
establish)
• Intermediate outcome that is likely to predict
clinical benefit (non-validated surrogate)
• Biomarker which measures biologic activity
Types of Endpoints from an Analytic
Point of View
• Binary
• Ordered categorical
• Continuous (single point in time, repeated
measures, slope)
• Counts
• Time to event and rates
Other Endpoint Considerations
1.
Training of evaluators (e.g., BP measurement)
2.
Ongoing quality assurance (e.g., laboratory QC)
3.
Endpoint classification committee
4.
Blinding of endpoint determination (as noted previously
this can be done even in open- label studies)
5.
Methods for reducing missing data
–
Informed consent
–
Training
–
Quality assurance procedures
–
Collect identifying information at entry
–
National Death Index
Outline
• General endpoint considerations
• Surrogate endpoints
• Composite endpoints
• Safety outcomes (adverse events)
Surrogate Endpoint
(Definition)
• Failure of treatment (relative to control) to
influence the surrogate implies failure to influence
“true” endpoint (Prentice, Stat Med, 1989)
• Surrogate must be able to capture “full”
dependence of “true” endpoint rate on
randomization group, i.e., no pathways whereby
randomization assignments affect “true” endpoint
that bypass the surrogate response
• Occurs with greater frequency than “true” endpoint
• Occurs sooner after treatment than “true” endpoint
Other Definitions of Surrogate Endpoints
• “a laboratory measurement or clinical sign used as
a substitute for a clinically meaningful endpoint
that measures directly how a patient feels
functions or survives” (Temple).
• “ A surrogate endpoint is expected to expected to
predict clinical benefit (or harm or lack of benefit or
harm) based on epidemiologic, therapeutic,
pathophysiologic, or other scientific evidence”
(Biomarker Definitions Working Group; also, IOM
report).
• “an outcome measure that substitutes for a clinical
event of true importance” (Grimes and Schulz).
Institute of Medicine Report: Evaluation of
Biomarkers and Surrogate Endpoints in
Chronic Disease
• Biomarker evaluation should consist of 3 steps:
– Analytical validation (e.g., performance of an assay)
– Qualification (assessment of association of biomarker
with disease and the effect of interventions on
biomarkers)
– Utilization (contextual analysis of available evidence on
the specific use proposed). A biomarker may be used
as a surrogate for some disease states and not in
others, e.g., HIV viral load in setting where suppression
is complete versus partial
IOM 2010, National Academies Press
Relationship Between Treatment (A or B), a
Surrogate Marker (S), and the Clinical
Outcome (T)
A or B
Treatment has many
mechanisms of action
Treatment
S
Other
Mechanisms of Action
Surrogate Marker
T
Clinical Outcomes
Fleming and DeMets, Ann Int Med, 1996
Surrogate Endpoint:
Not in Causal Pathway of Disease Process
Disease
Surrogate
Endpoint
True Clinical
Endpoint
Causal Pathway
Fleming and DeMets, Ann Int Med, 1996
A correlate does not a surrogate make!
Fleming TR and DeMets DL, Ann Int Med, 1996.
Age-adjusted CHD Mortality
(per 10,000 person-years)
90
80
70
60
50
40
30
20
10
0
<1 20
12 012 9
13 013 9
14 015 9
16 017 9
18 020 9
Systolic Blood Pressure (mmHg)
Data from the MRFIT Study
21 0+
Blood Pressure is Considered An
Acceptable Surrogate Endpoint by the FDA
• Substantial epidemiological and clinical trial
data.
• Demonstration that diverse BP-lowering
agents provide benefit.
• Considered to be the principal causal
pathway.
ALLHAT Results on Doxazosina:
Cumulative 4-Year Rate (%)
Doxazosin Chlorthalidone
No. Patients
Fatal/Non-Fatal CHD
6.3%
15,268
6.3%
Fatal/Non-Fatal Stroke
4.2%
3.6%
Congestive Heart Failure
8.1%
4.5%
All Cause Mortality
a
9,067
JAMA; 283:1967-1975, 2000
9.6%
9.1%
Multiple Pathways of the Disease Process
Intervention
Disease
Surrogate
Endpoint
True Clinical
Endpoint
Intervention
Disease
True Clinical
Endpoint
Surrogate
Endpoint
Best Situation for Assessing Surrogacy
Intervention
Disease
Surrogate
Endpoint
True Clinical
Endpoint
Interleukin -2 Trials for HIV
IL-2
Disease
•
CD4+
Count
AIDS or
Death
IL-2: known to increase CD4+ cell count
• IL-2: known to be associated with toxicities
• Unknown whether IL-2 is increasing functional CD4+ cells
Deaths and Serious AIDS Event Rates by Latest
CD4+ Count Following Initiation of ART
CD4+
Level
All-Cause Mortality
PY
Events Rate
Serious AIDS
PY
Events Rate
< 200
1327
29
4.29
907
74
8.16
200-350
2624
18
0.84
2284
38
1.66
350-499
3532
21
0.42
3228
18
0.56
500+
8425
22
0.30
7964
21
0.26
CASCADE Collaboration http://www.cascade-collaboration.org
ESPRIT Study Design
Patients taking ART with CD4+ counts ≥ 300/μL
N = 2071
N = 2040
IL-2
ART plus:
Control
ART without IL-2
• 3 cycles of IL-2 (7.5 MIU twice
daily for 5 days, 8 wks apart)
• additional cycles to maintain goal
(2x baseline or ≥ 1000 CD4+ cells)
Plan: 320 primary events
Closure date 15 Nov 2008
323 primary events observed
Median follow-up = 7 years
N Engl J Med 2009 361:1548-1559.
Median CD4+ During Follow-up
800
700
CD4+
600
500
IL-2
Control
400
300
Time spent
IL-2
200
< 300 cells
6%
9%
100
> 600 cells
57%
36%
Control
Avg Difference:
160 cells, p<.001
0
0
1
2
3
4
5
6
7
Year
No. pts
IL-2:
2071
1846
1829
1797
1757
1721
1410
878
Control:
2040
1928
1861
1803
1739
1648
1350
824
Primary Endpoint
Opportunistic Disease or Death
IL-2
No. Rate*
Control
No. Rate*
158
165
1.13
1.21
HR (95% CI)
p-value
0.93 (0.75, 1.16)
0.52
Predicted HR based on CD4+ difference = 0.74
* rate per 100 person years
Interventions having Mechanisms
of Action Independent of the Disease
Process
Intervention
Disease
Surrogate
Endpoint
True Clinical
Endpoint
Concorde Study Results
(Lancet 341:889-90, 1993)
Immediate
ZDV
Deaths
Deferred
ZDV
95
76
AIDS or Death
175
171
ARC, AIDS or Death
263
284
CD4 difference over 3 years
of follow-up (immediate - deferred) =
30 cells (p < 0.0001)
12-month Cumulative Mortality (%)
CD4+ Count and Mortality: Pre-HAART Era
40
35
30
25
20
15
10
5
0
< 25
25 49
50 99
10 0 19 9
Baseline CD4+ Lymphocyte Count
(cells/mm3)
CID 1996; 22:513-520
20 0 49 9
Overview of Trials
of ZDV vs. Placebo (Immediate vs.
Deferred)
Immediate
ZDV
Total
No. deaths
Deferred
ZDV (placebo)
4431
3291
734
617
Risk ratio = 1.04
No. AIDS/deaths
1026
882
Risk ratio = 0.96
Lancet 353:2014-2025, 1999.
Operational Criteria
for Valid Surrogates
• The surrogate (S) must predict the clinical
event (T)
• Treatment must effect surrogate
• The surrogate (S) must fully capture the
effect of treatment on the clinical event (T)
Prentice R, Stat Med, 1989.
Evaluation of Surrogacy
Determine relative risk (treatment versus
control) of long-term clinical outcome
Show that relative risk when adjusted for
marker in each treatment group is one
Not an optimal approach. Ideally, results from
several studies with surrogate and clinical
outcomes would be compared.
Statistical Analysis for Single Study
• Fit logistic regression models:
1) log odds (long-term clinical outcome) =
a + b (trt)
2) log odds (long-term clinical outcome) =
a + ba (trt) + c
(marker change)
• If marker change fully explains treatment
effect, then ba would be zero
• (b-ba)/b measures proportion of effect on
long-term clinical outcome explained by
effect on marker
Validation of Surrogate Endpoints
Statistical – want more than one study
· Meta-analyses of clinical trials data
Clinical
· Comprehensive understanding
of the causal pathways and intended
and unintended mechanisms of action
Overview of 16 Antiretroviral Trials
State-of-the-Art Conference 1993
Clinical Disease
Progression
Sig. Diff.
CD4+
Change
No Diff.
Sig. Diff.
7
6
13
No Diff.
1
2
3
8
8
Colon Cancer Example
• Traditional endpoint is overall survival (OS)
• Hypothesis: Disease free survival (DFS), assessed after 3
yrs, is an appropriate endpoint to replace overall survival
(OS) in adjuvant colon trials
 Allow more rapid completion, reporting of trials
 Allow promising agents to benefit patients more quickly
• Approach: Compare difference between treatment and
control (hazard ratio) within each trial for DFS and OS
Sargent DJ et al, J Clin Oncol, 2005;23:8664-8670.
Overall and Disease-Free Survival for
Adjuvant Treatment for Colon Cancer
Sargent DJ et al, J Clin Oncol, 2005;23:8664-8670.
“The validity of a surrogate endpoint should be
judged by the probability that the trial results
based on the surrogate endpoint alone are
‘concordant’ with the trial results that would be
obtained if the true endpoint were observed and
used for the analysis”
Begg and Leung, J R Statis Soc A 2000; 163:15-28
Examples
• Anti-arrhythmic treatment for sudden death
• HSV-2 suppressive treatment to prevent HIV
infection
• Estrogen/progestin treatment for coronary
heart disease
There are many other examples of failed
surrogates (e.g., HF treatment, drugs to
raise HDL cholesterol, weight-loss drugs)
Choice of Endpoint in Cardiac
Arrhythmia Suppression Trial (CAST)
[Antiarrhythmic Drugs]
Ventricular Premature Beats
Arrhythmias
Sudden Death
Total Mortality
CAST Study Design
Double-blind, placebo controlled
Eligible patients
Open-label titration
A. Encainide
B. Flecainide
C. Moricizine
Greater 80% suppression of VPDs
Yes
Flecainide
Placebo
for
Flecainide
No, excluded
Encainide
Placebo
for
Encainide
N Engl J Med 1989; 321:406-412.
Moricizine
Placebo
for
Moricizine
CAST Study Sample Size
Assumptions
Type I error () = .025 (1-sided)
Power (1-) = 0.85
Projected mortality in placebo group = 11% over 3 years
Expected reduction in mortality due to treatment = 30%
(No difference among active treatments)
Required sample size = 4400 patients
CAST Study Results
Encainide/
Flecainide
730
Placebo
725
Deaths from arrhythmia
or cardiac arrest
33
9
Other cardiac death
14
6
9
7
56
22
No. patients
Other deaths or
unclassified cardiac arrest
TOTAL
Acyclovir and HIV Acquisition
•
Background
– Herpes simplex virus type 2 (HSV-2 infection
is the most common cause of genital ulcers
– Observational studies indicate that HSV-2
infection is associated with 2-3 fold increased
risk for HIV infection
– Acyclovir is effective in suppressing HSV-2
•
Two trials were conducted to determine
if acyclovir treatment reduced HIV
acquisition
HSV-2/HIV Trial #1
HIV-negative HSV-2, seropositive men and women at risk
for HIV based on sex history
3,277 randomized
1637 Acyclovir
1640 Placebo
HR (acyclovir/placebo) for genital ulcers = 0.53
(95% CI: 0.46-0.62)
HR for HIV = 1.16 (95% CI: 0.83-1.62)
Lancet 2008, 371: 2109-2119
HSV-2/HIV Trial #2
HSV-2/HIV dually infected
persons in heterosexual relation
with HIV-negative partner
3,408 couples randomized
1707 acyclovir
1701 placebo
HR (acyclovir/placebo) for genital ulcers = 0.27 (95% CI: 0.20-0.36)
HR for HIV = 0.92 (95% CI: 0.60-1.41) among partners
N Engl J Med 2010; 362: 427-439
Estrogen + Progestin in
Healthy Postmenopausal Women: Lipids
after 1 year and Events after 5.2 Years
Estrogen + Progestin
vs.
Placebo
LDL
-12.7%
HDL
+7.3%
CHD
+29%
Stroke
+41%
All CVD
+22%
JAMA 288:321-333, 2002
Review of Trials Funded by NHLBI
Gordon D et al N Engl J Med 2013; 369:1926-1934.
• 244 trials completed in 2000 or 2011.
– 45 (18%) with clinical endpoints
– 199 with surrogates or health-related behaviors
• 156 published (23% <12 mos. and 57% < 30 mos.)
• Faster time to publication (predictors in
multivariable analysis)
– Clinical endpoints (median 10 vs 30 mos. for surrogate
endpoint studies)
– Cost ($5 million)
– Positive result
• Clinical endpoint trials accounted for 82% of
citations
Can be a big payoff for what usually is many years of work!
Summary
• There is no such thing as a risk-free intervention
(unintended effects of treatment are common)
• Failure of surrogates to predict clinical outcome differences
are common
• Trials with clinical endpoints have a greater impact on care
than trials with surrogate endpoints
• It is time-consuming (and expensive) to rigorously establish
surrogacy (need trials for which both the surrogate and
clinical outcome are measured)
• Some judgment about causal pathways is always needed
• Potential surrogates are important in early phase studies