Transcript Surrogate Endpoints in Clinical Trials

Surrogate Outcomes and
Handling Multiple Endpoints
in Clinical Trials
Benny Zee
Centre for Clinical Trials
The Chinese University of
Hong Kong
Medical Research Support in CUHK
Medical Research
Support Committee (MRSC)
Centre for
Epidemiology
and Biostatistics
Academic
Research
Centre for
Clinical Trials
Industry
Studies
Cochrane
Centre
International
Cooperative
Group Studies
Missions Statement for the
Centre for Clinical Trials (CCT)

Missions include:

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Provide methodological advice in clinical trials
Regulatory submission assistance and contract
negotiation with industry
Study and data management support
Act as a contract research organization
(CRO) in the management of clinical trials

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Academic single-institution trials
Multicentre cooperative group trials
Industry trials
Any differences between a CRO and CCT?
Commercial
Benefits
Comm &
Family Med
Medicine &
Therapeutics
Chem Path, ACP
Microbiology
Surgery
Diagnostic
Radiology
Big Pharma & Biotech
Companies, NCI US, etc.
Obs & Gyn
Pediatrics
Other
CRO’s
Centre for
Clinical
Trials
Clinical
Oncology
…others
Benefit Community
Clinical Research
Multicentre Trials
Services of CCT




Support Faculty with sound design
methodology and analysis of clinical trials
Provide infrastructure for conducting clinical
trials
Provide Good Clinical Practice (GCP)
training for personnel from pharmaceutical
and biotechnology companies, hospitals
and clinical trials centers in Asia
Promote clinical trials methodology through
research in biostatistics methodology, data
management, bioinformatics, etc.
Lunch Time Seminar Series
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Surrogate Outcomes and Handling
Multiple Endpoints in Clinical Trials
Repeated Measures in Randomized
Controlled Trials (Oct 15)
Other suggestions of Topics, Speakers,
Joint Events, etc?

Please contact me, Shirley Xu or Jennifer Mao
Introduction to Surrogate
Endpoint
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Why do we use surrogate endpoint?
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Can be measured earlier
Convenient or less invasive
Can be measured more frequently
Can accelerate the approval process
Advantages:

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May reduce the size of clinical trials
May shorten the duration of clinical trials
May reduce the cost of clinical trials
Endpoints inappropriately
characterized as surrogates

Quality of life


It is an outcome measure (not a
surrogate endpoint)
Morbidity scale

It is a clinical benefit endpoint (not a
surrogate endpoint)
Endpoints For Clinical Trials
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A surrogate endpoint does not directly
measure any clinical benefit to patient, it
only predicts the outcome
A mixed surrogate/clinical benefit
endpoint directly measures significant
benefit to patient and predicts an
additional, more substantial benefit to
patient
A clinical outcome directly measures
substantial clinical benefit to patient
When is the use of surrogate
endpoints justified?

Screening
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Caution in using surrogate endpoints:
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For promising new therapies
Evaluation of biological activity in phase I/II trials
Using biological markers as a surrogate endpoint,
one may obtain misleading false positive or false
negative conclusion when assessing treatment
effects of longer term clinical outcome
Requirements:

Before a surrogate endpoint can replace a
primary endpoint, it must be formally validated
Relationships between treatment,
surrogate and clinical outcome
Surrogate
Marker
S
Clinical
Outcome
T
Treatment
Z
Ideal treatment, surrogate and
clinical outcome relationships
Surrogate
Marker
S
+
Treatment
Z
T
o
+ positive effect
- negative effect
o no effect
+
Clinical
Outcome
Other Biological
Processes
Problems in Surrogate
Endpoint: Example in HIV
1. Treatments are chosen
based on their anticipated
effect on CD4 count
CD4
Lymphocyte
Count
2. Surrogate marker may be
strongly predictive of
the clinical outcome
AIDS
Event or
Death
AZT
vs
control
3. Treatments may
also affect other
biological processes
Other Biological
Processes Affecting
Prognosis
4. Clinical outcome
may be affected
by other biological
processes
Example in HIV
False Positive Case
1. Treatments are chosen
based on their anticipated
effect on CD4 count
AZT
vs
control
+
CD4
Lymphocyte
Count
2. Surrogate marker may be
strongly predictive of
the clinical outcome
+
Treatment
Effect Cancelled
-
+
3. Treatments may
also affect other
biological processes
AIDS
Event or
Death
Other Biological
Processes Affecting
Prognosis
4. Clinical outcome
may be affected
by other biological
processes
Example in HIV
False Negative Case
1. Treatments are chosen
based on their anticipated
effect on CD4 count
AZT
vs
control
AIDS
Event or
Death
o
+
3. Treatments may
also affect other
biological processes
CD4
Lymphocyte
Count
2. Surrogate marker may be
strongly predictive of
the clinical outcome
Treatment effect
Not detected
Other Biological
Processes Affecting
Prognosis
+
4. Clinical outcome
may be affected
by other biological
processes
Cardiac Arrhythmia
Suppression Trial (CAST)
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Patients with myocardial infarction

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Encainide and flecainide are known
effective anti-arrhythmic drugs

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Ventricular arrhythmia is a risk factor for
subsequent sudden death
Arrhythmia was considered a surrogate endpoint
Approved by FDA
Their effect on survival was not established
CAST randomized more than 2000
myocardial infarction patients to receive
either anti-arrhythmic drug or placebo
Cardiac Arrhythmia
Suppression Trial (CAST)

Results

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Death rates of the study treatment arm nearly
tripled that of the placebo arm
Conclusion


This study had shown that a false positive
conclusion can be made with a surrogate
endpoint
FDA prematurely released antiarrhythmic
drugs for patients with myocardial infarction
due to the use of surrogate endpoint
Chronic Granulomatous
Disease (CGD)

Background

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Childhood disease, disorders in immune system
Phagocytes ingest microorganism but fail to kill
them
International CGD Cooperative Group
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Randomized patients between interferon- and
placebo in a double-blind fashion
Superoxide measurements and bacterial killing
can be used as surrogate endpoints
After a lengthy debate, rate of infection was
finally used as primary endpoint
Individual follow-up extended from 1-month to
1-year
Chronic Granulomatous
Disease (CGD)
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Results
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Interferon- significantly reduced the rate
of recurrent of serious infections at interim
analysis using O’Brien-Fleming rule
FDA approved the use of Interferon- in CGD
patients
There were no significant differences
between treatment arms on surrogate
biological markers, superoxide
measurements and bacterial killing
Reliance on surrogate markers would have
led to false negative conclusion
Prentice’s Definition

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A “surrogate” endpoint for which a test of
the null hypothesis of no relationship to
the treatment groups is also a valid test of
the corresponding null hypothesis based
on the true endpoint
Let T and S be random variables denote
true and surrogate endpoints respectively,
Z be indicator variable for treatment, and
f(.) denotes p.d.f. such that S must
satisfy:
f(S|Z) = f(S)  f(T|Z) = f(T)
Validation

Criteria for checking if a triplet (T,S,Z) fulfills
the definition are:
(1) f(S|Z)  f(S), Z is significant on S
(2) f(T|Z)  f(T), Z is significant on T


However, this validation is impossible since one
may fail to detect differences due to lack of power
Other sufficient conditions:
(3) f(T|S)  f(T), S is informative about T
(4) f(T|S,Z)  f(T|S), S fully captures the
effect of Z on T
Comments on Validation
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The condition f(T|S,Z) = f(T|S)
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requiring the surrogate endpoint S fully capture
the effect of treatment on the true endpoint T
so restrictive that this condition rarely holds in
clinical application
even in a rare setting that data on treatment Z
allow us to view S as a valid surrogate for T, we
cannot extrapolate this to a new treatment Z*
Auxiliary variable
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S provides additional information if it strongly
correlates with outcome T
It can be used to increase efficiency
Freedman’s Proportion
Explained (PE)
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The Prentice’s criteria (1)-(3) are provided
by tests of significance of parameters , ,
and 
Sj|Zj = S + Zj + Sj
Tj|Zj = T + Zj + Tj
Tj|Sj =  + Sj + j
PE = 1 – (S/)


where  is the estimate of the effect of Z on T
and S is the estimate of the effect of Z on T
after adjustment for S
Tj|Zj,Sj = T + SZj + ZSj + Tj
Surrogate Endpoints
in HIV and AIDS Trials
HIV Infection & AIDS
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Early stages HIV infection
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Advanced disease
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Used progression of disease rather than
survival as endpoint
A decline of CD4+ cells count to less than 0.5
x 109/L has been used as endpoint
Mortality remained as primary endpoint
Biological markers

e.g. CD4+
How can we assess the validity of a
potential surrogate marker for trials of
AIDS treatment?
A strong biological rationale
 The marker value at a given time
is strongly predictive of ultimate
survival
 The effect of treatment on the
surrogate endpoint will reliably
predict the effect of treatment on
survival

Example: Concorde Trial
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Double-blind randomized trial for
asymptomatic HIV-infected individuals:
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Imm: immediate zidovudine (AZT)
Def: deferred AZT until AIDS-related complex
Targeted sample size = 2000
Endpoints:
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Progression, haemoglobin, total white cells,
total and CD4+ lymphocytes, CD4 percentage,
CD4/CD8 ratio, CD8 cells, CD8 percentage,
CD3+ cells, neutrophils, monocytes, platelets,
p24 antigen, 2 microglobulin and weight
Patient Characteristics
Reasons Stopped Treatment
Proportion of Total Time Spent on AZT
Adverse Events
Time to reduction of CD4
to < half of baseline or
time to AIDS or death
Change in CD4 counts
Concorde Trial: Summary
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Final Results on Primary Clinical Endpoint
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No significant difference between arms with
respect to time-to-progression and survival
More toxicity in the Immediate arm
Do not encourage early use of AZT in
symptom-free HIV infected adults
Results on immunological markers

In favor of Immediate arm:
• CD4 cells, CD4 percentage, CD4/CD8, CD3
percentage, platelets

It would have been a false positive conclusion if
based on surrogate endpoint
Surrogate Endpoints
in Cancer Trials
Advanced Colorectal Cancer
Meta-analysis

A Meta-analysis of 3791 patients
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First-line treatment with standard bolus
intravenous fluoropyrimidines versus
experimental treatment
•
•
•
•

5FU+LV
5FU+methotrexate
5FU continuous infusion
Hepatic-arterial infusion of floxuridine
To evaluate the relationship between
tumor response and survival
Advanced Colorectal Cancer
Meta-analysis

Tumor response

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CR: disappearance of all detectable tumor
PR: decrease of 50% or more in the tumor
surface area without new lesion
SD: decrease of less than 50% or increase of
less than 25%
PD: increase of more than 25%
• Tumor surface area is calculated by sum of the
products of the largest perpendicular diameters

Best overall response for each patient
was used as surrogate endpoint
Response odds ratios for Experimental vs Bolus
fluoropyrimidines
N=# patients; O=observed # of response; E=expected # response; V=variance
Survival hazards ratios
N=# patients; O=observed # of response; E=expected # response; V=variance
P=0.42
Survival hazards ratios by PS and Response
Treatment effect on survival vs. response
Summary

Increase response rate  increase survival?

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The benefits of experimental treatment are more
obvious in tumor response than survival
No survival benefit from treatment within any
tumor response categories
• The survival benefit in favor of experimental arm was
due to higher tumor response rates

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Treatment effect on survival associated with
treatment effect on tumor response, but with a
low coefficient of determination 0.38, i.e., only
38% variation was explained
Benefit in tumor response does not imply
survival benefit
Final Remarks

FDA review of first-line therapy for
advance colorectal cancer

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Required evidence of survival advantage
Control arm using 5-FU & leucovorin (LV) has
response rate of 15-20%
Experiences of two new agents reviewed
by FDA

Regarding the use of surrogate endpoint
Irinotecan Example

Irinotecan vs best supportive care as
second-line treatment
Induced partial responses in 10-15% of
patients who had not responded to
5FU/LV
 Demonstrated survival advantages as
second-line therapy in an European trial
 FDA approved for use as second-line
after 5FU/LV

Irinotecan Example

USA and Europe done studies on first-line
treatment

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comparing Irinotecan/5FU/LV versus 5FU/LV
Both studies showed significant improvement
in response rate (35% and 39% for
irinotecan-containing regimen vs. 21% and
22% for control)
Modest but significant improvement in
survival
Irinotecan/5FU/LV was approved by FDA in
Apr 2000
Oxaliplatin Example
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First-line therapy studied in Europe

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Response rate (51% for oxaliplatin/5FU/LV vs
23% for 5FU/LV)
Did not show significant improvement in
survival
Not approved by FDA
Is effective new drug being withheld
unnecessarily since FDA exclusively relies
on improvement in survival?


Survival may not be significant since patients
may benefit from second-line treatment
Can response be used as surrogate endpoint?
Surrogate Endpoints in
Practice
The surrogate must be in the causal
pathway of the disease process
 An intervention’s entire effect on the
clinical outcome of interest should
be fully captured by the surrogate
 We need to assess more than a
single study to decide on the
adequacy of a surrogate

Guideline in reviewing medical
literature on surrogate endpoint
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Is there a strong, independent, consistent
association between the surrogate and clinical
endpoint
Is there evidence from randomized trials in other
drug classes that improvement in the surrogate
has consistently led to improvement in the
outcome?
Is there evidence from randomized trials in the
same drug classes that improvement in the
surrogate has consistently led to improvement in
the outcome?
What were the results? How large, precise, and
lasting was the treatment effect?
Thank you
(Questions are welcome)