Percent Deaths by Laboratory Value

1
FDA Anti-Infective Drugs Advisory Committee
Design Issues in ABS Trials Surrogates
Endpoints Non-Inferiority Trials October 29,
2003 Thomas R. Fleming, Ph.D. Professor and
Chair of Biostatistics University of Washington
2
Design Issues in ABS Trials

• Criteria for Study Endpoints
• Use of Surrogate Endpoints
• Non-Inferiority Design Issues
• Choice of the NI Margin
• Bio-creep with Repeated NI Trials
• Active vs. Placebo controlled trials
• Time to Event Analyses in ABS Trials

3
Design Issues in ABS Trials

• Criteria for Study Endpoints
• Use of Surrogate Endpoints
• Non-Inferiority Design Issues
• Choice of the NI Margin
• Bio-creep with Repeated NI Trials
• Active vs. Placebo controlled trials
• Time to Event Analyses in ABS Trials

4
Criteria for Study Endpointsin ABS Clinical
Trials
Measurable/Interpretable Sensitive
Clinically relevant Resolution/Improvement of
ABS Symptoms Reducing the time to Resolution
5
Design Issues in ABS Trials

• Criteria for Study Endpoints
• Use of Surrogate Endpoints
• Non-Inferiority Design Issues
• Choice of the NI Margin
• Bio-creep with Repeated NI Trials
• Active vs. Placebo controlled trials
• Time to Event Analyses in ABS Trials

6
Use of Surrogate Endpoints
Treatment Effects on Surrogate Endpoints eg
Radiological Resolution of Disease
Microbiological Outcomes Establishes
Biological Activity But Not Necessarily
Clinical Efficacy
7
Time
Intervention
Surrogate True Clinical Endpoint Outcome
Disease
8
Illustration AIDS Patients with MAI
Bacteremia
Clarithromycin Dose (mg bid) 500
1000 2000 Bacterial Load 145 34
25 12 wk Mortality 5.7 25.5
28.0 Chaisson et al, 1994
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Time
Intervention
Bacterial 12 week Load
Mortality
Disease
10
Validation of Surrogate Endpoints
Property of a Valid Surrogate Effect of
the Intervention on the Clinical
Endpoint is reliably predicted by the
Effect of the Intervention on the
Surrogate Endpoint
11
Prentices Sufficient Conditions
1. The surrogate endpoint must be correlated
with the clinical outcome
2. The surrogate endpoint must fully
capture the net effect of treatment on the
clinical outcome
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Validation of Surrogate Endpoints
Statistical Meta-analyses of clinical trials
data Clinical Comprehensive understanding
of the Causal pathways of the disease
process Interventions intended and
unintended mechanisms of action
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Clinical Endpoints Surrogates in ABS Clinical
Trials
Clinical Endpoints Resolution/Improvement
of ABS Symptoms Surrogate Endpoints
Radiological Resolution of Disease
Microbiological Outcomes Validation of
Surrogate Endpoints requires more than
correlation with Clinical Endpoints
14
Design Issues in ABS Trials

• Criteria for Study Endpoints
• Use of Surrogate Endpoints
• Non-Inferiority Design Issues
• Choice of the NI Margin
• Bio-creep with Repeated NI Trials
• Active vs. Placebo controlled trials
• Time to Event Analyses in ABS Trials

15
Dual Goals of Non-Inferiority Trials
To enable a direct evaluation of
the clinical efficacy of EXP relative to
Active Control To contribute evidence to
the evaluation of efficacy
of EXP relative to Placebo
16
Non-Inferiority Trials Some Requirements
17
Non-Inferiority Trials Some Requirements
STD should have clinical efficacy that
is of substantial magnitude that is
precisely estimated with estimates that
are relevant to the setting in which the
non-inferiority trial is being conducted
18
Factors Influencing Choice of Margin
PLA AC Cure Rate

(
)
45 35 25 12.5 0
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Factors Influencing the Choice of Margin and
Interpretation of NI Trial Results
Clinical Relevance of Changes in
Benefits, Risks/Tolerance, Convenience,
Resistance, etc. Active Control Effect
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Factors Influencing Choice of Margin
Clinical Relevance of Changes in
Benefits, Risks/Tolerance, Convenience,
Resistance, etc. Clinical importance of -
reduction in efficacy by ? - altered
safety/tolerance profile - altered convenience
of administration - altered resistance or
drug/drug interactions
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The Choice of the Margin in an NI Trial
ICH E10 The determination of the margin
in a non-inferiority trial is based
on both statistical reasoning clinical
judgment, and should reflect uncertainties
in the evidence on which the choice is based,
and should be suitably conservative.

22
Bio-creep with Repeated NI Trials
Eg Anti-viral Drugs Advisory Comm (10/4/01)
Empiric Anti-fungal therapy of
febrile neutropenic patients
Amphotericin B Deoxycholate Ambisome
vs Amphotericin B 49.9 v 49.1 Mycosis
Study Gp 32 Voriconazole vs
Ambisome 23.7 v 30.1 95 CI ( 12, 0.1)
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Overview of Placebo-controlled ABS Trials
Fourteen Placebo-controlled Trials of
Antimicrobials conducted in 69 03 (with nine
conducted since 96) Outcome
Antimicrobial effect on Resolution or improvement
of ABS symptoms, assessed at fixed time
between 7-14 days
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1
14
2
11
3
4
10
7
5
12
6
8
9
16
13
15
Antimicrobial Efficacy ( 95 CI)
Study
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NI Trials vs Placebo Controlled Superiority
Trials
ICH E10 The determination of the
margin in a non-inferiority trial is
based on both statistical reasoning clinical
judgment, should reflect uncertainties
in the evidence on which the choice is
based, and should be suitably
conservative. When one cannot justify a
non-trivial margin, placebo controlled trials
provide an ethically and scientifically
reliable approach to assessing the
benefit-to-risk profile
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Design Issues in ABS Trials

• Criteria for Study Endpoints
• Use of Surrogate Endpoints
• Non-Inferiority Design Issues
• Choice of the NI Margin
• Bio-creep with Repeated NI Trials
• Active vs Placebo controlled trials
• Time to Event Analyses in ABS Trials

27
Time to Event Analyses in ABS Trials

• In self-resolving diseases, it may be
• more appropriate to measure time to
• resolution or improvement of symptoms
• To have 90 power to detect a reduction
• in time to resolution from 7 days to 5 days
• (with the standard 2.5 false positive error
  rate)
• one needs approximately 200 pts/arm.
• (Stat Significance if one obtains about 1.3
  days )

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Conclusions

• Criteria for Study Endpoints
• A Correlate does not a Surrogate Make
• Non-Inferiority Design Issues
• Choice of the NI Margin
• Bio-creep with Repeated NI Trials
• Placebo controlled trials
• Time to Event Analyses in ABS Trials