Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003
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Transcript of Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003
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
FDA Anti-Infective Drugs Advisory Committee
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
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
Criteria for Study Endpointsin ABS Clinical Trials
• Measurable/Interpretable
• Sensitive
• Clinically relevant ~ Resolution/Improvement of ABS Symptoms ~ Reducing the time to Resolution
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
Use of Surrogate Endpoints
Treatment Effects on Surrogate Endpoints eg: ~ Radiological Resolution of Disease ~ Microbiological Outcomes
• Establishes Biological Activity
• But Not Necessarily Clinical Efficacy
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
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
Prentice’s Sufficient Conditions
1. The surrogate endpointmust be correlated with
the clinical outcome
2. The surrogate endpointmust fully capture
the net effect of treatmenton the clinical outcome
Validation of Surrogate Endpoints
Statistical Meta-analyses of clinical trials data
Clinical Comprehensive understanding of the
~ Causal pathways of the disease process ~ Intervention’s intended and unintended
mechanisms of action
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
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
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
Non-Inferiority Trials… Some Requirements
• Active Control Effect
ICH E9: “A suitable active comparator… could be a widely used therapy
whose efficacy in the relevant indicationhas been clearly established & quantified
in well-designed & well documented superiority trials
& which can be reliably expected to have similar efficacy in the contemplated AC trial.”
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
Factors Influencing Choice of Margin
PLA – AC Cure Rate
• Active Control Effect
~ magnitude of Active Control effect Eg: = 45% – 80% = –35%
~ precision of estimate Eg: 2 s.e. = 10% ( 175/arm )
~ estimates relevant to setting of NI trial • Population • Supportive care • Endpoint assessment
*
( ) –45% –35% –25% –12.5% 0%
Factors Influencing the Choice of Marginand Interpretation of NI Trial Results
• Clinical Relevance of Changes in: Benefits, Risks/Tolerance,
Convenience, Resistance, etc.
• Active Control Effect
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
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.”
The Choice of the Margin in an NI Trial
“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 B49.9% v 49.1% Mycosis Study Gp #32
• Voriconazole vs Ambisome23.7% v 30.1% 95% CI: (– 12, – 0.1)
Overview of Placebo-controlled ABS Trials
• Fourteen Placebo-controlled Trials of Antimicrobials conducted in ’69 –’03
(with nine conducted since ’96)
• Outcome: Antimicrobial effect onResolution or improvement of ABS symptoms, assessed at fixed time between 7-14 days
-70
-50
-30
-10
10
30
50
70A
nti
mic
rob
ial
Eff
icac
y (
95%
CI)
11
33
44
22
55 6677
88 99
1010
1111
1212 1133
1144
1155
1166
StudyStudy
• 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
NI Trials vs Placebo Controlled Superiority Trials
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
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 )