Title: On Surrogate Endpoints in HIV Vaccine Efficacy Trials
1On Surrogate Endpoints in HIV Vaccine Efficacy
Trials
FDA/Industry Statistics Workshop, Sept 18-19,
2003 Statistics From Theory to Regulatory
Acceptance
- Steven Self, Peter Gilbert, Michael Hudgens
- FHCRC/UW
2Outline
- HIV Vaccine Trials Current Status
- Clinical Endpoints in Vaccine Trials
- Endpoints in HIV Vaccine Trials
- A Simulation Approach
- Goal
- Approach
- Example
- Conclusions/Discussion
3HIV Vaccine Trials Current Activity
- Phase I and II trials (ongoing)
- 27 trials involving 1,800 participants
- 16 different vaccine candidates
- 10 sponsors
- Phase III trials
- 1 completed
- 1 to be completed in Q4 03
- 1 planned to start in 04
- HVTN trials (Ph I, II) starting by Q3 04
- 9 different vaccine candidates
- 1,453 participants
4HIV Vaccine Trials Current Results
- Immune Responses
- Measurable cellular response in 50
- No broadly neutralizing Ab in sera, mucosa
- Non-human Primate Trials
- Amelioration of disease course but no protection
from infection upon challenge - Body of NHP literature difficult to assess
- Efficacy
- No overall efficacy in 1 completed efficacy trial
5HIV Vaccine Trials Summary
- Immune correlate of protection unknown
- Many candidate vaccines but full range of desired
immune responses poorly covered - Multiple efficacy trials will be required
- Plan for long-term, iterative development program
Klausner et. al. (2003) Science
6Classical Measure of Vaccine Efficacy
- VE reduction in population incidence or
morbidity/mortality rate
7Classical Endpoint for Vaccine Efficacy
- Clinically significant morbidity and mortality
- Pathogen specificity
- Standard of care
- For treatable infections
- Prevent/delay constellation of signs/symptoms
sufficient to trigger treatment initiation (save
cost/toxicity assoc with treatment) - Interact w/ treatment to improve risk/benefit
profile of vaccine/tmt vs tmt alone
8Measures of Vaccine Efficacy
- VE reduction in population incidence or
morbidity/mortality rate - VES reduction in population infection rate
- VEP reduction in rate of morbidity/mortality
- VEI reduction in rate of 2o transmission
- Halloran, Longini, Struchiner
9VE Reduction in Transition Intensities
VE
VES
VEP
Uninfected/ Seronegative
Infected/ Seropositive
Morbidity/ Mortality
VEI
2o Transmission
10Endpoints in HIV Vaccine Efficacy Trials
- Infection Endpoint (A biomarker-based
surrogate) - Operationally presence of Ab and detectable HIV
RNA - Aligned with one primary objective of HIV vaccine
- Acceptable by all
- However captures only one aspect of potential
vaccine effects on clinical outcomes
11Endpoints in HIV Vaccine Efficacy Trials
- Post-infection Endpoints Some Issues
- Long-term FU required for morbidity/mortality
endpoints esp with ARV treatment - Complicated dynamical process likely dominated by
treatment effects - Uncertainty of optimal treatment initiation
triggers - Variability in treatment initiation
- Analytics
- Key biomarker trajectories dependently censored
by treatment initiation - Conditional vs unconditional analyses
- Combination of analyses
12Post-Infection Endpoints Current Approach
- Provide treatment within trial
- standardized treatment initiation guidelines
(e.g. DHHS, UNAIDS) - standardized treatment monitoring/management
- Develop complementary array of endpoints to cover
key aspects of post-infection outcomes - Early Endpoints - pre-ART
- Mid-term Endpoints - peri-ART
- Long-term Endpoints - post-ART
- Reasonable conservatism for interpretation of
vaccine effects on surrogates
13HIV Vaccine Efficacy Trial Endpoints
Long-term Endpoints - vaccine/tmt effects
- CD4 - Morbidity/Mortality
Short-term Endpoints - Pre-ART VL
Uninfected/ Seronegative
Infected/ Seropositive
Morbidity/ Mortality
Treatment Initiation
Mid-term Endpoints - Composite (VL, tmt
init) - Biomarker trajectories (VL, CD4)
Infection
14 A Composite Endpoint
- Definition
- First event of ART initiation or virologic
failure - (VL gt X cps/ml)
- Composite endpoint directly tied to clinical
events - virologic failure places a subject at risk for
progression/transmission - starting ART exposes a subject to drug
toxicities, resistance, loss of future drug
options - Assess with standard statistical methods
(Kaplan-Meier, Cox regression)
15 A Composite Endpoint
- Surrogate vaccine efficacy parameter
- VEVLC(TX) percent reduction (vaccine vs.
placebo) in the risk of the composite endpoint by
T months post infection diagnosis - X calibrates the magnitude of virologic control
- (e.g., X 1,500 copies/ml)
- T calibrates the durability of virologic control
- (e.g., use T ? 18 months)
16(No Transcript)
17Example Analysis of VEVLC(18X)
18A Numerical Study Goal
- Provide an approach to facilitate the discussion
of how to use surrogate endpoints - specific to trial design
- specific to particular surrogate endpoints
- accommodate statistical uncertainties
- accommodate model uncertainties with desired
degree of conservatism
Gilbert et al (2003) JID
19A Numerical Study Approach
- adopt empirically-based joint model of biomarker
process and clinical outcomes as true
prediction model - modify model to incorporate degrees of
reasonable conservatism - proportion vaccine effect explained (attenuate
log RR relating surrogate to clinical outcome by
f percent ) - selection bias for conditional analyses
(attenuate observed vaccine effect on surrogate
outcome) - RCT simulation to identify minimum observed
effects on specific surrogate endpoints that
would generate 95 prediction intervals for VE
parameters exceeding 40, say
Albert et al (1998) Stat in Med
Freedman et al (1992) Stat in Med Hudgens et
al (2003) Stat in Med Gilbert et al (2003)
Biometrics
20Numerical Study An Example
- Question
- What inference on VEVLC(18X) reasonably
predicts a clinically significant VEP? - Numerical study based on the following
predictions - from the MACS Predicted(VEP) VEVLC(18X)
- for X ?
5,000-10,000 cps/ml -
- Albert et al (1998) Stat in Med
21 Hypothetical Efficacy Trial
The numerical study is based on the following
hypothetical trial
22 Prediction of VEP
- A lower 95 confidence bound for VEVLC(18X) gt
50 predicts VEP gt 40 with f 0.375
23Summary/Conclusions
- Use of surrogate endpoints in HIV vaccine
efficacy trials is question of how not whether - A framework is proposed to help interpret
observed effects on surrogate endpoints that is - specific to particular trial designs/endpoints
- captures relevant aspects of magnitude and
durability of effect on surrogates - uses available empirical information relating
biomarkers to clinical outcomes - is tunable with respect to degree of conservatism
w/r/t use of empirical information - flexible to evolve with development program
24Summary/Conclusions
- HIV vaccines showing strong and durable effects
on post-infection endpoints should be licensed - use of standardized ART guidelines important
- use simulation studies to assist in building
agreement about defining sufficiently strong
and sufficiently durable - design trials to detect significant levels of
either VES or VEVLC(TX) - use supporting data on other endpoints
- Long-term follow-up needed
- for assessing VE and VEP directly
- better understanding of surrogate endpoints