On Surrogate Endpoints in HIV Vaccine Efficacy Trials

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On 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

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Outline

• HIV Vaccine Trials Current Status
• Clinical Endpoints in Vaccine Trials
• Endpoints in HIV Vaccine Trials
• A Simulation Approach
• Goal
• Approach
• Example
• Conclusions/Discussion

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HIV 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

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HIV 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

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HIV 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
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Classical Measure of Vaccine Efficacy

• VE reduction in population incidence or
  morbidity/mortality rate

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Classical 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

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Measures 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

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VE Reduction in Transition Intensities
VE
VES
VEP
Uninfected/ Seronegative
Infected/ Seropositive
Morbidity/ Mortality
VEI
2o Transmission
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Endpoints 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

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Endpoints 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

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Post-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

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HIV 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
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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)

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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)

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(No Transcript)
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Example Analysis of VEVLC(18X)
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A 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
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A 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
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Numerical 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

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Hypothetical Efficacy Trial
The numerical study is based on the following
hypothetical trial
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Prediction of VEP

• A lower 95 confidence bound for VEVLC(18X) gt
  50 predicts VEP gt 40 with f 0.375

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Summary/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

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Summary/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