The design and analysis of Phase IIb Ebola vaccine trials Ira Longini Department of Biostatistics Center for Statistical and Quantitative Infectious Diseases (CSQUID) Emerging Pathogens Institute University of Florida
Near-Term Development Plan: Pre-exposure use Nonclinical evaluat ion NHPs GMP grade vaccine Phase 1 trials Safety and dose selection Phase 2 trials Large scale safety Phase 2b trials Preliminary efficacy Phase 3 trials Phase 4 trials Dec 2014 1st Quarter 2015 Peter talk about this Matthias talk about this Emergency use use under informed consent Data collection Mass vaccination Pending licensure Not affected areas Affected areas 2 Source: Ana Maria Haneo Restrepo, WHO
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Vaccine Effectiveness * Intervention Population: 1 Overall VE overall = 1- (AR 1ave / AR 2u ) Control Population: 2 Vac f AR 1v Nonvac 1-f AR 1u Nonvac AR 2u Direct Indirect VE direct = 1- (AR 1v / AR 1u ) VE indirect = 1- (AR 1u / AR 2u ) Total VE total = 1- (AR 1v / AR 2u ) * Halloran, M.E., Longini, I.M. and Struchiner, C.J.: The Design and Analysis of Vaccine Studies. Springer (2009).
Source: Halloran and Longini. Science 12,1292-4 (2014)
Measures of Vaccine Efficacy {VE(t) S, VE(t) P, VE(t) I } VE S Vaccine Effect on Susceptibility VE P Vaccine Effect on Clinical Disease Classical III vaccine trials Many times observe VE SP = 1 (1 VE S ) (1 VE P ) VE I Vaccine Effect on Infectiousness
Immune Correlates and Surrogates of Protection and Efficacy Can be estimated from RCT Possible antibody and CMI markers Compare immune markers in vaccinated infected and uninfected vaccinatedsubjects Surrogate is stronger than a correlate Main Prentice criterion p(inf S,V) = p(inf S) Inf infected, S surrogate marker, V- vaccinated
Vaccine efficacy definition VE = 1 RR = 1 - r v r u where r v is the rate in the vaccinated, and r u in the unvaccinated. Another view, where VE = 1 θ r v = θc v p and r u = c u p, c - contact rate, p - trans. Prob. VE = 1 - θc v p c u p = 1 - θ, when c v = c u, Per contact exposure must be the same in the vaccine and comparison groups to get unbiased estimate of the VE
Vaccine efficacy definition People in {v} and {u} must have equal levels of exposure (on average), i.e., statistically must be exchangeable Randomization accomplishes this! If no randomization Find comparable group Do a matched analysis Other tricks
Hierarchy of phase IIb and III vaccine trials 1. Double-blinded, randomized, placebo control trial (RCT) 2. Vaccine trials without placebo arm Step wedged design with randomized clusters or populations Opportunistic step wedged design 3. Vaccine trails without placebo arm or randomization Perspective with matched comparison arm Case control with matched controls Test negative case control design
Vaccination strategies The type of analysis depends on the strategies Who is vaccinated Health care workers and others with exposure to Ebola patients Others at high risk pre-exposure Contacts of cases Ring vaccination Vaccination of communities affected
Case ascertainment How are cases ascertained Active prospective observation or case finding Passive detection, e.g., people that show up a health facilities with early Ebola symptoms Most effective strategies will be targeted vaccination Pre vaccination Reactive vaccination
For prospective analysis of targeted groups Vaccinate groups of people Health care workers and front line workers Others at high risk pre-exposure Contacts of cases Ring vaccination Vaccination of communities affected
For prospective analysis of targeted groups Find set of controls matched by Age, gender Type and level of exposure Time Probably can not be in same location as vaccinated Can have small numbers vaccinated
Double-blinded, randomized, placebo control trial GSK (Rip) presentation yesterday was excellent Important features Powered to reject H 0 = 0 against some relatively low alternative. Sequential hypothesis testing frequently or even in continuous time such that if the null is rejected that the trial will be stopped and those in placebo arm with be immediately offered vaccine
Step wedged design
Vaccine trails without placebo arm or randomization
Simple prospective trial Pre-exposure vaccination of health workers or other high risk group Ascertainment at the health facility or high risk setting Comparisons Health works at another comparable health facility or high risk setting that does not have a vaccination program, further matching by level of exposure Prospective analysis
Test negative case control study for vaccine efficacy Case control design For each confirmed case select a matched control who has similar symptoms but tests negative for infection in question Do matched or unmatched analysis but using the subset of negative controls Must have relatively large number of people vaccinated
Retrospective and case-control designs Case Control (not case) Total vaccinated a b n v = a + b unvaccinated c d n u = c + d Total n c = a + c n nc = b + d n = a + b +c + d If the study were prospective, then VE = 1 - a/nv c/nu If the study were retrospective, then, VE 1 - a/c b/d 1 - ad/bc
De Serres, et al. Eurosurveillance, 18, Issue 37, 12 September 2013.
Statistics Variance, confidence intervals, hypothesis tests, power are all in approximate or exact closed forms Everything worked out for different methods for bias and confounding control Matching schemes Logistic regression can be used for more complex designs and multivariate analysis Cox proportional hazards model for rate ratios
The way forward Try to do RCT on a accelerated basis Stepped wedge could be done, randomized if possible Smaller, opportunistic prospective and case control designs could also be employed Test negative case control design could be used
Thank you