Sponsoring Section/Society: ASA-BIOPHARM
Session Slot: 4:00- 5:50 Sunday
Estimated Audience Size: 200-250
AudioVisual Request: none
Theme Session: no
Applied Session: yes
Session Title: Immunogenicity and Efficacy Issues in Vaccine Clinical Trials
Session Organizer: Wiens, Brian Merck Research Laboratories
Address: Merck Research Laboratories P.O. Box 4, BL3-2 West Point, Pa 19486
Phone: 610-397-2864
Fax: 610-397-2931
Email: brian_wiens@merck.com
Session Organizer: Lachenbruch, Peter A. FDA/CBER
Address: FDA/CBER/DBE 1401 Rockville Pike HFM-215 Rockville MD 20852
Phone: 301-827-6055
Fax: 301-827-3529
Email: lachenbruch@a1.cber.fda.gov
Session Timing: 110 minutes total (Sorry about format):
Opening Remarks by Chair-5 minutes First Speaker - 25 minutes Second Speaker - 25 minutes Third Speaker - 25 minutes Discussant - 15 minutes Floor Discussion - 15 minutes
Session Chair: Wiens, Brian Merck Research Laboratories
Address: Merck Research Laboratories P.O. Box 4, BL3-2 West Point, Pa 19486
Phone: 610-397-2864
Fax: 610-397-2931
Email: brian_wiens@merck.com
1. Time-to-Event Models For Vaccine Studies: Old Answers to New Questions
Moulton, Lawrence H., The Johns Hopkins University
Address: Department of International Health Room W5515 (W5602 office) The Johns Hopkins University School of Hygiene and Public Health 615 North Wolfe Street Baltimore, MD 21205
Phone: 410-955-6370
Fax: 410-502-6733
Email: lmoulton@jhsph.edu
Abstract: The routine analysis of vaccine efficacy trials consists of a simple summary of the data into attack rates or risks, and then estimating efficacy as (1-RR)x100%, where RR is the rate or risk ratio for vaccinated versus unvaccinated individuals. For many infectious disease settings, however, and particularly for vaccine studies in infants, these summaries ignore many important analytic features of the data. These include: 1) multiple disease episodes, and the corresponding within-child correlation; 2) seasonality of disease; 3) staggered enrollment; 4) other time-varying covariates, including age; 5) waning of vaccine efficacy. Such features may be accounted for using various implementations of the Cox proportional hazards model. Today's presentation illustrates how these techniques may be used in vaccine efficacy trials. Data from a rotavirus vaccine study are used to estimate efficacy in the face of multiple events, and to estimate the degree of immunity afforded by natural infection. Hib vaccine efficacy and effectiveness studies are combined to estimate the impact of indirect effects of the vaccine in reducing incidence in a closed population.
2. A Theroretical Framework for the Relationship of Correlates of Protection, Population Immunogenicity, and Vaccine Efficacy
Kohberger, Robert C., Wyeth-Lederle Vaccines and Pedatrics
Address: N. Middletown Rd. Pearl River, NY 10965
Phone: 914-732-4249
Fax: 914-732-5517
Email: Robert_Kohberger@internetmail.pr.cyanamid.com
Xie, Fang, Wyeth-Lederle Vaccine and Pediatrics
Abstract: Typical vaccine clinical trials study immunogencity or efficacy and sometimes both. In an immunogenicity trial, subjects are treated with an experimental vaccine and then antibody levels are measured at various times. There are three major types of outcome measurements of these trials: 1) pre vaccination and post vaccination titers are taken and the % seroconverters are used as the outcome measurement. 2) post vaccination titers are taken and the % above a certain level are used as the outcome measurement. 3) post vaccination titers themselves are used as the outcome measurement. This discussion will focus on the situation where the post vaccination titer, either as an absolute value or % above a certain level, is the outcome measurement. In an efficacy trial, subjects are treated with an experimental vaccine and disease rates compared between the treated group and a control group. This type of trial measures vaccine efficacy. The immunogenicity trial and the efficacy trial are linked with the concept of a correlate of protection. It is assumed that if populations have equivalent antibody titer distributions, they will have equivalent efficacy. This is true only if there is a linkage between efficacy and immunogenicity through protective correlates. For immunogenicity trials where percentages are the outcome measure then equivalency is determined not by distributions but by a single value. An equivalency trial has an implied concept of a difference in titer distributions that is not clinically relevant. In order to determine clinical relevancy, the link between efficacy and immunogenicity must be determined. This paper will develop an analytic framework that will combine correlates of protection, population antibody titer distribution and vaccine efficacy. Examples of typical correlate models and immunogenicity trials will be provided to demonstrate the effect of changes in titer distributions on vaccine efficacy.
3. Issues in Predicting the Duration of Vaccine Induced Protection
Bohidar, Norman R., Merck Research Laboratories
Address: Merck Research Laboratories P.O. Box 4, BL3-2 West Point, PA 19486
Phone: 610-397-2981
Fax: 610-397-2931
Email: Norman_Bohidar@merck.com
Pigeon, Joseph G., Villanova University
Wiens, Brian, Merck Research Laboratories
Abstract: When new vaccine products are marketed, they are generally supported by clinical studies lasting only several years. However, the duration of protection from disease is often expected to be considerably longer than the time spans of the clinical studies. Thus there are both methodological and conceptual problems in trying to estimate long term protection based on data from short term clinical studies. We discuss the utility of predicting the duration of protection based on extrapolating observed antibody data. Several methods that have appeared in the clinical and statistical literature are reviewed and some alternative strategies are proposed. A sample data set is used to illustrate these competing models. Finally, we discuss the advantages and disadvantages of the various methods and make some recommendations about predicting the duration of vaccine-induced protection from short term antibody data.
Discussant: Lachenbruch, Peter A. FDA-CBER
Address: FDA/CBER/DBE 1401 Rockville Pike HFM-215 Rockville MD 20852
Phone: 301-827-6055
Fax: 301-827-3529
Email: lachenbruch@a1.cber.fda.gov
List of speakers who are nonmembers: None