ISCB Vaccines Recent Events

Tuesday, Sept. 20; 1:00 - 2:15 PM. Issues on Correlates of Protection in Vaccine Development. Organizers: Charles Liss, Merck; Guoying Sun, FDA; Lihan Yan, USFDA. Chairs: Xiaoming Li, Merck Research Laboratories

Causal Inference of Vaccine Effects on Infectiousness. M. Elizabeth Halloran, Fred Hutchinson Cancer Research Center/University of Washington; Michael G. Hudgens, The University of North Carolina at Chapel Hill

Inferences from Tests of Biodefense Vaccines. Michael P Fay, NIAID-NIH

Experimental Designs and Statistical Methods for Post-licensure Immunological Correlates of Protection. Andrew Dunning, Sanofi Pasteur

Assessing the Predictive Value of Immunological Markers in Vaccines. Ivan Chan, Merck & Co., Inc

Correlates of Protection: What have we done, What do we do now? Tsai-Lien Lin, CBER/FDA

Tuesday, Sept. 20; 2.30 - 3:45 PM. Statistical Challenges Encountered in Assessing Immunogenicity Data from Vaccine Trials. Organizers: Barbara Krasnicka, FDA; Andrew Dunning, Sanofi Pasteur. Chairs: Mridul K Chowdhury, FDA; Anthony Homer, Sanofi Pasteur

Dealing with Missing Data in Vaccine Clinical Trials: from Academics to the Industry. Niel Hens, I-BioStat, Hasselt University

Application of Recent Guidance on Missing Data to Truncated Immunogenicity Data. John Jezorwski, Sanofi Pasteur

Comparing and Combining Data across Laboratories after Correcting for Inter-laboratory Variation via Integration of Paired-sample Data. Yunda Huang, Fred Hutchinson Cancer Research Center

Robust Inference from Multiple Statistics via Permutations. Jitendra Ganju, Amgen Inc.

Vaccine Papers at Joint Statistical Meetings 2011, Miami Beach, Florida, July 30 - August 4, 2011

A Comparative Analysis of Mixed Effects Models and Related Methods to Assess Physical and Mental Functional Status After Receipt of Anthrax Vaccine in a Human Clinical Trial. Brock Stewart, Centers for Disease Control and Prevention; Charles Rose, Centers for Disease Control and Prevention; Michael M. McNeil, Centers for Disease Control and Prevention

A Mixed-Effects Model to Estimate Duration of Antibody Responses to Anthrax Vaccine in Humans and Non-Human Primates. Charles Rose, Centers for Disease Control and Prevention; Lydia Foster, Centers for Disease Control and Prevention; Conrad Quinn, Centers for Disease Control and Prevention

Simulation Studies of Self-Controlled Case Series Methods in Vaccine Safety Research. Guoying Sun, U.S. Food and Drug Administration; Wei Hua, U.S. Food and Drug Administration; Nick Andrews, Health Protection Agency; Caitlin N. Dodd, Cincinnati Children's Hospital Medical Center; Silvana A. Romio, Erasmus University; Hector Izurieta, U.S. Food and Drug Administration; Heather J. Whitaker, Open University

Noninferiority and Superiority Tests for Multiple Immunogenicity Endpoints in Vaccine Clinical Studies. Lihan Yan, U.S. Food and Drug Administration

The Impact of Individual Decisions on the Equity of H1N1 Vaccine Distribution. Jessica L. Heier Stamm, Kansas State University; Nicoleta Serban, Georgia Institute of Technology; Julie Swann, Georgia Institute of Technology

Data Mining in Vaccine Manufacturing: Finding Needles in Biological Haystacks. Nelson Lee Afanador, Merck Sharp and Dohme Corp.

Use of Zero-Inflated Mixture Models to Compare Antibody Titers Among Asthma Subpopulations in Response to the H1N1 Vaccine. Leela M. Aertker, Rho; Daniel J. Zaccaro, Rho

An Alternative to ANCOVA When Standard Assumptions Are Untenable. J. Brooke Marshall, Merck Research Laboratories; Devan V. Mehrotra, Merck Research Laboratories

Threshold Methods for Immunological Correlates of Protection. Andrew Dunning, Sanofi-Pasteur; Xuan Chen, Sanofi-Pasteur; Huiling Xiong, Sanofi Pasteur; Fabrice Bailleux, Sanofi-Pasteur; Li Qin, Fred Hutchinson Cancer Research Center; Kamal Desai, University of London

Evaluation of Immune Response (gpELISA) as the Principal Surrogate Endpoint for Protection of Herpes Zoster Afforded by Zostavax. Xiaoming Li, Merck Research Laboratories; Xiaopeng Miao, Boston University; Ivan S. F. Chan, Merck Research Laboratories

Comparison of TLOVR Algorithm Versus Snapshot Approach for HIV Studies. Wei Zhang, Boehringer Ingelheim; Michael Pannucci, Boehringer Ingelheim; Junhai Guo, Boehringer Ingelheim; David Hall, Boehringer Ingelheim

Globalization of Clinical Trials: The Development of Treatments and Preventative Products for Diseases, with a Focus on Vaccines. Tammy Massie, U.S. Food and Drug Administration – Roundtable Luncheon

Sieve Analysis in HIV Vaccine Efficacy Trials with Multivariate and Missing Marks. Michal Juraska, University of Washington; Peter B. Gilbert, University of Washington

Use of Fixed-Effects Models to Analyze Self-Controlled Case Series Data in Vaccine Safety Studies. Stanley Xu, Kaiser Permanente Colorado; Chan Zeng, Kaiser Permanente Colorado; Sophia Newcomer, Kaiser Permanente Colorado; Jennifer Nelson, Group Health Research Institute; Jason Glanz, Kaiser Permanente Colorado

Vaccines Session at Second International Symposium on Biopharmaceutical Statistics, March 2011

This was a joint conference of the European Medicines Agency (EMA) and the International Biometric Society (IBS) - Deutsche Region. On the third day of the conference there was a session on Confronting Statistical Challenges in Vaccine Trials. The organizers of the session were G. Frank Liu (Merck & Co. Inc) and our sub-committee member Jingyee Kou (FDA/CBER). The invited speakers were sub-committee members Jos Nauta, Ivan Chan and Andrew Dunning. Jos Nauta gave a presentation on A generalized worst-case sensitivity analysis for a single seroresponse rate, Ivan Chan spoke on the Use of adaptive designs in vaccine studies, Andrew Dunning gave his thoughts on Post-licensure immunological correlates of protection: experimental designs and statistical methods. The presentations will be available on this website shortly.

Vaccine Clinical Assay Working Group formed (2010/11)

The Vaccine Clinical Assay Working Group (VCA-WG) was proposed at the 31st International Society for Clinical Biostatistics meeting, August 30, 2010, in Montpellier, France. The goal of the working group is to develop best statistical and scientific practices in vaccine clinical assay development, validation, and maintenance. The working group is composed of 25 clinical and nonclinical statisticians, laboratory scientists, and regulators from 6 vaccine companies (GSK, Merck, Medimmune, Novartis, Pfizer, and Sanofi Pasteur), 2 CRO’s (PPD and Arlenda), FDA and EMA.

The first face-to-face meeting of the working group was held March 1, 2011, at the Renaissance, King of Prussia site of GlaxoSmithKline. At that meeting the working group discussed topics, deliverables, and a work process moving forward. Topics span activities related to the quality of vaccine clinical assay readouts throughout the assay life cycle. These include assay development and optimization, pre-validation, validation, assay quality control, assay changes (e.g., assay transfer, technology changes, etc.), and standard calibration. Laboratory experimental designs and data analysis strategies will be considered across the range of vaccine clinical assay types: immunochemical, functional, molecular biological, and cell mediated immunity. Special emphasis will be given to “fitness for use.” The uses of vaccine clinical assay readouts, both for making decisions on individual subjects as well as for clinical study conclusions, will be considered.

The deliverable of the VCA-WG will be a white paper detailing the conclusions of the group. Sponsorship for publication is being sought from the Parenteral Drug Association, a global provider of science, technology and regulatory information and education for the pharmaceutical and biopharmaceutical community. Completion of the white paper is planned for the 1st quarter of 2012.

For further information please contact Tim Schofield at timothy.l.schofield@gsk.com.

Special Day on Statistics of Vaccines Research at ISCB Conference, Montpelier, France, 29 August 2010

Program (click on link for slides):

Allen Izu: Welcome and Short History of the ISCB Vaccines Sub-Committee

Jukka Jokinen: Analysis of Recurrent Events: Evaluating Treatment Effect in Vaccine Trials

Mey Wang: Statistical Challenges in the Evaluation of Vaccine Safety

Yin Bun Cheung: Estimation of Vaccine-Attributable Reduction

Mounia Hocine: Sequential Case Series Analysis for Pharmacovigilance

Jos Nauta: ANCOVA for antibody titers and a solution to the problem of heteroscedasticity

Forum discussion

Comments submitted on FDA Draft Guidance for Industry on Non-Inferiority Clinical Trials

In March 2010 the FDA issued Draft Guidance for Industry on Non-Inferiority Clinical Trials http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM202140.pdf. A working group consisting of committee member Júlia Singer and two vaccine statistician volunteers prepared comments, which were recently submitted.

Two comments classified as major pointed out inconsistencies in terminology. When discussing p values the draft guidance does not specify whether one-or two-sided p-values are intended. Also, when the term ‘sensitivity’ is used, trial sensitivity is not distinguished from assay sensitivity.

Among the most important of the 18 comments in the “nice to have” category were: the problem of non-inferiority for studies with multiple endpoints should be addressed; not only pharmaceutical products but other areas might also be covered; and the focus should not be on efficacy studies exclusively.

Ten comments suggested areas requiring clarification, and some figures were also considered to need clarifying. The comments were forwarded to the ISCB Statistics in Regulatory Affairs sub-committee for consolidation with other ISCB comments.

The complete comments can be viewed here.

Mini-Symposium: Statistics of Vaccines Research at ISCB conference, Prague, August 2009

(click on link for slides)

Session 1: Interim Analysis

Robert Kohberger: Practical Issues in Vaccine Trial Interim Analysis

Johathan Hartzel, Ivan Chan: Interim Analysis Strategies for Adaptation in Seamless Phase II/III Vaccine Trials

Open Discussion on Interim Analysis

Session 2: Multiple Comparisons

Bernhard Klingenberg: Simultaneous Confidence Bounds for Relative Risks in Multiple Comparisons to Control

Henry Hsu, Sang Ahnn, John Scott: Multiplicity Issues in Biologics Clinical Trials: Regulatory Perspectives

Open Discussion on Multiplicity

Session 3: Pandemic Vaccines

Allen Izu, Marc Fourneau: Challenges for Influenza (H1N1v) Pandemic Vaccines

Open Discussion

Mini-Symposium: Statistics of Vaccines Research at ISCB conference, Copenhagen, August 2008

The first part of the symposium covered problems related to safety.

Martin Kuldorff explained the US process followed to detect safety signals based on the Vaccine Safety Datalink sites. The process is operating every week based on sequential analyses related to accrued information. The maximised sequential probability ratio test is used. The process followed is based on hypothesis testing and not data mining. Click here for slides

Then Francois Beckers reviewed the statistical safety criteria that have been used to establish the safety of Rotarix. He described the challenges faced during the preparation and the conduct of the clinical trials and also put onto perspective the problem of multiplicity on playing with large safety database and using difference or ratio for risk evaluation. Click here for slides

Finally, Jingyee Kou talks about statistical issues in evaluating safety product. A perspective has been given on each phase of a clinical development and specific consideration has been shared on common and rare events. Click here for slides

These talks have been followed by a very interesting debate that put onto perspective methodologies (Farrington's approach vs Kuldorff's approach for the detection of a safety signal; use of risk difference or risk ratio) but also health perspectives evidencing the clear need of collaboration between partners from the academy, regulatory, health authorities and industry.

After a short break, the second part of the symposium was dedicated to correlate of protection.

First, Li Qin clarified the concept of immune correlate, correlate of protection and correlate of protective immunity and put a general framework to evaluate each of the level. Suggestion on study design and lab assay to be used concluded her talk. Click here for slides

Andrew Dunning covered advances and challenges in correlated of protection. He reviewed the evolution of approaches and put into perspective each step concluding by the challenges of this topic. View on perspectives on ideal situation and practicalities has been exchanged with fruitful intervention (questions/answers) from audience and speakers. Click here for slides