DESIGN OF VACCINE EFFICACY TRIALS TO BE USED DURING PUBLIC HEALTH EMERGENCIES – POINTS OF CONSIDERATIONS AND KEY PRINCIPLES 1 CONTENTS Contents ........................................................................................................................................................ 2 1 Acknowledgments ................................................................................................................................. 4 2 Abbreviations and Acronyms ................................................................................................................ 4 3 Glossary of Terms .................................................................................................................................. 5 4 Executive Summary ............................................................................................................................... 6 5 Scope and Objectives ............................................................................................................................ 7 Scope of the Document .......................................................................................................... 7 Target Audience ...................................................................................................................... 8 Related Documents ................................................................................................................. 8 6 Background ........................................................................................................................................... 9 Goal of Vaccine Efficacy Trials ................................................................................................. 9 Context of Public Health Emergencies .................................................................................... 9 Rationale for the Points of Considerations and Guidance .................................................... 10 Declaration of Interests ........................................................................................................ 11 7 Regulatory Considerations .................................................................................................................. 11 Regulatory Principles ............................................................................................................ 11 Correlates of Risk and Surrogates of Protection ................................................................... 14 8 Major Design Planning Considerations ............................................................................................... 15 Types of Vaccine Effects ........................................................................................................ 15 Study Endpoints .................................................................................................................... 16 8.2.1 Primary Endpoint ................................................................................................................ 16 8.2.2 Estimating Intention-to-Treat and Per Protocol Effects ..................................................... 19 8.2.3 Secondary Endpoints .......................................................................................................... 21 8.2.4 Safety Endpoints ................................................................................................................. 22 Study Population ................................................................................................................... 22 8.3.1 General Population ............................................................................................................. 23 8.3.2 High Risk Population ........................................................................................................... 23 8.3.3 Responsively Defined Population ....................................................................................... 24 8.3.4 Special Populations ............................................................................................................. 24 Comparator Arm ................................................................................................................... 26 8.4.1 Placebo or Active Control ................................................................................................... 26 8.4.2 Delayed Vaccination ............................................................................................................ 26 8.4.3 Another Vaccine Candidate (Studies of Non-Inferiority) .................................................... 27 2 9 Major Study Designs to Evaluate an Experimental Vaccine ............................................................... 29 Randomized Trial Designs ..................................................................................................... 29 9.1.1 Role of Randomization ........................................................................................................ 30 9.1.2 Individually Randomized Controlled Trial ........................................................................... 31 9.1.3 Parallel Cluster Randomized Controlled Trials .................................................................... 34 9.1.4 Stepped Wedge Cluster Randomized Trial ......................................................................... 40 9.1.5 Other Trial Designs .............................................................................................................. 43 Observational Study Designs ................................................................................................ 47 9.2.1 Role of Observational Studies ............................................................................................. 47 9.2.2 Cohort Studies ..................................................................................................................... 48 9.2.3 Case-Control Studies ........................................................................................................... 51 9.2.4 Other Observational Study Designs .................................................................................... 55 10 Additional Design and Conduct Considerations ................................................................................. 56 Data Monitoring .................................................................................................................... 56 10.1.1 Planning for Settings where Epidemic Wanes .................................................................... 58 Accumulating Evidence about Interventions across Outbreaks ........................................... 58 Missingness in Data............................................................................................................... 59 Simulating Trials for Planning and Interpretation ................................................................. 60 11 Operational and Implementation Issues............................................................................................. 60 12 Outbreak- and Vaccine-Specific Considerations ................................................................................. 62 Impact of Outbreak Characteristics ...................................................................................... 62 12.1.1 Natural History of Disease .................................................................................................. 63 12.1.2 Local Infrastructure ............................................................................................................. 64 12.1.3 Current and Future Spatiotemporal Incidence ................................................................... 65 Impact of Vaccine Candidate Characteristics ........................................................................ 66 12.2.1 Vaccine Efficacy and Immunogenicity ................................................................................. 66 12.2.2 Vaccine Safety ..................................................................................................................... 67 12.2.3 Operational Considerations ................................................................................................ 67 13 Dissemination of the Guidance Document ......................................................................................... 68 References .................................................................................................................................................. 68 3 1 ACKNOWLEDGMENTS The R&D Blueprint team of the World Health Organization (WHO) gratefully acknowledges the contributions that many individuals made to the development of this guideline. Work was initiated and coordinated by Ana Maria Henao-Restrepo and Pierre-Stéphane Gsell (WHO). The development of this document was led by Doctor Natalie E. Dean and Professor Ira M. Longini, as part of the WHO Working Group 1 for vaccine evaluation, which includes: Ron Brookmeyer, Victor de Gruttola, Christl Donnelly, Elizabeth Halloran, Mamodou Jasseh, Martha Nason, Ximena Riveros, and Conall Watson. WHO extend sincere thanks to the technical experts engaged in the three other WHO Working Groups for vaccine evaluation and who extensively contributed to the development of this document: Steve Bellan, Nele Berthels, Anton Camacho, Peter Dull, John Edmunds, Rosalind Eggo, Susan Ellenberg, Tom Fleming, Lourdes Garcia-Garcia, Julian Higgins, Peter Horby, Philip Krause, Adam Kucharski, Barbara Mahon, Frank Odhiambo,