Designing an adaptive phase II/III trial to evaluate efficacy, safety and immune correlates of new TB vaccines in young adults and adolescents R. Rustomjee a, * , B. McClain c , M.J. Brennan c , R. Mcleod b , C.M. Chetty-Makkan d , H. McShane e , W. Hanekom f , G. Steel g , H. Mahomed f , A.M. Ginsberg c , J. Shea h , S. Lockhart a, b , S. Self i , G.J. Churchyard d, j a Vaccine Development, Emergent BioSolutions, South Africa b Vaccine Development, Emergent BioSolutions, United Kingdom c Aeras, Rockville, United States d The Aurum Institute, Johannesburg, South Africa e Jenner Institute, University of Oxford, United Kingdom f South African Tuberculosis Vaccine Initiative, Institute of Infectious Diseases and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, South Africa g Management Sciences for Health, South Africa h Oxford Emergent Tuberculosis Consortium, United Kingdom i HIV Trials Network (HVTN), Fred Hutchinson Clinical Research Centre, Seattle, United States j School of Public Health, University of Witwatersrand, Johannesburg, South Africa article info Article history: Received 22 October 2012 Accepted 27 November 2012 Keywords: Tuberculosis Phase III clinical trial Vaccine Adaptive design Efficacy summary This article summarises the consensus arrived at a meeting of South African and international stake- holders on specific late phase clinical trial design issues integrating the investigation of immune correlates as an integral part of a phase III protocol for a preventative TB vaccine in an adolescent/adult population. The challenge ahead is to optimize the planning for phase 3 TB vaccine preventative trials, under resource constraints, given that there are no known correlates of protection to shorten and increase the efficiencies of efficacy trials. An adaptive, multi-arm, group sequentially designed trial protocol is proposed incorporating design features that address uncertainties arising from both advances in the field and dynamic study populations and disease states. Such a design allows modifications that protect research subjects, save time, and maximize the impact of scarce financial resources. Further, the protocol underwent joint review by regulators from several African nations at a meeting of the African Vaccine Regulatory Forum (AVAREF), a regional regulatory harmonization initiative, and recommenda- tions are included. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction As candidate tuberculosis (TB) vaccines advance through the development pipeline, the late stage clinical development plans for new TB vaccines present an exceptional challenge. 1,2 In the absence of predictive preclinical animal models of TB vaccine efficacy, a human challenge model or known correlates of immune protec- tion, 3 the need to use clinical endpoints for trials of novel vaccines is the norm for evaluating efficacy. In this respect, TB vaccines are no different than most other novel vaccines. The most challenging consequence of this is that clinical endpoints are required for efficacy trials and that there is not a “rational” approach for down- selection of multiple vaccine candidates in early stages of devel- opment based on biomarkers or animal model studies. In the absence of such down selection methods one option is to perform multiple efficacy trials, each of which would be long, large and expensive. The best hope is to conduct trials using protocols and clinical strategies that will inform rational down-selection of future candidates (e.g. find immune correlates), assuming that the first candidates will not fully meet the desired target product profile(s). 4,5 Over the next decade, multiple vaccines could enter late phase efficacy testing, of which three are already in phase IIb/III trials. 1,2 Planning is required to ensure efficient use of limited resources, including trial infrastructure, participant populations at high risk for TB, and funding. 5 This paper discusses issues in the design of efficacy trials to evaluate novel TB vaccines in young adults, based * Corresponding author. Emergent BioSolutions, BioSciences, 53 Jamieson Road, Rondebosch, Cape Town 7700, South Africa. Tel.: þ27 (0) 21 6850428. E-mail address: rustomjeer@ebsi.com (R. Rustomjee). Contents lists available at SciVerse ScienceDirect Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube 1472-9792/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tube.2012.11.005 Tuberculosis 93 (2013) 136e142