Guidance

Vaccine development is a complex and long endeavour that requires multiple expertise, management of activities running in parallel and decision points. The Stage Gate Criteria (SGC) is a project management methodology that assists in the management of such large, long and complex projects. SGC organises a project along two elements: (1) the stages, which describe packages of activities that occur in parallel and generate material and data, and (2) the gates that follow each stage and consist in a review of data from the preceding stage using defined criteria. These defined stages and gate criteria help to assess progress and decide to advance a project to the next stage, to stop, hold or recycle it. This methodology is applied by the TB Vaccine Development Pathway.

The tables describe the stages and gate criteria for the development of a vaccine against TB, from discovery and initial stage of the design of the vaccine and its Target Product Profile (TPP) (Stage A), to application for marketing authorisation application (Stage H). While the development path is organised by stages and gates, its management is structured by ‘functions’ or ‘expertise’ needed to execute activities. The management is integrated, meaning that these functions work together or in sequence, based on activities as vaccine candidates progress.

The stage gates that relate to the preclinical and clinical aspects of TB vaccine development are described under three separate functions: ‘safety’, ‘immunogenicity’ and ‘protection/efficacy’. In addition, there is a separate clinical ‘operations’ function.

TB specific considerations

A key challenge in TB vaccine development, is the lack of accepted or validated immune correlates or surrogates of protection. This has an impact upon pre-clinical screening of potential candidates and on fine tuning / optimisation of the vaccine formulation, since lengthy and costly protection experiments must be performed using animal models that have not yet been validated to predict clinical efficacy. The lack of a validated immune correlate also prevents the establishment of an accepted, qualified assay to measure potency which would accelerate and harmonise product characterisation and Quality Control. The TB Vaccine Development Pathway tool attempts to address and provide guidance for this TB vaccine-specific challenge.

Guidance for each of the functions and stages is supported by examples, references or guidelines, that are relevant to TB vaccines, in particular those which relate to the existing BCG vaccine. Whilst useful for the development of new live-attenuated vaccines, the guidelines for BCG are insufficient for the various novel TB vaccine candidates in development. Thus additional guidance is provided drawing upon existing expertise in TB vaccine development and, where relevant, using generic guidelines for example for technology platforms or for regulatory compliance.

Whilst it is recognised that different target populations exist, the aim of this current version of the guidance is to describe the key considerations for TB vaccine development in general. Future updates of the guidance will provide more detailed information about each specific target population.