The TPP and PDP are updated and include data on safety and immunogenicity from Phase 1.  While most Phase 1 studies are performed in a single clinical site, Phase 2a studies may be multi-site, and can involve several countries.  As clinical development progresses, the need for additional resources in clinical and regulatory aspects increases, and coordination is more complex.  The PDP further details the strategy related to the Phase 2 programme, and, if needed, a new GMP production for clinical trial material.  The PDP anticipates the need for a proof-of-concept efficacy study (Phase 2b) and describes its design, overall operations and resources needed, and regulatory strategy. The Gantt chart and budget are updated.

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As the project enters clinical development, the business plan will be refined according to emerging data and project needs.  Potential partnerships, in particular for clinical development and commercial aspects should be further evaluated.

The IP position and strategy should be further refined, owned IP filings should be pursued and potentially supplemented.  The patent landscape should be monitored on an ongoing basis.

Funding for activities covering the whole stage should be secured.  In particular, funding should be available to cover Phase 2 before the start of the trial.

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During Phase 1, the assays for Critical Quality Attributes (CQA) continue their qualification, progressing to validation.  The assays used for product characterisation could be slightly modified, to improve the sensitivity or accuracy of the test.  This should not change the qualification or later validation status of the assays.  Up to this point, the product reference would be from well described R&D production runs and be used to standardise assays.  It could now be replaced by a GMP compliant reference.  

The assays are used to release any new GMP material produced, or to document changes in the drug product (within certain limits), and in the continuing stability studies.

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Further process development involving scale-up towards targeted market scale and process validation are the aims of Stage E.

A live attenuated TB vaccine is used as an example.  The anticipated clinical dose is relatively low and, therefore, the scale could be 10 to 100L bioreactors, even for vaccines requiring multi-million doses because one mL of reactor volume could contain 10⁶doses.  Minimal purification is required with low impact on yield, although loss can be caused by lyophilisation.  A contrasting example is that of a non-live vaccine where the equivalent reactor volume (1 mL) is unlikely to produce a similar number of purified antigen doses as a live vaccine.

Assuming a down-stream process yield of 50%, and target dose of 10 µg, it means that for a multi-million dose requirement multiple 1000L reactor runs would be needed. In any event, the scale-up process for commercial batches should be defined at this stage.

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The regulatory strategy depends on the indication sought and goes hand-in-hand with the development of a market access strategy.

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The FIH trial is completed during this stage, as well as Phase1b in primary target populations.

Study protocols for Phase 2a studies to establish the optimal dose, formulation, route of administration and schedule of immunisation are developed and the PIs and study CRCs are selected.

Planning for a Phase 2b POC or integrated Phase2b/3 trial should be initiated.  A plan should also be drafted to generater eliable epidemiological data on TB disease endpoints in the target population in different regions and at the different study sites to be considered for Phase 2b and/or 3 trials.

The CDP will be updated to reflect any new relevant information that has become available from the pre-clinical programme and/or general advances in the field of TB vaccine research.

The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.

The safety data of the Phase 1a study and Phase 1b in the target population (e.g. healthy neonates, or Mtb non-exposed and/or exposed adults from endemic regions) should indicate an acceptable reactogenicity profile of the different vaccine doses which are being considered for Phase 2a studies.  No safety concerns precluding further clinical development should have been identified.

TB vaccinetarget population considerations

Adolescent/adultvaccine:  Safety data in both IGRA-negative and IGRA-positive adults are required.

Neonate/infant vaccine:  Develop a plan to assess safety in HIV exposed, as well as unexposed neonates and infants.   For a neonatal BCG-replacement vaccine candidate, plan to evaluate safety in comparison to BCG in HIV exposed neonates.  Similarly, an infant booster vaccine should be tested in comparison to a BCG prime alone.

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Immunogenicity data of the Phase 1a and Phase 1b studies will be analysed to characterise immunogenicity using primary, co-primary, secondary and exploratory endpoints.  The elicited immune responses must provide evidence that the candidate induces vaccine antigen-specific immune responses and an evaluation must be made of whether these responses are sufficient to progress development of the candidate vaccine.  In addition to safety, immunogenicity will guide the selection of the dose(s) to be further evaluated in Phase 2a studies.

Wherever possible a biomarker plan must be prepared prior to embarking on clinical efficacy studies: plans should be made for samples to be collected from Phase 1 studies and bio-banked for future correlates analyses – these samples will be vital for the potential discovery and characterization of correlates of protection or risk.

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Phase 1 FIH studies generally focus on safety and immunogenicity of a vaccine candidate entering clinical development. Evaluation of vaccine efficacy will occur at later stages of clinical development.  Of note, the immunological read-outs used to currently define infection may not be applicable to vaccines that include the antigens used to define Mtb infection.  

The study design for Phase 2b should reflect the statistical hypothesis: usually superior efficacy over either placebo or benchmark vaccine (e.g. BCG in an infant population). The magnitude of superiority should reflect the expected improvement in public health outcomes. The preferred primary endpoint for Phase 2b should be bacteriologically confirmed i.e., culture and/or GeneXpert positive TB disease using standardised case definitions.

TB vaccine target population considerations

Adolescent/adult vaccine: The study design for Phase 2b should reflect the statistical hypothesis of superior efficacy over placebo as there is no current recommendation for BCG booster immunisation.  The magnitude of efficacy should be consistent with an expected substantial impact on the epidemic, that is ≥50% efficacy in IGRA+ (Knight et al., 2014, WHO ECVP).

Neonate/infant vaccine: In infants, testing for superiority of efficacy over BCG will be conducted and the magnitude of superiority should reflect the expected improvement in reduced risk of TB disease.  Non-inferiority efficacy testing could be considered for an investigational vaccine offering a substantial benefit compared to BCG (e.g. safety in HIV exposed infants) (see also: WHO PPC for New TB Vaccines).

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The market assessment is refined according to new data.

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