Efficacy data are available from the Phase 2b and the TPP is updated accordingly for efficacy and more safety and immunogenicity data. Similarly, the updated PDP contains summaries of data collected to date, including from Phase 2b. The PDP describes and integrates the main activities in process development leading to lot consistency, and presents the design of the Phase 3 and its operations, regulatory aspects (anticipating registration) and marketing (anticipating implementation). It includes a revised Gantt chart and budget. The substantial cost of a large Phase 3 efficacy study is a particular challenge for a TB vaccine since there are limited sources and amounts of funding available. It is likely that a consortium-based approach will be needed in order to raise sufficient funds and the establishment and management of this consortium will need to be specifically resourced.
The business plan is reviewed. An initial plan of supply versus demand is developed, based upon latest market assessment and forecasts (see Market, Access and Implementation). The business plan is used to secure additional funds internally or with external investors and partners.
Funding for activities covering the whole stage should be secured. In particular, funding should be available to cover the Phase 3 before the start of the study.
As the vaccine candidate progresses to Phase 3, the IP strategy is revised as required. This includes a thorough review of the own IP position, the overall landscape and potential need for acquisition of third-party IP.
The process must be validated at this stage. For validation, it is recommended to use a down-scale model, where the set-points and specified ranges are confirmed for each unit process by monitoring the Critical Quality Attributes (CQA). If this model cannot be used, the multiple runs performed at a larger scale must demonstrate that the product meets pre-set criteria (CQA as recorded in the Bill of Testing, Quality Target Product Profile) and that critical process parameters stay within the original ranges tested during preclinical development. Otherwise, rework is required to implement a revised process, possibly besides process development and validations, running the risk of requirement for bridging clinical studies.
The final developed process and scale are used for the manufacturing of Phase 3 material. It has reached a stage close to the volume required for manufacturing for the market. The 3-5 consecutive consistency runs performed at market scale (according to GMP guidelines) finalise the process validation work and will also generate the vaccine product to be used for Phase 3. Now is also the time to perform the calculation of Cost of Goods for the large scale production process.
The Risk Management Plan (RMP) is drafted in collaboration with the Clinical Safety team, in preparation of Phase 3 study. See ICHE2E: Guideline on Pharmacovigilance Planning
Phase 2b data are presented to Regulatory Authorities and WHO. Phase 3 design is agreed to by Regulatory Authorities.
Dialogue is opened with Official Medicines Control Laboratory (OMCL) experts to agree on Quality Control assays, characterisation tests etc, as the official release of commercial vaccine batches will have to be performed by an OMCL of the country (or region) of manufacture. Official Batch Release is generally performed on review of batch protocol (showing results of agreed upon tests) and testing of batch samples. In the EU, OMCLs are coordinated by EDQM (European Directorate for the Quality of Medicines and HealthCare of the Council of Europe) and Batch Release certificates issued by an OMCL are recognized by all EU countries (EDQM). In the USA, the CBER (Center for Biologics Evaluation and Research) is in charge of batch release (CBER batch release).
The Phase 2b study is completed during this stage and data are available for statistical analysis. If data indicate protective efficacy equal to or greater than pre-set Go/ NoGo criteria, a study protocol for Phase 3 study is finalised and the identified study sites are prepared for conducting the Phase 3 study. Epidemiological data at the potential study sites are available to confirm the site selection and to determine Phase 3 sample size. The Phase 3 study should be conducted with at least one vaccine lot produced at the intended scale for marketing and its design should consider a clinical assessment of vaccine consistency.
The CDP will be updated to reflect the Phase 2 b data and possible consequences on the Phase 3 study.
The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.
Phase 2b studies are completed allowing decision- making process regarding initiation of Phase 3 conduct.
TB vaccine target population considerations
Adolescent/ adult vaccine: As pre-vaccination screening for infection status cannot be routinely considered for programmatic reasons, it is critical that Phase 3 study populations include both QTF- and QTF+ individuals. Although study design and power should ideally be for protective efficacy against TB disease in both strata, such a study would be extremely large and complex making it unlikely to be feasible. If powered to show vaccine efficacy against primary endpoint in QTF + strata, the study should offer an acceptable assessment of safety and trend for efficacy in QTF- strata.
The study population age should be consistent with the predominant age range in TB disease burden in the region.
Neonate/infant vaccine: Safety and immunogenicity data from study(ies) of concomitant administration with EPI vaccines should be available before conduct of Phase 3, or a rationale developed and agreed with National Regulatory Authorities justifying why this is not required.
Therapeutic vaccines: The Phase 3 study should be designed and powered to evaluate POR as primary endpoint. Separate analysis by relapse and reinfection could also be considered. The increase in the cure rate of antibiotic treatment regimens is likely to be a very difficult endpoint to reach under clinical trial conditions.
At stage G, the review of Phase 2b data should confirm the profile of common reactions in terms of nature, severity and duration and indicate that there are no unexpected, less common (frequency of 0.1% to 1%) adverse events. Altogether, experience from all studies should indicate an acceptable safety profile in the target population. The active monitoring of adverse events during Phase 3 may be modified in case of occurrence of any unexpected event during the Phase 2b trial.
A plan to assess vaccine safety in HIV infected individuals is prepared, if it has not already been conducted (for example, for subunit vaccines).
TB vaccine target population considerations
Neonate/infant vaccine: Safety data on concomitant administration with EPI vaccines should be acceptable.
Immunogenicity data from Phase 2b should be evaluated and be consistent with that observed in earlier studies and support continued development of the candidate vaccine. Biomarker samples collected during the Phase 2b study should be analysed for potential correlates of protection and/ or risk. These data, if available in time, should inform the development of the Phase 3 programme. A plan should be made for collection of further biospecimens for evaluation or discovery of biomarkers in Phase 3. Non-interference studies with concomitantly administered vaccines, if needed, should have been conducted during Phase 2b and no clinical or immunological interference demonstrated.
The study design for Phase 2b will reflect the statistical hypothesis: usually superior efficacy over either placebo or benchmark vaccine (e.g. BCG). 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 cases of TB disease using standardised case definition (WHO definitions of TB 2014). Culture confirmation or WHO approved rapid diagnostic (WRD) such as Gene Xpert technology-based test is required rather than the less sensitive and less specific smear microscopy.
Analysis of the data from the Phase 2b trial should demonstrate protective efficacy against the primary case definition endpoint that is greater than or equal to the minimum predefined efficacy criterion as set in the TPP, allowing for extending efficacy evaluation in a Phase 3 trial.
Market assessments are refined for further understanding and identification of potential early, middle or later adopters’ countries. A first demand and supply plan will be drafted, which will also contribute to an update of the business plan (see Business, Legal, IP).
The access team needs to define the data and tools that will be required to sustain the health economic rationale (modelling to support vaccine effectiveness, health and budget impacts, and willingness to pay (WTP) and build the evidence for the full value of vaccine/vaccination. This will identify the gaps between available data and evidence required by the different stakeholders. A second step would be to define a dedicated plan to address existing gaps during clinical Phase 3 development or beyond with the objective to quantify both clinical and economical outcomes of the use of the candidate vaccine. In order to build a gap analysis plan, Health Economic-Outcome Research (HEOR) activities should identify either trials or trial protocol adaptations and/ or modelling approaches to demonstrate the public health value of vaccination and to satisfy the perspective of the ultimate customer in terms of cost effectiveness and budget impact (Knight et al 2014, Bellini et al., 2016). The gap analysis plan will also provide the opportunity to prioritise among countries (feasibility/ cost approach) and draft an initial market access strategy.
Interactions with major stakeholders are key in order to further understand their requirements, gain their support and secure the relevance of the gap analysis plan.