As Phase 2a studies are completed and a proof-of-concept Phase 2a is contemplated, the TPP is updated for the characteristics of the product, which should be final at this stage, for the dose, route and safety profile. The PDP now includes data from Phase 2a and is updated with details on the operations for Phase 2b. There will need to be consideration of and planning for the large costs of a Phase 2b trial, which may require the involvement of multiple funding partners. The PDP contains a revised need for resources, Gantt chart, budget and risk management plan.

As the project progresses further in clinical development (Phase 2), the business plan is reviewed. This includes a first market forecast (see function ‘Market, Access and Implementation’) and a calculation of CoGs (see function ‘Production Process’). The business plan may be used to facilitate discussions with potential partners for further product development and commercialisation.

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

The own IP position is further consolidated and the patent landscape continues to be monitored. The status of IP to support commercialisation is confirmed.

As in previous Gate E.

Activities related to process development, scale up and validation described in Stage E continue during Stage F, up to process and scale for Phase 3 / commercial product.

After the end of the Phase 2 study, the regulatory strategy for global licensure is refined and follow-up advice can be requested from Regulatory Authorities to get alignment on the Phase 3 clinical study, involving the following questions: clinical design, clinical end-points, sample size, duration of active follow-up, at risk populations (HIV+), depending on the TPP of the product (preventive or therapeutic TB vaccine).

Phase 2a studies are completed during this stage. Safety and immunogenicity data are available for analysis and should provide data supporting the vaccine formulation, dose and regimen selected for subsequent efficacy trials. Whenever conducted, the pre-POC study is also completed.

The study protocol for Phase 2b is prepared, and study sites included in the Phase 2b are operational. Epidemiological data that have been collected at study sites confirm the expected TB disease incidence related to the primary efficacy endpoint or alternate sites are selected.

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

TB vaccine target population considerations

Adolescent/ adult vaccine: Whenever considered, pre-POC studies are completed and provide efficacy data that help decision-making regarding further development, ie Phase 2b and or Phase 3 efficacy trials.

The review of all cumulative reactogenicity and safety data across the different studies (Phases 1 and 2a, pre-proof of concept study whenever carried out) should indicate that the vaccine formulation, dose and vaccination schedule selected for Phase 2b study has an acceptable safety profile in terms of nature, severity and duration of adverse events.  

There should be no evidence of a clinically meaningful safety signal.

If the immunisation schedule consists of 2 or 3 vaccine administrations, there should be no evidence of an unacceptable dose-related increase in reactogenicity.    

TB vaccine target population considerations

Adolescent/adult vaccine: Phase 2 studies confirm that safety is acceptable in both QTF- and QTF+ adults.

Neonate/infant vaccine: Safety/tolerability data from Phase 1b and 2 studies compared to BCG should appear acceptable. In the hypothesis that a better safety profile is the rationale of the improvement upon current BCG vaccination, Phase 1b and 2 data should support this hypothesis.

Therapeutic vaccine: Phase 2 safety data should support the dose and timing of vaccine administration related to the antibiotic treatment.

Safe and well-tolerated dose(s) providing the most robust immune response, after evaluation of the dose response pattern, should be selected from the doses evaluated in Phase 2a and in pre-proof of concept study eg POI for further study in Phase 2b. Immunogenicity data from earlier studies should be evaluated to determine if additional assays should be considered for evaluation of immune response in Phase 2a.

Immunological assays should be validated prior to the Phase 2b study.

Biomarker studies should be designed prior to the onset of Phase 2b clinical efficacy studies.

If the candidate vaccine is likely to be administered at or around the time of other vaccines, non-interference studies should be planned.

TB vaccine target population considerations

Neonate/infant vaccine: Biomarker studies should be designed prior to the onset of Phase 2b clinical efficacy studies taking into consideration the limited volume of blood sample that can be drawn from infants. If the candidate vaccine is likely to be administered concomitantly with other vaccines recommended at birth (eg hepatitis B vaccine) or at later infant immunisation visits (e.g. EPI infant vaccines), non-interference studies should be planned.

If a POI study has been conducted, and POI study data show a statistically significant reduction in the defined primary endpoint and meet the Go criteria, one could prepare for a Phase 2b/3 POD trial (depending on magnitude and significance of the result and on an acceptable safety/tolerability profile). However, the absence of a vaccine’s ability to prevent infection does not necessarily mean absence of efficacy in preventing disease as the immune mechanisms by which a vaccine might prevent infection and disease could be different. Also, demonstration of POI does not guarantee POD since approximately 90% of infected individuals never progress to active TB in the absence of effective vaccination. To know that a vaccine will protect people from active TB and avert cases and deaths, it must be demonstrated that a vaccine candidate shown to prevent infection does so in individuals who, without vaccination, would have developed active TB. A convincing robust data package demonstrating pre-clinical and clinical safety, immunogenicity, and pre-POC human data will likely need to be assembled to proceed to Phase 2b. Robust protection data in a relevant animal model might be seen as adequate support even in the absence of pre-POC human efficacy data, although to date, none of the animal models have been demonstrated to be predictive for vaccine protection in humans.

Another approach to obtaining proof of concept is to conduct a Phase 2b POD trial in a population with high risk of disease (to keep size and cost of the trial as low as possible). This could be a QFT-positive adult population, as one example, if the vaccine candidate is hypothesised to prevent disease post-infection.

Primary and secondary endpoints of protective efficacy against TB disease in line with WHO definitions are agreed/ confirmed for the Phase 2b trial.

See Stage F function ‘Clinical Development and Operations’.

At this stage a first market forecast will be developed, also based on a first range of Cost of Goods (CoGs) (with input from Production Process function). This will be instrumental to validate pricing assumptions and ultimately product viability in targeted countries, considering the critical driver of affordability especially in low-income countries.

These elements will also sustain a further development of the business plan (see Business, Legal, IP).

At this stage a multidisciplinary access team is constituted, comprised of all functions that are necessary to support the development of a comprehensive process to successfully introduce a TB vaccine together with an adequate immunization program that will fulfill public health needs. This includes, though not restricted to, Epidemiology, Clinical, Regulatory, Health Economics and Business. Vaccines Europe is currently reviewing the so-called market access best practices focusing on European countries and comparing to non-European countries. The market access approach for novel TB vaccines should be aligned with those practices. However, since TB is a global disease with significant burden in low and middle income countries the market access strategy is likely to differ from a European-focused strategy (vaccineseurope.eu).

In addition, it is important to identify and map international (WHO, GAVI, UNICEF) and national (Ministry of Health, Ministry of Finance) stakeholders, including civil society and communities, that will influence the vaccine implementation decision-making processes. The aim is to understand their requirements and constraints in terms of data and studies, including for example Health Economic or logistics elements. In addition to desk research, external ad-hoc studies may be worth conducting, such as qualitative interviews with international and/ or national key opinion leaders in the TB field. The outcome of this analysis should be a specific mapping of all relevant stakeholders that will also contribute to identify the early countries adopters.

TB vaccine target population considerations

Adolescents/adults vaccine: Gain an initial understanding of vaccination calendars in targeted countries, vaccine coverage rates in such populations, and barriers to vaccine implementation.

Neonate/infant vaccine: Focus on motivation and evidence for replacing BCG and understand national and supranational barriers.

Therapeutic vaccine: Gain initial understanding of Standard of Care in different countries and regions. Stakeholders are likely to be different from preventive vaccination and need to be identified and initial requirements assessed. Specific barriers to implementation need to be identified.