- Update the Target Product Profile (TPP)
- Update the Product Development Plan (PDP)
- Set activities, deliverables and criteria to pass Gate F
- TPP updated with data from product characterization and from Phase 2
- PDP updated to include (a) details by functional area to prepare for efficacy studies; (b) summaries of data collected to date and (c) updated timelines and budget
- Activities, deliverables and criteria to pass Gate F agreed and finalised
As Phase 2a studies are completed and a proof-of-concept Phase 2b 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.
- Review business plan with first market forecast and estimate of Cost of Goods (CoGs)
- Consolidate IP
- Identify and secure funding for the whole stage
- Business plan reviewed with market forecast and CoGs
- Acceptable IP status to support commercialisation confirmed
- Funding secured
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 availableto cover the Phase 2b before the start of the trial, including for biobanking of specimens for future correlates of protection studies.
The own IP positionis further consolidated and the patent landscape continues to be monitored. The status of IP to support commercialisation is confirmed.
- Increase scale of the process, if required, for commercial batches
- Update Cost of Goods
- Commercial scale-up process determined
- Cost of Goods updated
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.
- Obtain approval for Phase 2 CT
- Consult national regulatory authority (NRA)/ World Health Organisation (WHO) /European Medicines Agency (EMA) for scientific advice, including alignment on endpoints leading to Marketing Authorisation
- Refine regulatory strategy for global licensure
- Update CCDS with new data
- Prepare and submit Phase 2b CTA
- Phase 2a CTA approved
- Scientific advice obtained and alignment on endpoints established
- Regulatory pathways updated
- CCDS updated
- Phase 2b CTA submitted
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.
- Complete operations and conduct subsequent Phase 2a study(ies)
- Prepare protocol and operational plans for Phase 2b
- Collect adequate epidemiology data in target population and in the countries of clinical studies
- Prepare plan and obtain funding for engaging communities in the Phase 2b studies in line with Good Participatory Practice guidelines
- Update CDP including synopsis for Phase 2b-Phase 3
- Provide and discuss results of earlier trials and obtain community input into Phase 2b-3 trial design.
- Phase 2a completed; data available and analysed
- Draft protocol and operation plan for Phase 2b available
- Adequate epidemiology data at sites of Phase 2b available
- Plan for engaging communities in the Phase 2b study and funding in place
- Community engaged on trial design
- CDP updated
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.
The study protocol fo rPhase 2b is prepared, and study sites included in the Phase 2b are operational. Epidemiological data that have been collected at study CRCs confirm the expected TB disease incidence related to the primary efficacy endpoint or alternate CRCs 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.
- Analyse all safety data from Phase 2a and combine with all data from earlier studies
- Safety profile of the dose selected for Phase 2b acceptable
The review of all cumulative reactogenicity and safety data across the different studies (Phases 1 and 2a) should indicate that the vaccine formulation, dose and vaccination schedule selected for Phase 2b study have an acceptable safety profile in terms of nature, severity and duration of adverse events. There should be no evidence of a clinically significant 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 targetpopulation considerations
Adolescent/adultvaccine: Phase 2 studies confirm that safety is acceptable in both IGRA- and IGRA+ adults.
Neonate/infant vaccine: Safety/tolerability data from Phase 1b and 2 studies compared to BCG should appear acceptable. Assuming a better safety profile is the rationale of the improvement compared to current BCG vaccination, Phase 1b and 2 data should support this hypothesis.
- Analyse all immunogenicity data from Phase 2a
- Select dose for Phase 2b
- Perform validation of primary immunological assays
- Review potential biomarkers from previous studies and identify assays for Phase 2b (including immunogenicity and correlate analyses)
- Prepare operations for immunological assays and sample collection/storage
- If relevant, prepare plans for non-interference study (ies) with co-administered vaccine(s)
- Data from Phase 2a indicate significant immune responses and dose-response pattern allows selection of a dose
- Immunogenicity at the dose selected for Phase 2b acceptable
- Validation of assays confirmed
- Potential biomarkers reviewed, plan for analyses established and primary endpoint immunological assays identified
- Operations for immunoassays prepared
- Plans for non-interference study prepared, if relevant
After evaluation of the dose response pattern, the optimal dose (with respect to immunogenicity inrelation to COG) that is safe and well-tolerated, should be selected from the doses evaluated in Phase 2a 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.
TB vaccine target population considerations
Adolescents/adults: Storage of clinical samples for later biomarker analyses is important to maximize opportunities for lessons learnt. Ideally, biomarker studies are designed and immunological assays qualified prior to the onset of Phase 2b clinical efficacy studies, but new candidate biomarkers could also be identified in a later stage and it will be valuable to have samples readily available for validation tests.
If the candidate vaccine is likely to be administered at or around the time of other vaccines (such as HPV, malaria vaccine), non-interference studies should be planned.
Neonate/infantvaccine: Same as above for adolescents/adults, but 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 (e.g. hepatitis B vaccine) or at later infant immunisation visits (e.g. EPI infant vaccines), non-interference studies should be planned.
For the priority population of PLWH: Impaired immunity due to HIV infection, even in those receiving ART, may affect the ability of PLWH to develop robust innate and adaptive vaccine induced immune responses. Trials of TB vaccine candidates should include PLWH with careful assessment of safety, but also immunogenicity.
- Confirm efficacy endpoints of Phase 2b
- Efficacy endpoints for Phase 2b confirmed
A convincing robust data package demonstrating pre-clinical and clinical safety and immunogenicity needs to be assembled to proceed to Phase 2b.
The current 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), but may increase the risk of obtaining a false negative trial result. [refer to ‘target population considerations’ at function 9] This could be a IGRA positive or TBST-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’.
- Based upon market analysis, conduct forecasting in targeted (low-, middle- and high-income) countries, and document that the product is viable
- Establish a multidisciplinary ‘Access Team’ that will enable development of a comprehensive value proposition for TB vaccine/vaccination
- Develop understanding of all relevant international (WHO, GAVI, etc.) and national stakeholders requirements
- Prepare international and national stakeholders mapping, including civil society and TB-affected communities to secure early community engagement and initiate engagement
- Initial forecasting in targeted countries developed, and supports a viable product
- The ‘Access team’ is created with capacity and expertise available to develop value proposition activities
- Processes and requirements of selected national & international stakeholders understood
- Map of stakeholders available and engagement underway
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 fulfil public health needs. This includes, though not restricted to, Epidemiology, Clinical, Regulatory, Manufacturing capacity (including in LMICs), 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 any high income country-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 identifying early country adopters.
TB vaccine target population considerations
Adolescents/adultsvaccine: 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