Stage 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
Stage/Gate F
Project Management
Main Activities
  • Update the Target Product Profile (TPP)
  • Update the Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate F
CRITERIA REQUIRED
  • 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
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Guidance
Guidance

As Phase 2a studies are completed and an efficacy study in the form of a Phase 2b is contemplated, the TPP is updated for the characteristics of the product, which should be final at this stage, the dose and route, and the 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. Anticipating success, it presents the design of the Phase 3 and its operations. It contains a revised Gantt chart, budget and risk management plan.

Stage/Gate F
Business/ Legal/ Market
Main Activities
  • Analyse and update Intellectual Property (IP)
  • Conduct initial forecasting and Cost of Goods (CoG) analysis for pricing parameters, scalability of process, and product viability in targeted countries
CRITERIA REQUIRED
  • Acceptable IP status to support commercialisation confirmed
  • Initial forecasting and CoG in targeted (low-, middle- and high-income) countries analysed and supportive of a viable product
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Guidance
Guidance

An initial forecasting and cost of goods (CoG) analysis for pricing parameters, scalability of process and product viability in targeted countries should be performed and the analysis integrated back into the TPP and PDP. An analysis of the IP situation should confirm that the IP status would support commercialisation.

Stage/Gate F
Product Characterization and quality
Main Activities
  • As in previous Stage
CRITERIA REQUIRED
  • As in previous Stage
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Guidance
Guidance

As previous stage

Stage/Gate F
Production process
Main Activities
  • Increase scale of the process, if required, for commercial batches
CRITERIA REQUIRED
  • Commercial scale-up process determined
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Guidance
Guidance

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.

Stage/Gate F
Regulatory
Main Activities
  • Prepare and submit Clinical Trials Application (CTA) and obtain approval for Phase 2
  • Consult national regulatory authority (NRA)/ World Health Organisation (WHO) /European Medicines Agency (EMA) for scientific advice, including alignment on endpoints leading to licensure
  • Update regulatory pathways for global licensure
CRITERIA REQUIRED
  • CTA for Phase 2 submitted and approval obtained
  • Scientific advice obtained and alignment on endpoints established
  • Regulatory pathways updated
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Guidance
Guidance

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.

A meeting with the WHO prequalification team can be organised to present the TB vaccine under development and to anticipate all programmatic aspects of vaccination with this vaccine in order to ensure the following:
• WHO recommendations and UN tender specifications are met,
• Stability meets the needs of immunisation programmes,
• The immunisation schedules are compatible with those existing in national immunisation programmes. No interference with co-administered vaccines,
• Samples, labels, inserts and packaging will suit the UN tender requirements.

Stage/Gate F
Clinical Development and Operations
Main Activities
  • Complete operations and conduct subsequent Phase 2a study(ies)
  • Conduct Pre- Proof of Concept (POC) study (if part of Clinical Development Plan (CDP))
  • 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 2 studies in line with Good Participatory Practice guidelines
  • Update CDP including synopsis for Phase 2b-Phase 3
CRITERIA REQUIRED
  • Phase 2a completed; data available and analysed
  • Pre-POC study completed
  • Draft protocol and operation plan for Phase 2b available
  • Preliminary epidemiology data at sites of Phase 2b available
  • Plan and funding in place for engaging communities in the Phase 2 studies.
  • CDP updated
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Guidance
Guidance

Phase 2a studies are completed during this stage. Safety and immunogenicity data are available for analysis and should demonstrate support for the vaccine formulation, dose and regimen selected for subsequent efficacy trials. Whenever conducted, 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.

Stage/Gate F
Clinical Safety
Main Activities
  • Analyse all safety data from Phase 2a
CRITERIA REQUIRED
  • Safety profile of the dose selected for Phase 2b acceptable
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Guidance
Guidance

The review of all cumulative reactogenicity and safety data across the different studies (Phase1 and 2a, pre-proof of concept study whenever carried out) indicate that the vaccine formulation, dose and vaccination schedule selected for Phase2b study has an acceptable safety profile in terms of nature, severity and duration of adverse events. There is no evidence of a clinically meaningful safety signal.

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

Stage/Gate F
Clinical Immunology
Main Activities
  • Analyse all immunogenicity data from Phase 2a
  • Select dose for Phase 2b
  • Confirm 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)
CRITERIA REQUIRED
  • 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
  • Primary endpoint immunological assays validated
  • Potential biomarkers reviewed and plan for analyses established
  • Operations for immunoassays prepared
  • Plans for non-interference study prepared, if relevant
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Guidance
Guidance

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.

Stage/Gate F
Clinical Efficacy
Main Activities
  • If applicable, analyse pre-POC data
  • Confirm efficacy endpoints of Phase 2b
CRITERIA REQUIRED
  • Whenever available, pre-POC data are supportive
  • Efficacy endpoints for Phase 2b confirmed
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Guidance
Guidance

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 even 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 has 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 high risk of disease population (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 definition are agreed/ confirmed for the Phase 2b trial.

Stage/Gate F
Market Access
Main Activities
  • Establish a multidisciplinary market access team
  • Based upon business strategy, develop understanding of all relevant international stakeholder’s requirements (WHO, GAVI, UNICEF, etc.) and develop mapping
  • Prepare international and national stakeholders mapping, including civil society and TB-affected communities
  • Start to analyse healthcare systems and requirements of countries for integration in National Immunization Program (NIP) and funding
CRITERIA REQUIRED
  • Capacity and expertise to support market access activities available
  • Processes and requirements of international stakeholders understood
  • Map of stakeholders available and engagement underway
  • Countries healthcare systems and requirements analysed
  • Initial identification of early, mid- and late adopters available
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Guidance
Guidance

A multidisciplinary market access team should be constituted at this Stage. The team is comprised of all functions that are necessary to support the process from initiation until completion of a market access plan. This includes, though is not restricted to, Epidemiology, Clinical Operations, Regulatory, Health Economics and Business. Vaccines Europe is currently reviewing 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 and in poor populations, the market access strategy may differ from a European-focused strategy on a case-by-case basis (vaccineseurope.eu). A dedicated project management tool would facilitate the process of establishing a market access plan.

The major purpose of the activities at this stage and according to the business strategy is to identify important international (WHO, GAVI, UNICEF) and national (Ministry of Health, Ministry of Finance) stakeholders, including civil society, that will influence the vaccine implementation decision-making processes. The aim is to understand their requirements in terms of data, studies, assessments, including for example Health Economic elements. In addition to desk research, external ad-hoc studies may be worth conducting at this stage such as qualitative interviews with international and/ or national 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 versus late countries adopters.