Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
Stage/Gate G
Project Management
Main Activities
  • Update the Target Product Profile (TPP)
  • Update the Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate G
CRITERIA REQUIRED
  • TPP updated with efficacy data from Phase 2b
  • PDT updated to include (a) details by functional area to prepare for Ph 3 and registration studies; (b) summaries of product data collected to date and (c) updated timelines and budget
  • Activities, deliverables and criteria to pass Gate G agreed and finalised
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Guidance
Guidance

Efficacy data are available from the Phase 2b and the TPP is updated accordingly for efficacy and added safety and immunogenicity data. Similarly, the updated PDT 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, expands upon the operations of the large Phase 3 efficacy clinical study, regulatory aspects (anticipate registration) and marketing (anticipate 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.

Stage/Gate G
Business/ Legal/ Market
Main Activities
  • Analyse and update Intelectual Property (IP)
  • Update partnership agreement(s) if necessary
  • Define pathway to commercialization
  • Obtain support from Principal Investigator(s) (PI) and Key Opinion Leaders (KOL)
  • Establish budget and secure financial plan to complete Phase 3
  • Update market assessments in potential early (middle and late) adopters
  • Fine-tune Cost of Goods (COG) and supply and demand plan
CRITERIA REQUIRED
  • Acceptable IP status to support commercialization confirmed
  • Strong industrial partnership in place
  • Pathway to commercialization defined
  • PI and KOL community are supportive
  • Phase 3 budget and funding plan in place
  • COGs and supply and demand analysis available, and support introduction of a viable product
  • Market assessments updated
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Guidance
Guidance

As the product progresses to Phase 3, the IP situation is further analysed as needed. Performing a large Phase 3 efficacy study and anticipating registration and the potential market requires new business development, and a pathway to commercialisation is defined. It might include seeking partnership, obtaining support from principal investigators (PI) and key opinion leaders (KOL). The market assessments made in the previous Stages are updated in potential early adopters as first priority, in middle and late countries as second priority. The initial COGs, supply and demand plan are also fine-tuned.

Stage/Gate G
Product Characterization and quality
Main Activities
  • Confirm specifications of final formulation
  • Compare drug product (DP) used in different studies, as relevant
  • Continue stability testing
  • Define and validate final Quality Control (QC) analytical methods, for the release of batches and final product
CRITERIA REQUIRED
  • Specifications for product from consistency runs in finalised Target Bill of Testing (BOT) are defined
  • Comparability of products used in different clinical studies is available
  • Stability acceptable
  • QC assays are validated
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Guidance
Guidance

At the end of this stage, the assays used for quality control should be validated, with final specifications, for the release of Phase 3 GMP material and of the consistency lots.

Stage/Gate G
Production process
Main Activities
  • Plan manufacturing batch for Phase 3
  • Establish final commercial-scale manufacturing process
  • Process validation: demonstrate that ranges for given specifications are valid
  • Validate facilities and equipment used
  • Scale up to commercial level
CRITERIA REQUIRED
  • Plan for manufacturing Phase 3 CTM available
  • Plan for consistency runs finalised
  • Process validation: specifications for process at relevant scale proven
  • Commercial manufacturing strategy in place
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Guidance
Guidance

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 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 BoT, QTPP) 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.

Stage/Gate G
Regulatory
Main Activities
  • Prepare and submit Clinical Trials Application (CTA) and obtain approval for Phase 2b
  • Define strategy for registration
  • Present Phase 2b data and design of Phase 3 to national regulatory authority (NRA) and WHO
  • Draft labels for launch
CRITERIA REQUIRED
  • CTA submitted for Phase 2b and approvals obtained
  • Registration strategy determined, including WHO prequalification
  • End of Phase 2b meeting with NRA and EMA/WHO held; Phase 3 design agreed to by relevant regulatory authority
  • Draft label for launch available
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Guidance
Guidance

The Risk Management Plan (RMP) is drafted in collaboration with the Safety team, in preparation of Phase 3 trial. 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.

In preparation of WHO prequalification, dialogue is opened with Official Control Medicines Laboratory (OMCL) experts to agree on Quality Control assays, characterisation tests etc. The official release of commercial vaccine batches will have to be performed by an OMCL.

Stage/Gate G
Clinical Development and Operations
Main Activities
  • Complete operations and conduct Phase 2b
  • Draft protocol for Phase 3
  • Prepare operational plans for Phase 3 (including selection of countries, study site, etc)
  • Prepare plan and obtain funding for engaging communities in the Phase 2b efficacy trial in line with Good Participatory Practice guidelines
  • Update Clinical Development Plan (CDP)
CRITERIA REQUIRED
  • Phase 2b completed and data available
  • Protocol for Phase 3 drafted
  • Operational plan for Phase 3 prepared. Epidemiology data available at all study sites
  • Plan and funding in place for engaging communities in the phase 2b efficacy trial
  • CDP updated
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Guidance
Guidance

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 is finalised and the identified study sites are prepared for conducting the Phase 3 study. Epidemiological data at the potential study sites are available and utilised in site selection and to determine Phase 3 sample size. Phase 3 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 Phase 3 study.

Stage/Gate G
Clinical Safety
Main Activities
  • Analyse all safety data from earlier trials, including Phase 2b
  • Draft Risk Management Plan (RMP) for Phase 3 and update active surveillance if needed/ justified
CRITERIA REQUIRED
  • Safety profile acceptable in target population
  • RMP drafted and active surveillance updated
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Guidance
Guidance

At stage G, the review of Phase 2b data confirm the profile of common reactions in terms of nature, severity and duration and indicate that there are no unexpected, less common (frequency of 0.01% to 1 %) adverse events. Altogether, experience from all studies indicates 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.

Plan to assess vaccine safety in HIV infected individuals is prepared, if it has not already been conducted (for example, for subunit vaccines).

Stage/Gate G
Clinical Immunology
Main Activities
  • Analyse all immunogenicity data from earlier trials, including Phase 2b
  • Conduct and complete non-interference studies with other vaccines used concomitantly
  • Analyse Phase 2b data for correlates of protection and incorporate into Phase 3
CRITERIA REQUIRED
  • Immune responses in target populations consistent in Phase 2b and earlier trials
  • Non-interference documented
  • Phase 2b data analysed and biomarker plan for Phase 3 established
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Guidance
Guidance

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, if needed, should have been conducted during Phase 2b and no clinical or immunological interference demonstrated.

Stage/Gate G
Clinical Efficacy
Main Activities
  • Establish clinical Proof of Concept (POC) efficacy
CRITERIA REQUIRED
  • Evidence of efficacy from Phase 2b or interim analysis consistent with minimal TPP criteria (based on predefined criteria)
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Guidance
Guidance

Analysis of the data from the Phase 2b trial demonstrates protective efficacy against the primary case definition endpoint that is greater or equal to the minimum predefined efficacy criterion as set in the TPP, allowing for extending efficacy evaluation in a Phase 3 trial.

Stage/Gate G
Market Access
Main Activities
  • Identify data gaps and options to close them in early (middle, late) adopter countries, aiming to build evidence and meet requirements from stakeholders
  • Identify complementary studies and/or protocol evolution (Phase 3) to close data gaps in early (mid, and late) adopters
  • Define Health Economics, Outcomes Research (HEOR) activities to support health economics (HE) rationale (cost-effectiveness, health and budget impacts, etc.) in early (middle and late) adopters
  • Initiate interactions with major stakeholders (countries, Global Fund, GAVI, UNICEF etc.)
  • Draft market access strategy
CRITERIA REQUIRED
  • Data gaps and options to close them identified
  • Complementary studies and/or protocols evolution (Ph3) to close data gaps identified
  • HEOR activities defined
  • Interactions with major stakeholders initiated
  • Market access strategy drafted
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Guidance
Guidance

The Market Access team needs to identify the gaps between data available and evidence required by the different stakeholders. A second step is to define in a dedicated plan how 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 novel 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 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 to understand their requirements and the relevance of the gap analysis plan.