Function

A project aiming to develop a vaccine is long and complex, requires multiple expertise working in a team and resources. Project management (PM) is the function that coordinates and integrates all activities of a given project, aiming to deliver intermediate data and ultimately the product (a novel TB vaccine), against the highest quality, on time, and within budget.  

An initial objective of PM is to coordinate the development of a Target Product Profile (TPP) and a Product Development Plan (PDP). The TPP lists the characteristics of the vaccine, with the final product and its use in mind. It should be aligned with relevant WHO Preferred Product Characteristics (PPC). The PDP lists, describes and integrates the main activities that have to be performed. The TPP and PDP are first drafted at Stages A and B respectively, and evolve as the project progresses. At this early stage, different indications might be pursued for the same vaccine candidate. A TPP should be developed for each indication, while the PDP should describe the planning of each. It is the responsibility of PM to revisit these documents to add data, update planning, re-assess the validity of assumptions, risks and gaps and to establish criteria for advancement to the next stage of development.

Stage 
A
Perform discovery, safety, immunogenicity and efficacy evaluation in initial animal model
Gate 
A
Progress to proof of concept (POC) studies in animals
Main Activities
  • Draft the Target Product Profile (TPP) with indication, target population, etc.
  • Set activities, deliverables and criteria to pass Gate A
CRITERIA REQUIRED
  • TPP with primary indication prepared
  • Activities, deliverables and criteria to pass Gate A agreed and finalised
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Guidance

The Target Product Profile (TPP) is first drafted at stage A. The TPP lists key characteristics of the vaccine candidate and evolves as the project progresses. A standard TPP specifies the primary indication (for example, prevention of TB disease), the target population (for example, adolescents and adults), a description of the active drug substance (for example, a live attenuated recombinant BCG that expresses new antigens), the drug product (with additional excipients), and the general characteristics of the vaccine candidate. Additional information includes presentation (liquid, lyophilized), dose route and schedule and manufacturing aspects (for example, number of doses per campaign, and affordability). Information related to clinical aspects will include: safety and reactogenicity, immunogenicity (immune response, mechanism of protection) and efficacy (prevention of disease, speed of onset of immunity), the number of administrations and schedule (multiple, time between doses), the route of administration, durability of protection (lifetime or time-limited), and whether co-administration with other vaccines (and potential interference) is anticipated. The safety, immunogenicity and efficacy of the vaccine candidate will be documented in animals first, then in humans.

Where possible, the targeted countries and an estimate of the market potential are included, as these might have an influence on the design of the vaccine and its geographic development. A formal market analysis is planned at Stage B.

At this initial stage of the TPP, the vaccine candidates are in construction with limited characterisation and supporting data. Still, it is recommended to set targets and specify how information will be obtained, for example, a specific type of study for safety or efficacy. Often, the TPP contains a column of minimal criteria that must be met, and another column of criteria that are desirable.

There are multiple sources for general guidance on preparation of a TPP, which include Lee and Burke, Vaccine 2010, FDA Guidance and UK MRC guidance. For guidance with more specificity for TB vaccines it is suggested to review the package insert for commercial BCG (BCG SSI, BCG SII and BCG Tice) and the WHO PPC for New TB Vaccines.

Stage 
B
Perform POC studies in animals
Gate 
B
Progress to Pre-Clinical
Main Activities
  • Update the Target Product Profile (TPP)
  • Prepare an integrated Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate B
CRITERIA REQUIRED
  • TPP revised
  • The PDP is drafted. It describes and integrates the main strategy across all functional areas, timeline and high-level estimated cost.
  • Activities, deliverables and criteria to pass Gate B agreed and finalised
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Guidance

The integrated Product Development Plan (PDP) is introduced at Stage B and is used in conjunction with the TPP. The PDP is a living document that contains an overview and history of the vaccine and describes the main activities per function, and how they integrate. As such, the PDP defines the roadmap to reaching a product with the characteristics described in the TPP. The initial PDP should list activities leading up to, at least, the end of the First-in-Human (FIH) or Phase 1 clinical study. The recommendation is to organise the PDP pe rfunction (PM, characteristics, process, pre-clinical and regulatory), and ensure that they are integrated and connected. The PDP contains a planning tool such as a Gantt chart which specifies tasks, timescales and their inter-dependencies. It also contains a budget and the required capacity (human resource, internal and external expertise). Importantly the PDP contains an assessment of risks, mitigations and a gap analysis. Once the pieces of the development plan are integrated and connected, milestones, decision points and a critical path can be established.

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Main Activities
  • Review the Target Product Profile (TPP)
  • Update the Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate C
CRITERIA REQUIRED
  • TPP revised, if necessary
  • PDP updated to include (a) details by functional area to prepare for First-in-Human (FIH) and other Phase 1 studies; (b) summaries of data collected to date; (c) updated timelines and budget
  • Activities, deliverables and criteria to pass Gate C agreed and finalised
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Guidance

The TPP and PDP are updated as the project prepares for clinical Phase 1. The PDP should include new information from the characterisation and process activities and data generated in pre-clinical studies. It should also include details of the preparation for the Phase 1, First-In-Human (FIH) study, with its design (population,doses, schedule etc.) or a synopsis of the protocol. It should also include other Phase 1 studies, if planned. The Gantt chart and budget are updated.

Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Main Activities
  • Update the Target Product Profile (TPP) and Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate D
CRITERIA REQUIRED
  • TPP and PDP updated
  • Activities, deliverables and criteria to pass Gate D agreed and finalised
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Guidance

The TPP and the PDP are updated as operations for FIH are prepared. The TPP contains the description of the vaccines that will enter into Phase 1. The PDP includes new information from characterisation and process development activities, as well as data from animal studies for safety, immunogenicity and efficacy. It also contains detailed activities for Chemistry, Manufacturing and Controls (CMC), regulatory and clinical aspects and how they integrate, for preparation of Phase 1. The PDP assumes success of Phase 1, and therefore expands on a description of activities in each function up to end of Phase(s) 2, together with revised analysis of resources needed, risks and mitigations and an updated Gantt chart and budget.

Stage 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
Main Activities
  • Update the Target Product Profile (TPP)
  • Update the Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate E
CRITERIA REQUIRED
  • TPP updated with data from Phase 1
  • PDP updated to include (a) details by functional area to prepare for phase 2; (b) marketing aspects ; (c) summaries of data collected to date, (d) updated timelines and budget
  • Activities, deliverables and criteria to pass Gate E agreed and finalised
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Guidance

The TPP and PDP are updated and include data on safety and immunogenicity from Phase 1. While most Phase 1 studies are performed in a single clinical site, Phase 2 studies are multi-centric, and often involve multiple countries. As clinical development progresses, the need for additional resources in clinical and regulatory aspects increases, and coordination is more complex. The PDP further details the strategy related to the Phase 2 programme, and, if needed, a new Chemistry, Manufacturing and Controls campaign with GMP production for clinical trial material. The PDP anticipates the need for proof of concept efficacy study (Phase 2b) and describes its design, overall operations and resources needed, and regulatory strategy. Moreover, the PDP now integrates activities related to Marketing and ideally a market analysis, the identification of targeted countries, and access strategy. The Gantt chart and budget are updated.

Stage 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
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

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. Anticipating success, the PDP presents the design of the Phase 3 and its operations. It contains a revised need for resources, Gantt chart, budget and risk management plan.

Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
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

Efficacy data are available from 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, expands upon the operations of the large Phase 3 efficacy study, regulatory aspects (anticipating marketing authorisation) 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.

Stage 
H
Perform Ph3
Gate 
H
Progress to licensure
Main Activities
  • Develop Company Core Information and leaflet versus Target Product Profile (TPP)
  • Update Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate H
CRITERIA REQUIRED
  • TPP becomes Company Core Information
  • The updated PDP now focuses on a description and integration of main activities in regulatory and marketing. It contains a planning and budget
  • Activities, deliverables and criteria to pass Gate H agreed and finalised
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Guidance

Efficacy is evaluated at this stage, leading to a major decision at Gate H to progress to registration. The PDP is focusing on the performance of Phase 3 and regulatory. Hopefully, efficacy and safety data meet TPP attributes and support the related product information in the leaflet. Additional indications should be sought in the Phase 4 clinical studies.

Stage 
I
Register vaccine with relevant Regulatory Authorities
Gate 
I
Obtain MA and Progress to launch
Main Activities
  • Update PDP
  • Set activities, deliverables and criteria to pass Gate I
CRITERIA REQUIRED
  • PDP updated to include (a) details by functional area to obtain MAA approval and prepare for launch; (b) summaries of all product data collected and (c) updated timelines and budget
  • Activities, deliverables and criteria to pass Gate I approved
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Guidance

The PDP is updated to include activities of each functional area to prepare the market authorization application, obtain approval and prepare for launch.

Stage 
J
Launch
Gate 
J
Implement vaccination programs
Main Activities
  • Update PDP
  • Set activities, deliverables and criteria to pass Gate J
CRITERIA REQUIRED
  • PDP updated to include (a) details by functional area to launch and implement vaccination programs; (b) summaries of additional product data collected and (c) updated timelines and budget
  • Activities, deliverables and criteria to pass Gate J approved
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Guidance

The PDP is updated to include activities of each functional area to launch and implement vaccination programmes.