Project management is the function that coordinates and integrates all activities of a given project, to deliver intermediate data and ultimately the product, with quality, on time, and within budget. A project aiming to develop a vaccine is long and complex and requires multiple expertise working in a team. The resources needed, both financial and from experts, are demanding. Management of a project and its budget, and coordination of expertise require formal project management methodology and adequate resources.
A key objective of this function 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. 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. It is the responsibility of PM to revisit these documents to 1) add updates and ensure accurately reflected inclusion of data 2) re-assess the validity of assumptions, risks, gaps etc. and to establish new criteria for advancement to the next stage of development.
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 given, 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 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.
In anticipation of the regulatory strategy the draft TPP should include registration (in relevant countries), as well as business (for example, analysis of competitive advantage). 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.
At the early, draft stage of the TPP, vaccine candidates are in construction with limited characterisation and data. It is recommended to avoid ‘unknown’ or ‘to be determined’, and rather 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 criteria that MUST be met, and another column of criteria that are ‘Nice to have’.
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 published Preferred Product Characteristics (PPC) for TB vaccines. TBVI will shortly publish a generic TPP for a TB vaccine for Therapeutic applications.
The integrated Product Development plan (PDP or iPDP) is introduced at Stage B and is used in conjunction with the TPP. The PDP is a living document that contains both an overview and history of the vaccine but also describes and integrates the main activities in all aspects of development and defines the roadmap to reaching the characteristics described in the TPP). The PDP lists 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 per function (PM, characteristics, process, pre-clinical and regulatory), and ensure that they are integrated and connected. It contains a planning tool such as a Gantt chart which specifies tasks, timescales and their inter-dependencies, and a budget. Importantly the PDP contains an assessment of risks, mitigations and a gap analysis. Once the pieces of the development plan are integrated and connected, decision points and a critical path can be established.
As the project prepares for clinical phases, the TPP and the PDP are updated. The PDP includes new information from characterisation and process activities and data generated in pre-clinical studies. It should 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.
The TPP and the PDP are updated as the project prepares operations for FIH. The TPP contains the description of the vaccines that will enter into Phase 1. The PDP includes new information from characterisation and process 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 clinic 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 2, together with revised risks and mitigation and an updated Gantt chart and budget.
The TPP and PDP are updated and include information on safety and immunogenicity data from Phase 1. While most Phase 1 trials are performed in a single clinical site, Phase 2 studies maybe multi-centric, and could involve multiple countries. As clinical development progresses, the need for additional resources in clinical and regulatory aspects, and coordination is more complex. The PDP further details the strategy related to the Phase 2 programme, and, if needed, a new CMC campaign. The PDP anticipates the need for an efficacy study (Phase 2b) and should describe its design, overall operations and resources needed and regulatory strategy for approvals. 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.
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.
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.
With efficacy and safety determined, the TPP develops into the Company Core Information (CCI), also called the Company Core Data Sheet (CCDS – see Regulatory, Stage D for further information), and the leaflet. The PDP now focuses on a description and integration of activities related to regulatory aspects aiming to obtain a Market Authorisation, and to marketing, leading to implementation.