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 per function (PM, product characteristion, 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 resources, 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.
Intellectual Property (IP) is an important element in a project. At this early stage the IP status of the technology and the vaccine candidate(s) should be analysed. This includes a review of the ‘state of the art’, what is known and published, and the status of own patents versus competition. Submission of patent applications to create an early patent position is important. Obstacles due to competing IP should be identified, and an initial mitigation plan established. The IP situation and strategy for resolution (of e.g. existing prior patents, uncertain freedom to operate) are defined at this stage and become part of the Product Development Plan (for more information on PDP, see function ‘Project Management’). Particular attention should be paid to IP in highly competitive fields such as formulation and adjuvants, vectors, and nucleic acid-based vaccines.
Adhering to best financial practices, funding of all activities leading to pre-clinical evaluation should be secured. The developer should consider if a partner will be needed in the near-term to assist and support the development of the vaccine candidate.
There are further characterisations of the vaccine substance / product for its identity, purity and potency. Evaluation of stability under the expected storage conditions must be performed at this stage, and this becomes a criterion for selection.
There is no correlate of protection for TB vaccines. This presents a challenge to determine the potency of a vaccine candidate. Beside its concentration, several different marker assays are used as indicated in Stage A. The recently developed mycobacterial growth inhibition assay (MGIA) could be considered as a surrogate measure of a protective immune response.
The assays required for the testing of Critical Quality Attributes (CQA), the most relevant criteria for product quality with respect to safety and efficacy, are selected.
The process parameters are explored and optimised at lab scale. Examples of parameters for cell culture are the expansion of cells, temperature, oxygen, pH, stirrer speed, and concentration of metabolites and vaccine product. For down-stream process (DSP), examples of parameters are temperature, flow rate, salt concentration, or column height for ion-exchange column chromatography. Critical parameters for each step of the process must be identified, and optimum set points and ranges defined experimentally. Critical are the yield, purity and stability of intermediate products.
Caution must be taken with raw material used for culture media and buffers. Lots of raw material should be evaluated to control input and identify potential sources of variation to establish specifications that will support a stable process performance and product quality. The same is true for the cells (expression system/ biological source organism) that are used to produce antigen, which must be stable for multiple production runs. A risk assessment would be appropriate to estimate the potential impact of process variations on product quality (based on literature, other development projects, and regulatory requirements).
The product quantity (yield) is optimised assuming that the product quality will not change, which will be demonstrated later. The selected set-points for the different process steps is confirmed with product testing in animals.
The cost of production of the antigen and its vaccine formulation can be calculated, and, combined with yield and dose, provide information on 'Cost of Goods (CoG)’. In addition, a risk assessment is performed to indicate areas where there is insufficient control, which have to be addressed in following development steps to mitigate these risks.
References and links to Guidelines on process and production of vaccines can be found here.
As pre-clinical testing of immunogenicity or efficacy continues in Stage B, safety characteristics should be documented to add to the safety profile of the candidate. Additional studies may be conducted to confirm and expand the safety data package for specific product targets or functions. Examples might include an evaluation of the tolerability to different doses of the vaccine or tests to investigate shedding of live viruses or bacteria. Safety should be confirmed if there are any changes to/ optimisation of the vaccine candidate (for example, removing the resistance marker from an attenuated strain of Mtb.)
Immunogenicity studies in Stage B should demonstrate that the candidate is immunogenic in the animal model chosen to confirm protection with the aim to link or correlate specific immune responses to protection. A more detailed characterisation of the immune response should therefore be performed, for example identifying specific T-cell subsets or cytokine secretion profiles and, as with Stage A the types of immune response should support the proposed mechanism of action of the candidate. The immune response profile identified in Stages A and B should also be used to assist the design of studies in the NHP (or other advanced) model in Stage C. This would include informing the optimal immunisation protocol (e.g. the timing of prime and boost vaccinations) and to identify the most appropriate assays and samples to be taken. Immunogenicity studies in Stage B might also include dose-finding in the context of live-attenuated mycobacteria in order to demonstrate that a relevant immune response is achieved with doses of vaccine that are safe and feasible (for example, for manufacture). The immunogenicity data generated in Stage B would be used as part of the data package to select between the candidates chosen to advance to Stage C.
At Stage B, the emphasis is on confirming the protective efficacy of the candidate. Confirmation should be shown in a second animal model to demonstrate that the effect is biologically robust. This second model might be a guinea pig model or a mouse model which is more stringent e.g. involves a more virulent M. tuberculosis challenge, or uses a mouse strain which is more susceptible to disease. However, if this is not feasible for the candidate (for example, if a virus is known to be permissive in only one of the standardised animal models available), then independent verification of protection in the same animal model in another laboratory is acceptable. Regardless, it is imperative that the data are robust and that the protective effect can be reproduced. Studies aimed at elucidating the mechanism of action should be considered (e.g., T-cell depletion or passive antibody transfer). Head-to-head evaluation of vaccine candidates in independent laboratories is available via TBVI (TBVI services - standard mouse and guinea pig primary infection models, post-exposure vaccination models in mice and guinea pigs, mouse models involving challenge with clinical strains and NIH (NIAID/NIH pre-clinical models - standard mouse and guinea pig models, therapeutic vaccination mouse models). These services provide standardised and well-characterised models and study designs to ensure that comparison of data is feasible and head-to-head testing is encouraged. Immunogenicity and efficacy studies conducted in Stages A and B should be used to support the design and execution of experiments in the advanced model(s) in Stage C, including the identification of a primary endpoint upon which Stage C studies will be powered.
It is important that Regulatory becomes involved at this early stage of development to ensure that the proper guidelines are consulted and followed. Depending on the nature and the TPP of the TB vaccine under development (live genetically modified vaccines, vectored vaccines, protein-based vaccines etc.), the relevance of the general and specific WHO, ICH and Pharmacopeia guidelines will be evaluated to identify a general regulatory path and possible barriers and, if feasible, mitigation will be defined. For more information refer to the references in the introduction of this function.
For example, for live TB vaccines, the regulations and guidelines applicable to BCG can be considered. These are the US Pharmacopeia (USP) and European Pharmacopoeia (EP BCG vaccine, freeze-dried 0163) monographs and WHO recommendations on BCG vaccine, which specify safety, genetic stability, detailed characterisation of Master and Working seeds, antibiotic resistance marker, BSE/TSE exposure. See references to guidelines for other vaccine technologies in the Introduction.
At this stage, a first draft of the clinical development plan (CDP) to generate safety and efficacy data supporting the TPP of the investigational TB vaccine should be prepared. For more information on CDP refer to the introduction of function ‘clinical development and operations’