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. Moreover, the PDP now integrates activities related to market assessment and ideally a market analysis, the identification of targeted countries, and access strategy.
A first business plan (see definition here) should be developed, based on the TPP and PDP (see Project Management) as the project advances towards the clinic. The business plan will rely on several elements, including market assessment (see Market, Access and Implementation, stage D), estimates of Cost of Goods (see function ‘Production Process’) and potential partnerships. The strategic value of potential partners to support early development is carefully evaluated and partnerships are established as needed. The business plan is used to convince potential investors and partners.
Adhering to best financial practices, funding for activities covering the whole stage should be secured. In particular, funding should be available to cover Phase 1 before the start of the trial.
In preparation for manufacturing of GMP material, meaning production of the antigen(s) and their formulation, the assays used for quality control and the Critical Process Parameters (CPP) must be qualified. The list of parameters that needs to be tested to release a product batch is confirmed and recorded in the Bill of Testing. Beyond this point the Product Specifications cannot be changed outside the original ranges without having major consequences (except for the excipients).
The material used for the toxicity study is produced according to cGMP or equivalent to GMP and must be characterised and released accordingly. The Phase I material is also produced and released.
At the end of the pre-clinical development, a detailed report presents the production process with a rationale for each specified step and data. The standardised production process is also described in concept documents (standard procedures and production protocols). From this point, the process is fixed and can be transferred to Manufacturing and documents used for Tech transfer.
The MCB and WCB now have to be released for use in production runs according to cGMP. The Phase 1 material is produced according to cGMP and to pre-set criteria generated previously. The documents are approved by production experts and QA.
At this stage the estimate of Cost of Goods can be calculated and confirmed based on the standardised pilot process.
Relevant safety and toxicity studies should be performed only once the manufacturing process has been locked and GMP-quality (or equivalent) material is available. At a minimum, Drug Product should be evaluated at the highest intended clinical dose, in an “N+1” regimen (i.e., including one more immunisation than will be performed clinically). Testing may be carried out using test/consistency lots or final process pre-release materials. Additional safety testing may be required for batch release of GMP material, and should be confirmed with the NRA.
Other studies such as bio-distribution, persistence, or stability of the insertion/ deletion in a genetically modified organism may be conducted as relevant for the vaccine. An example of such safety studies is given in Arbues et al. 2013 for the live attenuated Mtb vaccine – MTBVAC. Such studies are not an absolute requirement and therefore may not be described in regulatory documentation but can be informed by best practice and an understanding of the specific product characteristics.
As soon as preclinical data (chemistry, toxicology etc.), even if limited, are available, it is advisable to initiate the “CCDS” (Company Core Data Sheet), an internal “document containing safety information, material relating to indications, dosing, pharmacology and other information concerning the product”. The CCDS is a regulatory tool that is regularly updated with new data (in particular, safety and clinical data) throughout the development process. It is included in the investigator’s brochure in the frame of clinical trials and serves as a reference for safety reports generated during clinical trials and later for worldwide labelling. See the ICH-E2C(R2) Guideline: Periodic Benefit-Risk Evaluation Report (PBRER), Appendix A, Glossary for further CCDS information.
Study protocol for subsequent Phase 1b trials are completed. The Principal Investigators (PIs) and study sites for these trials also selected.
Study synopsis for Phase 2a study(ies) should be developed.
FIH and Phase 1b protocols completed and sites selected as per generic criteria.
The community engagement activities will continue at this stage of the development for more information on community engagement, refer to guidance under Stage C.
The local and systemic adverse events to be monitored during the Phase 1 and 1b studies are reviewed and approved.
In case of a live attenuated vaccine, a plan to assess vaccine shedding is prepared.
Immunological assays to characterise the immunogenicity profile of the candidate vaccine should be developed, optimised for clinical use, and qualified prior to FIH studies.
With the decision to move the vaccine candidate into development, a formal market assessment should be performed at this stage, refining the preliminary data collection in stage B (as part of the PDP, Project Management). The assessment includes medical need (from epidemiology data, incidence and disease burden), market characteristics and dynamics (economic situation, market size, standard of care (SOC), procurement and delivery processes), and positioning of the vaccine candidate versus the competitive landscape. The selection of the population and of the potential early adopter countries as first priority, and of middle and late adopter countries as second priority should also be made. It will highlight drivers and barriers that will contribute to the medical and economic value of the vaccine and ensure that a viable market will exist. A comprehensive review of recent literature would be a relevant way to gather data needed for market assessment and business case. This market assessment will contribute to an initial business plan that validates the upcoming investments (see Business, Legal, IP, stage D).