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.
Funding must be secured and available for the first-in-human (FIH)/Phase1 before the start of the study.
The decision to move the candidate(s) into clinic should trigger a more formal analysis and detailed analysis of the potential market and target countries are re-evaluated.
In preparation for manufacturing of GMP material, 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 BoT. 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 this 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.
Relevant safety and toxicity studies should be performed only once the manufacturing process has been locked and GMP-quality 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 draft 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 on 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 Principle Investigators (PIs) and study sites for these trials also selected.
Study synopsis for Phase 2a study(ies) should be developed.
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.