The TPP and PDP are updated as the project prepares the planning 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.
The developer could consider a formal evaluation by a patent attorney of the freedom to operate, with an opinion on risks. The analysis of IP should further confirm or solidify what would be an acceptable intellectual property position, and IP strategy. Further patent applications should be filed as appropriate based on emerging data. Follow-up of applications already submitted and evaluation of patents in the field is needed.
The assays selected for quality control and characterisation are developed, together with target specifications, for identity, potency, purity, etc. These quality parameters of the substance and the product are referred to a Bill of Testing (BoT), or Quality Target Product Profile (QTPP).
Note: the raw materials used for production of the substance and the product should be checked before being used in the lab. This quality control procedure is mandatory for current Good Manufacturing Practice (cGMP) operations. Certificates of Analysis of raw material must be collected and assays with target specifications selected for release.
The process is scaled up from lab-scale to pilot, at a scale calculated to generate sufficient material for toxicity studies and Phase 1 / 2 clinical studies.
MCB and WCB, or a combination of Master and Working Virus Seed Lot combined with a MCB and WCB of complementary host cells, are manufactured according to cGMP guidelines or equivalent quality level. After determining feasibility of the pilot-scale process performed with cells from the WCB, vials are sent for release testing.
Standardised production runs at pilot scale (pre-GMP runs) will confirm feasibility and reproducibility. Indeed, by demonstrating that repeated runs can be performed within certain ranges around the set-points for the relevant process parameters, the reproducibility of the process (or process steps) is established, as required for the pilot process according to GMP guidelines. The variation obtained in parameters which are considered critical should be within the ranges tested at lab scale. At the end of this Stage, the selected process now at pilot scale, can produce the right quantity of product with the correct quality (drug substance and contaminants) and, no further adjustments are required. Also, at this stage additional information on Cost of Goods could be gathered based on the standardised pilot process.
At the end of this stage, the process is fixed for manufacturing of Phase 1 GMP material. Later changes in the process can be required. It will have to be demonstrated that the implemented process changes do not affect the product quality attributes (product comparability). For TB vaccine candidates, later changes in the production process would likely need clinical bridging studies.
Synopsis protocols should be prepared for any safety and toxicity studies required by the relevant National Regulatory Authorities (NRAs) (also refer to Function ‘Regulatory’). At a minimum, this generally includes a local tolerance and repeat-dose toxicity study conducted under Good Laboratory Practices (GLP). However, additional studies may be required depending on the vaccine candidate. For example, genotoxicity and carcinogenicity studies may be required for novel vaccine adjuvants. Early consultation with NRAs is recommended to ensure the proposed studies meet their expectations.
Pre-clinical studies in Stage C are typically conducted in NHP or another highly relevant (and often resource-intensive) model. As the results of these studies are used as key gating criteria for advancement into clinical trials, they should be conducted as carefully and thoroughly as possible. Importantly, before proceeding to a challenge study, the vaccine dose and regimen should be optimised for the model selected and based upon the proposed mechanism of action (for example, dose or route selection for an adenovirus-based candidate may be based upon CD8+ T-cell responses characterised by intracellular cytokine staining, see Hokey et al., 2014). Immunogenicity evaluations should then be expanded in the challenge study. In addition to the inclusion of assays to confirm vaccine “take”, additional exploratory assays should be included to explore the mechanism of action and to identify potential correlates of protection. These may include the use of multiple or more extensive intracellular cytokine staining panels (to characterise Th1, Th17, gamma delta T-cells, etc.), antibody assays, and systems biology approaches. In order to conserve resources, samples for such exploratory assays can be collected and stored for analysis pending the challenge outcome. A recommendation is to consider the use of technologies provided by providers of platforms such as transcript- or other omics, e.g., GH-VAP (ghvap.org), and TRANSVAC (transvac.org), which offer unbiased and specialised expert assessments. Finally, consideration should be given to how key assays might bridge to the clinic.
Given the close similarity of non-human primates (NHP) to humans, data generated in NHP models are the most likely to predict clinical immunogenicity and efficacy and therefore efficacy data generated in an NHP model will provide the greatest confidence for funders / stakeholders to invest in further development. Studies conducted in NHP allow parallels to be drawn directly with data generated in humans which (i) inform the design of early clinical studies for example by providing information on vaccine doses/ routes/ regimen/ type of immunological read–out and (ii) provide added significance to the clinical immune responses because they can be correlated to a relevant signal of protection. Ethical and financial considerations restrict the testing of candidates in NHP to those which have the greatest potential, hence the system of screening in more tractable animal models in stages A and B is designed to identify the most promising of vaccines. The global capacity for candidate evaluation in NHP has been increased and there are now standardised methodologies for measuring vaccine efficacy across different NHP sites (Laddy et al., 2018). Thus, there is an expectation and encouragement that protection in NHPs should be demonstrated in order to pass Gate C. However, there may be situations where a different, advanced animal model would be equally appropriate. Examples where alternative models may be pursued include using cattle field trials to demonstrate prevention of naturally acquired infection or using prevention of relapse models. Animal models for TB vaccines are still being developed and refined and important developments (such as the establishment of a controlled human challenge system) may have an impact upon the selection of the model used but at stage C, it is imperative that the model used must be justifiable and highly relevant to the nature and TPP of the vaccine and must be robust and reproducible. At this Stage, proof of concept studies in non-standard models, or models still under development are discouraged. A primary endpoint should be selected and documented before initiation of the study, and the study adequately powered to produce clear, statistically significant results. Without setting specific levels of protection against myriad endpoints that would be required to support advancement of a candidate into the clinic, there is an expectation that protection be statistically significant. Investigators are encouraged to confer with the CTVD’s Nonhuman Primate Research Community for advice on the design and execution of NHP challenge studies.
Consultation with a Stringent Regulatory Authority (SRA, i.e. a regulatory body recognised to adhere to internationally accepted standards, notably those defined within the ICH) for formal advice will be most valuable prior to starting clinical development of a new TB vaccine. Data generated to this point are presented to the Authority, and advice is requested via specific questions. Topics for discussion and agreement with the regulatory agency usually include: (a) Manufacturing process and controls, characterisation of the antigen, release specifications for the MCB/WCB and drug substance/product and stability specifications. These discussions would include the choice of the relevant Quality Control and characterisation assays – especially for potency; (b) Pre-clinical and toxicology study programme; and (c) synopsis of protocol for Phase 1 and summary of clinical development plan.
Activities in Stage C are based around planning and preparation for FIH trial and subsequent Phase 1b trials that are designed to include target population individuals, in order to provide the data needed to support preparation and conduct of Phase 2 studies.
Community Engagement planning is a significant strategic process designed to build long-term relationships and working collaborations with the people most affected by TB disease. Community engagement initiatives should be planned and implemented at all clinical sites where the studies will be conducted in preparation for the future studies and these initiatives will be ongoing through the entire development programme. They should include consultation over study design and dissemination of results to trial participants and the broader community. The communication of expected and unexpected outcomes is a significant part of this activity as well as general education about TB and vaccines. A relevant reference is the Good Participatory Guidelines for TB Vaccines.
First in Human (FIH) Phase 1 study design should be double-blind, randomised, controlled and dose-escalating to evaluate safety and immunogenicity of the investigational vaccine in a limited number of healthy, BCG naïve and, potentially, BCG vaccinated adults with no evidence of exposure to TB. Subsequent Phase1b studies will be designed and conducted in the target population in TB-endemic areas. At this stage the design of Ph1 and the CDP could be presented to NRA at a scientific advisory meeting, for more information refer to function ‘Regulatory’.
A study synopsis for Phase 2a studies to select a dose(s) for further development should be drafted.
The CDP will be updated to reflect any new relevant information that has become available from the pre-clinical programme and/or general advances in the field of TB vaccine research.
TB vaccine target population considerations
Adolescent/ adult vaccine: FIH studies could be planned to evaluate the safety and immunogenicity of the investigational vaccine in BCG naïve and BCG vaccinated individuals, who have no evidence of latent TB infection, sequentially in the same study. In addition, Phase 1b studies are designed to evaluate the safety and immunogenicity of the investigational vaccine in subjects from endemic areas who have evidence of latent TB infection.
Neonate/ infant vaccine: Phase 1b studies are designed to evaluate the safety and immunogenicity of the candidate vaccine in neonates in TB endemic areas. Study design is dependent on the vaccination strategy, BCG replacement or BCG boosting vaccine.
Therapeutic vaccines: Phase 1b studies might not be required if safety and immunogenicity data are available from BCG vaccinated Mtb infected individuals. Proceed to Phase 2a (dose and regimen selection).
The assessment of safety is the primary objective of Phase 1 and 1b studies. An important aspect at this stage is therefore to define the safety endpoints for these studies.