The PDP is updated to include activities of each functional area to prepare the market authorisation application, obtain approval and prepare for launch.

The analysis of the current business situation is updated, and opportunities re-evaluated.

The analysis of supply versus demand is performed in more detail, with input from functions ‘Production Process’, ‘Clinical Development and Operations’ and ‘Market, Access and Implementation’. The business plan is updated with validated market assessments, forecasts and pricing from Market, Access and Implementation.

The business plan is used to communicate with investors, public bodies and partners. All aspects of commercialisation are looked at, with partnerships and operations implemented as needed. Consider increasing capacity and capabilities for manufacturing, commercialisation and distribution.

The business strategy is confirmed and implemented with a detailed operational plan.

Funding for activities covering the whole stage should be secured. In particular, funding should be available to cover the Phase 4 before the start of the study.

As for the production of product batches for Phase 3 (and final process validation), the initial vaccine product batches as commercial lots are produced.

An inventory and control system must be in place for the storage of biological source (master and working seeds), raw materials, in-process controls, reference standards, and purified product. The control system will have incorporated information of validation studies determining the stability of the different materials under the specified storage conditions. For the biological source stocks, the shelf life is often so long that it cannot be determined exactly and a new Working Seed Lot will be generated from the Master Seed lot when the vials of the existing Working Seed Lot have been (nearly) used for routine manufacturing. For the product reference standard, the shelf life will be generally coupled to the shelf life for the vaccine product.

The Risk Management Plan (RMP) is updated. Both the Summary of Product Characteristics (SPC) and RMP are included in the Marketing Authorisation Application (MAA) dossier.

The MAA dossier is assembled following the Common Technical Document format (CTD,) that eliminates the need for the applicant to reformat the information for submission to the different ICH regulatory authorities and allows for electronic submission (ICH M2 EWG). In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and the strongly recommended format of choice for NDAs submitted to the FDA, US.

The CTD is organised into five modules. Module 1 is region specific, for administrative information and prescribing information (SPC, Labelling and Package Leaflet (insert), Consultation with Target Patient Groups etc.). Modules 2, 3, 4 and 5 are common for all regions. CMC on Drug Substance and Drug Product is in Quality (Module 3). Nonclinical (pharmacology, pharmacokinetics and toxicology) is in Safety (Module 2 and Module 4). Clinical (biopharmaceutics, pharmacology, efficacy, safety and benefits/risks conclusions) is in Efficacy (Module 2 and Module 5).

The MAA dossier is submitted to the Regulatory Authorities of target countries as per the regulatory and market access strategy. The Regulatory Affairs team manages all contacts with Regulatory Authorities, leads response activities and product information activities (SPC, Package Leaflet (insert) and outer package/immediate package labelling) during MAA dossier review and until licence is granted. Marketing Authorisations (or scientific opinion from Article 58 procedure with EMA) are granted in those targeted countries which have functional Regulatory Authorities. Dialogue is engaged with an Official Control Laboratory for future official release of commercial vaccines. QC analytical methods are transferred to the designated Official Control Laboratory.

The different sections related to the clinical documentation of the dossier are prepared for inclusion in the MAA dossier.

Relevant Phase 4 study protocols are drafted to assess vaccine safety and effectiveness in terms of magnitude and duration of vaccine-induced protection under field conditions.

The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.

TB vaccine target population considerations.

Adult vaccine. Safety and effectiveness Phase 4 studies should also be considered in relevant populations that have not yet been fully studied, e.g. QTF- population to confirm Phase 3 efficacy trend or that would not have been studied in Phase 3 e.g. elderly, HIV-infected adults.

Neonate/infant vaccine. Safety and protective efficacy should also be considered in sub populations such as pre-term neonates, neonates born to HIV-infected mothers that may not have been assessed in Phase 3 trials.

Therapeutic vaccines. Phase 4 effectiveness studies will be designed to confirm the increase in cure rate of antibiotic treatments, to evaluate potential additional benefits of therapeutic vaccination such as antibiotic treatment shortening, and / or reduction in toxicity of antibiotic regimen.

Phase 4 safety study should be prepared to address any unexpected event of specific interest which would have occurred during pre-licensure clinical trials and to assess any adverse event that was too rare to be observed in clinical trials.

Phase 4 safety studies should be also be prepared to assess or confirm the safety profile in specific populations that were not fully evaluated in pre-licensure trials e.g. HIV infected individuals.

Biomarkers assays are performed on samples collected during the Phase 3 study. Biomarkers are measured and analysed to detect potential correlates of risk and/ or protection.

Study protocols should be prepared for Phase 4 studies designed to confirm vaccine effectiveness in the target population under field conditions, to evaluate the duration of protection and possible need for booster immunisations.

A study protocol should also be established for Phase 4 effectiveness studies in specific sub-populations e.g. HIV infected populations.  

See also Function ‘Regulatory’

During the regulatory file review, updates of the market assessment based on Phase 3 results will be conducted and the market access plan finalised

The value pricing strategy dossier and is finalised, complemented by data from Production Process on Cost of Goods, Clinical operations on Phase 3 and Regulatory. Dissemination at national and international level will be executed to gain support for an early implementation. Assessing barriers to uptake and proposing implementation strategies should be an essential part of the value dossier. National value dossiers also need to be prepared at least for targeted early adopter countries.

Consultations and coordination with WHO, GAVI (see GAVI vaccine investment strategy) and other regional or national decision makers including civil society and communities are essential to minimise time between vaccine registration and implementation.

Global and national marketing plans and activities need to be developed especially for early adopter countries.

TB vaccine target population considerations

For adolescents/adults, the value dossier needs to describe different possible implementation strategies (delivery platform for primary vaccination and for catch up). Co-administration strategies with existing recommended vaccines (HPV) will provide significant public health and economic value. The potential need for implementation studies based on Phase 3 data also has to be addressed.

For neonates/infant vaccines, Market Authorisation Approval will likely be required to convince national authorities to consider BCG replacement. Manufacturers may have to provide supply guarantees.

For prevention of recurrence, the value dossier needs to describe a preferred implementation strategy and be aligned with existing TB treatment infrastructure. Existing drug pricing and reimbursement mechanisms need to be taken into account.

For therapeutic vaccines, the value dossier needs to describe the added value of adjunct vaccination. The implementation strategy needs to be aligned with existing TB treatment infrastructure and practices. Existing drug pricing and reimbursement mechanisms need to be taken into account.