- Update PDP
- Set activities, deliverables and criteria to pass Gate I
- PDP updated to include (a) details by functional area to obtain MAA and prepare for launch; (b) summaries of all product data collected and (c) updated timelines and budget
- Activities, deliverables and criteria to pass Gate I approved
The PDP is updated to include activities of each functional area to prepare the market authorisation application, obtain approval and prepare for launch. (see function ‘Market, Access and Implementation’).
- Update the business plan with supply, demand, and market assessments
- Seek support from investors and partners, as needed.
- Confirm the business strategy and develop a detailed operational plan
- Secure funding for the whole stage
- Business plan updated with validated market assessments
- Investors and partners established, as needed
- Business strategy confirmed, and operation plan detailed
- Funding secured
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. For the latter, guidance is developed by WHO.
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.
- Finalise CMC section of the MAA dossier
- Manufacture commercial lots in launch facility
- Secure capacity, equipment, resources, raw material for sustainable manufacturing and delivery of required amount of vaccines
- CMC section of the MAA dossier completed
- Commercial lots manufactured
- All elements for manufacturing secured
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.
- Prepare and submit Marketing Authorisation Application (MAA) dossier to Competent Authorities for approval
- Engage dialogue with Official Medicines Control Laboratory (OMCL) for the official batch release of commercial batches
- Marketing Authorisation delivered by Competent Authorities
- Dialogue with OMCL engaged, with transfer of QC testings to OMCL
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.
- Finalise clinical section of the MAA dossier
- Update protocol and update operational plans for Phase 4
- Provide and discuss results of previous trials, and obtain community input into Phase 4 trial design
- Clinical section of the MAA dossier finalised
- Protocol and operational plan for Phase 4 updated
- Community engaged on trial design
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.
Adolescent/adult vaccine: Safety and effectiveness Phase 4 studies should also be considered in relevant populations that have not yet been fully studied, e.g. IGRA or TBST negative populations to confirm Phase 3 efficacy trend or that would not have been studied in Phase 3 e.g. elderly, HIV-infected adults, if not already studied, pregnant and breastfeeding individuals, people deprived of liberty. [TB vaccine target population considerations]
Neonate/infant vaccine. Safety and protective efficacy should also be considered in sub populations such as pre-term neonates and neonates born to HIV-infected mothers that may not have been assessed in Phase 3 trials.
- Finalise post-marketing Risk Management Plan (RMP), including evaluation of safety in priority populations (for example PLWH)
- Phase 4 safety study drafted
- Post-licensure RMP finalised and approved
A Phase 4 safety study should be prepared to address any unexpected event of special interest identified during pre-licensure clinical trials and to assess the presence of any adverse event that was too rare to be observed in pre-licensure clinical trials.
Phase 4 safety studies should also be prepared to assess or confirm the safety profile in relevant specific populations that were not fully evaluated in pre-licensure trials e.g. HIV infected individuals or pregnant and breastfeeding individuals.
- Conduct assays on samples collected in Phase 3 to identifycorrelates of protection and/or risk
- Immunological assays performed, in search of CoP
Biomarker assays are performed on samples collected during the Phase 3 study. Biomarkersare measured and analysed to detect potential correlates of risk and/or protection.
- Finalise post-licensure evaluation plan for Phase 4 effectiveness under field conditions, including concomitant vaccines, if relevant
- Evaluationplan for post-licensure effectiveness, including administration of concomitant vaccines finalized and approved
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 and other subpopulations such as pregnant and breastfeeding individuals, if not already done. Of note, new draft guidelines on inclusion of pregnant and breastfeeding individuals in clinical trials were released by WHO and for public consulting by EMA and FDA.
See also Function ‘Regulatory’
- Update market assessment based on Phase 3 data
- Finalise pricing strategy as per HE outcome
- Finalise value proposition and core value dossiers with priority to early adopters
- Finalise market access plan
- Further execute HEOR activities to close data gaps in early adopter countries
- Continue to consult and engage national and international stakeholders
- Identify and test options for introduction in National Immunization Programs (NIP) and for funding of early adopters in low, middle and high income targeted countries
- Market assessment updated
- Pricing strategy finalised
- Core value dossier for international stakeholders and early (priority), mid and late (option) adopters finalised
- Market access plan finalised
- Complementary studies to close data gaps implemented; data to build rationale of HEOR available
- Stakeholders, including communities and civil society engaged
- Option identified to support introduction in NIP and funding in targeted countries
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 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/infantvaccines, Market Authorisation Approval will likely be required to convince national authoritiesto consider BCG replacement. Manufacturers may have to provide supply guarantees.