Project Management
Main Activities
  • Update PDP
  • Set activities, deliverables and criteria to pass Gate I
CRITERIA REQUIRED
  • PDP updated to include (a) details by functional area to obtain MAA approval 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
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Guidance
Guidance

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

Business/ Legal/ Market
Main Activities
  • Update partnership agreement(s), if necessary
  • Establish budget and financial plan for post-market commitments
  • Review and complement business case
  • Validate COGS, demand and supply plan
  • Refine Market plan
CRITERIA REQUIRED
  • Commercial partnership established
  • Budget for post-marketing commitments established
  • Business case complemented
  • COGS, demand and supply plan validated
  • Market plan ready
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Guidance
Guidance

The PDP is updated to include activities of each functional area to launch and implement vaccination programmes.

Production process
Main Activities
  • 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
CRITERIA REQUIRED
  • CMC section of the MAA dossier completed Commercial lots available
  • All elements for manufacturing secured
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Guidance
Guidance

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.

Regulatory
Main Activities
  • Prepare and submit Marketing Authorisation Application (MAA) dossier to Competent Authorities for approval
  • Engage dialogue with Official Medicines Control Laboratory (OMCL) for official batch release of commercial batches
CRITERIA REQUIRED
  • Marketing Authorisation delivered by Competent Authorities
  • Dialogue with OMCL engaged, transfer of QC testings to OMCL on going
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Guidance
Guidance

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, link to 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.

Clinical Development and Operations
Main Activities
  • Finalise clinical section of the MAA dossier
  • Update protocol and update operational plans for Phase 4
CRITERIA REQUIRED
  • Clinical section of the MAA dossier completed
  • Protocol and operational plan for Phase 4 updated
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Guidance
Guidance

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.

Target-specific 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.

Clinical Safety
Main Activities
  • Finalise post-marketing Risk Management Plan (RMP), including evaluation of safety in specific target populations (HIV+)
CRITERIA REQUIRED
  • Post-marketing RMP finalised and approved
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Guidance
Guidance

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.

Clinical Immunology
Main Activities
  • Conduct analyses for CoP establishment
  • Perform assays
CRITERIA REQUIRED
  • Immunological assays performed
  • Analyses completed
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Guidance
Guidance

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.

Clinical Efficacy
Main Activities
  • Finalise post-marketing evaluation plan with Phase 4 effectiveness protocol and concomitant vaccines, if relevant
CRITERIA REQUIRED
  • Post-marketing effectiveness evaluation plan finalized and approved.
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Guidance
Guidance

A study protocol 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 written for Phase 4 effectiveness studies in specific sub-populations e.g. HIV infected populations.  

See Stage I Function ‘Regulatory’

Market Access
Main Activities
  • Continue to consult and engage international stakeholders (WHO) and develop dialogue to include new TB vaccine in GAVI’s “Vaccine Investment Strategy“ (VIS)
  • Execute HEOR activities to close data gaps in early adopter countries
  • Identify and test options for introduction in NIP and for funding of early adopters in low, middle and high income targeted countries
  • Finalise value proposition and core value dossiers for early adopters (priority)
  • Update pricing strategy as per HE outcomes
  • Finalise market access plan
  • Begin engaging communities and civil society to prepare market entry, including demand generation and education
CRITERIA REQUIRED
  • National and international stakeholders engaged
  • Complementary studies to close data gaps implemented; all data to build the rationale of the HEOR are available
  • Product value demonstrated to support introduction in NIP and funding according to identified options
  • Core value dossier for international stakeholders and early (priority), mid and late (option) adopters finalised
  • Pricing strategy updated
  • Communities and civil society engaged
  • Market access plan finalised
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Guidance
Guidance

During the Regulatory file review, consultations and coordination with WHO, GAVI (see GAVI vaccine investment strategy) and other regional or national decision makers are essential to minimise the delay between vaccine registration and implementation.

Pricing strategy and core value dossier are finalised, complemented by all relevant data gathered in the course of Phase 3 and 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

Target-specific 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 guaranties.

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.