Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Stage/Gate D
Project Management
Main Activities
  • Update the Target Product Profile (TPP) and Product Development Plan (PDP)
  • Set activities, deliverables and criteria to pass Gate D
CRITERIA REQUIRED
  • TPP and PDP updated
  • Activities, deliverables and criteria to pass Gate D agreed and finalised
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Guidance
Guidance

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.

Stage/Gate D
Business/ Legal/ Market
Main Activities
  • Identify and secure funds for First-in-Human (FIH)/Phase 1
CRITERIA REQUIRED
  • Funding for FIH/Phase 1 secured
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Guidance
Guidance

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.

Stage/Gate D
Product Characterization and quality
Main Activities
  • Release batch for the toxicology studies
  • Qualify assays related to critical quality attributes (CQA, product) and critical process parameters (CPP)
  • Release seed lots and banks
  • Release drug substance (DS) and drug product (DP) for FIH/Phase 1
  • Optimise buffer formulation and generate stability data on DS and DP
CRITERIA REQUIRED
  • Batch for toxicology studies released
  • Critical assays qualified
  • Seed lots and banks released
  • Clinical DS and DP meet specifications and are released. Equivalence to batch used for toxicology confirmed
  • Stability data on formulated vaccine sufficient to support clinical trial
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Guidance
Guidance

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.

Stage/Gate D
Production process
Main Activities
  • Complete technical transfer to GMP manufacturer and develop manufacturing process (pilot and/or Phase 1 scale) for production of (DS) and formulation of (DP)
  • Manufacture Good Manufacturing Practices (GMP) Master and Working seeds and banks
  • Produce a batch for toxicology studies (pre-GMP or GMP)
  • Qualify process for safety-related aspects (adventitious agents, mycoplasma, sterility)
  • Produce GMP Clinical Trial Material (CTM) for FIH
CRITERIA REQUIRED
  • Manufacturing process at Phase 1 scale locked
  • Master and Working seeds and banks produced under GMP, released for cGMP
  • Batch for toxicology studies produced with a process equivalent to the process used in GMP
  • Safety-related aspects of the process qualified
  • FIH CTM produced under GMP, in sufficient quantity to support FIH/Phase 1, Toxicology, QC, archives and possibly Phase 2
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Guidance
Guidance

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.

Stage/Gate D
Preclinical Safety
Main Activities
  • Perform toxicology studies using DP from GMP run (or equivalent)
  • Perform safety studies such as bio-distribution, persistence and for Genetically Modified Organism (GMO) requirements, as relevant for the vaccine
CRITERIA REQUIRED
  • Safety and toxicology profile of the DP acceptable
  • Bio distribution, persistence and GMO requirements met, as relevant
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Guidance
Guidance

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.

Stage/Gate D
Preclinical Immunogenicity
Main Activities
  • Not applicable, meaning that no additional data are required, on top of what was provided in the previous stage(s)
CRITERIA REQUIRED
  • Not applicable
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Guidance
Guidance
Stage/Gate D
Regulatory
Main Activities
  • Prepare FIH Clinical Trial Application (CTA) with protocol, Investigator’s Brochure (IB), Chemistry, Manufacturing and controls (CMC)
  • Submit to National Regulatory Authority (NRA) and Ethics Committee (EC) for approvals
CRITERIA REQUIRED
  • CTA prepared
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Guidance
Guidance

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.

Stage/Gate D
Clinical Development and Operations
Main Activities
  • Prepare operations for FIH/Phase 1 (including completion of protocol, identification of PI and study site etc)
  • Draft synopsis for subsequent Phase 2a, aiming at selection of doses, route, etc.
CRITERIA REQUIRED
  • Operations for FIH/Phase 1 prepared
  • Draft Phase 2a synopsis prepared
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Guidance
Guidance

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.

Stage/Gate D
Clinical Safety
Main Activities
  • Safety endpoint approved
CRITERIA REQUIRED
  • Safety endpoint approved
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Guidance
Guidance

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.

Stage/Gate D
Clinical Immunology
Main Activities
  • Develop primary and exploratory clinical immunological assays and qualify performance of primary assays
CRITERIA REQUIRED
  • Clinical immunological assays optimised and qualified
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Guidance
Guidance

Immunological assays to characterise the immunogenicity profile of the candidate vaccine should be developed, optimised for clinical use, and qualified prior to FIH studies.