Function

The aim of this function is to prepare and submit regulatory documents, to liaise with authorities, to monitor legislation and to ensure compliance to regulatory requirements and applicable quality guidelines (including but not limited to Good Manufacturing Practices, Good Laboratory Practices and Good Clinical Practices). Since the regulatory environment is constantly changing, a key objective of the regulatory function is to provide advice on necessary adaptations to development plans and Target Product Profiles (TPPs). This applies to all stages of the development process and sustained regulatory support is required to address the complexities, in the face of limited guidance, for the development of new TB vaccines.

Stage 
B
Perform POC studies in animals
Gate 
B
Progress to Pre-Clinical
Main Activities
  • Identify regulatory path and potential barriers
CRITERIA REQUIRED
  • Regulatory strategy outlined, issues identified, and mitigation defined
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Guidance

It is important that Regulatory becomes involved at this early stage of development to ensure that the proper guidelines are consulted and followed. Depending on the nature and the TPP of the TB vaccine under development (live genetically modified vaccines, vectored vaccines, protein-based vaccines etc.), the relevance of the general and specific WHO, ICH and Pharmacopeia guidelines will be evaluated to identify a general regulatory path and possible barriers and if feasible, mitigation will be defined.

For example, for live TB vaccines, the regulations and guidelines applicable to BCG will be taken into consideration. These are the US Pharmacopeia (USP) and European Pharmacopoeia (EP BCG vaccine, freeze-dried 0163) monographs and WHO recommendations on BCG vaccine, which specify safety, genetic stability, detailed characterisation of Master and Working seeds, antibiotic resistance marker, BSE/TSE exposure. For an antigen-based TB vaccine containing a new adjuvant, the WHO guidelines on the non-clinical evaluation of vaccine adjuvants and adjuvanted vaccines, 2103 will have to be taken into consideration.

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Main Activities
  • Identify regulatory path and possible barriers
  • Consult Regulatory Authority (RA) with questions for scientific advice in a pre-Phase 1 meeting
CRITERIA REQUIRED
  • Regulatory input/scientific advice obtained
  • Regulatory risks assessed; no major roadblocks to product and clinical development indicated
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Guidance

Consultation with a regulatory agency for formal advice will be most valuable in the pre-Phase 1 stage, prior to starting clinical development of a new TB vaccine. Data generated to this point are presented, and advice is requested via specific questions. Topics for discussion and  agreement with the regulatory agency usually include:
• 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
• Pre-clinical and toxicology study programme
• Synopsis of protocol for Phase 1 and summary of clinical development plan.

Of note, the second Geneva Consensus meeting (Walker et al., 2010) has given recommendations for novel live TB vaccines and can be referred to.

Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
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

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 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
Main Activities
  • Prepare and submit Clinical Trial Application (CTA) and obtain approval for First-in-Human (FIH)/Phase 1
  • Propose regulatory pathways for global licensure
CRITERIA REQUIRED
  • CTA for FIH/Phase 1 submitted and approval obtained
  • Proposed regulatory pathways aligned with CMC, clinical and marketing
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Guidance

The regulatory strategy towards licensure in the various potential markets is developed at this stage. It goes hand-in-hand with the development of a market access strategy.

There are three potential pathways to licensure, relevant to TB vaccines that will guide and influence the regulatory strategy:

a) WHO prequalification once licence has been obtained from a stringent Regulatory Authority (or EMA article 58 positive opinion). Prequalification is a service provided by WHO (WHO prequalification) to health agencies that purchase vaccines, to determine the acceptability, in principle, of vaccines from different sources for supply to these agencies. It allows  GAVI-eligible low income countries, non-GAVI eligible middle income countries or PAHO (Pan American Health Organisation) countries to be reached:
      • The WHO prequalification ensures that vaccine efficacy data and studies are relevant to the target population, that vaccines used in immunisation programmes are safe and effective and meet the specific needs of the programme (programmatic aspects)
      • WHO prequalification process: review of general production process and quality control procedures, testing of consistency of lots and audit of the manufacturing facilities with observers from the responsible agency.

b) Application for national marketing authorisation (in-country licensing) (e.g. South Africa).

c) In-country manufacturing and licensing (e.g. China, India).

In Africa, the WHO African Vaccine Regulatory Forum (AVAREF) can be used as a collaboration platform enabling regulators, ethics committees and sponsors to reach consensus on key ethical and regulatory questions. For more information about AVAREF refer to Africa Network.

Stage 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
Main Activities
  • Prepare and submit Clinical Trials Application (CTA) and obtain approval for Phase 2
  • Consult national regulatory authority (NRA)/ World Health Organisation (WHO) /European Medicines Agency (EMA) for scientific advice, including alignment on endpoints leading to licensure
  • Update regulatory pathways for global licensure
CRITERIA REQUIRED
  • CTA for Phase 2 submitted and approval obtained
  • Scientific advice obtained and alignment on endpoints established
  • Regulatory pathways updated
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Guidance

After the end of the Phase 2 study, the regulatory strategy for global licensure is refined and follow-up advice can be requested from Regulatory Authorities to get alignment on the Phase 3 clinical study, involving the following questions: clinical design, clinical end-points, sample size, duration of active follow-up, at risk populations (HIV+), depending on the TPP of the product.

A meeting with the WHO prequalification team can be organised to present the TB vaccine under development and to anticipate all programmatic aspects of vaccination with this vaccine in order to ensure the following:
• WHO recommendations and UN tender specifications are met,
• Stability meets the needs of immunisation programmes,
• The immunisation schedules are compatible with those existing in national immunisation programmes. No interference with co-administered vaccines,
• Samples, labels, inserts and packaging will suit the UN tender requirements.

Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
Main Activities
  • Prepare and submit Clinical Trials Application (CTA) and obtain approval for Phase 2b
  • Define strategy for registration
  • Present Phase 2b data and design of Phase 3 to national regulatory authority (NRA) and WHO
  • Draft labels for launch
CRITERIA REQUIRED
  • CTA submitted for Phase 2b and approvals obtained
  • Registration strategy determined, including WHO prequalification
  • End of Phase 2b meeting with NRA and EMA/WHO held; Phase 3 design agreed to by relevant regulatory authority
  • Draft label for launch available
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Guidance

The Risk Management Plan (RMP) is drafted in collaboration with the Safety team, in preparation of Phase 3 trial. See ICHE2E: Guideline on Pharmacovigilance Planning

Phase 2b data are presented to Regulatory Authorities and WHO.  Phase 3 design is agreed to by Regulatory Authorities.

In preparation of WHO prequalification, dialogue is opened with Official Control Medicines Laboratory (OMCL) experts to agree on Quality Control assays, characterisation tests etc. The official release of commercial vaccine batches will have to be performed by an OMCL.

Stage 
H
Perform Ph2b Efficacy
Gate 
H
Progress to Ph3
Main Activities
  • Submit CTA and obtain approval for Phase 3
CRITERIA REQUIRED
  • CTA for Phase 3 submitted and approval obtained
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Guidance

After completion of the Phase 3 trial and production of its Clinical Study Report, the CCDS is updated with safety, immunogenicity and efficacy data from Phase 3 and this becomes the Summary of Product Characteristics (SPC). The RMP is updated in collaboration with the Safety team. Both SPC and RMP are included in the Marketing Authorisation Application (MAA) dossier.

The MAA dossier is completed and submitted to the Regulatory Authorities of target countries as per the regulatory and market access strategy.
The Regulatory Affairs team manage all contacts with Regulatory Authorities, lead response activities and product information activities (SPC, Patient Information Leaflet and outer package/immediate package labelling) during MAA dossier review and until licence is granted.

When licence has been obtained from a stringent Regulatory Authority (or scientific opinion from Article 58 procedure with EMA), the WHO prequalification dossier is completed and submitted. WHO prequalification allows supplying the vaccine to the health agencies of GAVI eligible low income countries, non-GAVI eligible middle income countries or PAHO countries.