Introduction
The aim of this function is to develop a regulatory strategy towards Marketing Authorisation in the potential markets, prepare and submit regulatory documents, liaise with authorities, monitor legislation and ensure compliance with regulatory requirements and quality guidelines. These guidelines include, but are not limited to, Good Manufacturing Practice, Good Laboratory Practice and Good Clinical Practice. Since the regulatory environment is constantly changing, an objective of the regulatory function is also to advise on necessary adaptations to the Target Product Profiles (TPP) and Product Development Plan (PDP). This applies to all stages of the development and sustained regulatory support is required to address the complexities, in the face of limited guidance, of the development of new TB vaccines. A useful tool to for developing a regulatory plan can be the ‘A regulatory plan for TB vaccines – points to consider’.
For neonates/infant and adolescent/adult vaccines there are different pathways to Marketing Authorisation.
The regulatory strategy for marketing authorisation could rest on the following pathways:
a) Obtain Marketing Authorisation from a stringent Regulatory Authorities or positive scientific opinion from EMA under article 58 of Regulation (EC) No. 726/2004)
Marketing Authorisation procedures are well described with stringent Regulatory Authorities (SRAs) and follow defined review processes and timelines that are described in the corresponding websites. In addition, some SRAs have in place expedited regulatory pathways aimed at supporting the applicant with their product development and/or registration. In this context, it is recommended to also scrutinise those expedited pathways and to evaluate whether the TB candidate vaccine would benefit from such approaches. Examples of expedited pathways available worldwide at some of the SRAs such as the EMA or the US FDA are listed in the table below. While the majority focus on reducing overall review timelines at the time of registration, there are still some which aim at reinforcing dialogue with the applicant already from very early stages of development.
The European Medicines Agency (EMA), in cooperation with the World Health Organization (WHO), can provide scientific opinions on high priority human medicines, including vaccines, that are intended exclusively for markets outside of the European Union (EMA/CHMP evaluation done in collaboration with WHO under Article 58 of Regulation (EC) No. 726/2004)
Regulatory authority
Expedited pathway(can be expedited development or expedited registration)
EMA (European Union, EU)
Priority Medicines Scheme (PRIME)
Accelerated Assessment
Conditional Approval
Exceptional Circumstances
US FDA (USA)
Fast track designation
Accelerated approval
Priority review
Breakthrough therapy
Health Canada (Canada)
Priority review
Notice of Compliance with Conditions (“Conditional”)
Swissmedic (Switzerland)
Fast track
TGA (Australia)
Priority review
Provisional approval
PMDA (Japan)
Sakigake
Priority review
b) Apply for national Marketing Authorisation (in-country licensing) to the Regulatory Authorities of the country
c) 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. For reference, Dellepiane et al, 2018.
d) For GAVI (Global Alliance for Vaccines and Immunisation, GAVI, the Vaccine Alliance) eligible low-income countries, non-GAVI eligible middle-income countries or PAHO (Pan American Health Organisation) countries, apply for WHO prequalification once a Marketing Authorisation has been obtained from stringent Regulatory Authorities or once an EMA article 58 positive scientific opinion has been obtained (EMA/CHMP evaluation done in collaboration with WHO under Article 58 of Regulation (EC) No. 726/2004). 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.
For therapeutic TB vaccines. The regulatory strategy will greatly depend on the countries where the vaccine is to be marketed. In countries which hold stringent Regulatory Authorities, a full Marketing Authorisation will be required. Of note, if the indication sought concerns MDR- and XDR-tuberculosis whose prevalence is below 5/10 000, an orphan drug status designation may be applied for in those countries which have implemented a combination of legislations, regulations and policies for orphan drugs, e.g. the European Union, USA, Japan, Australia. Such legislation includes a variety of incentives to encourage orphan drug research, development and marketing. These often include tax credits for research costs, grants, waived application fee, several years of marketing exclusivity that prevents marketing approval of generic drug or brand name for the same rare disease indication, free scientific advice, fast track/ priority review for Marketing Authorisation and pre-licensing access initiatives, including off-label and compassionate use programmes. For developing countries, a meeting with WHO will have to be organised quite early to discuss the possibility for WHO to prequalify a therapeutic TB vaccine because, unlike BCG, therapeutic TB vaccines are not on the current WHO vaccine prequalification priority. The regulatory strategy will thus depend on the acceptability or non-acceptability by WHO to prequalify therapeutic TB vaccines.
Vaccine technology and target population specific references:
Guidelines concerning different types of vaccines should be considered:
- Antigen-based TB vaccines containing a new adjuvant: WHO guidelines on the non-clinical evaluation of vaccine adjuvants and adjuvanted vaccines, 2013.
- DNA vaccines: WHO Guidelines for assessing the quality, safety and safety of DNA vaccines and FDA Guidance forIndustry, Considerations for plasmid DNA vaccines for infectious disease indications, Nov 2007.
- Viral vectored vaccines: EMA/CHMP/VWP/141697/2009,Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines.
- Liposome containing vaccines: Liposome drug products, FDA Guidance for Industry, April2018 (https://www.fda.gov/media/70837/download)
- The second Geneva Consensus meeting (Walker et al., 2010) gives recommendations for novel live TBvaccines and can be referred to
- Identify regulatory path and potential barriers
- Regulatory strategy outlined, issues identified, and mitigation defined
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 more information refer to the references in the introduction of this function.
For example, for live TB vaccines, the regulations and guidelines applicable to BCG can be considered. 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. See references to guidelines for other vaccine technologies in the Introduction.
- Identify regulatory path and possible barriers
- Consult Regulatory Authority (RA) with questions for scientific advice in a pre-Phase 1 meeting
- Regulatory input/scientific advice obtained
- Regulatory risks assessed; no major roadblocks to product and clinical development indicated
Consultation with a Stringent Regulatory Authority (SRA, i.e. a regulatory body recognised to adhere to internationally accepted standards, notably those defined within the ICH) for formal advice will be most valuable prior to starting clinical development of a new TB vaccine. Data generated to this point are presented to the Authority, and advice is requested via specific questions. Topics for discussion and agreement with the regulatory agency usually include: (a) 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; (b) Pre-clinical and toxicology study programme; and (c) synopsis of protocol for Phase 1 and summary of clinical development plan.
- Prepare FIH Clinical Trial Application (CTA) with protocol, Investigator’s Brochure (IB), Chemistry, Manufacturing and controls (CMC)
- Submit CTA to National Regulatory Authority (NRA) and Ethics Committee (EC) for approvals
- Draft Company Core Data Sheet (CCDS)
- CTA prepared
- CTA submitted to NRA and EC for approvals
- CCDS drafted
As soon as preclinical data (chemistry, toxicology etc.), even if limited, are available, it is advisable to initiate 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 for worldwide labelling. See the ICH-E2C(R2) Guideline: Periodic Benefit-Risk Evaluation Report (PBRER), Appendix A, Glossary for further CCDS information.
- Submit and obtain approval for First-in-Human (FIH)/Phase 1
- Update CCDS with new data
- Propose a regulatory pathway for global licensure, aligned with CMC, clinical and marketing
- Prepare and submit CTA for Phase 2a
- FIH CTA approval obtained
- CCDS updated
- Proposed regulatory pathway approved
- Phase 2a CTA submitted
The regulatory strategy depends on the indication sought (preventive vaccine or therapeutic vaccine) and goes hand-in-hand with the development of a market access strategy.
- Obtain approval for Phase 2 CT
- Consult national regulatory authority (NRA)/ World Health Organisation (WHO) /European Medicines Agency (EMA) for scientific advice, including alignment on endpoints leading to Marketing Authorisation
- Refine regulatory strategy for global licensure
- Update CCDS with new data
- Prepare and submit Phase 2b CTA
- Phase 2a CTA approved
- Scientific advice obtained and alignment on endpoints established
- Regulatory pathways updated
- CCDS updated
- Phase 2b CTA submitted
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 (preventive or therapeutic TB vaccine).
- Submit CTA Phase 2b and obtain approval
- Refine regulatory strategy for global licensure, including WHO prequalification (WHO-PQ)
- Present Phase 2b data and design of Phase 3 to relevant regulatory authorities and WHO
- Draft labels for launch
- Update CCDS with new data
- Phase 2b CTA approved
- Registration strategy determined, including WHO-PQ
- End of Phase 2b meeting with NRA and EMA/WHO held; Phase 3 design agreed to by relevant regulatory authority
- Labels drafted
- CCDS updated
The Risk Management Plan (RMP) is drafted in collaboration with the Clinical Safety team, in preparation of Phase 3 study. 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.
Dialogue is opened with Official Medicines Control Laboratory (OMCL) experts to agree on Quality Control assays, characterisation tests etc, as the official release of commercial vaccine batches will have to be performed by an OMCL of the country (or region) of manufacture. Official Batch Release is generally performed on review of batch protocol (showing results of agreed upon tests) and testing of batch samples. In the EU, OMCLs are coordinated by EDQM (European Directorate for the Quality of Medicines and HealthCare of the Council of Europe) and Batch Release certificates issued by an OMCL are recognized by all EU countries (EDQM). In the USA, the CBER (Center for Biologics Evaluation and Research) is in charge of batch release (CBER batch release).
- Submit CTA and obtain approval for Phase 3
- Update CCDS with new data
- CTA for Phase 3 submitted and approval obtained
- CCDS updated
After completion of the Phase 3 study 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). Start compiling data for the Marketing Authorisation Application dossier.
- 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.
- Register with additional NRAs
- Submit WHO prequalification following stringent NRA MAA or EMA Article 58 positive opinion
- NRA additional registrations obtained
- WHO prequalification obtained
When Marketing Authorisation 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 supply of the vaccine to the health agencies of GAVI eligible low-income countries, non-GAVI eligible middle-income countries or PAHO countries.
The WHO prequalification process includes a review of production and quality control, testing of consistency lots and audit of the manufacturing facilities. WHO 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),which are: 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, data on no interference with co-administered vaccines are available, and finally samples, labels, inserts and packaging will suit the UN tender requirements.
A model Package Leaflet for BCG vaccines has been prepared by WHO to provide guidance to manufacturers on format and content for preparation of Package Leaflet for their vaccine. It is not intended to provide information specific to any particular vaccine brand. Vaccine manufacturers using this model to prepare their own Package Leaflet, should ensure that the information on their vaccine Package Leaflet is specific to their vaccine. Specific information should be consistent with (does not contradict) the model but can be more comprehensive and detailed.
WHO has published guidelines on international packaging and shipping of vaccines (WHO/IVB/05.23).
The vaccine can then be launched in the countries. Launch involves a number of regulatory activities that depend on countries regulations. For example, after release of commercial batch by the manufacturer, application for official batch release by the Official Medicines Control Laboratory of the country of manufacture should be sought. Another example is the application for export licence. Another is to create, as per national/regional requirements, packaging elements with prescribing information derived from the authorized Summary of Product Characteristics (Package Leaflet, legible, clear and easy to use, labelling, primary and secondary packages). These may require approval by regulatory authorities before launch. Finally, to notify regulatory authorities of initial placing on the market of the product as per national/regional requirements.