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Regulatory requirements for influenza vaccines - Marco Cavaleri EMA

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DRIVE Annual Forum
17th -18th September 2018, Rome

Published in: Health & Medicine
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Regulatory requirements for influenza vaccines - Marco Cavaleri EMA

  1. 1. An agency of the European Union Regulatory requirements for influenza vaccines Perspective from the EMA Dr. Marco Cavaleri Head of Anti-infectives and Vaccines, EMA IMI-DRIVE Annual Meeting 17-18 September, 2018
  2. 2. Influenza vaccines centrally authorised Indication of use • Seasonal vaccines • Pandemic preparedness vaccines (authorised in the interpandemic period) • Pandemic vaccines, authorised during a pandemic (from the above - or via emergency procedure) • Zoonotic influenza vaccines Type of vaccine construct • Inactivated non-adjuvanted (split, subunit and whole virion) • Inactivated adjuvanted (split, subunit) • Live attenuated 1
  3. 3. Guidelines for Vaccines • The new influenza vaccines guideline entered into force Feb 2017; covers seasonal, zoonotic and pandemic influenza in modules: 1) Quality 2) Non-clinical and Clinical 3) Procedural • Revision based on current knowledge and past experience (lessons learned from 2009 pandemic, scientific advice) • Scope: inactivated (un)adjuvanted split, subunit, whole virion vaccines and live attenuated vaccines • Concepts are broadly applicable to other vaccine constructs, including alternative antigens (e.g. not full HA), recombinant surface antigens, DNA- or VLP-based vaccines expressing surface antigens • Revision of Guideline on Clinical development of new vaccines currently ongoing; consultation during 2018 2
  4. 4. Main Changes in the Influenza Guideline • Immune correlates of protection: HI 1:40 no longer accepted as a threshold determining seroprotection; the prior ‘CHMP criteria’ that were applied to annual strain change clinical trials have been withdrawn • Annual strain change for seasonal vaccines: small safety and immunogenicity trials no longer required based on decades of experience • Continuous monitoring of vaccine effectiveness via studies and enhanced safety surveillance plans to be conducted yearly • Demonstration of clinical efficacy required in infants 6-36 months (naïve population) in principle for all seasonal vaccines 3
  5. 5. Correlates of protections (inactivated HA vaccines) So far:  HI titre 1:40 represented a reasonable CoP for efficacy of 50-70% against influenza  Since 1970s, evidence indicates need to better define CoPs, may vary according to e.g. specific age group or vaccine type New recommendations:  Efforts in development encouraged to support identification of CoPs  immunity against HA: HI/SRH and VN; HI titre 1:40 no longer sufficient for approval, distribution of titres across population and % of vaccinees above specified cut off levels; GMTs, SC, pre/post-vacc comparisons;  broader investigation of immune responses by measure of anti-NA and CMI, especially in elderly 4
  6. 6. Kick-off meeting - Lyon 2015 5
  7. 7. FLUCOP - Objectives of the full project 6 Improve and standardise the existing immunological assays and develop new tools to better evaluate efficacy of future seasonal human influenza vaccines Goal to be achieved through 3 objectives: 1. MAIN achieving standardisation of HAI and VN assays to be used by both the public and the private sectors (primary goal) 2. advancing the understanding and applicability of CMI and NA assays as tools for evaluating influenza vaccine performance (research driven, secondary goal) 3. consideration of new technology yet to be applied to population based evaluations of influenza vaccines (exploratory goal)
  8. 8. 7 Non-clinical Investigations • Primary pharmacodynamics (immunogenicity and protection) – Humoral and cell-mediated response in appropriate animal model for influenza to indicate dose, schedule and route of administration for clinical studies – Protection from disease established by challenge studies: i) most important for LAIV and pandemic vaccines ii) naïve (or primed) animals, such as ferrets (disease and infection markers and lethality as endpoints) iii) cross-protection to heterologous viruses could indicate breadth of protection – Passive immune transfer studies may be relevant if neutralising antibodies are associated with protection
  9. 9. Characterisation of the Immune Response Considerations for novel influenza vaccines:  Contribution of animal models of protection (e.g. ferret model) in directing investigations on specific immune markers  Human challenge studies may provide an early indication of which immune parameters are most likely to correlate with protection  Try to identify immune correlate(s) of protection in efficacy clinical trials  Investigate CMI using different methodologies in early development  Neutralising (e.g. ADCC) antibody should be investigated and thereafter measured as appropriate  The assays used in pivotal trials should be validated 8
  10. 10. Clinical Trials (I) • Exploration of immune response and dose relationship • Impact of previous immunity to influenza • In the absence of an immune correlate of protection one approach is to determine the antigen level above which there is no appreciable increment in immune response (unless there are dose-limiting safety issues) • Human challenge studies could help to support early dose selection • Persistence of immune responses and need for revaccination to be addressed 9
  11. 11. Clinical Trials (II) • Pivotal efficacy trials should be designed as prospective randomised controlled studies, ideally using a double-blind design • Whenever possible the control group should not receive influenza vaccine • Active-controlled non-inferiority trials may sometimes be necessary (e.g. in the elderly, in other populations depending on where and when the trial is conducted) • Stratification by age or by comorbidities or frailty should be employed; trials do not need to be powered to demonstrate efficacy in subgroups 10
  12. 12. Clinical Trials (III) • Primary endpoint based on all cases of influenza-like illness (ILI) laboratory confirmed by PCR or culture or both • Secondary endpoints include ILI due to strains that are “well-matched” to those in the vaccine, all-cause mortality, hospitalisation, ILI syndromes, all- cause pneumonia and, in children, otitis media • Trial duration depends on accrual of sufficient cases for primary analysis of efficacy, which may require more than one season 11
  13. 13. “traditional” HA-based seasonal inactivated influenza vaccines • Non-adjuvanted: • Non-inferior immunogenicity vs. a comparable authorised vaccine in adults and elderly. • In children 6-36m efficacy trial required. • Immuno-bridging or comparative immunogenicity to licensed vaccine in children >3yrs • Adjuvanted: • advantage needs demonstration, e.g. by superior immunogenicity vs. non-adjuvanted authorised comparable vaccine in adults and elderly. • Children 6-36m efficacy trial. • Immuno-bridging in children >3y or NI vs. another licensed adjuvanted vaccine12
  14. 14. Special populations • Immunocompromised: • specific studies not required pre-authorisation • Immunogenicity in selected types of conditions including for paediatrics • Extrapolation to other settings to be discussed • Co-morbidities • Specific studies not required pre-authorisation • Immunogenicity studies not predictive of impact of co-morbidity • To be evaluated as needed as part of vaccine effectiveness studies Pregnant Women: based on vaccine type, data available with IIVs might support inclusion of recommendation in SmPC Applicants encouraged to generate effectiveness data for maternal vaccination13
  15. 15. Safety Pre-licensure: • As a general rule, the total size of the safety population for any influenza vaccine should consist of at least 3000 individuals BUT this should be discussed on a case by case basis since alternative requirements may apply by vaccine type and construct • Total safety population may need to be supplemented depending on the age group representation so that there are data on ~300 subjects in other age groups of relevance to the proposed vaccine usage; similar consideration for supplementary safety data applies to any specified risk groups Post-Authorisation (RMP): • Appropriate measures or studies to address i) rare and very rare AEs ii) emerging safety concerns 14
  16. 16. Seasonal influenza vaccines Post-authorisation - Enhanced safety surveillance • Challenges with Pharmacovigilance for flu vaccines: • mass immunisation in short and fixed time each year; • need for product-specific surveillance in spite of multiplicity of vaccines on the market; • changes in quality spec may lead to unexpected reactogenicity; • expansion of vaccination programs to include new target groups. 15
  17. 17. Seasonal influenza vaccines Post-authorisation - Enhanced safety surveillance • AIM: • detect a potential increase in frequency or severity of expected (vs. previous season) reactogenicity (local, systemic, allergic) that may indicate a potential serious risk as exposure increases. • TIME is key to allow for early risk mitigation. • 3 OPTIONS are proposed: • active surveillance; • passive surveillance; • data mining or use of electronic health record data – yearly sustainability 16
  18. 18. Pandemic Preparedness Vaccines (I) • Sponsors are recommended to submit a MAA for a ‘pandemic preparedness vaccine’, formerly known as a ‘mock up’ pandemic vaccine. • This ‘core dossier’ should provide data on the safety and immunogenicity of the vaccine construct when it contains a potential pandemic strain that is poorly immunogenic and to which the vast majority of humans are immunologically naïve (e.g. H7N9) Whether a separate submission for a pandemic preparedness vaccine for new vaccines that are expected to be broadly cross-protective is necessary, needs to be further discussed on case by case basis 17
  19. 19. Requirements for applications to change vaccine composition • it may include quality data only -- recommended that some clinical data indicative of the likely immunogenicity of the pandemic strain are included in the strain change variation dossier. • Immunogenicity/protection studies in animals could be supportive if human data not available. POST-AUTHORISATION • Immune data in all age group and in risk groups required as specific obligations to the MA, to be submitted within specified timelines. • At this time the RMP plans for estimating vaccine effectiveness/safety should be activated and results should be reported in the pre-agreed timeframes. 18 Pandemic preparedness vaccines (II)
  20. 20. 19 2015-2016 LAIV/IIV VE estimates for H1N1 in 2-17 years In US ACIP withdrew recommendation for LAIV for 2016-2017
  21. 21. Influenza Vaccine Effectiveness (IVE) studies(I) • Rationale: continuous VE monitoring due to change in vaccine composition:  from a regulatory perspective, need to generate brand-specific data to contribute with important information to the overall clinical evidence available for each influenza vaccines, especially new vaccines  Studies to be conducted in line with Good Epidemiological Practice (GEP) guidelines and with ENCePP guidelines. Companies should liaise with organisations/institutions/public health authorities who have experience in IVE and infrastructure to conduct multicentre studies  Studies currently included in RMP Pharmacovigilance plan to make them enforceable, but not related to safety concern20
  22. 22. Influenza Vaccine Effectiveness (VE) studies (II) • Study design: i) case-control study (e.g. ECDC protocol) ii) cohort study (e.g. ECDC protocol) iii) screening method (taking into account data on vaccination coverage) • Endpoints: • laboratory-confirmed influenza for all study designs • ECDC case definition for ILI • prevention of pneumonia, influenza related hospitalisation, all cause mortality etc. depending on the setting and the design • Encouraged to undertake antigen analysis in subset of samples 21
  23. 23. Influenza Vaccine Effectiveness (VE) studies (III) • Target population: • according to the vaccine indication for use • stratification for age effects, children, adolescents, <65y, >65y and >75y • Assessment of effectiveness in patients with underlying diseases and conditions (e.g. pregnancy) encouraged • Selection of cases: • Standardised approaches in studies with active data collection • Data on confounders, e.g. previous flu vaccination, chronic conditions, health-seeking behaviour, previous hospitalisation • In DB studies, plan to address possible biases 22
  24. 24. 23 • Crude and adjusted data to be gathered yearly and brand-specific • difficulties to reach this objective are acknowledged and to be considered at the time of assessment • time lag for setting up efficient system providing consistent results • Interpretation of the data not always straight forward • results of IVE studies may yield potential signals that require further investigation to determine the drivers of estimated IVE • results from different seasons would have to be collected before any conclusion could be drawn • regulatory actions may be considered if a specific concern (e.g. of a manufacturing nature with a specific vaccine) is identified or strongly suspected by the deviation of the results from the expected pattern Influenza Vaccine Effectiveness (VE) studies (IV)
  25. 25. In the EU influenza vaccines may be registered under Mutual Recognition Procedure or Decentralised Procedure with different Reference Member States, or Centralised Procedure, which raised concerns around implementation of requirements for NAPs. Influenza Manufacturer Influenza Vaccine Procedure to register the vaccine Abbott Influvac Influvac Tetra MRP with Netherlands as RMS DCP with Netherlands as RMS GlaxoSmithKline Fluarix Tetra DCP with Germany as RMS Sanofi Pasteur Vaxigrip Vaxigrip Tetra MRP with France as RMS DCP with Germany as RMS Seqirus Agrippal Fluad Afluria MRP with Italy as RMS MRP with Italy as RMS MRP with Germany as RMS Astra Zeneca Fluenz tetra CP
  26. 26. Study protocols: Potential requests for protocol agreement preferably via formal Scientific Advice, or ad-hoc informal discussions with the DRIVE consortium could be considered. VWP will input into protocol review. Study results: PSURs not intended for primary submission of new data, may include a summary of the NCA assessment. Product-specific VE data require type II variation (regardless of PI changes) at the end of study for each season. Interim data not foreseen, but MAHs should inform EMA and NCA of any unexpected findings of concern in a timely manner and before any public disclosure. In future seasons results to be timely submitted as available, ideally by September each year. Pathway for submission of vaccine effectiveness data:
  27. 27. The assessment will be carried out by CHMP for CAPs and by MSs for NAPs. For harmonisation across CAPs and NAPs, Vaccine Working Party will provide advice on all products’ assessments. The VWP will be enlarged with experts from reference MSs for NAPs that are not already part of VWP. Review of vaccine effectiveness data:
  28. 28. Protocols should be included in the RMP Annex 3 for completeness and information. High level description of the study included in part 3 or part 4 of the RMP (template revision 2) indicating that it will be conducted annually and the results will be provided every year in e.g. September (to avoid repeated updates of the RMP with due dates). Each season study will be considered as one individual study. There is no need to include study results in the RMP. description of flu effectiveness studies in the RMP
  29. 29. 28 Conclusions • Regulatory pathways for approval of new influenza vaccines, including for pandemic influenza vaccines, are available and defined • Exploration of potential immune correlates of protection strongly encouraged • Demonstration of efficacy and safety in randomised controlled clinical studies is expected for new vaccines • For traditional inactivated vaccines, non-inferiority based on immunogenicity is acceptable, but for young children clinical efficacy data expected • Effectiveness studies and enhanced safety surveillance as part of the post- authorisation commitments
  30. 30. Thank you for your attention Contact me at marco.cavaleri@ema.europa.eu European Medicines Agency 30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact Further information Follow us on @EMA_News

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