Regulatory requirements for universal flu vaccines Perspective from the EU regulators

Transcription

1 Regulatory requirements for universal flu vaccines Perspective from the EU regulators EDUFLUVAC workshop June Marco Cavaleri Head of Anti-infectives and Vaccines Scientific & Regulatory Management Department EMA An agency of the European Union

2 Outline Regulatory pathways Considerations on non-clinical and clinical development Labelling aspects 1

3 Regulatory Pathways for Vaccines Full approval based on efficacy (e.g. rotavirus vaccines, HPV vaccines) or immunological data (e.g. MenB vaccine) Conditional marketing approval (e.g. H5N1 live attenuated pandemic preparedness vaccine for use in a declared pandemic) Approval under exceptional circumstances (e.g. smallpox vaccine) Art. 58 Scientific Opinion for use outside of EU (e.g. malaria vaccine) 2

4 Conditional Marketing Authorisation On the basis of less comprehensive data and subject to specific obligations Scope (at least one): for seriously debilitating diseases or life-threatening diseases; to be used in emergency situations; orphan medicinal products. Criteria (all): the risk-benefit balance is positive; it is likely that the applicant will be in a position to provide comprehensive clinical data; unmet medical needs will be fulfilled; the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required. 3 unmet medical needs means a condition for which there exists no satisfactory method of diagnosis, prevention or treatment authorised in the Community or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected 22 March 2017 Regulation (EC) No 507/2006

5 Missing Elements * of Comprehensive Data ** Data at the time of CMA Data based on an intermediate endpoint (e.g. overall response rate) Data from limited study/-ies Data in overall population Data on certain endpoints Data in a certain combination therapy Immunogenicity data Data generated through specific obligations Data on clinically most relevant efficacy endpoint (e.g. survival data) Data from a larger database or for longer duration, with the same endpoint(s) (e.g. response rate at a later time cut-off) Further data in important sub-populations (e.g. in patients with resistance or a particular biomarker) Further data on additional endpoints / specific issues identified Data with other co-medication for combination therapies Vaccine effectiveness data 4 * justified based on the strength of available results and taking into account the requirement for a positive B/R balance ** data requirements laid down in Annex I of Directive 2001/83/EC, including confirmatory studies normally required in the particular indication for respective type of the medicinal product 22 March 2017

6 Marketing Authorisation under Exceptional Circumstances Art 22 of Dir 2001/83/EC: Comprehensive data on safety and efficacy cannot be provided under normal conditions of use due to reasons set out in Annex I, leading to MA granted subject to conditions Must meet criteria: i)indications are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence ii) in the present state of scientific knowledge, comprehensive information cannot be provided iii) it would be contrary to generally accepted principles of medical ethics to collect such information MA valid for 5 years subject to annual reassessment of the conditions 5

7 Features of the PRIME Scheme Early access tool, supporting patient access to innovative medicines Written confirmation of PRIME eligibility and potential for accelerated assessment; Early CHMP Rapporteur appointment during development; Kick off meeting with multidisciplinary expertise from EU network; Enhanced scientific advice at key development milestones/decision points; EMA dedicated contact point; Fee incentives for SMEs and academics on Scientific Advice requests. 6

8 Outline Regulatory pathways Considerations on non-clinical and clinical development Labelling aspects 7

9 Guidelines for Vaccines 8 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

10 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 9

11 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 when human data not available 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 10

12 Characterisation of the Immune Response For novel antigens the relevant investigations may include: Total binding antibody and functional antibody vs. each antigen Kinetics of immune responses (onset, persistence) Assessment of antibodies based on delivery route, e.g. secretory IgA responses after mucosal administration Cross-reactive antibodies Immune memory Cross-priming Effect of pre-existing antibodies on immune responses CMI (quantity and quality of T-cell response, e.g. ICS, ELISpot) 11

13 Characterisation of the Immune Response Considerations for 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 12

14 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 13

15 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 14

16 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, allcause 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 15

17 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 (e.g. immunocompromised) Post-Authorisation (RMP): Appropriate measures or studies to address i) rare and very rare AEs ii) emerging safety concerns 16

18 Vaccine Effectiveness Study design: i) prospective observational study (ECDC protocol for case-control study) ii) alternatives: e.g. ECDC protocol for cohort study or screening method (VE estimation by comparison with reference group) Endpoints: laboratory-confirmed influenza or prevention of pneumonia and hospitalisation depending on the setting and the design Target population: according to the vaccine (e.g. chronically ill and elderly for inactivated vaccines) with stratification for age effects in children and >65y and sub-analysis for subjects with underlying conditions Careful consideration on confounders 17

19 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 18

20 Pandemic Preparedness Vaccines (II) For a new vaccine construct would need convincing evidence that the vaccine is protective against influenza in humans as a starting point Assess cross-protection across strains to which most humans are naïve Identification of dose regimens could include trials in which naïve subjects receive the candidate vaccine primary series (one or more doses); at a later time point these subjects and a new control group of matched unvaccinated subjects could receive a dose of inactivated non-adjuvanted vaccine containing a strain to which most humans are naïve to determine the priming effect of the candidate vaccine 19

21 Outline Path for licensure Considerations on non-clinical and clinical development Labelling aspects 20

22 What does Universal mean in Regulatory Terms? Wording of indication for seasonal influenza vaccine in SmPC: 4.1 Therapeutic indications Prophylaxis of influenza in [age range]. The use of XXX should be based on official recommendations. Wording of indication for pandemic preparedness influenza vaccine in SmPC: 4.1 Therapeutic indications Prophylaxis of influenza in an officially declared pandemic situation in [age range]. Pandemic influenza vaccine XXX should be used in accordance with official guidance. 21

23 What does Universal mean in Regulatory Terms? Universality claims per se should not be the main focus The intended use of the vaccine and the evidence provided will shape the wording of the indication, e.g. if the vaccine is developed as a stand-alone vaccine or as priming strategy for other licensed vaccines Other parts of the SmPC will describe the evidence provided on crossprotection and duration of protection Need for booster/revaccination with the candidate or other vaccine should be addressed 22

24 Conclusions Regulatory pathways for approval of new influenza vaccines, including for pandemic influenza vaccines, are available and defined Demonstration of efficacy and safety in randomised controlled clinical studies is expected Investigation of the humoral and cellular immune response is expected; exploration of potential immune correlates of protection strongly encouraged Options for supporting breadth and durability of protection, including use in a pandemic scenario, needs to be addressed and discussed SmPC will reflect the actual evidence provided 23

25 Thank you for your attention Further information Contact me at European Medicines Agency 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0) Facsimile +44 (0) Send a question via our website Follow us