Regulatory Challenges for Influenza Vaccines 1

Regulatory Challenges for Influenza Vaccines 1

Regulatory Challenges for Influenza Vaccines Leonoor Wijnans - Influenza Summer School Siena, 19 July 2012

Regulatory challenges for influenza vaccines Regulatory environment & pathways Europe Benefit risk assessment for vaccines Trivalent inactivated influenza vaccines Pandemic Influenza vaccines Establishing benefits: Correlates of Protection Safety assessment Regulatory Challenges for Influenza Vaccines 3

Regulatory Environment: EMA National Competent Authorities (~40 in 30 EU & EEA EFTA countries) Responsible for expertise EU institutions: Commission Parliament ECDC Committee for Veterinary Medicinal Products Committee for Advance Therapies Committee for Herbal Medicinal Products Committee for Orphan Medicinal Products Committee for Human Medicinal Products (CHMP) Paediatric Committee PDCO Working parties: SAWP, VWP, BWP, PhVWP 4 Regulatory Challenges for Influenza Vaccines SAGs: Scientific Advisory Group on Vaccines

National Competent Authorities (~40 in 30 EU & EEA EFTA countries) Regulatory Environment: Europe Committee for Human Medicinal Products (CHMP) MRP / DCP procedures Regulatory Challenges for Influenza Vaccines 5

Regulatory Pathway T-36/48 MO T-36/12 MO T-24/0 MO T 0 ORPHAN DESIG- NATION SCIENTIFIC ADVICE REGULATORY FILING STRATEGY MAA PREPARATIONS MAA EVALUATION Changes for MA / Pharmacovigilance COMP SAWP CHMP CHMP SAG CHMP/ PhVWP Regulatory activity Development Evaluation Regulatory Challenges for Influenza Vaccines 6 Post Authorisation

Regulatory Pathway Assessment Report Day 80 Primary Evaluation Phase MAA EVALUATION A marketing authorisation CHMP List of Day 121 Questions Response to results from Day 120 LoQ Stop a positive benefit-risk Clock Stop Max. 6 Start Clock assessment months Clock Hearing? Day 180 Hearin g Day 181 Start Clock Secondary Evaluation Phase Day 1 Day 150 Joint Rapp/ Co-rapp AR SAG? Day 210 Adoption of Opinion (in English) Regulatory Challenges for Influenza Vaccines 7

Benefit Risk Assessment case by case evaluation reflects the balance between efficacy & safety adequate safety data base generally studied in the population at risk catch 22 - if effective trouble is all we see Vaccines are not beneficial by definition but by evidence Regulatory Challenges for Influenza Vaccines 8

Regulatory Challenges for Influenza Vaccines 9 Benefit Risk Assessment

Trivalent inactivated influenza vaccines How is benefit demonstrated? CHMP criteria adults elderly GMT increase 2.5 2 Seroconversion /significant increase 40% 30% Seroprotection* 70% 60% *post-vaccination titre 40 for the HI assay essentially a quality parameter trivalent, inactivated non-adjuvanted no criteria for children Regulatory Challenges for Influenza Vaccines 10

Trivalent inactivated influenza vaccines Meta-analysis 10 years annual update trials *seroprotection: titre 40 for the HI assay Regulatory Challenges for Influenza Vaccines 11 Voordouw ACG et al. Vaccine. 2009 Dec 11;28(2):392-7

Trivalent inactivated influenza vaccines Annual performance of TIV based on: experience Pre-vaccination antibody titre - vaccination / infection history (vs naivety) revaccination (v.s. priming) accepted effectiveness (?) & non-validated correlate Challenges: need for (validated) CHMP criteria? need for annual reassessment? vaccine improvements (adjuvants, delivery systems etc.) populations (data in children, specific risk groups) Regulatory Challenges for Influenza Vaccines 12

Pandemic Influenza Vaccines Context: Unexpected virus unknown Rapid assessment, rapid availability vaccine Pandemic expectations: Population naïve to antigen priming! Use of adjuvants Dose & schedule for different groups Regulatory Challenges for Influenza Vaccines 13

Pandemic Influenza Vaccines Mock up vaccines H5N1 +adjuvant+ excipients Pandemic PHASE 6 H1N1 +adjuvant+ excipients Regulatory Challenges for Influenza Vaccines 14

Regulatory Challenges for Influenza Vaccines 15 Source: EPAR Focetria

Pandemic Influenza Vaccines Assessment criteria Challenges: Immunological / serological data Effect of different strains (H5N1 H1N1, H9N2, H16N23???) Populations (children, specific risk groups) Regulatory Challenges for Influenza Vaccines 16

New influenza vaccines New influenza vaccines are: Novel? Seasonal, pandemic, pre-pandemic (?) Immunology stronger, broader, quality More effective More reactogenic CHMP criteria compliant Regulatory Challenges for Influenza Vaccines 17

New influenza vaccines New influenza vaccines require: full characterisation of immune response (HI, MN, NA, CMI) Without proper definition of correlates of protection any immunogenicity assessment of new (novel) vaccines is nonpredictive of clinical protection protective efficacy data against clinical endpoints long term protection, cross protective immunity What about the CHMP criteria??? Regulatory Challenges for Influenza Vaccines 18

Establishing benefit CHMP criteria adults elderly GMT increase 2.5 2 Seroconversion /significant increase 40% 30% Seroprotection* 70% 60% *post-vaccination titre 40 for the HI assay Regulatory Challenges for Influenza Vaccines 19

Establishing benefit Where does the 1:40 cut-off come from? Regulatory Challenges for Influenza Vaccines 20

Establishing benefit Hobson et al 1972: HI 1:40 correlates with 50% protection in challenge model Healthy adults Challenged with attenuated virus not possible to forecast that similar low titres of serum HI antibody would protect against natural infection with highly virulent epidemic strains of virus. observational data of this type can obviously not confirm that a quantitative relationship between antibody and resistance to infection is a causal relationship. Regulatory Challenges for Influenza Vaccines 21

Establishing benefit Focetria: SmPC Regulatory Challenges for Influenza Vaccines 22

Regulatory Challenges for Influenza Vaccines 23

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Establishing benefit: redefining CoP What are correlates? At present, widely accepted immunological correlates of protection exist for certain antigens only and consist of defined humoral antibody responses above which there is a high likelihood of protection in the absence of any host factors that might increase susceptibility to the infectious agent. Guideline on clinical evaluation of new vaccines (EMA/CHMP/VWP/164653/2005) Vaccine Immune Marker Protection Regulatory Challenges for Influenza Vaccines 25

HA assay NA assay CMI Neutralisation assay Regulatory Challenges for Influenza Vaccines 26

Without proper definition of correlates of protection any immunogenicity assessment of new (novel) vaccines is nonpredictive of clinical protection In order to facilitate the evaluation of influenza vaccines and therefore facilitate the development of new and improved vaccines collaborative efforts are needed to increase understanding into immune markers, their correlation to protection, and to overcome limitations of existing assays to measure these markers. Regulatory Challenges for Influenza Vaccines 27

Summary so far Benefit-risk before license: Clinical efficacy trials with common research protocols: validated standardised assays choice of assay: relevant response to predict protection We need to know what to measure, when to measure it, how to measure it, and how it relates to protection against infection or disease Benefit-risk at strain change: Risk Management Program TRIAGE based on antigenic drift e.g.: no action in vitro data clinical data Based on the assumption of a validated correlate towards 1 common guideline & evidence based assessment criteria Harmonised regulatory requirements? (EMEA, FDA, WHO ) Regulatory Challenges for Influenza Vaccines 28

The challenge goes on Adverse events happen! Regulatory Challenges for Influenza Vaccines 29

Safety assessment NfG new vaccines: Study protocols should provide details of the methods for collection of safety data (i.e. diary cards, questionnaires) including intervals for collection of the data (e.g. after each dose) and the total duration of follow up. Case definitions developed by the Brighton Collaboration for specific events should be referred to if appropriate (http://brightoncollaboration.org)..sufficient to reliably determine the frequency of uncommon local and systemic adverse events i.e. that occur at a frequency between 1/100 and 1/1000 vaccinated persons... Unless otherwise justified.at least 3000 Check size safety database, consistent reporting, follow up Regulatory Challenges for Influenza Vaccines 30

Safety assessment But it all starts after licensure That s when the vaccine really gets used: Large numbers Heterogenous population: comorbidities, drug use, life styles Events happen. So we need to be prepared! Regulatory Challenges for Influenza Vaccines 31

Safety assessment Regulatory Challenges for Influenza Vaccines 32

Safety assessment So we were prepared. Regulatory Challenges for Influenza Vaccines 33

But

Safety assessment events happen Regulatory Challenges for Influenza Vaccines 35

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Regulatory Challenges for Influenza Vaccines 37 Safety assessment

Figure 1. The temporal associations of pandemic vaccination, onset of narcolepsy (with four different definitions), and August 16, 2010, i.e. the date when the Swedish Medical Agency published the press release on the observation on the association between narcolepsy and Pandemrix vaccination (vertical dotted line). Nohynek H, Jokinen J, Partinen M, Vaarala O, et al. (2012) AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland. PLoS ONE 7(3): e33536. doi:10.1371/journal.pone.0033536 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033536

Safety assessment Can we be certain? Narcolepsy is difficult to diagnose: delays ranging from 1-60 years 1 Diagnosis is especially difficult in children 2,3 : daytime sleep requirements are often considered normal Cataplexy in children may present with atypical features lack of objective diagnostic criteria specific to the paediatric phenotype narcolepsy in childhood is claimed to be one of the most underdiagnosed diseases 4 Regulatory Challenges for Influenza Vaccines 39 1) Morrish E, et al. Sleep Med Rev 2004;5:37-41. 2) Serra et al Mov Disord 2008; 23:858-65 3) Plazzi et al Brain 2011; 134: 3480-92 4) Nevsimalova Sleep Med Rev 2009; 13(2):169-80

Safety assessment 1) Silber et al SLEEP 2002; 25 (2): 197-202 2) Narcolepsy Background Rate Study presented at ICPE, Chicago 2011 Regulatory Challenges for Influenza Vaccines 40

Safety assessment So do we see more cases because of Pandemrix or because more (vaccinated) people are getting diagnosed due to awareness? Regulatory Challenges for Influenza Vaccines 41

Safety assessment Timeliness of post licensing studies is it ever on time? Can post licensing studies ever determine whether an association is causal? Do we need to know more before licensing? Can we know more? Do we need improved infrastructure to monitor safety of vaccines?

Where next? New vaccines evaluated in clinical efficacy trials with common research protocols in relevant risk groups Collaborative research into correlates of protection Triage to determine data needs at strain change Improved systems for safety monitoring towards 1 common guideline & evidence based assessment criteria Regulatory Challenges for Influenza Vaccines 43

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