Public Assessment Report
Scientific discussion
Innoflu (IT)/Fluad (UK)
IT/H/525/001/DC
Applicant: Seqirus S.r.l
Date: 08/01/2019
This module reflects the scientific discussion for the approval of INNOFLU. The procedure was
finalised at 19/07/2017 For information on changes after this date please refer to the module
‘Update’.
I.
INTRODUCTION
“Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for INNOFLU. The therapeutic indication of INNOFLU is applied for: active
immunization against influenza in the elderly (65 years of age and over), especial y for those with an
increased risk of associated complications. The use of INNOFLU should be based on official
recommendations A comprehensive description of the indications and posology is given in the
SmPC.”
“The marketing authorisation has been granted pursuant to to Article 8.3 of Directive
2001/83/EC.
II.
QUALITY ASPECTS
II.1
Introduction
This application concerns the Marketing Authorisation for the medicinal product adjuvant Trivalent
Influenza aTVI - INNOFLU. It is an inactivated influenza virus subunit vaccine formulated with
MF59C.1 adjuvant. The vaccine is available as a 0.5 ml single dose sterile suspension for injection,
contained in a pre-fil ed syringe.
The aTIV contains purified haemagglutinin (HA) and neuraminidase (NA) antigens from the surface of
each of the three influenza virus strains, types A and B, recommended annual y for immunisation by
the WHO and CHMP for the Northern Hemisphere.
The influenza virus strains are individual y grown in embryonated chicken eggs and inactivated by
formaldehyde treatment before purification of the surface antigens and formulation with the
MF59C.1 adjuvant into a sterile suspension. The MF59C.1 adjuvant contained in aTIV is an oil-in-
water emulsion composed of squalene as the oil phase, together with the surfactants polysorbate 80
and sorbitan trioleate, in citrate buffer.
The potency of the vaccine is expressed as the amount of the HA protein per dose.
The composition of aTIV is the same of Fluad that was first registered in Italy in 1997 for the
prophylaxis of influenza in elderly people (65 years of age and over). Since then, it has been approved
in 12 European countries through a Mutual Recognition Procedure that concluded on April 23rd
2000.
Since its first registration, the vaccine has obtained approval in 30 countries worldwide (of which 15
are in Europe). The product complies with Ph.Eur. monograph for influenza vaccines, surface antigen,
inactivated and includes MF59C. l as adjuvant.
The application is submitted under the legal base of Ful Dossier referring to Article 8.3 of Directive
2001/83/EC.
The IT is the Reference Member State, UK is the Concerned Member State and the procedure
number is IT/H/0525/01/DC. The submitted documentation in relation to the proposed product is of
sufficient quality and is consistent with the current EU regulatory requirements. Satisfactory overal
quality, non-clinical and clinical overviews have been submitted. They represent an adequate
summary of the dossier.
The therapeutic indication of INNOFLU is applied for: active immunization against influenza in the
elderly (65 years of age and over), especial y for those with an increased risk of associated
complications.
The use of INNOFLU should be based on official recommendations.
The posology is a single 0.5 ml dose that should be administered by intramuscular injection into the
deltoid muscle. Due to the presence of the adjuvant, the injection should be carried out by using a 1
inch needle.
The Pharmaceutical form and dosage is a suspension for injection in pre-fil ed syringe (the vaccine
appears as a milky-white suspension).
The Pharmacotherapeutic group is Influenza vaccine, ATC code: J07BB02
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II.2
Drug Substance
The Drug Substance is a sterile suspension containing predominantly the purified outer membrane
proteins, haemagglutinin (HA) and neuraminidase (NA), of one of the influenza virus strains selected
annual y by the WHO/CHMP/CBER/CDC. Traces of viral envelope parts may be present. The Drug
Substance (Monovalent Pooled Harvest) from each of the three selected viral strains wil be
combined to produce the trivalent bulk product.
The chemical-pharmaceutical documentation and Quality Overal Summary in relation to INNOFLU
are not of sufficient quality in view of the present European regulatory requirements. Stability studies
have been performed with the drug substance.
II.3
Medicinal Product
The development of the product has been described, the choice of excipients is justified and their
functions explained.
The stability reports provided for the pre-fil ed syringes refer to the product Fluad, however, as aTIV
has the same composition, the stability data can be accepted.
As regards season 2015-2016, results up to 9 months only are provided; the applicant should provide
the final report.
Data supporting the stability of Fluad influenza vaccine fil ed in syringes luer cone with tip cap new
formulation are acceptable.
The Company should commit to report stability data if outside specification.
II.4
Discussion on chemical, pharmaceutical and biological aspects
III.
NON-CLINICAL ASPECTS
III.1
Introduction
The nonclinical support for Fluad is based on pharmacology and toxicology studies in several species.
Primary pharmacology studies were performed in mice. Mice are appropriate for the study of
influenza because they respond immunological y to vaccination, and can be infected with the
influenza virus. These studies, performed via the subcutaneous or intramuscular routes,
demonstrated that immunization of both young and old mice with influenza vaccines, either alone or
in combination with MF59, elicits a dose-related antigen-specific antibody response, even in
seropositive mice.
Excipients or chemical substances used in the manufacturing process or in the final product do not
raise a concern in relation to potential carcinogenicity. Extremely low levels of exposure to any
contaminant or impurity would result from annual dosing of Fluad.
Other potential safety concerns with respect to the use of Fluad in humans include hypersensitivity
reactions to vaccine ingredients or residuals from the manufacturing process, and interactions with
ongoing therapy that could diminish antibody response to active immunization. These concerns wil
be addressed by means of appropriate labeling.
In conclusion, the immunogenicity, protection, toxicity, and tolerability of Fluad have been
demonstrated in the nonclinical program, and the nonclinical results have been confirmed in clinical
testing and marketing experience.
III.2
Pharmacology
Immunogenicity and chal enge experiments with Fluad were performed in mice and rabbits. The
mouse is an appropriate species because, although the mouse is not a natural host for the influenza
virus, it can be a good predictor of the human response to influenza infection and vaccination.
Rabbits are commonly used to assess the local and systemic toxicity of vaccines, because vaccines
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elicit an appropriate pharmacological response (antibodies), and the rabbit is of sufficient size to
al ow administration of the ful clinical dose of vaccine, using the clinical route of administration and
multiple blood draws.
Primary pharmacology studies were performed using the subcutaneous or intramuscular routes of
administration.
In accordance with guidelines on the nonclinical development of vaccines, no secondary
pharmacodynamic, safety pharmacology, or pharmacodynamic drug interaction studies were
performed with Fluad. Safety pharmacology was assessed fol owing administration of MF59 in dogs;
there were no effects on cardiovascular and neurological parameters.
III.3
Pharmacokinetics
No pharmacokinetics studies of any type were performed with Fluad because these studies are not
relevant for vaccines.
Studies performed with MF59 adjuvant to assess distribution and clearance are described. No
pharmacokinetic studies were performed to assess drug interactions with MF59, and no other
pharmacokinetic studies were performed with MF59, because these studies are normal y not needed
according to The Note for Guidance on Preclinical Pharmacological and Toxicological Testing of
Vaccines (CPMP/SWP/465/95).
III.4
Toxicology
The nonclinical support for Fluad is based on pharmacology and toxicology studies in several species.
Primary pharmacology studies were performed in mice. Mice are appropriate for the study of
influenza because they respond immunological y to vaccination, and can be infected with the
influenza virus. These studies, performed via the subcutaneous or intramuscular routes,
demonstrated that immunization of both young and old mice with influenza vaccines, either alone or
in combination with MF59, elicits a dose-related antigen-specific antibody response, even in
seropositive mice. Other beneficial effects associated with immunization included proliferation of
spleen-derived lymphocytes, reduction in lung viral load fol owing subsequent chal enge with
influenza virus, and, more importantly, protection against chal enge with lethal doses of influenza
virus up to 200 days post-vaccination. In al cases, the presence of the adjuvant significantly increased
the immune response, in both young and old mice.
Fluad was also administered to female rabbits by intramuscular injection at the clinical dose and
volume twice before mating and twice during gestation. Fluad was immunogenic in maternal rabbits,
developing fetuses had comparable titers, and antibodies persisted through the first 4 weeks of life in
F1 kits.
Fluad, and vaccine lots that are equivalent to Fluad, were tested in toxicology studies. The species
selected for these studies, the rabbit, was chosen because influenza antigens elicit an immunologic
response, and the ful clinical dose and volume of vaccine can be administered using the clinical route
of administration. The toxicology program fulfil s current regulatory expectations for the nonclinical
testing of vaccines (CPMP/SWP/465/95 and WHO Technical Report No. 927, 2005) and adjuvants
(EMEA/CHMP/VEG/134716/2004) with the fol owing exception: al tissues specified in the WHO
Technical Report were not evaluated histopathological y in the pivotal Fluad repeat-dose toxicity
studies. This is not considered a deficiency because influenza vaccines are wel understood
toxicological y, as is MF59 adjuvant, and al major organs and tissues of the immune system were
evaluated.
A GLP Guinea pig study was conducted to assess potential for delayed contact hypersensitivity using
the Magnusson-Kligman Maximization Test. Fluad did not cause hypersensitivity.
Mutagenicity and carcinogenicity studies have not been conducted with Fluad. These studies are not
required for vaccine products that are administered infrequently. Regarding MF59, the adjuvant is
not genotoxic (Ames test) or clastogenic (mouse micronucleus), is not a dermal sensitizer (Guinea
pig), and was not teratogenic (rat and rabbit) or a developmental toxicant (rat).
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Excipients or chemical substances used in the manufacturing process or in the final product do not
raise a concern in relation to potential carcinogenicity. Extremely low levels of exposure to any
contaminant or impurity would result from annual dosing of Fluad.
Other potential safety concerns with respect to the use of Fluad in humans include hypersensitivity
reactions to vaccine ingredients or residuals from the manufacturing process, and interactions with
ongoing therapy that could diminish antibody response to active immunization. These concerns wil
be addressed by means of appropriate labeling.
In conclusion, the immunogenicity, protection, toxicity, and tolerability of Fluad have been
demonstrated in the nonclinical program, and the nonclinical results have been confirmed in clinical
testing and marketing experience.
III.5
Ecotoxicity/environmental risk assessment (ERA)
Inactivated vaccine products are exempted due to the nature of their constituents
(EMA/CHMP/VWP/457259/2014)
III.6
Discussion on the non-clinical aspects
The Applicant has provided the updated sections of the Dossier as requested
IV.
CLINICAL ASPECTS
IV.1
Introduction
Clinical immunogenicity and safety studies submitted have demonstrated the non-inferiority of aTIV
with respect to non-adjuvanted comparators, but also an increase of magnitude of HI antibody
responses in elderly vaccine recipients, even if, after adjustment for multiplicity, a superiority with
respect to TIV has not been demonstrated for general studied population nor for high risk
subpopulation. Moreover, these differences have been observed also for heterologous strains,
potential y as a result of expanded epitope recognition, even if a superiority has not been
demonstrated after adjustment for multiplicity. Immunogenicity data also show an enhancement of
HI antibody persistence.
Although it remains to be established in randomized clinical trials whether the incremental
improvements in immunogenicity associated with aTIV wil translate to improved clinical efficacy,
available experimental evidence suggests that a relationship exists since higher levels of HI antibody
are directly related to clinical protection.
Enhancements in immunogenicity in comparison to non-adjuvanted TIV are also evident upon
repeated (annual) vaccination, regardless of whether the same or an updated antigen is
administered, with no demonstrable changes in safety profile.
Clinical effectiveness studies support the potential for improved clinical efficacy fol owing vaccination
with aTIV, as confirmed by the results of the observational study C70P1 (a.k.a. “LIVE”) conducted in
Italy and the observational case-control study V70_49OBTP conducted in Canada.
The therapeutic indication applied for is: Active immunization against influenza in the elderly (65
years of age and over), especial y for those with an increased risk of associated complications.
IV.2
Pharmacokinetics
No clinical pharmacology studies, including pharmacokinetic studies, were performed in the aTIV
development program because kinetic properties of influenza vaccines do not provide relevant
information for establishing adequate dosing recommendations. In the absence of specific
requirements in the May 2007 CBER Guidance Document, the vaccine dose, schedule, and
formulation have been based on those of licensed influenza vaccines; and pertinent data from clinical
studies V7P38 and V104P3.
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IV.3
Pharmacodynamics
Pharmacotherapeutic group: Influenza vaccine, ATC code: J07BB02
The immune response of aTIV has been evaluated in 16 randomized control ed trials including 16.974
subject vaccinated with aTIV (n=5869) or a non-adjuvanted vaccine (n=5236).
Seroprotection is general y obtained within 2 to 3 weeks. The duration of post vaccination immunity
to homologous strains or to strains closely related to the vaccine strains varies, but it is usual y 6-12
months.
Although comparative field efficacy trials have not been performed, the antibody response to aTIV is
increased when compared to the response to vaccines without adjuvant, and is most pronounced for
B and A/H3N2 influenza antigens.
This increased response is seen particularly in elderly subjects with low pre-immunisation titre
and/or with underlying diseases (diabetes, cardiovascular and respiratory diseases) who are at
increased risk of complications of influenza infection. A similar immunogenicity profile has been
noted after a second and third immunisation with aTIV. Significant antibody rises after immunisation
with aTIV have also been shown against heterovariant strains, antigenical y different from those
included in the vaccine.
IV.4
Clinical efficacy - Clinical safety
The immune response of aTIV has been evaluated in 16 randomized control ed trials including 16.974
subject vaccinated with aTIV (n=5869) or a non-adjuvanted vaccine (n=5236).
Seroprotection is general y obtained within 2 to 3 weeks. The duration of post vaccination immunity
to homologous strains or to strains closely related to the vaccine strains varies, but it is usual y 6-12
months.
Although comparative field efficacy trials have not been performed, the antibody response to aTIV is
increased when compared to the response to vaccines without adjuvant, and is most pronounced for
B and A/H3N2 influenza antigens.
This increased response is seen particularly in elderly subjects with low pre-immunisation titre
and/or with underlying diseases (diabetes, cardiovascular and respiratory diseases) who are at
increased risk of complications of influenza infection. A similar immunogenicity profile has been
noted after a second and third immunisation with aTIV.
Significant antibody rises after immunisation with aTIV have also been shown against heterovariant
strains, antigenical y different from those included in the vaccine.
The clinical effectiveness of aTIV has been evaluated in two observational studies:
Observational studies:
The first study (Study C70P1) was an observational prospective cohort study performed in 5 Northern
Italian health districts during the 2006-7, 2007-8 and 2008-9 influenza seasons. The study objective
was to assess the relative risk of hospitalizations for influenza or pneumonia during the influenza
season amongst subjects 65 years of age or older who received either aTIV or a non-adjuvanted
vaccine. The choice of influenza vaccine for each study subject, either aTIV or a non-adjuvanted
vaccine, was left to the individual provider to be determined on the basis of local influenza
vaccination policy. This multi-year study enrol ed 107,661 elderly subjects, 65 years of age or older,
with 43,667 subjects participating for more than 1 year. In total, 88,449 doses of aTIV and 82,539
doses of non adjuvanted vaccine were administered. Predefined windows during the influenza
season were used to determine the primary endpoint of hospitalization due to influenza or
pneumonia, but laboratory based confirmation of influenza was not performed. Due to local
immunization policy, subjects who received aTIV often had worse baseline health status than those
subjects who received a non- adjuvanted vaccine. After adjusting for confounding variables (baseline
health status, others), the risk of hospitalization for influenza or pneumonia was 25% lower for aTIV
relative to non-adjuvanted vaccine (relative risk = 0.75, 95% confidence interval: 0.57, 0.98).
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The second study (study V70-49OBTP) was a retrospective case-control study evaluating vaccine
effectiveness of aTIV, a non-adjuvanted comparator, or no vaccination. Cases and controls were
identified from the influenza tests performed in the population served by three main health
authorities in British Columbia and analysed at a central provincial laboratory. In total 84 cases and
198 controls of 65 years of age or older were enrol ed (165 vaccinated with aTIV, 62 with a non-
adjuvanted influenza vaccine and 55 unvaccinated subjects). The majority of the participants
reported at least one chronic disease (89%). The most commonly reported chronic disease categories
were cardiac (72%) fol owed by neurological (39%) and respiratory condition (30%). Cases were
defined as RT-PCR confirmed influenza fol owing onset of influenza-like il ness (ILI). Controls were
individuals with similar characteristics, but who tested negative for influenza. After adjusting for
confounding variables (age, sex, residency in a long-term care facility, chronic conditions, region and
week of testing), the absolute vaccine effectiveness for aTIV was 58% (CI: 5-82, p<0.04) and non-
adjuvanted vaccine was ineffective. The relative vaccine effectiveness for aTIV was 63% (CI: 4-86.
P=0.04) as compared to non-adjuvanted influenza vaccine.
Randomized controlled interventional studies:
Study V70-27-01 is a Phase 3, randomized, control ed, observer-blind, multicenter study to evaluate
the immunogenicity, the safety and the consistency of three consecutive lots of aTIV in comparison
to non-adjuvanted vaccine and it was conducted in 2010-2011. Subjects were randomized in a 1:1:1:3
ratio to receive a single 0.5 mL dose of 1 of 3 consecutive lots of aTIV or a single lot of a non-
adjuvanted influenza vaccine. Al subjects were fol owed for approximately one year post-vaccination.
A total of 7082 subjects were randomized and vaccinated, including 3541 subjects in each of the
pooled aTIV and non-adjuvanted vaccine groups. A total of 2573 subjects (1300 in aTIV and 1273 in
non-adjuvanted vaccine group) were regarded as “high risk” subjects (underlying chronic diseases
including congestive heart failure, chronic obstructive pulmonary disease, asthma, hepatic disease,
renal insufficiency and/or neurological/neuromuscular or metabolic disorders including diabetes
mel itus).
The primary objective of a superiority of aTIV versus non-adjuvanted vaccine was not achieved for al
homologous strains; the co-primary objective of a non-inferiority of aTIV versus non-adjuvanted
vaccine was achieved for al homologous strains; however significantly higher HI titers rates against
al three homologous strains of influenza at day 22 post vaccination were seen in subjects that
received aTIV compared with non-adjuvanted influenza vaccine (Table 1). The results were similar for
high risk subjects with predefined comorbidities. Immunogenicity data supported similar antibody
responses across aTIV lots; CHMP criteria were met for aTIV.
In addition, in a subset of subjects (n=1649 subjects), aTIV was compared to the non-adjuvanted
influenza vaccine for heterologous strains, i.e. influenza variants of the same type/subtype that were
not included in the vaccine composition (secondary objective). Superiority of aTIV as compared to
non-adjuvanted influenza vaccine was not achieved for al 3 heterologous strains at day 22; however
non-inferiority was demonstrated for al 3 heterologous strains at day 22. Results were similar for
high risk subjects (609 subjects)
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A specific analysis for safety in the “high risk” population was not performed; for the complete
population an higher percentage of subjects in the aTIV group than in the non-adjuvanted vaccine
reported local reaction (32% vs 17%) and systemic reactions (32% vs 26%). The overal safety profile
showed similar incidences of unsolicited AEs and SAEs for aTIV and non-adjuvanted influenza vaccine.
The second study (M63P1) is a phase 3, randomized, active-control ed, observer-blind, multicenter
study to evaluate immunogenicity and safety of aTIV in subjects 65 years of age and older with
underlying chronic medical conditions. 350 frail elderly subjects were enrol ed and randomized 1:1 to
receive aTIV (n=175) or non-adjuvanted influenza vaccine (n=175), al of whom had underlying
chronic medical conditions including congestive heart failure, chronic obstructive pulmonary disease
(COPD) or asthma, hepatic or renal insufficiency, arteriosclerotic disease or diabetes mel itus and
rheumatoid arthritis.
The GMT against A/H3N2 influenza strain 21 days after administration of aTIV did not meet the
superiority criteria when compared to a non-adjuvanted inactivated split influenza virus vaccine
(primary objective). Seroconversion was obtained for 85% (A/H3N2), 87% (A/H1N1) and 88% (B) of
subjects. CHMP criteria for efficacy were met for aTIV.
A smal increase in primarily mild local reactogenicity and a slightly higher percentage of systemic
reactions were noted for aTIV compared to non-adjuvanted influenza vaccine. The overal safety
profile showed similar incidences of unsolicited AEs and SAEs for aTIV and non-adjuvanted influenza
vaccine.
IV.5
Risk Management Plan
The MAH has submitted the Risk Management Paln version 4.0 as requested in accordance with the
requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and
interventions designed to identify, characterise, prevent or minimise risks relating to INNOFLU.
This version of RMP was already evaluated (Type IB variation IT/H/102/01/1B/114) with positive
outcome the 09/05/2017.
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V.
USER CONSULTATION
The MAH declares that the consultation with target groups has not been performed because the
label ing of the adjuvanted trivalent influenza vaccine (Innoflu in Italy and Fluad in UK) included in the
new marketing authorization application with procedure IT/H/0525/01/DC are the same as the ones
already authorized for the same product FLUAD registered via MRP (IT/H/0104/01) which already
complies with EU regulation and no significant change has been introduced.
VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION
The balance of benefits and risks supports the use of aTIV for active immunization of adults 65 years
of age and older against influenza disease caused by influenza virus subtypes A and B contained in
the vaccine.
However in al clinical sections of the dossier, the Applicant states that the marketing authorization is
requested for the aTIV vaccine intended for the US market, that is equivalent to the formulation
marketed in other countries since 2000.
Furthermore the Applicant states that non-inferiority and superiority studies have been conducted
using as comparator Agriflu (trivalent non adjuvated vaccine) authorized in US and equivalent to
Agrippal, that was approved in the US on 2009 for individuals 18 years of age and older.
Al above considered, the marketing authorization request is approvable.
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