Regulatory Decision Summary for Foclivia

Pandemic influenza is a significant global public health threat. The availability of safe and effective vaccines will reduce the spread and severity of pandemic influenza disease and reduce its social and economic consequences.

Foclivia is a mock-up, pandemic influenza vaccine against strain A/Vietnam/1194/2005 (H5N1) This vaccine is adjuvanted with MF59C.1. In case of a novel influenza pandemic, the potential vaccine should contain purified hemagglutinin (HA) and neuraminidase (NA) antigens from the pandemic influenza virus strain, as directed by the World Health Organization (WHO).

Foclivia is an egg-derived, monovalent vaccine, manufactured with the same process and has the same adjuvant used for the Health Canada authorised influenza vaccine "Fluad", a trivalent influenza vaccine. Evidence was provided to demonstrate that the vaccine is manufactured under Good Manufacturing Practices (GMP) at all manufacturing sites providing supply to Canada and that in-process control, process parameters and quality control release tests have been established to monitor product quality throughout the process. The specifications used to evaluate key quality attributes and consistency of production were found acceptable. This information, together with the terms and conditions, support authorization.

The clinical evaluation of Foclivia relies on immunological data (mainly the former CHMP serological criteria), as the vaccine has not been evaluated in efficacy trials against H5N1 influenza disease.

Immunogenicity was demonstrated in a randomized-controlled Phase II trial conducted in 486 adult and elderly (>60 years) subjects. Participants were randomly assigned to receive either a 7.5 µg (n = 244) or 15 µg (n = 242) dose of MF59-adjuvanted aH5N1 vaccine, administered in 2 doses, 3 weeks apart, with a 6 months booster dose. The immune responses, assessed by HI, SRH assays, met the CHMP serological criteria for immunogenicity against the A/Vietnam/1194/2004 strain contained in the vaccine. With the 7.5 µg dose, adults achieved 73% seroprotection, 73% seroconversion and a GMR of 16 as measured with the HI assay, while elderly subjects achieved 75% seroprotection, 67% seroconversion and a GMR of 9.52. With the 15 µg dose adults achieved 72% seroprotection, 69% seroconversion and a GMR of 15 as measured with the HI assay, while elderly subjects achieved 76% seroprotection, 70% seroconversion and a GMR of 10. Results obtained with the SRH assay were similar. A high percentage of subjects achieved MN-titers ≥40 in both the non-elderly adult (85% and 81% in the 7.5 and 15 µg groups, respectively) and elderly groups (79% and 76% in the 7.5 and 15 µg groups, respectively).

A Phase III study was conducted in 3,647 adult and elderly subjects, to evaluate the safety, tolerability and immunogenicity of two doses of a MF59-adjuvanted aH5N1 influenza vaccine, administered 3 weeks apart, compared to a MF59-adjuvanted seasonal trivalent influenza vaccine comparator (Fluad-aTIV). While a subset of patients (n = 530) were evaluated for immunogenicity, showing homologous strain immunogenicity (3/3 CHMP criteria met when assessed by SHR and 2/3 CHMP criteria met when assessed by HI), the study was designed to assess safety. The safety profile (local and systemic adverse reactions, unsolicited AEs and SAEs) of the treatment group was similar to that of the placebo group for both adults and elderly. Solicited local (pain) and systemic (fatigue, myalgia, malaise, headache) reactions were more frequent in adults compared to the elderly subjects, and after the first vaccine dose compared to the second dose. Overall, the vaccines were well tolerated. Results from the 6 month follow up have shown that the safety profile of the treatment group was similar to that of the placebo group for both adults and elderly.

A Phase II study was conducted in 472 children from 6 months to <18 years of age. This study demonstrated the immunogenicity, safety and tolerability of two doses (administered 3 weeks apart) of MF59-adjuvanted aH5N1 pandemic influenza vaccine 7.5 µg (n = 335), when compared with a MF59-adjuvanted seasonal influenza vaccine (n = 137). Subjects in the aH5N1 vaccine group also received one booster vaccination 12 months after the second dose.

The subjects were separated in 3 age cohorts: toddlers (6 to <36 months), children (3 to <9 years) and adolescents (9 to <18 years). As assessed by HI and SRH serology assays, naïve populations needed two vaccinations of MF59-adjuvanted H5N1 vaccine to meet the all three CHMP criteria for immunogenicity, as assessed by HI and SRH. Although GMTs/GMAs decreased significantly after the primary vaccinations series to the booster vaccination, antibodies remained detectable: 26% to 46% of each age cohort were seroprotected at day 382 when assessed by HI, and 61% to 88% of each age cohort were seroprotected when assessed by SRH. After the booster vaccination, all age cohorts met all three of the CHMP criteria when assessed by HI and SRH assays. The GMTs/GMAs by HI and SRH were highest after the booster vaccination across all age cohorts.

The safety profile of the treatment group was similar to that of the placebo group. Overall reactogenicity (mainly erythema, local tenderness and irritability) was highest after the first vaccination and decreased after the second vaccination. Most solicited reactions were mild or moderate, with no more than 2% of each solicited local or systemic reaction classified as severe in either vaccine group. In total, 11 subjects were reported to have SAEs (toddlers: 8 subjects in the aH5N1 group and 1 subject in the Seasonal group, adolescents: 2 subjects in the aH5N1 group), and none were related to the study vaccines.

Clinical data is limited at this time, given the current lack of sustained circulation of pandemic influenza strains, which precludes vaccine efficacy testing. In the event of a pandemic, Foclivias immunogenicity, vaccine efficacy and safety will have to be assessed against the pandemic strain.

In conclusion, the data provided supports favorably the immunogenicity of the Foclivia Vaccine, as well as its safety. The vaccine meets former CHMP criteria regarding seroconversion, seroprotection and GMR, in adult, elderly and pediatric populations. The vaccine was well tolerated by participants and has no important safety concerns. The benefit to risk assessment for the Foclivia is considered favorable. A Notice of Compliance was granted for Foclivia (a MF59C.1-adjuvanted pandemic influenza vaccine, containing H5N1 influenza antigens from A/Vietnam/1194/2004 strain).