Summary Basis of Decision for Arepanrix H5N1

 

Clinical Pharmacology

Since 1959, instances of human infection with an avian influenza virus have been documented on only a few occasions. The highly pathogenic H5N1 virus has been documented among humans since 1997.

The mechanism of action of the Arepanrix H5N1 vaccine is based on its ability to induce antibodies against viral hemagglutinin (HA), a key viral protein for cell entry, thereby blocking viral attachment to human respiratory epithelial cells. Specific levels of hemagglutination-inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated directly with protection from influenza illness but the antibody titers have been used as a measure of vaccine activity. In some human challenge studies of other influenza viruses, antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.

Pharmacokinetic studies were not conducted during the clinical development of Arepanrix H5N1 as they are not directly applicable to vaccines. However, immune responses were assessed to evaluate clinical efficacy of the Arepanrix H5N1 vaccine.

For additional information, please refer to the Arepanrix H5N1 Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

As part of this New Drug Submission, no efficacy studies were submitted given that efficacy data for a pandemic/pre-pandemic influenza vaccine can only be generated in the presence of an actual circulating pandemic strain. As a result, the efficacy of the Arepanrix H5N1 vaccine was estimated based on immunogenicity, in accordance to regulatory guidance as specified by the WHO and other major regulatory agencies. The immunogenicity data collected during the development of a vaccine is based on three main aspects:

• Immunogenicity against the vaccine strain (homologous response);
• Cross-reactive immunity against drift strains (heterologous response); and
• Persistence of the immune response.

In the clinical studies submitted, the immunogenicity of the Arepanrix H5N1 vaccine was evaluated based on its ability to induce antibodies against viral hemagglutinin (HA) as detected by the hemagglutination-inhibition (HI) assay. The level of antibodies against HA is expressed as geometric means titers (GMT). The following serological parameters are generated by the HI assay and were used as endpoints to assess the Arepanrix H5N1 vaccine immunogenicity:

• Seroconversion rate (SCR) - the proportion of subjects who were seronegative at pre-vaccination and have a potentially protective post-vaccination titer of ≥1:40, or who were seropositive at pre-vaccination and experienced a 4-fold increase in titer post-vaccination;
• Seroprotection rate (SPR) - the proportion of subjects with an HI antibody titer ≥1:40 following vaccination;
• Seroconversion Factor (SCF) or Geometric Mean Fold Increase (GMFI) - the ratio of the post-vaccination HI antibody titer divided by the pre-vaccination antibody titer.

In addition, the immunogenicity of the Arepanrix H5N1 vaccines was assessed by virus neutralization assay. A virus neutralization response was defined as the percentage of subjects having at least a 4-fold increase in serum neutralizing antibody titer (between the pre- and post-priming or pre- and post-booster vaccination time points).

The first H5N1 vaccine, referred to as 'Q-Pan', and subject of this marketing authorization application, is formulated with the H5N1 split-virus antigen produced by ID Biomedical Corporation of Quebec, doing business in Canada for GlaxoSmithKline, with facilities located in Quebec (Canada). The manufacturing of the Q-Pan (Arepanrix H5N1) vaccine by ID Biomedical Corporation of Quebec consists of the same manufacturing process as that of their seasonal influenza vaccine, Fluviral (also known as FluLaval internationally). The second H5N1 vaccine, referred to as 'D-Pan', is formulated with the H5N1 split-virus antigen produced in GlaxoSmithKline facilities located in Dresden (Germany), according to similar manufacturing process as the GlaxoSmithKline seasonal influenza vaccine, Fluarix also manufactured in Dresden, Germany. Studies from two H5N1 vaccines manufactured by GlaxoSmithKline were submitted as part of this New Drug Submission (NDS) filing.

The antigen used in the Q-Pan H5N1 studies, is derived from the A/Indonesia/5/2005 strain in support of the AS03-adjuvanted Quebec H5N1 influenza vaccine. Although differences exist between the two H5N1 antigen manufacturing processes, both vaccines (Q-Pan and D-Pan) contain the same amount of antigen (3.75 μg) and the same adjuvant (AS03); however, the antigen used in each vaccine is different. The antigen used in the D-Pan H5N1 studies that was reviewed as supportive information, is derived from the A/Vietnam/1194/2004 strain in support of the AS03-adjuvanted Dresden H5N1influenza vaccine.

The clinical study data submitted with this NDS consisted of the following:

• Six Q-Pan-H5N1 studies: 001, 002 (pivotal study), 005, 009, 010, and 011; and
• Three D-Pan-H5N1 supportive studies: 007, 009/022/023, and 012.

The clinical study data which formed Health Canada's primary basis for approval was that of the Q-Pan-H5N1-002 Phase III study.

Study Q-Pan-H5N1-002 (Pivotal)

Study Q-Pan-H5N1-002 was a Phase III, observer-blind, randomized, placebo-controlled, multicentre study. The purpose of this study was to evaluate the safety and immunogenicity of a two-dose schedule (administered on Days 0 and 21) of the Q-Pan H5N1 vaccine antigen in association with AS03 adjuvant in adults aged ≥18 years. A saline placebo was used as an inactive control.

The primary immunogenicity endpoint was determined by measuring the post-immunization vaccine-homologous virus HI titers 21 days post-administration of the second dose of the vaccine (Day 42). The immunogenicity was assessed against a two age strata: 18 to 64 years of age and >64 years of age.

Another objective of the study was to assess the lot-to-lot consistency of three consecutive lots of the Q-Pan H5N1 vaccine antigen in association with three consecutive lots of AS03 adjuvant. The lot-to-lot consistency was tested on the basis of GMTs (HI response to vaccine-homologous virus).

The study protocol comprised of an eight-arm design where subjects were stratified by age and randomized in a 1:1:1:1 ratio to receive one of four treatments (three lots of study vaccine and placebo) as follows:

• Group A (18-49 years): Q-Pan H5N1 antigen (lot A) with adjuvant (lot 1);
• Group B (18-49 years): Q-Pan H5N1 antigen (lot B) with adjuvant (lot 2);
• Group C (18-49 years): Q-Pan H5N1 antigen (lot C) with adjuvant (lot 3);
• Group D (18-49 years): Placebo;
• Group E (50-64 years): Q-Pan H5N1 antigen (lot A, B, or C) with adjuvant (lot 1, 2, or 3);
• Group F (50-64 years): Placebo;
• Group G (>64 years): Q-Pan H5N1 antigen (lot A, B, or C) with adjuvant (lot 1, 2, or 3);
• Group H (>64 years): Placebo.

The treatment schedule consisted of subjects receiving one dose of either the Arepanrix H5N1 vaccine or placebo on Day 0 and a second dose on Day 21. The appropriate randomized treatment was administered intramuscularly in the deltoid muscle of the non-dominant arm on Day 0, and the second dose was administered in the dominant arm on Day 21.

The duration of the study (from enrolment through to the last study follow-up) was approximately 1 year (364 days) for each subject. A total of 4,561 subjects were enrolled in the Q-Pan-H5N1-002 study and vaccinated, with 3,422 subjects in the Q-Pan group and 1,139 subjects in the placebo group.

Immunogenicity analysis

The immunogenicity was based on a subset of subjects referred to as the According-To-Protocol cohort for Immunogenicity analysis (ATP-I). The ATP-I cohort consisted of all evaluable subjects [that is (i.e.) those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study] for whom a complete set of data concerning immunogenicity endpoint measures required for the primary endpoints were available. The primary immunogenicity endpoints consisted of Day 42 HI antibody responses (SCR, and SPR) against vaccine-homologous virus in subjects receiving two doses of the Q-Pan vaccine. The SPR and SCR were calculated and presented in accordance to a two-age stratum.

Immunogenicity results (Day 42)

Immunogenicity results obtained from the Q-Pan-H5N1-002 study at Day 42 showed that the Arepanrix H5N1 vaccine elicited a strong immune response against the vaccine strain A/Indonesia/05/2005 in both age groups in comparison to subjects in the placebo group who had a low immune response, as shown in Table 1 below.

Table 1: A/Indonesia/5/2005 Hemagglutination-Inhibition (HI) Antibody Response
at Day 42 (21 days post second dose)

Table 1: A/Indonesia/5/2005 Hemagglutination-Inhibition (HI) Antibody Response at Day 42 (21 days post second dose)

Treatment Group	Seroconversion rate (SCR): % of Subjects Seroconverted [95% Confidence Interval (CI)]	Seroprotection rate (SPR): % of Subjects with Reciprocal Hemagglutination-Inhibition (HI) Titer ≥ 40 [95% Confidence Interval (CI)]
Q-Pan, 18-60 years	91.0 (89.4, 92.4)	91.0 (89.4, 92.4)
Placebo, 18-60 years	1.5 (0.0, 7.9)	1.5 (0.0, 7.9)
Q-Pan, >60 years	76.4 (72.3, 80.1)	76.8 (72.8, 80.5)
Placebo, >60 years	2.1 (0.1, 11.1)	2.1 (0.1, 11.1)

The results obtained at Day 42, after two doses of Q-Pan vaccine, showed that HI immune response induced by the Arepanrix H5N1 vaccine fulfilled the internationally accepted immunogenicity criteria.

Results of the virus neutralization response, twenty-one days following the second dose, showed that vaccine response rates against the vaccine strain were 94.4% for subjects aged 18 to 60 years and 80.4% for subjects above 60 years.

Persistence of immune response (Day 182)

The persistence of antibody responses at Day 182 was also evaluated in the Q-Pan-H5N1-002 study for homologous HI antibodies only. Analysis of immunogenicity was performed in the ATP-I cohort. Results of the analysis showed that, at Day 182, the SCR of HI antibodies against the A/Indonesia/05/2005 strain was 62.0% in the 18 to 60 year age group and 62.5% in the >60 year age group. The SPR was 62.0% in the 18 to 60 year age group and 63.5% in the >60 year age group.

Lot-to-lot consistency

Lot-to-lot consistency was tested by forming pair-wise ratios of GMT values for A/Indonesia/5/2005 reciprocal HI titers induced by the three treatment groups representing the three consecutive lots of antigen combined with three consecutive lots of adjuvant. The criterion for success was that the 2-sided 95% confidence bounds for all three pair-wise ratios were entirely within the interval of 0.67 to 1.5. Results from the Lot-to-lot consistency testing are presented in Table 2 below.

Table 2: Adjusted Geometric Means Titer (GMT) ratios of Hemagglutination-Inhibition (HI) antibodies A/Indonesia/5/2005 at Day 42 for all Q-Pan vaccine lots in subjects 18-49 years of age

Adjusted Geometric Means Titer (GMT)	Q-Pan Lot A		Q-Pan Lot B		Q-Pan Lot C
	N	GMT	N	GMT	N	GMT
	394	275.8	379	291.7	394	333.5
	Adjusted GMT Ratio (95% CI*)
Q-Pan Lot A and Q-Pan Lot B	0.95 (0.78,1.15)
Q-Pan Lot A and Q-Pan Lot C	0.83 (0.68, 1.00)
Q-Pan Lot B and Q-Pan Lot C	0.87 (0.72, 1.06)

*Confidence Interval (CI)

Lot-to-lot consistency was demonstrated for all the pair-wise ratios of GMT values.

Cross-reactive immune response against a heterologous strain

The cross-reactive immune response against a heterologous strain A/Vietnam/1194/2004 (H5N1) was evaluated as part of the Q-Pan-H5N1-001 clinical study, where subjects 18 to 64 years of age (n = 144) received two doses of vaccine 21 days apart. Twenty-one days after the second dose, the SPR, SCR and SCF against A/Vietnam/1194/2004 (H5N1) were 63.9%, 61.8% and 7.6, respectively.

In addition to the Q-Pan-H5N1-001 trial, cross-reaction was also measured in other clinical studies against three H5N1 heterologous strains (i.e. A/Vietnam/1194/2004, A/turkey/Turkey/1/2005, and A/Anhui/01/2005). Although the vaccine appeared to induce some cross-reactive immune response to these heterologous H5N1 strains, the HI responses obtained were much lower against heterologous strains compared to the homologous strain (vaccine strain), especially with respect to the GMT. In addition, the immune responses appeared stronger against heterologous strains that are in the same clade as the vaccine strain than against the strains that are in different clades.

It was also noted during the review that cross-reaction results in terms of the HI responses appear to vary among the studies evaluated. Additionally, it was noted within the studies that the analysis of cross-reactive immune response was not an explicitly pre-defined study objective in the relevant studies submitted. Given these observations, it was concluded by Health Canada that there was insufficient evidence to support an indication for Arepanrix H5N1 (A/Indonesia/5/2005) against influenza caused by H5N1 subtype variants other than that of the specific strain contained within the vaccine. Health Canada therefore approved the indication of Arepanrix H5N1 for active immunization of adults 18 years or older, against influenza caused by the H5N1 subtype virus contained within the vaccine i.e., A/Indonesia/5/2005], although some cross-reaction protection data were included in the Arepanrix H5N1 Product Monograph.

Immune response after heterologous boosting

There were two studies (Q-Pan-H5N1-005 and Q-Pan-H5N1-010) providing data with Arepanrix H5N1 (containing strain A/Indonesia/5/2005) for priming, and with the H5N1 vaccine containing strain A/turkey/Turkey/1/2005 for boosting. However, the priming and boosting strains were closely related (both clade 2 strains), and the results may not be extrapolated more broadly with any other Arepanrix H5N1 strain for boosting, after priming with Arepanrix H5N1 (Indonesia). Although in Study D-Pan-H5N1-012, the H5N1 strains in different clades were used for the priming (strain A/Vietnam/1194/2004) and boosting (strain A/Indonesia), data from this study are only supportive, as it was a study with a different vaccine (D-Pan, with the A/Vietnam/1194/2004 strain).

Health Canada concluded that there is insufficient evidence supporting the use of Arepanrix H5N1 (A/Indonesia/5/2005) as priming for a H5N1 vaccine containing another H5N1 strain. The supportive studies, Q-Pan-H5N1-005, Q-Pan-H5N1-010, and D-Pan-H5N1-012 were all Phase II studies, include multiple study groups and multiple analyses, involving multiple primary and secondary objectives, and no definitive conclusions can be drawn from such analyses.

Clinical studies in children

No clinical studies have been conducted in children with the Arepanrix H5N1 (Q-Pan) vaccine. However, clinical study D-Pan-H5N1-009/022/023 has been conducted in children with use of the D-Pan-H5N1 vaccine. In the D-Pan study, children 3 to 5 and 6 to 9 years of age received two doses of one of the following three formulations : a full-dose D-Pan vaccine (3.75 μg HA/AS03A), or a half-dose vaccine (1.9 μg HA/AS03B), or a formulation containing  a full-dose of antigen and half-dose AS03 (3.75 μg HA/AS03B). The two doses administered were given twenty-one days apart.

At Day 42, 21 days after the second dose, SCR rates for HI antibodies against vaccine strain A/Vietnam/1194/2004 were high (95.9-100%) with the three formulations of the AS03-adjuvanted H5N1 vaccine. At Day 42, no seroconversion or seroprotection (0%) was observed in the control group that received Fluarix. The data obtained generally favoured the full adult dose of HA and AS03 over the formulations using half-AS03 with full-or half-dose HA, particularly in terms of HI antibody GMTs.However, these results have to be balanced with safety and reactogenicity data when choosing the adequate formulation for this age group.

Effectiveness studies

Additional support for the efficacy of the Arepanrix H5N1 vaccine was also obtained through the publication of three independent effectiveness study reports conducted in Canada during the H1N1 2009-2010 pandemic vaccination program. Results from each of these reports showed a high level of effectiveness (86-100%) following vaccination with the Arepanrix H1N1 vaccine formulated with the A/California/7/2009 (H1N1) strain and the adjuvant AS03.

For additional information, refer to the Arepanrix H5N1 Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety profile of the Arepanrix H5N1 vaccine has been established based on the results obtained from a total of 5,078 Q-Pan vaccine recipients aged 18 years or older.

In the pivotal Phase III study (Q-Pan-H5N1-002), adverse events (AEs) were collected through solicitation of local and general symptoms during a 7-day follow-up period where subjects self-recorded AEs in a diary card. Adverse events were also collected through the recording of unsolicited symptoms up to Day 42. Serious adverse events (SAEs) were collected up to Day 182 (6 months) following vaccination.

When comparing subjects who received the Arepanrix H5N1 vaccine to those who received a placebo, the incidence of solicited local and general AEs was reported to be higher among subjects receiving the Arepanrix H5N1 vaccine compared to the placebo group, with 87.4% and 51.9% of subjects reporting at least one event (solicited or unsolicited) during the 7-day follow-up period, respectively. These reported AEs were not generally severe in nature. Solicited local AEs included pain, redness, swelling, induration, and ecchymosis. Solicited general AEs included fever, fatigue, headache, myalgia, shivering, arthralgia, and increased sweating. The most commonly reported solicited local AE in both the vaccine and placebo groups was pain at the injection site. Upon analysis by age group (18 to 64 versus >64 years old), a slightly lower reactogenicity was observed among elderly subjects.

Among unsolicited AEs, the incidence of reported AEs was quite similar between both the vaccine and placebo groups, with 38% and 35% of subjects reporting at least one event respectively.

There was no apparent increase in the incidence of SAEs between the Arepanrix H5N1 vaccine and placebo groups, in Study Q-Pan-002. When assessing for causal relationship, none of the SAEs reported were considered related to the vaccine.

To further confirm the safety profile of the Arepanrix H5N1 vaccine, an integrated safety summary was performed in 2011. This safety summary included a combination of 28 studies conducted with D-Pan or Q-Pan, H5N1 or H1N1 vaccines. The primary focus of these integrated safety analyses was the contrast between AS03-adjuvanted monovalent vaccines and non-adjuvanted controls. When examining the integrated safety data and limiting the analysis to the H5N1 clinical studies alone, an imbalance of potential immune mediated disease (pIMD) count was observed between treatment groups which may be due to asymmetry in the H5N1/AS03 and the control sample sizes. Yet, when data from H1N1 clinical studies are considered together with the H5N1 clinical study data, the imbalance in the counts of pIMDs was no longer observed.

The currently available data are insufficient to assess the likelihood of a causal relationship between the adjuvanted vaccines and potential immune-mediated diseases, due to the small numbers of events and overall limitations of the integrated safety summary (such as different study designs, use of different vaccines and controls, differences in safety data collections among studies, etc... ).

Pediatric Population

A clinical supportive study (D-Pan-H5N1-009/022/023) evaluated the reactogenicity and safety in children 3 to 5 and 6 to 9 years of age who received two doses of one of the following three formulations: a full-dose D-Pan vaccine (3.75 μg HA/AS03_A), or a half-dose vaccine (1.9 μg HA/AS03_B), or a formulation containing a full-dose of antigen and half-dose AS03. The two doses administered were given twenty-one days apart.

The most frequently reported solicited local symptom was pain, with incidence ranging from 41.0 to 73.5% overall per dose, and with grade 3 symptoms incidences from 2.0 to 6.0%. Other symptoms were reported less frequently with a maximum of 24.7% overall per dose. No apparent differences can be observed between different vaccine formulations, except for pain, which tended to be reported more frequently in the group receiving the full-dose vaccine. Pain was also reported more frequently in older children.

Loss of appetite and irritability were the most frequently solicited general AEs reported by children 3 to 5 years, followed by fever and drowsiness. Incidences of general symptoms were higher in subjects receiving full-dose vaccine compared to half-dose vaccine.

In children 6 to 9 years receiving the formulations using half-dose AS03 with full- or half-dose HA, headache and myalgia were the most frequent symptoms, with no clear difference between the 2 groups. In children receiving the full-dose vaccine, more solicited general symptoms were reported, with the highest incidence for headache, and fever.

Increases of fever incidences were observed between the first and the second dose in the group receiving the full-dose vaccine, from 8.2 to 31.3% in children 3 to 5 years and from 12.2 to 32.7% in children 6 to 9 years.

No deaths or other SAEs were reported during the active vaccination phase of the study (through Day 51).

Post-marketing experience

There is no post-marketing experience with Arepanrix H5N1. However, two AS03-adjuvanted vaccines, Pandemrix H1N1 and Arepanrix H1N1, were widely used during the 2009-2010 H1N1 pandemic campaigns. The two H1N1 pandemic vaccines were generally well tolerated in adults and children. Epidemiological studies relating to Pandemrix H1N1 (manufactured in Dresden, Germany) conducted in several European countries have indicated a 5- to 14-fold increased risk of narcolepsy, with or without cataplexy, in vaccinated children/adolescents, as compared to unvaccinated children and adolescents. This corresponds to an absolute risk ranging from 3 to 7 additional cases in 100,000 vaccinated subjects. This risk increase has not been found in adults 20 years or older. Although the relationship between Pandemrix (H1N1) and narcolepsy is still under investigation, and to date, no cases of narcolepsy have been reported from H5N1 clinical trials, information on narcolepsy was added in the Arepanrix H5N1 Product Monograph, as a precautionary measure.

No clinical safety or immune data have been generated in pregnant women with the Arepanrix H5N1 vaccine. Data from vaccinations with seasonal trivalent influenza vaccines in pregnant women do not indicate that adverse fetal and maternal outcomes were attributable to the vaccine.

A Risk Management Plan (RMP) for the Arepanrix H5N1 vaccine was submitted by the sponsor to Health Canada. The RMP describes known and potential safety issues, presents the monitoring scheme, and describes measures that will put in place to minimize risks associated with the vaccine. Upon review, the RMP was considered to be acceptable.

For more information, refer to the Arepanrix H5N1 Product Monograph, approved by Health Canada and available through the Drug Product Database.