Australian Public Assessment Report for purified antigen fractions of inactivated split virion A/Indonesia/05/2005 (H5N1), as03 adjuvanted

Yüklə 253,66 Kb.

səhifə	5/7
tarix	30.04.2018
ölçüsü	253,66 Kb.
	#40475

1 2 3 4 5 6 7

IV. Clinical findings

A summary of the clinical findings is presented in this section. Further details of these clinical findings can be found in Attachment 1.

Introduction

Clinical rationale

There are two types of vaccines prepared for pandemic situations. The first is a pandemic “mock up” vaccine which in the event of an evolving influenza pandemic would be produced once the pandemic strain has been identified and technical data would be submitted as a variation. This vaccine Pandemrix is currently approved in Australia. The second vaccine, Prepandemrix, is a prepandemic vaccine that is produced prior to the onset of a pandemic. The vaccine contains a strain derived from a currently circulating highly pathogenic avian influenza that has the potential to cause a pandemic. The prepandemic vaccine could be used either before a pandemic is declared or during the early stages of a declared pandemic situation. The usage of these vaccines (for example, only in a pandemic period, or during pandemic alert period) would depend on the recommendations issued by individual governments and their Public Health Authorities. This prepandemic vaccine can be made available to governments for stockpiles.

Such a prepandemic vaccine needs to have the capacity induce cross reactivity among variants of the same influenza subtype virus in case the strain causing the pandemic is different to the one in the vaccine. The sponsor states that the H5N1 vaccine with the AS03 adjuvant is able to induce such cross reactivity. In addition, it is claimed that the adjuvant in the vaccine increases immunogenicity of the vaccine and thereby provides the potential to decrease the antigen content of the vaccine. This may result in increased vaccine supplies, which is necessary during a pandemic situation.

Guidance

The most relevant guidance documents for development of pandemic influenza vaccines are:

Committee for Proprietary Medicinal Products (CHMP): Guideline on influenza vaccines prepared from viruses with the potential to cause a pandemic and intended for use outside the core dossier context (EMEA/CHMP/VWP/263499/2006)

Committee for Proprietary Medicinal Products (CHMP): Guideline on dossier structure and content for pandemic influenza vaccine marketing authorisation application (EMEA/CPMP/VEG/4717/2003-Rev.1)

Committee for Proprietary Medicinal Products (CPMP): Note for guidance on harmonisation for requirements for influenza vaccines (CPMP/BWP/214/96)

Center for Biologics Evaluation and Research (CBER): Guidance for industry. Clinical data needed to support the licensure of Pandemic Influenza Vaccines. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, May 2007.

Contents of the clinical dossier

The submission contained the following clinical information:

10 reports of bioanalytical methods.

18 clinical trials (presented in 54 clinical study reports) as follows:

H5N1-007 (dose-finding)*

H5N1-002 (Phase III adults and lot consistency) and extensions H5N1-030# and H5N1-038# (booster studies)

H5N1-010# (elderly adults) and extension H5N1-021

Paediatric studies: H5N1-009# and extensions H5N1-022# and H5N1-023# (3 to 9 years); H5N1-013 (6 m to <36 months with booster); and H5N1-032 (3 to 17 years with booster)

H5N1-008* (adult safety) and extension H5N1-011

H5N1-041 (formulation equivalence)

H5N1-012 and H5N1-015 (booster studies)

Q-Pan-001+ (vaccine formulation, antigen equivalence) and Q-Pan-009 (accelerated schedules)

Comment:

* Studies H5N1-007 and H5N1-008 were submitted in the original Prepandemrix dossier in 2007.

# Studies H5N1-010, the extension Studies H5N1-030 and H5N1-038, and the paediatric Studies H5N1-009, H5N1-022 and H5N1-023 were submitted in 2012 in the dossier for Pandemrix.

+ Study Q-Pan-001 was submitted in the Arepanrix submission.

Paediatric data

The submission included paediatric efficacy and safety data from three clinical trials (H5N1-009 with its additional phases H5N1-022 and H5N1-023 [3 to 9 years]; H5N1-013 [6 to <36 months]; and H5N1-032 [3 to 17 years]).

Good clinical practice

The sponsor stated for each clinical trial that it was conducted in accordance with Good Clinical Practice (GCP) guidelines as well as local ethical and regulatory requirements.

Pharmacokinetics

As mentioned in the Note for Guidance on Clinical Evaluation of New Vaccines,¹⁵ pharmacokinetic studies are generally not required for injectable vaccines as the kinetic properties of vaccines do not provide information useful for establishing adequate dosing recommendations. Pharmacokinetic studies were therefore not conducted.

Pharmacodynamics

Studies providing pharmacodynamic data

Pharmacodynamic evaluations were performed as part of the clinical efficacy studies and therefore results are discussed below. As efficacy can only be assessed in the event of the circulation of a pandemic strain of virus, the efficacy of the vaccine is based on surrogate immunogenicity markers.

Dosage selection for the pivotal studies

The selection of antigen dose and schedule were evaluated in D-Pan Study H5N1-007. This was a Phase I, observer blind, randomised, single centre study, with 400 adults enrolled aged between 18 and 60 years. It was designed to evaluate the reactogenicity and immunogenicity of one and two administrations of pandemic monovalent (H5N1) influenza vaccines (split virus formulation) administered at different antigen doses (3.8 µg, 7.5 µg, 15 µg and 30 µg HA) adjuvanted or not with AS03. The study was previously evaluated and was also included in the current dossier. Given its previous evaluation, the study design and results have been summarised here.

Subjects were randomised into parallel groups with vaccination on days 0 and 21 and blood sampling on days 0, 21, 42 and 180. The primary endpoint was the serum anti-HA antibody titre against the vaccine strain A/Vietnam/1194/2004 (H5N1).

The HI immune response against the H5N1 strain found that after the second dose (Day 42) all antigen groups using the adjuvanted formulation met the CHMP immunogenicity criteria, while only the highest antigen dose of the non adjuvanted groups met the criteria. At Day 42, seroconversion and seroprotection rates were both 83.3% in initially seronegative subjects who received 3.8 µg HA adjuvanted with AS03, with a seroconversion factor of 29.8. The results on SCR, SPR and SCF are shown in Figures 2-4.

Figure 2: Study H5N1-007: SCR for serum HI antibody at Days 21 and 42 (ATP immunogenicity cohort).

Figure 3: Study H5N1-007: SPR for serum HI antibody at Days 0, 21 and 42 (ATP immunogenicity cohort).

Figure 4: Study H5N1-007: SCF for serum HI antibody at Days 21 and 42 (ATP immunogenicity cohort).

In annexed study reports, the seropositivity for anti HA antibodies to the vaccine strain at Day 180 remained high at 60-74.0% with adjuvanted vaccine and lower with non adjuvanted vaccine (10-45.8%). Seroprotection rates were 54-64% and 4.0-37.5% in the adjuvanted and non adjuvanted groups, respectively. The seroconversion factor at Day 180 was 2.9-4.5% in the adjvanted groups and 1.0-2.2% in the non adjuvanted groups.

The study demonstrated a clear benefit of AS03 adjuvanted formulation compared to non-adjuvanted formulation when assessing the GMTs of the HI antibody. This was seen across antigen doses (Figures 5 and 6).

Figure 5: Study H5N1-007: GMTs for serum HI antibody at Days 0, 21 and 42 (ATP immunogenicity cohort).

Figure 6: Study H5N1-007: “Adjuvantation” over “HA-dose effect” after the second dose (Day 42) (ATP immunogenicity cohort).

Cross reactive immunity was assessed by measuring anti HA antibody titres against an H5N1 heterologous strain (A/Indonesia/5/2005). For all non adjuvanted formulations, protective levels of antibodies were not reached at any time point (Days 21 or 42). In the adjuvanted vaccine groups, a significant increase in SPRs of 20-33% was observed between Days 0 and 42. The SCFs in the adjuvanted vaccine groups ranged from 1.0 to 1.2 after the first dose and from 2.0 to 2.8 after the second dose compared to no response in the non adjuvanted groups.

Neutralising antibody responses against vaccine strain H5N1 A/Vietnam/1194/2004 were induced with all adjuvanted formulations. In the lowest dose group (3.8 µg HA/AS03), all subjects except one were seropositive after the second dose, with a seroconversion rate of 85.7%. The NA response was notably higher after the second adjuvanted dose and only the adjuvanted vaccine elicited a heterologous NA response.

Comment: The study demonstrated a clear benefit of the adjuvanted compared to the non adjuvanted vaccine formulation across all parameters.

The results indicated the need for a 2 dose schedule.

The sponsor stated that considering the limited manufacturing capacities in the case of a pandemic, the formulation containing the minimum amount of antigen which fulfilled all three CHMP criteria would be selected for the adult population. Given this, the lower dose of 3.75 µg was selected.

Efficacy

Studies providing efficacy data

As the selected vaccine strain is not circulating in human populations, efficacy trials are unable to be carried out. Efficacy therefore is based on surrogate immunogenicity endpoints and these data are included in this section.

The clinical studies enrolled healthy subjects. The exclusion criteria for the adult studies were similar and are listed here:

use of immunosuppressants, immune modifying or cytotoxic drugs (generally within 6 months and including ≥ 0.5mg/kg/day of corticosteroids);

confirmed or suspected immunosuppressive or immunodeficient condition or autoimmune disease;

allergy or hypersensitivity to any component of the vaccine, allergic disease or reactions which could be exacerbated by the vaccine;

acute moderate or severe disease with or without axillary temperature ≥ 37.5 °C at time of vaccination;

administration of immunoglobulins or blood products (generally within 3 months);

prior vaccination with pandemic candidate vaccine or vaccine containing AS03;

lactating or pregnant women, or women of childbearing potential without appropriate contraception;

In addition, in general the studies also excluded:

vaccination between Day 0 and 51 with seasonal influenza vaccine;

administration of licensed vaccines within 2 weeks for inactivated and 4 weeks for live vaccines;

prior contact with H5N1 wild type virus;

clinically significant disease on screening test/examination;

serious chronic disease including pulmonary, cardiovascular, renal, neurological, psychiatric or metabolic disorder;

chronic alcohol consumption or drug abuse;

diagnosis or treatment of cancer within 3 years;

receipt of analgesic or antipyretic medication on the day of vaccination.

Evaluator’s conclusions on efficacy

The dossier included 18 clinical trials, 16 carried out in Europe and Asia and the two Q-Pan studies were conducted in the US and Canada. Study duration ranged from 6 months up to 48 months (H5N1-002/-030/-038) and enrolled healthy adult volunteers (with well controlled diseases in H5N1-008 and -010). Two studies included adults >60 years (H5N1-010 and -008/-011). There were three paediatric studies, H5N1-013, H5N1-009 and H5N1-032, which enrolled children aged 6-35 months, 3-9 years and 3–17 years, respectively. Most of the adult subjects were Caucasians (range 85.0-100%), except for study H5N1-041 and H5N1-002 and its extensions where subjects were predominantly Asian. For the paediatric studies, H5N1-009 included Caucasians, and -013 and -032 mainly Asians.

All studies had a primary vaccination schedule of 0 and 21 days, except some groups in H5N1-012 and the paediatric Study H5N1-032, and Study Q-Pan-009 which assessed accelerated vaccination schedules. Booster vaccination was assessed in several studies: homologous booster in H5N1-012; heterologous booster in H5N1-015, -030, -038, -012 and the paediatric Studies H5N1-013 and -032.

The submitted Prepandrix vaccine contains the D-Pan antigen strain A/H5N1/Indonesia/5/2005 while the registered mock up pandemic vaccines contain D-Pan A/H5N1/Vietnam/1194/2004 or Q-Pan A/H5N1/Indonesia/5/2005. Immunological equivalence of the D-Pan and Q-Pan vaccines was demonstrated in study Q-Pan-001 and so the data were included in this submission. Apart from the different manufacturing sites of the vaccine antigen, there are differences in the vaccine with respect to excipients used in the formulation (Tween-80, Triton X-100 and Magnesium Chloride).

The composition of the H5N1 vaccines use in the clinical program are summarised in Appendix 1. The proposed vaccine contains adjuvant AS03A which was used in all studies apart from paediatric studies which used AS03B and some groups of Q-Pan-001. AS03A is the so called full dose and AS03B contains half of this dose. The proposed antigen dose is 3.75 µg. In general, the paediatric studies assessed half the adult dose.

All serology testing of HI antibody response and serum neutralisation was performed in GSK Biologicals’ central laboratory using standardised procedures which have been validated by the sponsor. The HI antibody titre was used as the main measure of the immunogenicity response to the vaccine. The use of this surrogate efficacy endpoint is accepted by EU and US guidelines.

The studies were well conducted and the overall rate of premature discontinuation was low at 1.5% (157/10208). The most frequent reasons were consent withdrawal, moved from study area and lost to follow-up.

Antigen dose

Antigen dose was based on Study H5N1-007 where it was demonstrated that in presence of the AS03 adjuvant, antigen content as low as 3.75 µg was sufficient to induce the immune response meeting all three CHMP criteria. This dose was selected as it was the lowest dose which still yielded high immunogenicity. No lower doses were assessed in Study 007. In children, there was a higher response with full (3.7 µg) HA dose in Study -009 however the half strength dose (1.9 µg) elicited a satisfactory immune response across the age groups in all three trials.

Adjuvant dose

Adjuvant dose selection was based on results from Study Q-Pan-001 which found that adjuvanted vaccine (both full and half strength) was superior to non-adjuvanted vaccine as determined by SCR and GMT at day 42. Post hoc analyses found the reduction of the AS03 adjuvant dose (full to half) had a modest effect on vaccine homologous virus immunogenicity in subjects 18 to 40 years old, but led to a significant reduction in GMT and proportion of subjects attaining reciprocal titres ≥40 (SPR) among subjects 41-64 years old. For this reason, the full dose was recommended. Study H5N1-007 provided supportive evidence for the benefit of the adjuvanted formulations.

Primary vaccination homologous response

The included studies provided strong evidence for the immunogenicity of a two dose primary vaccination course at days 0 and 21 (3.75 µg HA, AS03_Avaccine). All regulatory criteria (SCR, SPR and SCF) for HI homologous antibody response were met for adults, including those aged >60 years, at 21 days following the second vaccination (Table 2). The response was seen for the A/Indonesia and the A/Vietnam strains. Similarly, in children, the homologous response (A/Vietnam in -009 and A/Indonesia in -013 and -032) following a two dose priming course with the half strength vaccine met the adult regulatory criteria (Table 3).

Table 2: Studies H5N1-007, H5N1-002, H5N1-010, H5N1-041, H5N1-015 and Q-Pan-001: HI antibody responses against the homologous vaccine strain after two doses of H5N1 vaccine (3.75 µg HA) with or without AS03_A at Day 42 in adults (ATP immunogenicity cohort).

table 2: studies h5n1-007, h5n1-002, h5n1-010, h5n1-041, h5n1-015 and q-pan-001: hi antibody responses against the homologous vaccine strain after two doses of h5n1 vaccine (3.75 µg ha) with or without as03a at day 42 in adults (atp immunogenicity cohort).

Table 3: Studies H5N1-009, H5N1-013 and H5N1-032: HI antibody responses against vaccine homologous strain after two doses of H5N1 vaccine at Day 42 in children (ATP immunogenicity cohort).

The homologous neutralising antibody response was high with adjuvanted vaccine, although the VRR in adults >60 years was notably less than those 18-60 years which may have been due to high baseline seropositivity in the elderly (93%)(Table 4). Children also demonstrated a strong homologous neutralising antibody response (Table 5).

Table 4: Studies H5N1-007, H5N1-002, H5N1-010, H5N1-015 and Q-Pan-001: Neutralising antibody responses against the homologous vaccine strain after two doses of H5N1 vaccine (3.75 µg HA) with or without AS03_A at Day 42 in adults (ATP immunogenicity cohort).

Table 5: Studies H5N1-009, H5N1-032, H5N1-013: Neutralising antibody responses against vaccine homologous strains at Day 42 (ATP immunogenicity cohort).

Primary vaccination heterologous response

The adjuvanted vaccine demonstrated cross reactive immunity to drifted strains although not all CHMP criteria were met on Day 42 following a 2 dose course (Table 6). The cross reactive immune response in children was high (Table 7). There was evidence of a heterologous neutralising antibody response with the adjuvanted vaccine in adults although results were more variable (Table 8). Children 3-9 years had a high heterologous NA response with a VRR of 95-97% and seropositivity of >95% after two doses of half strength adjuvanted vaccine (Day 42).

Table 6: Studies H5N1-007, H5N1-002, H5N1-010, H5N1-041, H5N1-015 and Q-Pan-001: HI antibody responses against the heterologous vaccine strain after two doses of H5N1 vaccine (3.75 µg HA) with or without AS03_A at Day 42 in adults (ATP immunogenicity cohort).

table 6: studies h5n1-007, h5n1-002, h5n1-010, h5n1-041, h5n1-015 and q-pan-001: hi antibody responses against the heterologous vaccine strain after two doses of h5n1 vaccine (3.75 µg ha) with or without as03a at day 42 in adults (atp immunogenicity cohort).

Table 7: Studies H5N1-009 and H5N1-032: HI antibody responses against the heterologous strain after two doses of H5N1 vaccine at Day 42 in children (ATP immunogenicity cohort).

Table 8: Studies H5N1-007, H5N1-002, H5N1-010, H5N1-041, H5N1-015 and Q-Pan-001: Neutralising antibody responses against heterologous strains at Day 42 (ATP immunogenicity cohort).

Vaccination schedule

Study Q-Pan-009 demonstrated that an accelerated schedule of 0 and 14 days led to an immune response that was satisfactory and could be employed if required. Shorter schedules of 0,7 days and two doses on day 0 resulted in lower responses. Study -012 found that an increased period of 0 and 6 months or 12 months led to a robust immune response.

Booster response

In adults, when given a booster dose of the same strain as the 2 dose primary vaccination course (A/Vietnam) at 6 or 12 months, the HI immune response met all CHMP criteria (Study H5N1-012). The response was notable by 7 days post vaccination. When the booster vaccination was a heterologous strain (A/Indonesia) to the priming course (A/Vietnam) the HI immune response against the booster strain also met CHMP criteria (day 21 post booster). This was the case if the priming course was one or two doses and the booster was at 6 or 12 months. These data were supported by NA response to the booster strain (H5N1-012). Heterologous booster vaccination was able to be given at 6, 12, 14 or even 36 months post a two dose priming course and induce a strong immune response meeting CHMP criteria (H5N1-030,-038 and -015) (Table 9).

Table 9: Studies H5N1-030, H5N1-038, H5N1-015: HI antibody responses against booster vaccine strain H5N1 A/Indonesia after two doses of primary vaccination with A/Vietnam (ATP immunogenicity cohort).

table 9: studies h5n1-030, h5n1-038, h5n1-015: hi antibody responses against booster vaccine strain h5n1 a/indonesia after two doses of primary vaccination with a/vietnam (atp immunogenicity cohort).

Heterologous booster was given at 6 months after the two dose primary vaccination course in the paediatric Studies H5N1-013 and -032. Study H5N1-032 found a superior booster response in 3-17 year olds primed with two doses of heterologous vaccine compared to those not primed. The HI antibody response to the booster strain 10 days after vaccination met all CHMP criteria in the 6 to 36 month old children in H5N1-013 (Table 10).

Table 10: Studies H5N1-032 and H5N1-013: HI antibody responses against booster vaccine strain 10 days after the booster dose (ATP immunogenicity cohort).

Persistence of immune response

Persistence of immune response up to 6 months following administration of two doses of D-Pan vaccine was assessed in all D-Pan studies. Data were available up to 36 months in adult subjects from H5N1-002 and its extension and up to 24 months in a subset of the elderly in H5N1-011 and the paediatric population of H5N1-009. In general, the GMTs were declining at 6 months although still above pre vaccination levels, the SCF met CHMP criteria at 6 months, then it and other immune measures waned (Table 11). HI antibody to heterologous strains also declined and did not meet regulatory criteria. Seropositivity to neutralising antibodies remained high to 24 months. Twelve months after booster vaccination, the immune response meet CHMP criteria and at 48 months after booster vaccination in H5N1-038, 64% of subjects were seropositive.

Table 11: Studies H5N1-007, H5N1-010, H5N1-041 and Q-Pan-001: Persistence of H1 antibody responses against vaccine strain (ATP persistence cohort).

table 11: studies h5n1-007, h5n1-010, h5n1-041 and q-pan-001: persistence of h1 antibody responses against vaccine strain (atp persistence cohort).

In children, HI immune response persistence at 6 months was greater in those who had received full dose vaccine compared to half strength particularly against the heterologous strain (H5N1-009); however neutralising antibody data in the half strength group were high (seropositivity 92-93% and VRR 95-100%). Data from Studies 013 and 032 found robust persistence to 6 months of HI antibody and neutralising antibody response for homologous and heterologous strains. This was also the case after booster vaccination.

Overall, the immunogenicity data from the clinical trials included in the dossier are accurately reflected.

Safety

Studies providing safety data

The following 14 studies provided evaluable safety data:

Adult primary vaccination studies: H5N1-007, H5N1-008, H5N1-002, H5N1-010 (elderly adults), H5N1-041

Adult booster studies: H5N1-012, H5N1-015, H5N1-030, H5N1-038

Paediatric primary vaccination studies: H5N1-009 (3 to 9 years)

Paediatric booster studies: H5N1-013 (6 to <36 months), H5N1-032 (3 to 17 years)

Supportive studies: Q-Pan-001 and Q-Pan-009

The sponsor also submitted two Integrated Summaries of Safety (ISS) which included relevant data from adult trials. These were compiled at the request of the FDA. The first (2008) included eight studies performed with the AS03 adjuvanted Q-Pan and D-Pan H5N1 vaccines (six D-Pan studies: H5N1-007, H5N1-002/030, H5N1-008/011, H5N1-010/021, H5N1-012 and H5N1-015; two Q-Pan studies: Q-Pan-001 and Q-Pan-002). The second ISS (2011) included studies performed with the AS03 adjuvanted D-Pan and Q-Pan H5N1 vaccines, as well as studies conducted more recently with the D-Pan and Q-Pan H1N1 vaccines (total of 28 studies). The first ISS aimed to develop estimates of AEs and to examine for rarer events. The second ISS aimed to assess less common and more serious AEs, in particular medically attended events (MAEs), SAEs, and potential immune mediated diseases (pIMDs).

Comment: The ISSs were discussed in the Summary of Clinical Safety however the data were not included. A question has been raised on this.

Much of these safety data have been evaluated previously: Study H5N1-007 and -008 in the original Prepandemrix dossier (2008); Study Q-Pan-001, H5N1-007 -008, -002 and the first ISS (2008) in the Arepanrix H5N1 dossier (2011); and H5N1-010 and -009 in the Pandemrix dossier.

Patient exposure

The A/Indonesia/5/05 strain was used in the D-Pan studies H5N1-041, H5N1-013, H5N1-032 and in Q-Pan-001. All other studies had primary vaccination with A/Vietnam/1194/04. Booster vaccination strain was either A/Vietnam/1194/04 or A/Indonesia/5/05 in all studies except H5N1-013 and H5N1-032, where the booster strain was A/turkey/Turkey/01/2005.

In the two Q-Pan studies, 1336 doses of AS03 adjuvanted H5N1 vaccine have been administered as primary vaccination to 715 subjects. Of these 1336 doses, 838 doses in 464 subjects were of the registered formulation (3.75 μg HA adjuvanted with AS03A). The strain in both Q-Pan-001 and Q-Pan-009 was A/Indonesia/5/05.

For the paediatric studies, H5N1-009 there were 195, 196 and 201 doses given in the 3.8 µg HA /AS03A, 3.8µg HA/AS03B (half dose adjuvant) and 1.9 µg HA/AS03B groups, respectively. In Study H5N1-013, 113 subjects received a total of 333 doses of 1.9 μg AS03B D-Pan vaccine. Of these, 225 were priming doses containing half dose AS03-adjuvanted A/Indonesia/05/2005 antigen and 108 were boosters containing half-dose AS03-adjuvanted A/turkey/Turkey/01/2005 antigen. In study H5N1-032, 520 subjects received a total of 1,349 study doses (including doses of both D-Pan and Havrix) to Day 182, with 156 subjects receiving 468 doses of D-Pan 1.9 µg HA/AS03B vaccine for priming and boosting (group H5N1_H5N1).

Safety issues with the potential for major regulatory impact

In all phases of Study H5N1-009, a total of three potentially immune mediated diseases were observed: one case of autoimmune hepatitis in the H5N1 full/half adult dose group (Phase B) that appeared to be present pre vaccination; one case of unilateral uveitis in the H5N1 full adult dose group (Phase C); and one insulin dependent diabetes mellitus in the Fluarix control group (Phase B). No meaningful conclusions about a potential causal relationship between the H5N1 vaccine and immune mediated diseases can be drawn from the limited number of cases observed in Study H5N1-009 in children aged 3-9 years.

Post marketing experience

There were no post marketing data in the dossier for the H5N1 vaccine. The sponsor summarised post marketing surveillance data for the adjuvanted H1N1 pandemic influenza vaccine in the Clinical Overview. It was reported that approximately 31 and 59 million doses of Pandemrix H1N1 and Arepanrix H1N1, respectively, have been administered, including at least 9.5 million doses to children and 300,000 doses to pregnant women. The main risk reported from this surveillance is the risk of narcolepsy, particularly in adolescents (Table 12 and 13).

Comment: This risk has been included in the Precautions section of the draft PI.

Table 12: Post marketing H1N1 surveillance – summary of narcolepsy risk estimates in Europe, children.

table 12: post marketing h1n1 surveillance – summary of narcolepsy risk estimates in europe, children.

Table 13: Post marketing H1N1 surveillance – summary of narcolepsy risk estimates in Europe, adults.

The RMP also discusses 25 reports of solid organ transplant rejection (and 2 reports of graft versus host disease post bone marrow transplantation). Of these cases, 8 had other risk factors involved (such as non compliance with immunosuppressive regimen, discontinuation of immunosuppressants, acute infection, cyclosporine nephropathy and prior rejection episodes), 2 had biopsies not revealing acute rejection and 4 cases had insufficient clinical information.

Evaluator’s conclusions on safety

In total, 16541 doses of AS03 adjuvanted H5N1 split influenza vaccine containing the Dresden-derived antigen have been administered as primary or booster vaccination to 8676 subjects in the evaluation of safety. Of these, 6558 doses in 3687 subjects were of the proposed formulation (3.75 μg HA adjuvanted with AS03A). In the paediatric subset, 300 children aged 3 to 9 years old received 592 D-Pan doses, 520 3-17 year olds received 728 priming and 156 booster doses and 113 6-<36 month olds received 225 priming doses and 108 booster doses.

In adults, there was increased reactogenicity with the adjuvanted formulation compared to the non adjuvanted formulation particularly pain, nonetheless the rate of grade 3 solicited local AEs was generally low. General solicited events of fatigue and headache were also more frequent with adjuvanted vaccine. Symptoms were generally mild to moderate in intensity and resolved within several days. Overall, rates of unsolicited AEs were unremarkable. Lymphadenopathy was reported with higher antigen dose and with adjuvanted vaccine. The risk however was low, non severe, and resolved.

There was a trend for higher rates of general symptoms such as mylagia, fatigue and headache following booster than priming doses but no notable findings on unsolicited AEs following booster vaccination.

In the elderly (>60 years) the double strength vaccine dose resulted in an increased risk of local and general solicited AEs.

In children 6 months to 17 years of age, reactogenicity was found to increase with each subsequent vaccine dose whether full or half strength. The full dose vaccine, compared to half dose vaccine, resulted in a higher rate of solicited local and general AEs. Fever, particularly that >39°C, was a notable risk particularly with the full dose vaccine and rates increased with subsequent doses. There were however no reports of febrile convulsions.

There were 13 deaths in the clinical program, none of which were classed as vaccine related. Of the 294 subjects with SAEs, there was one of pneumonia that was treatment related in an elderly subject; however, the event was 299 days post vaccination. Of the 19 paediatric subjects with an SAE there was one, autoimmune hepatitis, which was treatment related. The child however was reported to have elevated transaminases predating the first vaccination. Premature study discontinuation due to an AE was infrequent across all ages.

Where laboratory assessments were undertaken (>60 years olds in H5N1-010, 3-9 year olds in H5N1-009 and adults in Q-Pan 001) there were no notable findings.

There was little difference in the rate of solicited local and general AE and unsolicited AEs between the thiomersal containing and thiomersal free formulations of vaccine. The Q-Pan vaccine studies were not remarkably different to the D-Pan studies in terms of reactogenicity. The reactogenicity with an accelerated immunisation schedule was acceptable.

The relationship between the candidate vaccine and the onset of any new chronic disease or medically significant condition was assessed in detail in the integrated safety summaries. The ISS (2008) included eight completed adult trials evaluating either Q-Pan or D-Pan adjuvanted vaccines. The analysis did not reveal any unexpected safety findings and there was no strong evidence to support a causal relationship between the use of AS03 adjuvanted H5N1 vaccine (Q-Pan or D-Pan) and the incidence of AESI/pIMDs. Drawing definitive conclusions from the data were however not possible due to the limited number of events.

The second ISS (2011) included data from 22,000 subjects in 28 studies, with close to 20,000 in controlled studies, exposed to H5N1 or H1N1 vaccines. It was undertaken to assess the incidence of MAEs, SAEs, and detect rare AEs and in particular pIMDs associated with the adjuvanted vaccine. There were a number of limitations with this ISS including the lack of correction for multiplicity, the 3:1 randomisation limiting the control numbers, the lack of specific pIMD surveillance in the H5N1 studies which was present in the H1N1 studies and a high level of discordance on pIMD status between the investigator’s reports and the sponsor’s assessment. Nonetheless, no imbalance was seen in adjuvanted vaccine recipients compared to control product recipients for MAEs, grade 3 MAEs or SAEs. A higher RR of pIMDs of 1.69 (95% CI 0.81,4.11) in the combined H1N1+H5N1 group was due to an effect seen in the H5N1 group (RR = 6.85, 95% CI: 1.10, 283.6). While there were specific diagnoses (facial nerve paralysis/paresis, PMR/temporal arteritis, uveitis, UC and RA) with suggestions of higher risk there were no specific patterns evident and the evaluator accepts the sponsor’s arguments on the lack of consistency, specificity and lack of power to detect a biological gradient.

There were two paediatric cases of pIMD: autoimmune hepatitis (also an SAE) and uveitis. The first was assessed as predating vaccination and the second was non serious and resolved with treatment. The paediatric safety database however is relatively small and integrated data did not cover this age group.

First round benefit-risk assessment

First round assessment of benefits

The benefits of Prepandemrix, pandemic influenza vaccine (H5N1), in the proposed usage are:

Demonstrated immunogenicity for the homologous vaccine strain which meets regulatory criteria for pandemic influenza vaccines. The response was consistent across clinical trials and age groups and achieved with a schedule of two doses 21 days apart.

Ability of the vaccine to elicit both HI and neutralising antibody responses with notable cross-reactive immune response to drift variant strains.

Anticipated benefit in the event of an influenza pandemic which could have significant public health impacts.

Immunological equivalence (as measured by GMT ratio) of vaccine manufactured at the two facilities (Q-Pan and D-Pan).

Ability to shorten primary vaccination schedule to 0 and 14 days if required without compromising immunogenicity.

Strong booster response after single or dual dose priming. The booster can be a heterologous strain and is immunogenic when administered from 6 to 36 months after priming.

Immunogenicity demonstrated in children from 6 months to 17 years of age.

First round assessment of risks

The risks of Prepandemrix, pandemic influenza vaccine (H5N1), in the proposed usage are:

The actual degree of protection the vaccine may provide in the event of a future influenza pandemic is not able to be gauged from the available data.

It is not known whether a lower antigen dose would be satisfactorily immunogenic.

There is evidence that the immune response is waning by 6 to 12 months.

Reactogenicity both local and general, which is higher than non adjuvanted vaccine and increases with subsequent doses. It is acknowledged that these events, which are well documented, are generally mild to moderate in severity and resolve.

Notable risk of fever in the paediatric population.

There are limited safety data in the paediatric population and the risk of pIMDs has not been established in this population.

Possible increased risk of pIMDs in adults, although integrated safety data from 16,000 adults exposed to AS03 adjuvant have not identified any specific concerns.

No data on pregnancy and lactation or on immunosuppressed subjects.

Theoretical potential risks of narcolepsy in adolescents and of solid organ transplant rejection due to the post marketing signals with adjuvanted H1N1 vaccine.

No data on co-administration with other vaccines.

No long term safety data on the AS03 adjuvant.

First round assessment of benefit-risk balance

The clinical development program for Prepandemrix was extensive and well conducted. It assessed populations from infants of 6 months through to adults over 60 years, different primary vaccination schedules, differing booster intervals and booster response with homologous and heterologous vaccines to the primary course. Immunogenicity evaluations were thorough with assaying for both HI and neutralising antibodies.

The immune response to the D-Pan vaccine containing 3.75µg HA and adjuvanted with AS03_A, when given in the proposed priming regimen of two doses 21 days apart, was strong and met all CHMP immunogenicity criteria. While the addition of the adjuvant increased reactogenicity, these events were generally mild or moderate and were outweighed by the marked increased immunogenicity of the vaccine when it was included.

The proposed product contains the A/Indonesia strain compared to the A/Vietnam strain in the original dossier. The adult D-Pan primary vaccination studies were conducted with A/Vietnam, except study H5N1-041 which had the proposed A/Indonesia strain in a study which compared thiomersal containing and free formulations. It was therefore relevant to have an immune response in that study which met CHMP criteria. The immunological equivalence of the Q-Pan and D-Pan vaccines in study Q-Pan-001 and immunogenicity results meeting threshold criteria also provided supporting evidence as the vaccine in that study contained A/Indonesia strain.

The original Prepandemrix submission had two areas of concern which led to its rejection: lack of data on booster response and a possible safety signal of increased risk of NOCD in adults over 60 year of age in Study H5N1-008. Both issues have been addressed in this dossier which presents a far more thorough clinical development program than that evaluated in 2007. A number of booster studies assessing both homologous and heterologous booster to the priming strain have been conducted in adults and children and at different intervals from the priming course. All demonstrated a robust booster response for HI and neutralising antibodies to the booster strain as well as cross reactive response to heterologous strains.

Regarding the risk of NOCD, since the earlier evaluation the Sponsor has conducted further studies, including a study in adults >60 years, as well as compiling two integrated summaries of safety. The safety of the vaccine and adjuvant has now been assessed from a database of approximately 16,000 subjects who received AS03-adjuvanted H5N1 or H1N1 antigens, of who 9300 received H5N1 with AS03_A, together with about 6000 control subjects. The Sponsor stated that the size of this safety database provides 99.3% confidence that at least one instance of any AE occurring with a frequency of at least 0.05%. This analysis found an increased relative risk of pIMDs with the H5N1 adjuvanted vaccine (RR=6.8, 95% CI:1.1,283) compared to no increased risk with H1N1 (RR=1.0, 95% CI: 0.4,2.7). The pIMDs identified covered a broad range of diseases without any specific areas being identified. The evaluator agrees with the sponsor that the imbalance in person years of observation between the H5N1 and control groups may have contributed to the observed imbalance. It is concluded that while the data do not suggest a causal link the risk will still need to be closely monitored.

It has been noted in this evaluation, as well as one relating to Pandemrix, that while the standard dose (3.75 µg HA) vaccine in adults >60 years resulted in an immune response which met CHMP criteria it was less than that of a double dose vaccine. The safety profile as regards solicited local and general AEs after vaccination, however was better with the single dose. The European Summary of Product Characteristics (SmPC) for Prepandrix summarises HI antibody responses at day 42 based on age subgroups (61 to 70; 71-80, and > 80 years) and this shows that the H5N1 HI antibody response (SPR, SCR, SCF) in subjects aged >80 was greater in the double dose group (n=10) than in the single dose group (n=13). It also comments that “based on very limited data, adults aged >80 years may require a double dose of [the vaccine] ..... in order to achieve an immune response”. This recommendation is not included in the Australian PI which recommends a single dose vaccination regimen in adult adults aged 18 years and above, irrespective of age. These data appear to be from post hoc analyses as they were not available to the evaluator and the sponsor has been asked to clarify immunogenicity and dosing in the elderly population.

The paediatric clinical development covered children from 6 months to 17 years and demonstrated that two doses three weeks apart (using half the adult dose) was immunogenic with adult CHMP criteria being achieved. There was also strong booster response. It was found that the full adult dose led to increased reactogencity and, given the high rate of fevers with the adjuvanted vaccine, the benefit-risk balance is therefore in favour of the half strength dose. As there are no paediatric dosage instructions in the draft PI, the sponsor has been asked to clarify this issue.

With the number of children with grade 3 fever it was reassuring to find no reported cases of febrile convulsions, nonetheless the sponsor has been asked to confirm that this is the case. In addition, this risk of fever has not been adequately covered in the draft PI. The overall safety of the vaccine in the paediatric population has been based on relatively small numbers. There were two pIMDs identified, autoimmune hepatitis and uveitis, although the former was believed to predate vaccination and the latter resolved with treatment. There were no integrated data on the paediatric population presented and the sponsor should provide further information to justify the safety of the product in children.

Overall, it is not clear if the indication for the vaccine seeks to cover children as there is a lack of dosage instructions, inadequate coverage of paediatric clinical trial immunogenicity and safety data in the PI, a Consumer Medicine Information (CMI) which includes no instructions relating to children and inconsistencies in the RMP. These issues all need to be addressed before an assessment of benefit-risk in this population can be undertaken.

With regard to the indication, the current wording is Prophylaxis of influenza caused by the H5N1 strain with a pandemic potential. As there are no data to confirm prophylaxis of influenza, the evaluator believes preferable wording would be along the lines of that in the European SPC which states active immunisation against H5N1 subtype of Influenza A virus.

There are substantial public health risks of pandemic influenza and so there is a high need for immunogenic vaccines. Prepandemrix vaccine was found to be immunogenic with evidence of cross reactive antibodies at a relatively low antigen dose. There was some flexibility with priming dose schedule, a robust and rapid booster response, and manageable reactogenicity risks. Integrated safety data found an increased relative risk of pIMD with the adjuvanted H5N1 vaccine while detailed assessment did not appear to support any specific findings. The evaluator believes the causal risk is not sufficiently strong to outweigh the potential public health benefit of the vaccine. Nonetheless, it is a case where there will need to be ongoing vigilant safety monitoring and it will be essential that the sponsor has highly developed plans for the monitoring of the candidate vaccine in the event of a pandemic influenza outbreak.

In summary, the evaluator found that the benefit-risk balance of Prepandemrix given the proposed usage is favourable for adults subject to satisfactory responses to questions and comments below. The evaluator found that there were a number of issues still to be addressed regarding the paediatric population and so the benefit-risk balance in this group is currently unfavourable.

First round recommendation regarding authorisation

It is recommended that Prepandemrix pandemic H5N1 influenza vaccine (A/Indonesia/05/2005 3.75 µg adjuvanted with AS03) is authorised for use in adults. The recommendation is subject to:

Addressing questions raised

Rewording of the proposed indication

Satisfactorily addressing changes to the PI and CMI

Close post marketing safety monitoring.

It is not currently recommended that Prepandemrix is authorised for use in the paediatric population as issues raised need to be addressed by the sponsor and evaluated by the TGA.

Clinical questions

Pharmacokinetics

None.

Pharmacodynamics

None.

Efficacy

The EU SPC for Prepandrix includes what appears to be a post-hoc immunogenicity analysis of study H5N1-010 by age subgroups. These data were not located in the clinical study report. The data point towards an improved immune response in subjects aged >80 years with the double dose vaccine regimen. From this there is a statement in the EU SPC dosage and administration section which suggests a double dose of vaccine may be necessary in this age group. Discuss these findings and whether or not the information is relevant in the Australian context.

Safety

In the Summary of Clinical Safety it states that 6558 doses of D-Pan 3.75 µg HA adjuvanted with AS03A have been given to 3687 subjects (page 43) while in the Clinical Overview it states that these 6558 doses were given to 2804 subjects (Table 35). Please explain the difference and verify the number of subjects who have been exposed to the proposed vaccine.

In the Summary of Clinical Safety, results of the two ISSs were discussed. Neither ISS had corresponding data located in the dossier. The first ISS (2008) has been previously evaluated, however the evaluator believes that the second ISS (2011) has not been previously evaluated and so the data should be submitted to the TGA.

Given the risk of fever with the adjuvanted vaccine it was reassuring that no reports of febrile convulsions were identified in the three paediatric clinical trials. Could the Sponsor confirm that there have indeed been no cases of febrile convulsion or discuss any cases that may have occurred in infants, children or adolescents with the administration of the H5N1 vaccine.

The safety of the vaccine in the paediatric population has been evaluated in the three clinical trials in the dossier. There is a however no broader integrated summary of safety in children, either for the H5N1 vaccine alone or for combined adjuvanted H5N1 and H1N1 vaccines. Discuss any integrated data on paediatric safety and post-marketing safety data including information on cases of pIMDs.

Second round evaluation

The sponsor submitted a response where they requested to change the trade name from Prepandemrix to Prepandrix, which is the approved name in Europe. Below is a summary of the sponsor’s responses to the questions followed by the evaluator’s comments.

Efficacy

Question 1

In Study H5N1-010, exploratory post hoc analysis was conducted in age subgroups (60-65, 66-70, 71-75, 76-80 and >80 years) at the request of the European Authorities. These data were included with the sponsor’s response to this question.

There were only 10 and 13 subjects aged >80 years who received single and double dose adjuvanted vaccine, respectively. There was a high rate of seropositivity for HI antibodies to A/Vietnam so the age-stratified analysis also assessed results by baseline serostatus. The baseline seropositivity rates to A/Vietnam increased with age (50-60% in the >80 year olds). No seropositivity was seen for HI antibodies against A/Indonesia.

Prevaccination GMTs for HI antibodies against A/Vietnam were low in all age groups (7.0-14.1). At Day 42 post vaccination, GMTs were found to be lower in subjects aged >80 years, particularly in those who received one dose of vaccine.

Seroprotection rates at Day 42 against A/Vietnam were >60% in all age groups whether they received single or double dose vaccine. When assessed by baseline serostatus, those who were seropositive had higher SPRs. In the seronegative subjects >80 years (n = 5), there was no seroprotection when only one vaccine dose was given. The SPR threshold was not met by any age group for HI antibodies against A/Indonesia.

A seroconversion rate of >30% against A/Vietnam was achieved in all age groups at day 42 whether a single or double dose was given. When assessed by baseline serostatus, again the 5 seronegative subjects aged over 80 years failed to demonstrate seroconversion. The SCR threshold for HI antibodies against A/Indonesia was met by all age groups when vaccinated with two doses but not when only one dose was given.

The seroconversion factor of >2.0 against A/Vietnam was achieved in all age groups at day 42 regardless of serostatus. The threshold of >2.0 was met against A/Indonesia in all age groups when two vaccine doses were given but not in the >80 year age group with only one dose (SCF 1.3, 95% CI: 1.0, 1.8).

The sponsor’s conclusion was:

All CHMP criteria are met for the HI response against the vaccine strain at Day 42, regardless of age, and for both the single and the double injection dose. The baseline serostatus of the subjects does not impact on the ability to meet the criteria, except for the oldest subjects (aged above 80 years), in case they were seronegative before vaccination and vaccinated with the 1x3.8AD formulation. In this latter group, for which it should nevertheless be noted that the sample size is very limited (n = 5), SCR and SPR criteria are not met, although SCF is met at Day 42. It was stated that the trend towards improved immunogenicity with a double dose has to be interpreted with caution.

Second round assessment of risks

After consideration of the responses to clinical questions, the risks of Prepandemrix/Prepandrix in the proposed usage are unchanged from those identified in Round 1.

Second round assessment of benefit-risk balance

The sponsor has submitted a thorough response to the questions asked after the first round evaluation. Comments on the PI have been satisfactorily addressed and resulted in substantial modifications to the document.

The major change in the second round evaluation is that the sponsor no longer proposes an indication which covers the paediatric population. Given this alteration, the evaluator recommends that it is made clear in the indication that the vaccine is for the active immunisation of adults only. In addition, a precaution relating to use in children should be included in the PI.

Submitted post hoc data analysis of the elderly study pointed towards possible reduced immunogenicity of the vaccine in those aged >80 years and improved response with double vaccine dose. While these analyses are post hoc and the subgroup sample size very small, the evaluator agrees with the EU’s decision to include a statement outlining these facts in the PI.

In summary, evaluator finds the benefit-risk balance for Prepandemrix/Prepandrix pandemic H5N1 influenza vaccine use in adults is favourable. This is subject to the remaining few questions relating to the PI being satisfactorily addressed.

Second round recommendation

It is recommended that Prepandemrix/Prepandrix, pandemic H5N1 influenza vaccine (A/Indonesia/05/2005 3.75 µg adjuvanted with AS03) is authorised for use in adults. The recommendation is subject to:

Making the indication specific for adults.

Finalising the PI

Close post-marketing safety monitoring.

Yüklə 253,66 Kb.

Dostları ilə paylaş:

1 2 3 4 5 6 7