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

VI. Overall conclusion and risk/benefit assessment

The submission was summarised in the following Delegate’s overview and recommendations:

Introduction

This is a submission for registration of a new vaccine Prepandrix – H5N1 monovalent, inactivated, split virion, vaccine containing 3.75 μg of HA surface antigen adjuvanted with the proprietary AS03 system. This is a resubmission, with new data, of an earlier rolling submission in 2007 which was withdrawn by the sponsor in 2008.

Initially, the proposed indication was

Prophylaxis of influenza caused by the H5N1 strain with a pandemic potential. Prepandrix should be used in accordance with official recommendations.

A revised indication, agreed by the sponsor following recommendation from the clinical evaluator, is

Active immunisation against H5N1 subtype of Influenza A virus. Prepandrix should be used in accordance with official recommendations.

There are no explicit recommendations for booster dose or for use in children, although the clinical trial experience for both situations is included in the Clinical Trials section of the PI. For children, the Dosage & Administration section also states that “experience in children is limited”.

The previous submission to register this vaccine for pre‐pandemic use, based on clade 1 strain A/Vietnam/1194/2004/NIBRG‐14, was withdrawn following negative recommendation from the Delegate and the ACPM. The reasons for rejection were inadequate data on duration of immunity/booster, and unfavourable risk/benefit due to a higher incidence of ‘New Onset Chronic Disease’ (7 reports; 1.8%) versus no reports (0.0%) in the control seasonal trivalent vaccine arm in elderly subjects in study 008 in the original dossier. At the same time and based on the same dataset, the product was approved as ‘mock‐up’ vaccine (Pandemrix H5N1 submission 2007/2842/2) and remains on the ARTG (AUST R 145924; also AREPANRIX H5N1; ARTG 166254).

As a regulatory mechanism in Europe and Australia, a ‘mock up’ vaccine is intended to be updated to an actual pandemic strain after identification and official declaration of an influenza pandemic, whereas a ‘pre‐pandemic vaccine’ based on a registered strain (highly pathogenic with potential to cause a pandemic) may be stockpiled and used in the prepandemic phase according to official guidelines.

Following the declaration of the 2009 H1N1 pandemic, Pandemrix H5N1 was updated and approved as Pandemrix H1N1 vaccine in 2010 (ARTG 174554). It was not used in Australia during the H1N1 pandemic but was used extensively in Europe (nearly 90 million doses). It is currently approved in Australia for use in adults above 20 years of age (following investigation of association with narcolepsy).

Both Pandemrix and Prepandrix were approved simultaneously by EMA in 2008 for use in adults. The Prepandrix vaccine strain has been updated in Europe to the A/Indonesia. A renewal of approval for a further period of 5 years was granted to Prepandrix in 2012 in Europe.

The H5N1/AS03 vaccine was approved in Canada (‘pandemic use’) and the USA (‘in persons 18 years of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine’) in 2013.

Quality

The antigen suspension and the adjuvant are supplied in separate containers and require mixing prior to use resulting in multidose vial with 10 doses. There are no outstanding issues. Approval is supported and batch release conditions of registration have been provided.

Nonclinical

The submission included new and the previously evaluated nonclinical studies. In accordance with the pre pandemic and pandemic vaccine guidelines, additional toxicity testing with the A/Indonesia/05/2005 antigen (updated from the initial A/Vietnam strain) was not required. New nonclinical studies included additional data on AS03 adjuvant. Registration is supported and recommendations for the product information (PI) have been provided. The toxicology data includes challenge study in ferrets (n = 6) which is also proposed for inclusion in the Clinical Trials section in the proposed PI as vaccine efficacy in humans has not been determined.

Clinical

The human clinical dataset is limited to immunogenicity studies. Vaccine efficacy studies were not possible as the incidence of H5N1 is limited and so far does not appear to involve independent human‐human airborne transmission. Most studies have been previously reviewed. The clinical evaluator supports approval.

Efficacy

Most studies were randomised, controlled, observer blinded trials. All studies examined immunogenicity endpoints using the CHMP criteria (SCR >40%, SPR >70%, SCF >2.5 fold) in adults for antibody response against the surface HA antigen for seasonal influenza. Immune response to heterologous vaccine strain and to neutralising antibodies were also was assessed. All studies used the vaccine product manufactured at Dresden (D‐Pan) except where specified Q‐Pan (Quebec site) in this report. The equivalence between D‐Pan and Q‐Pan has been established, although D‐Pan is intended for supply in Europe/Australia and Q‐Pan in USA/Canada.

Study 007 was a dose finding study in adults (18‐60 years age) and assessed 3.75, 7.5, 15 and 30μg doses of HA with or without AS03 given intramuscularly on 0 and 21 days (n = 400; 8 treatment arms with 50 subjects in each). The study was carried out using the A/Viet vaccine virus strain. Its extension Study 015 is new to this submission.

The 3 CHMP criteria were met only with adjuvanted formulation and only after 2 doses. The 15 μg was the most immunogenic dose. However, the lowest tested dose 3.75 μg (hereafter called 3.8 μg) adjuvanted with AS03 induced sufficient immune response (homologous anti HA antibodies on Day 42) to fulfil all 3 CHMP criteria. The results for the 3.8/AS03 arm are summarised in Table 16.

Table 16: Results for the 3.8/AS03 arm.

Loss of response was noted by Day 180. Neutralising antibodies and Cell Mediated Immune response was also reported (CD4 response; nil CD8 response).

The extension Study 015 (n = 350) was a booster in subjects primed with 2 doses approximately 14 months earlier in the Study 007. Subjects primed with non adjuvanted vaccine were given 2 booster doses of heterologous A/Indo (3.8/AS03) vaccine on days 0 and 21. Subjects previously primed with adjuvanted vaccine were given one heterologous booster. There was a control group of previously unprimed subjects who received two doses of adjuvanted vaccine. The anti HA immune response 21 days following a single booster dose of heterologous vaccine (A/Indonesia) to subjects previously primed with two adjuvanted doses (A/Vietnam) met the CHMP criteria as shown in Table 17.

Table 17: Anti HA immune response 21 days following a single booster dose of heterologous vaccine (A/Indonesia) to subjects previously primed with two adjuvanted doses (A/Vietnam).

In 3.8/AS03 group the anti HA immune response against A/Vietnam was 87.2% [95%CI 72.6, 95.7], 42 fold [95%CI 25, 73] and 89.7% [95%CI 75.8, 97.1] for SCR, SCF and SPR, respectively. In this group, the pre‐booster neutralising antibody GMTs to A/Indo were 157 [95%CI 130, 191] and rose to 3708 [95%CI 2458, 5594] 21 days post booster.

Study 002 was the main study (n = 1206) examining the selected 3.8 μg dose in adults (18‐60 years old) using 0, 21 day schedule (A/Viet 3.8μg with and without AS03) with 12 months follow up. The study also examined lot to lot consistency. Pooled results for 3.8/AS03 group were as shown in Table 18.

Table 18: Pooled results for 3.8/AS03 group.

Non adjuvanted groups did not meet CHMP criteria. The results for the heterologous anti HA were as shown in Table 19 (pooled 3.8/AS03 group).

Table 19: Heterologous anti HA (pooled 3.8/AS03 group).

The neutralising antibodies response at 21 days post Dose 2 (Day 42) was as shown in Table 20 (pooled 3.8/AS03 group).

Table 20: Neutralising antibodies response at 21 days post Dose 2 (Day 42).

A subset of subjects from the adjuvanted groups was followed for persistence of immune response until Month 36. Only the SCF against A/Vietnam met the CHMP criteria at Month 6, declining thereafter until Month 36. None of the CHMP criteria were met against A/Indonesia strain from Month 6 onwards. A higher neutralising response (SCR) was observed until Month 12 against A/Vietnam (87.0%) and A/Indonesia (65.2%).

Its extension Study 030 introduced booster with heterologous vaccine strain (A/Indonesia/AS03) at 6 months in a subset (single booster in n = 265 previous 3.8/AS03 primed subjects; 2 booster doses (0, 21 days) in n = 236 in previous 3.8/non adjuvanted primed subjects and no booster control in n = 672 in previous 3.8/AS03 primed subjects).

A further extension Study 038 (n = 845) was in subjects who did not receive booster in study 030. They received a single booster (A/Indonesia/AS03) at 12 or 36 months after initial priming in Study 002. The studies showed that single heterologous booster vaccine at 6, 12 or 36 months in subjects primed with 2 (adjuvanted) doses lead to robust immune response which meets CHMP criteria for homologous and heterologous vaccine strains. Neutralising antibody data were supportive. The subjects without booster no longer met CHMP criteria against either homologous or heterologous strain at 12 or 18 months.

Study Q‐Pan 001 demonstrated equivalence of adjuvanted products manufactured in Quebec (Q‐Pan) and Dresden (D‐Pan). In addition, the study (n = 780 in 7 arms) demonstrated superior immune response (0 and 21 day doses with A/Indo strain) with 3.8μg antigen adjuvanted with full dose adjuvant compared to 3.8 μg adjuvanted with ½ dose adjuvant as well as compared to the non‐adjuvanted formulations. Adjuvantation with both full and half strength AS03 was superior to non adjuvanted formulation. Half strength AS03 had only a modest effect on homologous immune response in 18 to 40 years age group, but led to a significant reduction in GMTs and SPR% in 41‐64 years age group.

Study 008 (n = 5075) was a safety study in adults and elderly with 2 administrations on Days 0 and 21 of 15 μg/AS03 formulation (A/Viet) compared to Fluarix with 6 months follow up as extension study 011. The initial safety signal for ‘new onset of chronic disease’ was reported in this study in elderly > 60 years old.

Study 010 (n = 437) was in elderly subjects >60 years (mean age 70 years; range 61‐89) with extension Study 021 for long term persistence. Subjects received single (3.8 μg) or double (2 x 3.8 μg) dose of adjuvanted or unadjuvanted vaccine (A/Viet) on days 0 and 21. The elderly population was noted to have a high anti HA antibody positivity (38%) to A/Vietnam (2% for A/Indo) at baseline. The adjuvanted vaccine at either dose met all criteria after one dose for the homologous strain and after 2 doses for the heterologous strain (except for SPR). The double dose adjuvanted vaccine (7.5/AS03) resulted in a greater immune response than the single dose adjuvanted vaccine (3.5/AS03). The response of 2 doses of 3.8 μg adjuvanted vaccine 21 days apart was better than a double dose given on same day. In seronegative subjects 2 doses of vaccine were required for the immune response to meet CHMP criteria.

Paediatric studies in 3‐9 year old children (stratified for 3‐5 and 6‐9 age) included study 009 (½ dose antigen/½ dose adjuvant; n = 138), study 022 (full dose antigen/½ dose adjuvant; n = 134) and study 023 (full adult dose i.e. 3.8/AS03; n = 133). The study used the A/Viet vaccine strain. The 2 dose primary vaccinations on days 0 & 21 resulted in fulfilling regulatory requirements (SCR, SCF, SPR) against the homologous A/Viet strain and SCR and SCF against the heterologous (A/Indo) strain. Declining titres were noted with follow up to 24 months.

This submission included 2 new paediatric studies as follows.

Study 013 (n = 120) was in 6‐35 months old children (stratified age categories 6‐11 months, 12‐23 months, 24‐35 months; mean age 17 (SD 9) months) in which heterologous prime boost strategy was examined, consisting of 2 primary doses (½ adult dose) at 0 and 21 days of adjuvanted A/Indonesia followed by a single booster (½ adult dose) of adjuvanted A/Turkey at 6 months (Day 182). Overall results (all age strata) were as follows (ATP cohort for immunogenicity) in Table 21.

Table 21: Study 013 data (ATP cohort for immunogenicity).

The results across the 3 age strata were generally consistent. The Day 21 (i.e. post dose 1) response appears not to have been reported.

Study 032 study (n = 520) was in 3‐17 years (mean age 9.5 (SD 4) years) old children (stratified age groups 3‐9 and 10‐17 years). A heterologous prime boost strategy was also adopted in this study, that is, 2 priming doses with ½ adult dose adjuvanted A/Indo followed by a single ½ adult dose booster at 6 months using adjuvanted A/Turk vaccine (hepatitis A vaccine control). Overall (that is, both age strata) results (total vaccinated Cohort) were as follows (results shown only for the group receiving 3 H5N1 doses) in Table 22.

Table 22: Study 032 data (ATP cohort for immunogenicity).

Three more studies were new to this submission (Studies Q‐Pan 009, 041 and 012).

Study Q‐Pan 009 (n = 312) was in adults (18‐60 years) conducted using 3.8/AS03 formulation (A/Indo) and compared 4 vaccination schedules, each consisting of 2 doses, that is, 0 and 21 day (Group A), 0 and 14 day (Group B), 0 and 7 day (Group C), and 2 doses on day 0 (Group D). The anti HA immune response was assessed 14 days post two doses in each schedule. The results, indicating efficacy of accelerated priming with 0, 14 dosing, were as follows in Table 23.

Table 23: Study 032 data (ATP cohort for immunogenicity).

Study 012 was another prime boost study (n = 512) in adults (18‐60 years) for assessing primary vaccination with 1 or 2 dose of 3.8/AS03 and booster at 6 or 12 months such that the following 8 groups were compared:

A/Viet at Day 0 and Month 6

A/Viet at Day 0 and Month 12

A/Viet at Day 0 and A/Indo at Month 6

A/Viet at Day 0 and A/Indo at Month 12

A/Viet at Days 0 & 21 and A/Viet at Month 6

A/Viet at Days 0 & 21 and A/Viet at Month 12

A/Viet at Days 0 & 21 and A/Indo at Month 6

A/Viet at Days 0 & 21 and A/Indo at Month 12

The results indicated that after single priming dose and a 6 month booster with heterologous strain, the regulatory requirements were met against the booster strain. A heterologous strain booster administered at 12 months after one or two priming doses provided satisfactory immune response.

Study 041 (n = 320) was a non inferiority trial in adults for thiomersal containing vs. thiomersal free formulation using vaccination schedule of 2 doses at 0 and 21 days (A/Indo 3.8/AS03). At 21 days after dose 2, the GMT ratio was 1.20 (95%CI 1.01, 1.42) indicating non inferiority (UL <2.0) between the 2 formulation. Both formulations met regulatory requirements for homologous A/Indonesia and heterologous A/Vietnam strains after 2 priming doses.

Safety

The total experience is based on 9,082 study participants consisting of 7,010 (H5N1/AS03), 558 (H5N1/unadjuvanted) and 1,514 (placebo or active control trivalent seasonal influenza vaccine Fluarix or hepatitis A vaccine Havrix) subjects.

The exposure of subjects to H5N1 vaccine antigen consisted of 6,657 (A/Vietnam), 1,319 (A/Indonesia), 512 (both A/Vietnam and A/Indonesia), 373 (A/Turkey) and 269 (both A/Indonesia and A/Turkey) vaccines.

Individual study results were presented.

In adults, the most common solicited (any grade) local reactions (within 7 days of vaccination) with H5N1/AS03 vaccine versus placebo (saline) respectively were injection site pain (83% versus 20%), injection site swelling (10% versus 1%) and injection site erythema (9% versus 1%).

The most common solicited (any grade) general adverse reactions (within 7 days of vaccination) with H5N1/AS03 vaccine versus placebo (saline) respectively were myalgia (45% versus 21%), headache (35% versus 28%), fatigue (34% versus 23%), arthralgia (25% versus 12%), shivering (17% versus 10%), sweating (11% versus 7%) and fever (5% versus 3%). The unsolicited AEs were reported during the 21 day post vaccination period and included (H5N1/AS03 vaccine versus placebo (saline), respectively) injection site pruritus (1.8% versus 0.4%), dizziness (1.4% versus 0.7%), injection site warmth (1.3% versus 0.2%), injection site reaction (0.6% versus 0.2%), and rash (0.6% versus 0.3%).

Serious adverse events (SAEs) through to 42 days (that is, 21 days post Dose 2) were reported in 0.5% recipients of H5N1/AS03 compared to 0.3% recipients of placebo. In safety follow‐up of up to one year, SAEs were reported in 3.3% recipients of H5N1/AS03 compared to 4.1% recipients of placebo.

In the paediatric studies, 300 children aged 3 to 9 years old received 592 doses, 520 children aged 3‐17 year olds received 728 priming and 156 booster doses and 113 children aged 6 to <36 months received 225 priming doses and 108 booster doses. A summary of results for the 2 new paediatric studies is as follows:

In Study 013, there was an increase in incidence of local reactions following each dose of study vaccine. Local symptoms (solicited and unsolicited) were reported in 32%, 34%, and 52% children following Dose 1, Dose 2, and Dose 3 (booster) respectively. Grade 3 symptoms (local, general, solicited or unsolicited) were reported in 4.5%, 5.4% and 17.6% children following Dose 1, 2 and 3, respectively. Other effects included injection site pain (28.6%, 33.3%, 49.1%), local redness (3.6%, 5.4%, 16.7%), fever (12.5%, 32.4%, 50.0%), grade 3 fever (1.8%, 5.4% 10.2%) and antipyretics use (31.0%, 50.0%, 65.7%) following dose 1, 2 and 3 respectively. MAEs were reported in 63.0% children 6 < 12 months of age, 55.9% children 12 < 24 months of age and 60.2% children 24 < 36 months of age for follow up to Day 364. The most frequently reported events were upper respiratory tract infections (23.0%), cough (17.7%), rhinorrhoea (10.6%), pyrexia (7.1%) and nasopharyngitis (7.1%). From Day 0‐364, seven SAEs including asthma (n = 2), upper respiratory tract infection, gastroenteritis (rotavirus), wheezing, pneumonia and bronchiolitis were reported in 5 children 6 < 12 months of age. Eleven SAEs including viral gastroenteritis, lobar pneumonia, second degree burns, gastroenteritis, upper respiratory tract infection (n = 2), viral gastritis, diarrhoea, bronchiolitis and dehydration (n = 2) were reported for 4 children 12 < 24 months of age. No fatal events or pIMDs were reported.

In Study 032, at least one AE (solicited or unsolicited) was reported in 84.6%, 88.5%, 76.0% and 58.7% children in Groups H5N1_H5N1 (Group 1), H5N1_Havrix (Group 2), Havrix_H5N1 (Group 3) and Havrix_Havrix (Group 4) respectively in the 7 days post vaccination observation period. Overall, at least one unsolicited AE with a medically attended visit (up to Day 182) was reported 115 children (36.9%; 95%CI 31.5%, 42.5%) in the pooled H5N1 groups (H5N1_H5N1 and H5N1_Havrix) and 64 children (30.8%; 95%CI 24.6%, 37.5%) in the pooled control groups (Havrix_H5N1 and Havrix_Havrix).

Injection site pain was reported in 81.4%, 82.7%, 70.2% and 51.0% respectively in children in the 4 groups, respectively.

In Group 1, local pain was reported in 67.9%, 59.6% and 67.3% children following Dose 1, 2, and 3, respectively. In Group 1, in children under 6 years of age, there was an increase in frequency of reported fever following Dose 2 and especially after Dose 3 with 10.0% & 0% reporting fever ≥38.0°C and ≥39.0°C respectively following Dose 1, and 13.3% and 6.7% following Dose 2 and 30.0% and 3.3% following Dose 3.

The most commonly reported MAEs were URTI (20.2% in pooled H5N1 versus 13.9% in pooled control groups), nasopharyngitis (4.2% in pooled H5N1 versus 3.4% in pooled control groups) and rhinitis (2.9% in each pooled group).

From Day 0 up to the Day 364 visit, SAEs were reported in 4 children (2.6%) in H5N1_H5N1 group, one child in H5N1_Havrix group and none in Havrix_H5N1 and Havrix_Havrix groups. The reported SAEs included bronchitis, gastroenteritis, periorbital cellulitis, typhoid fever, open wound, and asthma. No fatal events or pIMDs were reported. Pregnancy was reported for 6 participants during the study period until Day 364 with birth to healthy live infants in four and ongoing pregnancy in the remaining 2 participants.

Integrated summaries of safety (ISS)

The sponsor has submitted 2 integrated summaries of safety. The integrated analyses did not cover paediatric age group. The first analysis (ISS‐1) was completed in 2008 and consisted of eight H5N1 studies.

An expanded second analysis (ISS‐2) was completed in 2011 which included H1N1 studies in addition to the H5N1 studies with at least 6 months of post vaccination follow up. ISS‐2 comprised of 28 studies (including 15 controlled trials) of which 14 were H5N1 only trials (including 8 controlled trials).

The analysis of interest was occurrence of potential immune‐mediated diseases (pIMDs) in recipients of the adjuvanted H5N1/AS03 vaccine.

Based on a list of 122 MedDRA preferred terms (PTs) for pIMDs, an overall total of 57 pIMDs were retrospectively identified (28 studies) in 56 subjects including 43 pIMDs in 42 subjects in controlled trials.

Among the 42 pIMDs (diagnosis withdrawn by investigator in one case) reported in controlled trials, a total of 31 pIMDs occurred in the AS03 adjuvanted H5N1 or H1N1 recipients compared with 11 pIMDs in the control group (non adjuvanted H5N1 or H1N1 or saline or trivalent influenza vaccine recipients) indicating a relative risk (RR) of 1.69 (95%CI 0.81, 3.81) as follows in Table 24.

Table 24: Relative risk of pIMDs.

* AS03 adjuvanted H5N1 or H1N1 vaccine

** Controls = unadjuvanted H5N1 or H1N1 vaccine or placebo (saline) or seasonal trivalent influenza vaccine

Further stratified analysis of these data demonstrated that the treatment effect was entirely located in the AS03/H5N1 recipients (21/10,132) compared to the subjects in the control group (1/3164). The estimated RR was 6.85 (95%CI 1.10, 283.38).

There was no effect in AS03/H1N1 recipients (10/3193) compared to the subjects in the control (10/3197). The estimated RR was 1.00 (95%CI 0.37, 2.68).

Table 25: Subjects with any pIMD per PY.

The ISS‐2 analysis was provided to the US and Canadian regulators prior to approval in 2013 and was provided to the EMA as part of RMP at the time of renewal of registration in 2012.

Risk management plan

The EU‐RMP (Version 11, dated July 2013) with an updated ASA (dated 28 October 2014) applies to this submission. ACSOV advice was not sought for this submission. The submission is subject to a final agreement with RMP evaluators for any outstanding issues with respect to the RMP/ASA.

Risk-benefit analysis

Delegate’s considerations

This was a resubmission, with new data, of a previous submission for Prepandemrix (H5N1/AS03) vaccine which was withdrawn in 2008 because of insufficient data on persistence of immunity/need for booster and a safety signal for ‘New Onset of Chronic Disease’.

The current dossier includes adequate data with respect to persistence of immunity and the use of booster in adults, including vaccine strain homologous and heterologous anti HA immune response and functional (neutralising) antibody response, to support the proposed use. Thus this deficiency is considered to have been adequately addressed in this dossier.

Note that vaccine efficacy has not been determined as the infection is not occurring in general population. The dossier is based on immunogenicity endpoints modelled on the current criteria for seasonal influenza.

Although, there are substantial data in children (> 6months age), there is lack of clarity on optimum dose, vaccination schedule and booster, as well as sufficient concern because of very high reactogenicity and long term safety based on adult data in ISS‐2, to preclude its use in children and adolescents at present. A separate submission in future dealing with these issues in a comprehensive manner will be more appropriate.

The issue of association with ‘New Onset of Chronic Disease’, which has since evolved into a list of 122 MedDRA Preferred Terms for potentially immune mediated diseases, remains unresolved.

The magnitude of RR estimated in ISS‐2, for pIMDs in association with the use of Prepandrix (H5N1/AS03) was 6.85 fold (95%CI 1.1, 283) in controlled clinical trials.

The sub‐analyses also demonstrated that the higher RR was not associated with the use of H1N1/AS03 (RR 1.0, 95%CI 0.37, 2.68).

The ISS‐2 was completed in 2011. The sponsor has confirmed that no additional data are available.

The sponsor provided detailed arguments about the limitations of the ISS‐2 analysis (including the sponsor’s slide presentation in a teleconference following completion of Round 2 evaluations and record of the meeting). These arguments include exploratory nature of the AEs disproportionality analysis, which was post hoc and did not take multiplicity into account. The analysis was intended for hypothesis generation and was necessarily biased towards identification of safety signal.

It is also argued that the comparator groups were not balanced (3 times more participants in H5N1/AS03 (n = 10,132) group than in the ‘no AS03’ control (3,164) group) which increased the likelihood of reported rare events in H5N1/AS03 group compared to controls. It is shown that balanced comparison such as that between AS03/H1N1 (n = 3193) and controls (n = 3197) indicated similar frequency of pIMDs in both groups (Table 26).

Table 26: Number of subjects included in the ISS‐2.

The sponsor has also sought to argue against imputation of study vaccine related causality for the reported pIMDs based on the WHO Global Advisory Committee on Vaccine Safety (GACVS) criteria in terms of consistency of effect, strength of association, temporality, specificity and biological plausibility.

Furthermore, a descriptive analysis of the reported pIMDs and an internal review (‘sensitivity analysis’) undertaken by the sponsor to validated the reported events led to a reduced incidence of 12 events in place of the reported 21 in H5N1/AS03 group and 0 in place of the reported single event in controls with undefined RR (slides 17‐18). The events of polymyalgia rheumatica and VIIth nerve palsy were the only events with occurrence of more than one. The sponsor has also noted that (letter of application) pIMDs were reported predominantly in females (24 of 31 subjects with reported pIMDs).

The Delegate is of the view that limitations such as post hoc analyses and multiplicity are not of relevance in assessment of safety in the case of a vaccine where the concern is a potential association with serious chronic adverse outcome such as immune related disease. This heightened concern for safety is further underscored where the baseline risk of disease is not known, clinical efficacy cannot be determined and the proposed use is in pre pandemic phase.

The imbalance in comparator groups is an important consideration. However, the magnitude of difference in incidence (21 events in 10,132 H5N1/AS03 subjects versus 1 endpoint in 3,164 controls) cannot be explained by the 3 fold imbalance in the number of subjects in the two groups.

In addition, the imbalance was not reflected in estimated RRs for MAEs, Grade 3 MAEs, SAEs and deaths based on the same dataset (Table 27).

Table 27: MAEs, Grade 3 MAEs, SAEs and deaths.

Furthermore, the residual imbalance in events persisted (12 pIMDs in H5N1/AS03 versus none in controls) even after a vigorous internal review was undertaken by the sponsor.

Regarding the WHO GACVS criteria, in my view none of the causality criteria can be adequately shown to indicate a lack of association/causality between H5N1/AS03 and pIMDs as asserted by the sponsor.

In fact, consistency (pooled data from 8 controlled trials), strength (RR ≈ 7), temporality (prospective, controlled, clinical trials), specificity and biological plausibility (potential immune related mechanism for all reported events) all favour consideration of existence of a potential association.

Proposed action

The Delegate is of the view that the RR estimate of pIMDs based on ISS‐2 is sufficiently robust, reliable and large to be of clinical concern so that the overall risk/benefit of the H5N1/AS03 vaccine (Prepandrix) for the proposed pre‐pandemic use is not favourable.

Although consideration may be given to a qualified indication (“Active immunisation against A/Indonesia/05/2005 (H5N1) subtype of Influenza A virus contained in the vaccine in persons 18 years of age and above at increased risk of exposure. This indication is based on immunogenicity data in healthy subjects. Prepandrix should be used in accordance with official recommendations”) along with inclusion of the ISS‐2 results in the PI, this approach does not control or modify the identified risk. Additional factors favouring registration include high mortality associated with H5N1 infection and the antigen sparing advantage of the vaccine (3.75 μg per 0.5mL dose) for an egg grown virus.

Submitted to the ACPM for advice.

Request for ACPM advice

The Delegate is seeking advice from the ACPM prior to proposing action regarding registration of this vaccine.

Does the Committee agree that the estimate of relative risk of pIMDs (RR 6.85, 95%CI 1.1, 283) obtained in ISS‐2 is a valid safety signal and of sufficient clinical concern to preclude approval of Prepandrix for pre pandemic use?

Response from sponsor

Executive summary

There is substantial public health impact due to pandemic influenza and therefore there is a need for immunogenic vaccines, such as Prepandrix to protect people in the event of a pandemic threat or to protect people at increased risk of H5N1 infection.

Prepandrix (D-H5N1)¹⁷ was approved by the EMA on 14 May 2008. EMA has also approved the pandemic vaccine, Adjupanrix (D-H5N1)¹⁸ on 19 October 2009.

Health Canada and the FDA approved the sponsor’s Q-H5N1¹⁹ pandemic vaccine, on 13 February 2013 and 22 November 2013 respectively, with flexibility in the label to use in a prepandemic setting if required by the Government. Of note, the US advisory committee (VRBPAC) voted 14-0 in favour of approval of the immunogenicity and safety of the vaccine.

Both Round 1 and 2 TGA clinical evaluation reports included the clinical evaluator recommending approval of Prepandrix; the revised indication being “Active immunisation of adults against H5N1 subtype of influenza A virus. Prepandrix should be used in accordance with official recommendations”. The TGA notified the sponsor on 4 March 2015 that the application would not be referred to ACPM for advice, however, a late request for ACPM advice was made on 18 March 2015 to address the risk associated with developing pIMDs with Prepandrix use.

The Delegate is restricting ACPM advice to this safety concern prior to making a decision on the registration of Prepandrix. No issue with efficacy data has been raised. The sponsor contends that Prepandrix should be registered based on the following:

The extensive clinical data package has demonstrated the favourable quantitative and qualitative immunological responses supportive of the intended use of the vaccine;

The clinical trial safety database of 22,521 subjects who received an AS03 adjuvanted H5N1 or H1N1 influenza or control vaccine could not establish a causal relationship between H5N1 adjuvanted vaccination and pIMDs;

Statements on the risk of pIMDs have been added to the Australian PI for Health Care Professional awareness;

A robust RMP is in place to manage the known and potential risks; and

Supply of Prepandrix will be restricted for use either before a pandemic is declared, potentially including persons at risk of exposure to H5N1 virus through laboratory or field work, or in the early stages of a declared pandemic in accordance with official recommendations. Prepandrix will not be commercialised privately in Australia.

The Delegate noted that “Additional factors favouring registration [of Prepandrix] include high mortality associated with H5N1 infection and the antigen sparing advantage of the vaccine (3.75 μg per 0.5 mL dose) for an egg grown virus.”

A clinical opinion has been sought from a leading Australian vaccine expert with respect to the specific question on pIMDs raised by the Delegate and his opinion supports registration.

The sponsor’s viewpoint is that in a public health emergency, where an H5N1 pandemic is anticipated or there is an increased risk, the benefit-risk profile of vaccination with Prepandrix is favourable.

Regulatory history

The sponsor completed an Integrated Summary of Safety (ISS) in 2009 (ISS-1) and in 2011 (ISS-2) as exploratory analyses for hypothesis generation of rare AEs such as pIMDs that might be associated with vaccination; intentionally biased toward identifying safety signals.

ISS-1 included data from 12,917 subjects 18 years of age or older enrolled across 8 clinical studies, of which 9,873 subjects received either D-H5N1 or Q-H5N1. The analysis did not reveal any unexpected safety findings. There was a numerical imbalance for pIMDs associated with receipt of H5N1 vaccine though 95% CIs included 1.0; a causality analysis failed to support a causal relationship. ISS-1 was previously evaluated by the TGA for the Arepanrix licence (Q-H5N1, registered 22 February 2011).

ISS-2 included data from 22,521 subjects 18 years of age or older enrolled across 28 studies, with 16,160 subjects receiving adjuvanted H5N1 or H1N1 vaccine. The purpose of this analysis was to enlarge the adjuvanted pandemic vaccine dataset from the previous ISS-1 by also including data from the adjuvanted H1N1 vaccine programs. As for ISS-1, ISS-2 was an exploratory analysis seeking to identify potential safety signals and, as such, used composite endpoints (for example, pIMDs consisting of 122 MedDRA preferred terms) and has the limitation that statistical corrections for multiplicity were not applied. ISS-2 was included in the Prepandrix application.

EMA, Health Canada and FDA evaluated the ISS-2 data and have raised no major safety concerns in relation to pIMDs.

EMA: In review of an annex to the Prepandrix EU-RMP version 10, the EMA concluded that “no signals of serious AEs or AEs of special interest/with potential immune-mediated causation have been confirmed for Prepandrix”. Prepandrix licence was subsequently renewed in 2012 for a period of 5 years in accordance with the standard renewal procedure.

Health Canada: For registration of the Q-H5N1 pandemic vaccine, five of the nine questions raised by Health Canada concerned pIMDs with Health Canada concluding that: (a) the ISS-2 data is not adequately powered and must be interpreted with caution, and (b) a causal relationship is unlikely. Health Canada approved the vaccine on 13 February 2013.

FDA: For registration of the Q-H5N1 pandemic vaccine, the FDAs advisory committee (VRBPAC) unanimously voted (14-0) in favour of approval for a label that allowed the use of the vaccine in a prepandemic setting if required by the Government (for example, population at risk like laboratory workers or those deployed to outbreak areas). FDA approved the vaccine on 22 November 2013.

The TGA clinical evaluator recommended approval of Prepandrix for use in adults in a pandemic situation subject to the finalisation of the PI to the satisfaction of the TGA noting that “... the benefit-risk balance for Prepandemrix/Prepandrix pandemic H5N1 influenza vaccine use in adults is favourable”. Two positive clinical evaluation reports were issued, neither of which highlighted any significant safety concerns to preclude registration of the vaccine.

The sponsor was informed that Prepandrix would not be referred to the ACPM. This decision was reversed following further deliberations by the Delegate, who raised concern on the apparent risk of pIMDs developing post vaccination which was based on the ISS-2 data set. Following a teleconference meeting between the TGA and the sponsor on 16 April 2015, in which the sponsor further clarified the ISS-2 data with respect to pIMDs and also shared the EMA, Health Canada and FDA feedback on ISS-2, the Delegate’s view was modified (GSK Presentation). The Delegate seeks advice from the ACPM, as to whether the risk associated with developing pIMDs is acceptable for a prophylactic vaccine. The Delegate has indicated that were the ACPM to deem the risk of pIMDs acceptable for a pre pandemic vaccine, they would align and recommend registration of Prepandrix.

Specific question raised by delegate for ACPM advice

Does the Committee agree that the estimate of relative risk of pIMDs (RR 6.85, 95%CI 1.1, 283) obtained in ISS-2 is a valid safety signal and of sufficient clinical concern to preclude approval of Prepandrix for pre pandemic use?

The only outstanding issue remaining with the Prepandrix application is the risk of pIMDs with H5N1 containing vaccines. Specifically, the concern relates to the higher RR of pIMDs observed in ISS-2 in the H5N1 subgroup (RR = 6.85, 95% CI 1.10, 283.4).

The sponsor’s position is that the results of ISS-2 do not support a causal association between the use of AS03 adjuvanted H5N1 influenza vaccines and pIMDs, although small increases in the risk of such events cannot be ruled out. In the setting of an advancing pandemic where persons are at increased risk of exposure, with attendant morbidity, mortality, and economic and social disruption, the benefit-risk profile associated with vaccination is deemed acceptable.

The sponsor’s view is supported by the Clinical Evaluator: “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.”

The opinion of a leading Australian vaccine expert, consultant general paediatrician, and medical head of immunisation services supports registration. This expert states:

I do not believe the relative risk of pIMDs RR 6.85, 95% CI 1.1, 283) obtained in ISS-2 is of sufficient clinical concern to preclude approval of Prepandrix for pre pandemic use.

Acceptable AE safety profile

In ISS-2, no differences were evident across the H5N1, or combined H5N1/H1N1 AS03 adjuvanted vaccine groups compared to control groups for MAEs, grade 3 MAEs, or SAEs which was acknowledged by the clinical evaluator. Of note, the total number of such events collected during the H5N1 clinical trials was much higher compared to pIMDs (for example, in controlled studies MAEs were reported by 1,865 subjects who received H5N1 vaccine and by 557 subjects who received control). For individual preferred terms reported less frequently, numerical imbalances in the analyses of MAEs and other events were detected as well, either towards the vaccine group or to the control group.

Even though the H5N1/H1N1 combined analysis as well as the separate H1N1 analysis showed no increased relative risk, a higher relative risk of pIMDs was observed in the H5N1-AS03 adjuvanted vaccines subgroup (RR 6.85; 95% CI: 1.1, 283.4) compared to the control group (see table below). Overall, the data supports the notion that imbalance allocation of subjects across groups (approximately 3 to 1) in H5N1 trials may have contributed to differences in RRs for rare events such as pIMDs (Table 28).

Table 28: Number of subjects reporting pIMDs and estimated RR.

The pIMDs are a subset of AEs that include both autoimmune diseases and other inflammatory and/or neurologic disorders which may or may not have autoimmune etiologies. For the ISS-2, a total of 57 pIMDs were identified for 56 subjects (from controlled, uncontrolled and booster studies), of which 16 subjects were included from ISS-1, 15 additional subjects were identified from more recent H5N1 studies and 25 subjects with new pIMDs were from H1N1 studies.

Limitations of ISS-2

The sponsor re-iterates that the rationale behind ISS-2 was to maximise sensitivity for hypothesis generation and caution should be taken in interpreting the imbalances seen for the composite endpoint of pIMDs. Specifically the latter is addressed by the following:

Unbalanced subject allocation and duration of safety follow up in H5N1 studies: More subjects received the vaccine compared to controls. The follow up for H5N1 studies was 5,672 person-years for vaccine recipients versus 1,771 person years for control recipients. In contrast, for the majority of the H1N1 studies, the randomisation was 1:1 between vaccine and control recipients. The follow up for H1N1 studies was 3,175 person-years for vaccines versus 3,192 person years for control recipients. This results in an increased likelihood of capturing rare events in H5N1 groups relative to controls.

Composite vaccines: Data originated from 4 different vaccines, 4 influenza virus subtypes, 5 vaccine antigen dosages, 2 adjuvant dosages, and 4 control products.

Composite endpoint: pIMDs = 122 preferred terms encompassing diseases of different pathophysiological pathways (9 MedDRA system organ classes).

Evolution of methodology for collection and analyses of pIMDs: Prior to 2009, collection and analyses of pIMDs was not standardised. Investigators were requested to identify “New Onset Chronic Disease” which covered a much broader range of events including several non immune mediated AEs. For the purpose of these ISSs, a search of the clinical database for the 122 pIMD preferred terms was done retrospectively for the H5N1 studies without an opportunity to seek clarification from investigators. In contrast, for H1N1 studies, a standardised prospective method was agreed with FDA and applied.

Multiplicity was not considered for analyses of disproportionality: Each 95% CI of RR that excluded 1.0 was accepted as suggestive of a potential treatment effect without adjusting for the risk for false positive signals (for example, several MAEs were associated with receipt of control product).

Conservative approach for hypothesis (signal) generation: All pIMDs reported in the studies were included for the analyses. This included pIMD reports that were assessed as pre existing, occurred late, with a diagnosis later changed by the investigator, or attributable to another cause. Furthermore, a signal was considered present for RR with non overlapping 95% CIs; for such events causality assessments were conducted as set forth by Hill in 1965²⁰ and applied to vaccines in 2001 by the World Health Organization (WHO) Global Advisory Committee on Vaccine Safety (GACVS).

No causal relationship confirmed for the association of pIMDs with H5N1 adjuvanted vaccines

GSK contends that it is not possible to determine causality for the association of pIMDs with adjuvanted H5N1 vaccines given the number of subjects included in the vaccine development and the low incidence of such events. The WHO GACVS criteria for causality were applied as summarised below:

Consistency (a purported AE should be replicable in different localities, by different investigators, using different methods): The assessment of AEs, such as pIMDs, occur at incidence rates too low to be evaluated in individual clinical trials (facial palsy ~25 per 100,000; ulcerative colitis ~9 per 100,000) and thus do not allow for a comparison across multiple clinical trials and by different clinical investigators. This was the rationale for pooling several clinical trials into an ISS, which is exploratory in nature and seeks to identify potential safety signals. The pooled studies use different study design, different influenza pandemic antigens (origin as well as amount), different adjuvant strength, different controls and are conducted in different populations. Therefore, the small number of individual pIMDs precludes a robust assessment of consistency; the composite endpoint of all pIMDs occurred in only 56 subjects overall (42 subjects in controlled studies).

By increasing the size of the data set from ISS-1 (controlled H5N1 studies that included 7,224 vaccinees and 2,408 control subjects) to ISS-2 (size increased primarily through addition of data from H1N1 studies with n = 13,325 vaccinees plus 6,361 control subjects), there was a regression towards the mean from a RR of 4.67 for pIMDs in ISS-1 with numbers of subjects as the denominator (broad 95% CI of 0.71 to 196.08) to 1.69 (0.81, 3.81) with safety follow-up in person-years as the denominator.

Incidence rates of new onset pIMDs or worsening of pIMDs may have been unexpectedly low in the H5N1 study control groups based on the following: Rates reported were similar to background rates in the literature. ISS-1 rates among adjuvanted vaccine recipients were similar to rates in a historical control group of 11,721 subjects receiving licensed TIV or saline. The rates for H1N1 studies (315 per 100,000 person-years for vaccines and 313 per 100,000 person-years for H1N1 for control recipients) suggest that the rates in H5N1 vaccine recipients (370 per 100,000 person-years) may be appropriate while the rate among H5N1 study controls (56 per 100,000 person-years) was low.

Strength of the association (that is, the proposed association with the AE should be strong in magnitude with a dose response relationship): None of the calculated RRs for the 24 individual pIMDs identified among 122 monitored preferred terms in controlled studies suggested an increased risk (neither for H1N1+ H5N1 nor H5N1 alone). The ISS approach did not consider the statistical uncertainties introduced by multiplicity.

Temporal relation (there should be a clear temporal relationship between the AE and vaccine): All studies included in the ISSs were prospective clinical trials. The assessment of temporal relationship was done by assessing time to onset of events after vaccination. There was no consistency or distinctive patterns with respect to time to onset (varying from Day 0 to 2 years post vaccination) or clustering of reported events.

Specificity (an association with the AE should be distinctive, uniquely linked to the vaccine concerned): In ISS-1, the sponsor cited a historical cohort with similar rates of pIMDs as seen for H5N1. Rates observed were similar to reported background rates. pIMD is a composite endpoint encompassing events corresponding to 122 preferred terms of which 15 preferred terms (or groupings of preferred terms) were identified in H5N1 studies. Of note, 12 of 15 preferred terms (or groupings) identified occurred only once. Specificity of diagnosis as a post vaccination occurring event of immune-mediated pathogenesis was questionable for many specific individual diagnoses as discussed in the next section.

Biological plausibility (the association should be biologically coherent and consistent with the biology of the disease): The mechanisms of action for AS03 adjuvant do not support the plausibility of inducing autoimmune disease as there is no direct activation of T and B cells and unlike, Alum, AS03 does not promote cell necrosis minimising presence of self antigen. In addition, the different etiological/pathophysiological mechanisms among the observed pIMDs do not support one mechanism of action. Some are thought to be prominently antibody mediated (Hashimoto), others T cell mediated (rheumatoid arthritis) as well as others primarily non-immunologic (infectious causes for uveitis). This is line with our expert’s opinion:

The aetiology of these pIMD conditions is also highly variable, with some primarily antibody mediated and others believed to be T-cell mediated or even primarily non-immunologic.

The clinical evaluator accepts the sponsor’s position noting:

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.

The sponsor contends that data from ISS-2 are insufficient to assess the likelihood of a causal relationship between H5N1 AS03 adjuvanted vaccine and pIMDs. For individual pIMDs, currently available data and available information do not support a causal association. To this point, the clinical evaluator has also stated there may be a

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.

Few cases of pIMDs with adjuvanted H5N1 vaccines

A GSK internal panel performed a further analysis of the 21 reported pIMDs in the H5N1 AS03 adjuvanted group. This review found that many case reports, although included in the analysis, did not fulfil the exposure-response criterion for a causal association (either the event did not constitute a pIMD (radiculitis likely to be a radiculopathy from spinal nerve compression for example), or the onset was prior to vaccination without worsening, or the onset was too rapid to be immune mediated, or there was another more likely cause for the event). Twelve subjects (out of 21 in the initial analyses) from the H5N1 group were retained and the corresponding RR was not calculable with a 95% CI: 0.89, 283 (INF). Of the 12 subjects, 8 subjects (case reports) came from the H5N1 group from the original analysis for ISS-1 and only 4 new cases were reported in ISS-2. Six of the 12 study subjects received D-Pan H5N1 with 2 subjects with polymyalgia rheumatic, and one subject each with facial paralysis, Basedow’s disease, uveitis, and scleroderma.

Robust risk management

1. Restricted distribution of Prepandrix

The supply of Prepandrix will be restricted for use either immediately before a pandemic is declared, potentially for use in persons at risk of exposure to H5N1 virus through laboratory or field work, or in the early stages of a declared pandemic, and used in accordance with recommendations issued by the Australian Government and Public Health Authorities, thus allowing the establishment of stockpiles for the Government. Prepandrix will not be commercialised privately thereby limiting access of the vaccine to the general public.

2. Ongoing safety monitoring of pIMDs

Through implementation of the EU-RMP (version 11) with an ASA (version 1.0), the sponsor commits to continue the monitoring of pIMDs. As per CHMP recommendations,²¹ a limited list of pIMDs is currently explicitly included within the list of potential risks in the EU-RMP (that is, autoimmune hepatitis, Bell’s palsy, preferred terms under demyelinating disorders, encephalitis, Guillain Barré syndrome, neuritis and vasculitis) in addition to narcolepsy. The sponsor commits to amend the listing of potential risks in the RMP to include all of the sponsor’s predefined pIMDs and monitor them by routine and enhanced pharmacovigilance in both pre pandemic and pandemic settings. The anticipated benefit of vaccination with Prepandrix during an H5N1 influenza pandemic, and the acceptable safety profile demonstrated in clinical trials, which continues to be monitored through the EU RMP, supports a positive benefit-risk profile.

Conclusion

Vaccines are recognised as the single most effective intervention for preventing influenza-associated morbidity and mortality during a pandemic. In view of the case fatality rate of over 50% following confirmed H5N1 infections, availability of Prepandrix (D-H5N1) for pre-pandemic use would address the public health need in a pre pandemic setting. The safety data should be assessed in its entirety, giving due consideration to the intended purpose of use, to protect people at increased risk of exposure and to provide protection in the period between the identification of a pandemic and the availability of a matched-strain pandemic vaccine, which is aligned with the US and Canadian approvals of a similar vaccine. The sponsor asserts that the clinical data submitted supports a favourable benefit-risk assessment for the registration of Prepandrix for use in adults.

Advisory committee considerations

The ACPM resolved to recommend to the Delegate that the evidence provided in the sponsor’s submission did not satisfactorily establish the safety and efficacy of Prepandrix (formerly Prepandemrix), emulsion and suspension for emulsion for injection, containing 3.75 μg of the new biological entity, pre pandemic influenza vaccine (split virion, inactivated, A/Indonesia/05/2005 PR8-IBCDC-RG2 (H5N1, Clade 2.1) and 0.25 mL AS03 adjuvant.

The ACPM taking into account the submitted evidence of pharmaceutical efficacy, safety and quality considered this product to have an overall negative benefit-risk profile in the proposed population for pre pandemic use.

In making this recommendation, the ACPM:

Noted the sponsor’s arguments including that the product will only will be used in accordance with the official recommendations where the balance of risk and benefit would be different.

Expressed concern that the safety signal noted in the earlier 2007 dossier had, if anything, become clearer based on the relative risk reported with larger dataset in the current dossier.

Was of the view that there is a substantial safety signal and its use particularly in a healthy population would be unwarranted.

Specific advice

The ACPM advised the following in response to the Delegate’s specific questions on this submission:

Does the Committee agree that the estimate of relative risk of pIMDs (RR 6.85, 95%CI 1.1, 283) obtained in ISS-2 is a valid safety signal and of sufficient clinical concern to preclude approval of Prepandrix for pre-pandemic use?

The ACPM advised there is clearly a safety signal; there were an unusual range of AEs including several AEs where the baseline rate would be very low and some AEs that appear related (for example, radiculitis, mononeuritis, uveitis, neuritis).

The Australian Health Management Plan for Pandemic Influenza (AHMPPI) notes that pre-pandemic vaccines would be prioritised to “individuals at greater risk, such as healthcare workers, or individuals at high risk of severe outcomes” in the early stages of a pandemic. It further notes that “Acceptability will depend on public perception of the impact of the pandemic and candidate vaccine safety”. Particularly in otherwise healthy “first responders”, the clear safety signals in the use of this product are a substantial risk.

Outcome

On 3 September 2015, GlaxoSmithKline Australia Pty Ltd wrote to the TGA asking for the application for Prepandrix (formerly Prepandemrix) to be withdrawn.

Attachment 1. Extract from the Clinical Evaluation Report

Therapeutic Goods Administration

PO Box 100 Woden ACT 2606 Australia Email: [e-mail] Phone: [phone] Fax: [phone] https://www.tga.gov.au

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10^ European Medicines Agency, “European Medicines Agency reviews hypothesis on Pandemrix and development of narcolepsy (EMA/CHMP/676755/2012)”, 22 October 2012.

11^ European Medicines Agency, “Guideline on influenza vaccines: Non-clinical and clinical module (EMA/CHMP/VWP/457259/2014)”, 25 July 2014.

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16^ European Medicines Agency, “CHMP Recommendations for the Pharmacovigilance Plan as Part of the Risk Management Plan to be Submitted with the Marketing Authorisation Application for a Pandemic Influenza Vaccine (EMEA/359381/2009)”, 25 September 2009.

17^ GSK has two pre(pandemic) H5N1 vaccines, one produced at the Dresden (Germany) manufacturing facility (D-H5N1) and the other produced at the Quebec (Canada) manufacturing facility (Q-H5N1). Both are adjuvanted with Adjuvant System 03 (AS03).

18^ GSK has two pre(pandemic) H5N1 vaccines, one produced at the Dresden (Germany) manufacturing facility (D-H5N1) and the other produced at the Quebec (Canada) manufacturing facility (Q-H5N1). Both are adjuvanted with Adjuvant System 03 (AS03).

19^ GSK has two pre(pandemic) H5N1 vaccines, one produced at the Dresden (Germany) manufacturing facility (D-H5N1) and the other produced at the Quebec (Canada) manufacturing facility (Q-H5N1). Both are adjuvanted with Adjuvant System 03 (AS03).

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21^ European Medicines Agency, “CHMP Recommendations for the Pharmacovigilance Plan as part of the Risk Management Plan to be submitted with the Marketing Authorisation Application for a Pandemic Influenza Vaccine (EMEA/359381/2009)”, 25 September 2009.