Summary Basis of Decision for Ixiaro ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Ixiaro®
Japanese encephalitis vaccine (inactivated, adsorbed), 6 µg/0.5 mL, Suspension, Intramuscular
Intercell AG
Submission control no: 120330
Date issued: 2010-07-20
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02333279
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On October 29, 2009, Health Canada issued a Notice of Compliance to Intercell AG for the vaccine Ixiaro®.
Ixiaro® is a purified and inactivated Japanese encephalitis whole virus vaccine derived from the attenuated Japanese encephalitis virus strain SA14-14-2.
Ixiaro® is indicated for active immunization against Japanese encephalitis for persons 18 years of age and older. Ixiaro® should be considered for use in individuals at risk of exposure through travel or in the course of their occupation. Japanese encephalitis is one of the most common types of viral encephalitis in Asia and over 50,000 cases are reported annually worldwide. Ixiaro® triggers the immune system to produce antibodies against the Japanese encephalitis virus that are most often protective.
The market authorization was based on quality, non-clinical, and clinical information submitted. Two pivotal studies as well as several supporting clinical studies were evaluated to assess the immunogenicity and safety of Ixiaro®. The first pivotal study (IC51-301) was a Phase III, randomized, active-controlled, observer-blinded, non-inferiority study which compared the immunogenicity of Ixiaro® to Je-Vax®, a comparable Japanese encephalitis vaccine. Subjects in the Ixiaro® group (n = 365) were given one 0.5-mL intramuscular (IM) injection of Ixiaro® on Day 0 and Day 28, as well as one 0.5-mL IM injection of placebo on Day 7. Subjects in the Je-Vax® group (n = 370) were given one subcutaneous injection of Je-Vax® on Day 0, Day 7, and Day 28. By Day 56, both treatment groups exhibited a good immune response and the immune response elicited by Ixiaro® was non-inferior to that induced by Je-Vax® . The second pivotal study (IC51-302) was a Phase III, randomized, placebo-controlled, double-blind, multicentre study that investigated the safety and tolerability of Ixiaro®. Subjects were randomized to receive one IM injection of Ixiaro® on Day 0 and Day 28 (n = 1993) or one IM injection of placebo on Day 0 and Day 28 (n = 657). Local symptoms were most common on Day 0, decreasing over time for both treatment groups. The incidence for most reported symptoms on Day 1 after vaccination was slightly higher in the Ixiaro® group; however, Ixiaro® was generally well tolerated and most reactions were mild.
Ixiaro® is presented as suspension for injection in a single-dose pre-filled syringe. Each 0.5-mL dose of Ixiaro® contains 6 µg of purified, inactivated, Japanese encephalitis virus preparation and 0.1% aluminium hydroxide as an adjuvant, hydrated corresponding to 0.25 mg aluminium per dose. The vaccine is administered intramuscularly as two doses given four weeks apart. Dosing guidelines are available in the Product Monograph.
Ixiaro® is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Individuals who show hypersensitivity reactions after receiving the first dose of the vaccine should not be given the second dose. As with other vaccines, Ixiaro® must be postponed in persons with acute severe febrile conditions. Ixiaro® should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Ixiaro® are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Ixiaro® is favourable for the active immunization against Japanese encephalitis for persons 18 years of age and older.
3 Scientific and Regulatory Basis for Decision
A Notice of Deficiency (NOD) was issued on February 9, 2009 for the New Drug Submission (NDS) for Ixiaro® as deficiencies and/or significant omissions, specifically in terms of chemistry and manufacturing information, precluded the review of the NDS.
The sponsor addressed all issues of concern in their response to the NOD received May 5, 2009. The response to the NOD was accepted on May 14, 2009 and a screening acceptance letter was issued.
3.1 Quality Basis for Decision
General Information
Ixiaro® is a vaccine against Japanese encephalitis. It contains whole, inactivated virus derived from the attenuated Japanese encephalitis virus (JEV) strain SA14-14-2.
The JEV is a mosquito-borne virus that belongs to the genus Flavivirus and the family Flaviviridae, which includes yellow fever and dengue viruses. Once an individual is infected with JEV, he or she can develop JE disease. Studies in animals have shown that Ixiaro® triggers the immune system to produce antibodies against JEV that are most often protective.
3.1.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
The vaccine is prepared by propagating the attenuated JEV strain (SA14-14-2) in Vero cells. Virus harvests are collected, filtered, and concentrated by ultrafiltration. The virus suspension is treated to remove contaminating deoxyribonucleic acid (DNA) followed with purification by sucrose gradient centrifugation. The purified virus is then inactivated through treatment with formaldehyde and adjusted to a specified protein concentration with phosphate-buffered saline (PBS).
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that the purified, inactivated JEV preparation consistently exhibits the desired characteristic structure and biological activity.
The sponsor has provided a summary of all drug-related impurities. Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substance. The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
Stability
Stability data for the drug substance were not required as there is no holding time.
3.1.2 Drug Product
Description and Composition
Ixiaro® is a purified inactivated, aluminium hydroxide adsorbed sterile vaccine suspension for IM immunization. Each 0.5-mL dose of Ixiaro® contains 6.0 µg of purified inactivated JEV preparation and 0.1% aluminium hydroxide, hydrated corresponding to 0.25 mg aluminium/dose. The aluminium hydroxide excipient is an adjuvant that is commonly used in human vaccines to enhance the immunological response. Ixiaro® does not contain any preservatives or antibiotics.
The final vaccine is supplied in pre-filled syringes that contain a 0.5-mL single dose. The syringes are made of Type I borosilicate glass and are equipped with a Luer Tip and cap both tested according to European Pharmacopoeia (Ph.Eur.) and United States Pharmacopeia (USP) requirements.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable.
Changes to the manufacturing process and the formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The final vaccine is formulated by mixing the drug substance bulk with a 0.1% aluminium hydroxide adjuvant to form the final bulk vaccine. Once mixed, the final bulk vaccine is transported to the filling plant where the syringes are aseptically filled, stoppered, labelled, packaged and stored.
The validated process is capable of consistently generating product that meets release specifications.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Ixiaro® is tested to verify that its identity, appearance, pH, sterility, protein content, extractable volume, bacterial endotoxins, pyrogenicity, potency, aluminium content, free formaldehyde content, and degree of adsorption are within acceptance criteria. In addition, a general safety test is conducted by administering Ixiaro® to mice and guinea pigs prior to lot release and analysing its effects.
The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product. Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, an 18-month shelf-life at 2 to 8°C for Ixiaro® is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
An on-site evaluation of the facilities involved in the manufacture and testing of Ixiaro® has been conducted by the Biologics and Genetic Therapies Directorate, Health Canada .
The design, operations and controls of the facilities and equipment that are involved in the production of Ixiaro® are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
The excipients used in the drug product formulation are not from animal or human origin. Adequate programs are in effect that provide sufficient and often redundant control steps applicable to all classes of relevant adventitious agents, thus ensuring the safety of Ixiaro® with respect to adventitious viral and non-viral agent contamination.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Ixiaro® has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Immunogenicity
Studies to assess the immunogenicity of Ixiaro® were conducted in mice, rats, and rabbits. Ixiaro® was immunogenic when administered subcutaneously or intraperitoneally in mice, and intramuscularly in rats and rabbits. A dose-related increase in immunogenicity occurred with increasing doses of Ixiaro® .
Lethal Challenge
Further studies in mice evaluated active protection following immunization, passive protection following injection of human Ixiaro® antisera (pooled human serum from volunteers vaccinated with Ixiaro® ), and cross-protection to different strains of JEV following lethal challenge with JEV. Efficacy was based on the number of mice that survived 21 days after the JEV challenge.
Active protection was evaluated in challenge studies in mice that were immunized twice, 2-weeks apart, with different concentrations of Ixiaro® . Following immunization, the mice were challenged with a lethal dose of the wild-type JEV strain SA14. The results demonstrated a dose-related increase in protection against lethal challenge.
In a second study, Ixiaro® and Je-Vax® (a comparable JEV vaccine) were administered to mice at various doses following a similar protocol as described above . The vaccines were evaluated for their ability to protect mice against lethal challenge with the JEV strains SA14 and Beijing. Ixiaro® provided equal or better protection than Je-Vax® against both JEV strains.
In passive-protection studies, mice were administered human Ixiaro® antisera diluted 1:2 with non-immune human serum for the high titre group or further diluted 1:10 for the low titre group. The studies showed that almost all mice that had a Plaque Reduction Neutralization Test (PRNT) titre of at least 1:10 were protected from death when challenged with either the SA14 or the KE093 strain of JEV. These studies suggest that protection is mediated by antibodies raised against the vaccine. It is also noted that the KE093 strain belongs to JEV Genotype I, while the SA14 strain belongs to Genotype III. As the results were similar for both challenge viruses it is suggested that the human antibodies produced in response to immunization with Ixiaro® are active against JEV strains other than that used to produce the vaccine.
Overall, the animal studies support the claim of efficacy for Ixiaro® with evidence of cross-strain protection. A dose-dependent increase in neutralizing antibody titre which correlated with protection was demonstrated for Ixiaro® in each of the above mentioned studies.3.2.2 Pharmacokinetics
Non-clinical pharmacokinetic studies are not directly applicable to vaccines.
3.2.3 Toxicology
Single- and Repeat-Dose Studies
One study was conducted in female rabbits and rats that were administered four IM doses of Ixiaro®, 2-weeks apart. No evidence of toxicity was observed. Repeat-dose toxicity studies are not typically applicable to vaccines; however, the above study did use four doses, which is twice the normal number of doses.
Carcinogenicity and Mutagenicity
Carcinogenicity and mutagenicity were also not conducted as these studies are not normally required for vaccines.
Reproductive and Developmental Toxicity
One formal toxicology study was conducted to evaluate the pre- and post-natal developmental toxicity in rats immunized with Ixiaro®. Dosing was initiated up to 3 weeks prior to mating as follows:
| Dosing Schedule | Groups | ||
|---|---|---|---|
| Control | Vaccine I | Vaccine II | |
| Dose 3 weeks prior to mating | All | All | not administered |
| Dose 1 week prior to mating | All | All | All |
| Dose Day 6 of gestation (1 week after mating) | All | All | All |
The IM route of administration was chosen for this study as it represented the intended route for humans. The dams and first filial generation (F1) were followed up to 21 days after birth such that the animals were exposed to both the vaccine itself and to antibodies generated by the vaccine, during critical time periods likely to affect fertility, organogenesis, early to late embryo-foetal development, birth, maternal function, and post-natal development.
Results of the study indicated that there were no significant effects of treatment on the adult females (as measured by clinical signs, bodyweight, or food consumption), or on reproductive performance in terms of fertility, pregnancy outcome, or post-natal care. There were no effects on F1 neonatal pup bodyweight, survival or development, as assessed by the physical and functional tests applied.
One statistically significant finding was noted. In some regions, particularly the pelvis and skull, incomplete ossification was observed in a few foetuses whose mothers were administered the vaccine twice (Vaccine II) as compared to both the group who was administered three doses (Vaccine I) and the control group. The relevance of these findings for the use of Ixiaro® in humans was further investigated by considering historical control data on the strain of rats used in this study. The results from the control group used in this study were comparable to historical data obtained in this strain of rats.
There were no other indications of in utero growth delays and no indication of any post-natal growth retardation. As the observed delay in ossification occurred in isolation and was not corroborated by other evidence of delayed development and was without consequence (based on the extensive post-natal evaluations conducted in the study), it is not considered to be an adverse effect. Further, the group affected was given just two doses and had a lower antibody titre at the beginning of gestation with a similar titre at the end of gestation (when ossification occurs) as compared to the Vaccine I group that received three doses. It is therefore unlikely that this effect can be attributed to treatment with the vaccine and it appears that these findings are not indicative of reproductive toxicity.
To further investigate the delayed ossification observed in this study a consultant report was commissioned by Intercell AG. The report indicated that these findings were not considered to be significant, as there were no ossification delays in other parts of the skeleton known to be sensitive to delayed ossification, and there no other abnormalities or low birth weights.
Local Tolerance
Local tolerance studies were not conducted as Phase I/II clinical studies had already been performed on human subjects.
3.2.4 Summary and Conclusion
Data from the non-clinical studies demonstrated that Ixiaro® was immunogenic, safe, and well-tolerated. The observations of incomplete ossification could not be attributed to treatment with Ixiaro® and were considered to be a spurious event although of unknown significance to the use of this vaccine in humans.
3.3 Clinical basis for decision
Two pivotal studies as well as several supporting non-pivotal clinical studies were evaluated to assess the immunogenicity and safety of Ixiaro®.
No studies have been performed in pregnant or nursing women and there are no significant safety data relevant to non-Caucasian populations.
3.3.1 Clinical Efficacy
The efficacy of Ixiaro® was assessed by the immune response elicited by the vaccine. The serological parameter 'seroconversion' was used as a measure of efficacy. Seroconversion was identified as a PRNT50 titre. The PRNT50 assay is a neutralizing antibody assay and is expressed as the serum dilution giving a 50% plaque (or virus) reduction compared to 100% plaque formation in a virus only control. The protective titre of ≥1:10 has been recommended by a World Health Organization consultation group on JEV vaccines and is supported in other literature.
The actual levels of neutralizing antibodies are reported as Geometric Mean Titre (GMT).
One pivotal study (IC51-301) assessed the efficacy of Ixiaro®. Study IC51-301 was a Phase III, randomized, active-controlled, observer-blinded, non-inferiority study that compared the immunogenicity of Ixiaro® to Je-Vax®. The study enrolled subjects who were ≥18 years of age at three sites in Europe (Austria and Germany) and seven sites in the United States. The Ixiaro® group consisted of 399 subjects who were administered two IM injections of Ixiaro® (6 µg/0.5 mL) on Days 0 and 28 and an IM injection of a PBS/aluminium hydroxide placebo (0.5 mL) on Day 7. The Je-Vax® group consisted of 397 subjects who received three subcutaneous (SC) injections of Je-Vax® (1.0-mL dose) on Days 0, 7, and 28.
The primary endpoint was a demonstration of non-inferiority of Ixiaro®
(two 6.0 µg/0.5-mL doses) compared to Je-Vax® (three 1.0-mL doses) in terms of seroconversion rate and GMT at Day 56, four weeks after the last vaccination.
The results of the study demonstrated that the immune response elicited by Ixiaro® was non-inferior to that elicited by Je-Vax®. Four weeks following the last vaccination, the proportion of subjects who had seroconverted was 96.4% for those treated with Ixiaro® and 93.8% for Je-Vax®. The GMT levels were 243.6 for Ixiaro® and 102.0 for Je-Vax®.
Overall, the efficacy of Ixiaro® in terms of eliciting a level of anti-JEV neutralizing antibody at 56 days after the start of the two-dose vaccination schedule was satisfactory.
Booster Dose
Limited data exist on the effect of a booster dose following completion of primary immunization in subjects whose neutralizing antibody titre had dropped below the threshold for seroconversion (PRNT50 ≥1:10). In the per-protocol population, sixteen subjects received a booster dose 11 months after the first dose leading to an seroconversion rate (SCR) of 100% [95% confidence interval (CI): 80.6 to 100.0] and GMT of 676.2 (95% CI: 365.0 to 1252.5). An additional twenty-four subjects received a booster dose 23 months after the first dose resulting in an SCR of 100% (95% CI: 86.2 to 100.0) and a GMT of 2496.1 (95% CI: 1407.5 to 4426.7). Clinical trials on duration of protection up to five years after vaccination are currently ongoing.
3.3.2 Clinical Safety
The safety and tolerability of Ixiaro® were investigated in two pivotal studies (IC51-301 and IC51-302) and in a series of non-pivotal studies. The largest safety study was
IC51-302, a Phase III, randomized, placebo-controlled, double-blind, multicentre study.
Study IC51-302
A total of 2600 subjects participated in Study IC51-302 at thirty-nine centres in Europe, Australia, New Zealand, Israel, and the United States. Subjects were randomized approximately 3:1 with 1962 subjects in the Ixiaro® group and 638 in the placebo group. The study population was predominantly Caucasian (92.2% in the Ixiaro® group) and was young with a mean age of 34 years and a median age of 29 years. There was a significant lack of representation of older individuals in this safety population.
Subjects in the Ixiaro® group were administered two IM injections of Ixiaro® (6 µg/0.5 mL) on Days 0 and 28. Control-group subjects were administered two injections of placebo (0.5 mL) according to the same schedule.
The primary endpoint of this study was to investigate the safety and tolerability of Ixiaro® as compared to an inactive control for the duration of a 28-day vaccination period up until 4 weeks after the last vaccination.
For the length of the study period, 58.9% of the subjects in the Ixiaro® group experienced at least one treatment emergent adverse event (TEAE) as compared to 56.6% of subjects in the placebo group. There was no statistically significant difference in the number of TEAEs experienced between the two groups.
The most common TEAEs which occurred at similar frequencies in both groups included: myalgia (15.6% - Ixiaro®; 15.5% - placebo), influenza-like illness (12.4% - Ixiaro®; 11.9% - placebo), and fatigue (11.4% - Ixiaro®; 11.7% - placebo). Headache was the most common symptom and was reported in 28.0% of subjects receiving Ixiaro® and 26.3% of those receiving placebo. As well, nasopharyngitis and diarrhea were more common in the Ixiaro® group and were reported in 4.7% and 1.6% of subjects, respectively.
Five withdrawals due to infections were noted in the Ixiaro® group compared to none in the placebo group. Subjects withdrew due to gastroenteritis (1), pharyngitis (2), influenza (1), and urinary tract infection (1). Overall, fewer subjects receiving Ixiaro® (0.6%) withdrew from the study than those receiving placebo (0.8%).
A low incidence of haematuria (0.6%) was observed in subjects administered Ixiaro® as compared to 0.3% in the placebo group. As there is the possibility of an anti-renal cell component in the vaccine (which is manufactured using kidney epithelial cells for viral reproduction), haematuria TEAEs were reviewed in all other studies.
Throughout the vaccination period, slightly higher rates of headache (27.9% versus [vs.] 26.2%), influenza-like illness (12.3% vs. 11.7%), myalgia (15.6% vs. 15.5%), bronchitis (0.7% vs. 0%), and nasopharyngitis (4.7% vs. 4.0%) were observed in the Ixiaro® group as compared to the placebo group. Severe myalgia was reported in the Ixiaro® group, but at a low rate (0.5%). There were no changes in laboratory parameters that raised concern.
Overall, the adverse event (AE) profile for Ixiaro® in Study IC51-302 was as expected for an inactivated virus vaccine except that there was an increase in nasopharyngitis and marginal increases in bronchitis, tonsillitis, conjunctivitis, and urinary tract infection.
Study IC51-301
A secondary endpoint of the pivotal study IC51-301 was to assess the safety of Ixiaro® as compared to Je-Vax®. A description of the study design is found in section 3.3.1 Clinical Efficacy. The safety population for this study consisted of 428 subjects from the Ixiaro® group and 435 subjects from the Je-Vax® group.
Pharyngolaryngeal pain was more commonly experienced in the Ixiaro® group (2.8%) vs. the Je-Vax® group (1.1%). Myalgia was also more frequent (Ixiaro® - 20.6% vs. Je-Vax® -15.9%). Possibly and probably related TEAEs that occurred ≥1% more frequently in the Ixiaro® group included fatigue, influenza-like illness, pyrexia, and myalgia.
TEAEs leading to withdrawal of study drug were experienced by 1.6% of the subjects in the Ixiaro® group and 1.8% of the subjects in the Je-Vax® group.
There was no evidence of an increase in infectious AEs in the safety analysis of Study IC50-301.
Summary
In general, the safety profile appears as expected for an inactivated vaccine with local reactivity and mainly mild systemic symptoms such as influenza-like illness and headache.
Severe TEAEs affected only a small proportion of the subjects. Only myalgia and pyrexia were reported at a higher rate in the Ixiaro® group than in the placebo group.
Overall, Ixiaro® appears to have an acceptable AE profile for an inactivated vaccine when used in the indicated population.
3.3.3 Additional Issues
As part of the marketing authorization for Ixiaro®, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) the following:
- to provide reports on studies of the administration of Ixiaro® in paediatric subjects (<18 years of age), and
- to provide reports on vaccination in pregnant women.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Ixiaro® has demonstrated efficacy in stimulating an immune response to JEV. In mouse and rat studies, the human antibody induced by Ixiaro® has been shown to block fatal doses of live JEV in these animals.
There is a clear benefit from the use of Ixiaro® in individuals who may be exposed to JEV, primarily as a result of travel to endemic or epidemic areas. Infection with JEV can lead to JEV disease which may leave the individual with permanent neurological sequelae or could lead to death.
Although there is an existing licensed vaccine, Je-Vax®, manufacture of this vaccine has ceased. Although Je-Vax® has generally been demonstrated as safe and effective at preventing encephalitis, in recent years it has come under increased scrutiny for its reactogenicity and the fact that it is produced in neural tissue. Ixiaro® is propagated through a cell line as opposed to neural tissue.
The population exposed to Ixiaro® in the clinical studies was almost entirely Caucasian. All subjects were ≥18 years of age, apart from 48 subjects aged 1 to 3 in a non-blinded study. In the adult studies, the age range was predominantly a younger population with the median age in some studies of approximately 30 years.
There have been no studies involving pregnant or nursing women. A small number of women have become pregnant during studies, and no obvious related AEs were reported.
The AEs reported in the pivotal and non-pivotal studies were mainly non-specific including influenza-like illness and headache, as well as local vaccination site events such as swelling, redness or hardening.
Most AEs were mild or moderate in severity, although a small number of cases of myalgia were reported as severe. There were some reports of oro-pharyngeal infections and nasopharyngeal pain. A review of the placebo-controlled pivotal study IC51-302, including the post-hoc analyses, showed no statistically significant differences between subjects receiving Ixiaro® and those receiving the PBS/aluminum hydroxide placebo.
Adverse events in the vaccination period (as opposed to the follow-up period) that were more frequent in the Ixiaro® group than in a placebo group were headache, influenza-like illness, myalgia, bronchitis, and nasopharyngitis. No other AEs in the vaccination periods in the safety study occurred with a difference of ≥1% between treatment groups.
There were no long-term effects, and although some AEs resulted in subjects discontinuing the study (0.79% of AEs, 0.96% of subjects), the numbers were small and there was no evidence of long-term sequelae, although the duration of follow-up was limited (24 months in two follow-up studies).
There was a small number of reports of haematuria or proteinuria but the Phase III studies did not report any cases. No long-term effects have been reported, and laboratory results did not show any significant changes from baseline for serum creatinine levels.
Given that Ixiaro® should only be administered to individuals who may be at risk of JEV infection and given that JEV infection has severe and occasional fatal consequences although in a small number of those infected, the benefit/risk profile of Ixiaro® is acceptable.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Ixiaro® is favourable for active immunization against Japanese encephalitis for persons 18 years of age or older. The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations .
4 Submission Milestones
Submission Milestones: Ixiaro®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-04-02 |
| Submission filed: | 2008-06-20 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-08-12 |
| Review 1 | |
| Quality Evaluation complete: | 2009-02-03 |
| Clinical Evaluation complete: | 2009-01-22 |
| Notice of Deficiency (NOD) issued by Director General (safety, efficacy, and quality issues): | 2009-02-09 |
| Response filed: | 2009-04-20 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2009-05-14 |
| Review 2 | |
| On-Site Evaluation: | 2009-08-21 |
| Quality Evaluation complete: | 2009-10-29 |
| Clinical Evaluation complete: | 2009-09-21 |
| Labelling Review complete: | 2009-09-21 |
| Notice of Compliance (NOC) issued by Director General: | 2009-10-29 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| IXIARO | 02333279 | VALNEVA AUSTRIA GMBH | INACT.JAPANESE ENCEPHAL VIRUS(ATTENUAT. STRAIN SA14-14-2 PRODUCED IN VERO CELLS) 6 MCG / 0.5 ML |