Summary Basis of Decision for Ixchiq

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.


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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Ixchiq is located below.

Recent Activity for Ixchiq

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Ixchiq. When the PAAT for Ixchiq becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Ixchiq

Date SBD issued: 2024-11-12

The following information relates to the New Drug Submission for Ixchiq.

Chikungunya virus live-attenuated

Drug Identification Number (DIN): 02548984 - 3.0 log10 50% tissue culture infectious dose (TCID50)/0.5 mL chikungunya virus live-attenuated, powder for solution, intramuscular injection

Valneva Austria GmbH

New Drug Submission Control Number: 275762

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): J07 Vaccines

Date Filed: 2023-05-29

Authorization Date: 2024-06-20

On June 20, 2024, Health Canada issued a Notice of Compliance to Valneva Austria GmbH for the vaccine Ixchiq.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-risk profile of Ixchiq is favourable for active immunization in individuals 18 years and older for the prevention of disease caused by the chikungunya virus, as a single-dose immunization.

1 What was approved?

Ixchiq, a live-attenuated vaccine, was authorized for active immunization in individuals 18 years and older for the prevention of disease caused by the chikungunya virus, as a single-dose immunization.

Ixchiq is not authorized for use in the pediatric population (less than 18 years of age), as its safety and effectiveness have not been established in this population.

Clinical studies of Ixchiq include participants 65 years of age and older and their data contribute to the overall assessment of safety and immunogenicity.

Ixchiq (3.0 log10 50% tissue culture infectious dose [TCID50]/0.5 mL chikungunya virus live-attenuated), is presented as a powder for solution for intramuscular injection. In addition to the medicinal ingredient, the powder contains D-sorbitol, L-methionine, magnesium chloride, potassium phosphate, recombinant human albumin, sucrose, and trisodium citrate dihydrate.

The use of Ixchiq is contraindicated in individuals with a history of immunodeficiency as well as in patients who are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container. Ixchiq is also contraindicated in pregnancy. Women of child-bearing potential should be advised to avoid pregnancy for one month following vaccination.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Ixchiq Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Ixchiq approved?

Health Canada considers that the benefit-risk profile of Ixchiq is favourable for active immunization in individuals 18 years and older for the prevention of disease caused by the chikungunya virus (CHIKV), as a single-dose immunization.

Chikungunya is a mosquito-borne viral disease caused by the CHIKV. Symptoms and signs of chikungunya are most often characterized by sudden onset of high fever, myalgia, arthralgia and pronounced lymphopenia and/or moderate thrombocytopenia, which typically begin 3 to 7 days after being bitten by an infected Aedes genus mosquito. These changes typically resolve within 7 to 10 days, but up to 40% of patients may suffer from debilitating arthralgia and other symptoms for months to years.

The chikungunya virus has been identified in over 100 countries in Asia, Africa, Europe, and the Americas. Chikungunya is not endemic to Canada and occurs from international travel to risk areas.

The CHIKV is an enveloped ribonucleic acid (RNA) virus with a positive-sense, single-stranded RNA genome containing two open reading frames that encode four non-structural proteins (nsP1 to nsP4) and six structural proteins. Ixchiq is a live-attenuated CHIKV strain (CHIKV Δ5nsP3) derived from the parent infectious wild-type CHIKV strain (La-Reunion strain LR2006-OPY1) through reverse genetics, resulting in a 61 amino acid deletion in the C-terminal part of the non-structural replicase protein 3 (nsP3). It is hypothesized that the live-attenuated CHIKV (Δ5nsP3) may have a reduced risk to cause CHIKV disease due to attenuated viral replication in humans but may elicit sufficient CHIKV-specific immune responses to prime the immune system for prevention of chikungunya disease.

Currently, there are no specific anti-viral treatments or preventives (e.g., vaccines or monoclonal antibodies) available to manage or prevent chikungunya disease in Canadians travelling internationally to high-risk countries. The treatment of chikungunya disease is supportive. Relief of pain is the standard and the only effective treatment option for management of the disease.

The clinical efficacy of Ixchiq was supported by data provided from three prospective, double-blinded clinical studies: the pivotal Phase III Study VLA1553-301 (placebo-controlled), the Phase III Study VLA1553-302 (lot-to-lot consistency), and the Phase I Study VLA1553-101 (dose-finding). These studies were designed to evaluate the immunogenicity and safety of Ixchiq in healthy adults without prior known or suspected CHIKV infections.

The pivotal study compared the intramuscular administration of Ixchiq (1 x 104 TCID50/dose) to 3,093 subjects or placebo to 1,035 healthy subjects. Clinical efficacy was assessed using seroresponse as the surrogate immunogenicity endpoint of efficacy, defined as achieving a CHIKV-specific neutralizing antibody titer in 50% reduction in micro plaque reduction neutralization titer (μPRNT50) of 150 or higher. The primary immunogenicity endpoint was seroresponse rate at 28 days post vaccination with 70% seroresponse rate in the Ixchiq group as the non-acceptance threshold. The study showed that the seroresponse rate on Day 28 post-vaccination was 98.9% (95% confidence interval [CI]: 96.7, 99.8) in the Ixchiq group and 0% (95% CI: 0, 3.8) in the placebo group. The geometric mean titer (GMT) for CHIKV-specific neutralizing antibodies in μPRNT50 peaked at 3,361.6 (95% CI: 2,993.8, 3,774.5) on Day 29 post vaccination and then dropped by about 80% to 752.1 (95% CI: 665.9, 849.5) on Day 180 post vaccination.

Ixchiq was considered safe in non-pregnant adults 18 years of age and older, based on the assessment of data generated from the pivotal study. Data included solicited post-vaccination local and systemic reactions in the first 10 days, unsolicited adverse events (AEs) in the first 28 days and in the first 6 months, AEs of special interest (i.e., Chikungunya-like illness) in the first 30 days, and serious adverse events (SAEs), including deaths and withdrawals, in the first 6 months.

Overall, in the pivotal study, 50.2% of Ixchiq recipients experienced at least one solicited systemic adverse reaction (AR) as compared to 26.9% of placebo recipients. In the Ixchiq group, 15.0% of recipients experienced at least one injection site AR versus (vs.) 11.1% of placebo recipients. Most solicited site reactions resolved within 1 to 5 days. Of those graded severe, 2.1% occurred in Ixchiq recipients vs. 0.1% among placebo recipients. The majority were due to fever. Overall, 21.8% of participants receiving Ixchiq reported at least one unsolicited AE compared with 13.3% among those receiving placebo. Most unsolicited AEs up to 28 days after vaccination were graded as mild or moderate. Eighteen participants (0.6%) in the Ixchiq arm and six (0.6%) in the placebo arm experienced at least one severe unsolicited AE. Unsolicited AEs were more frequently considered to be related to the vaccination in the Ixchiq arm (9.2%) than in the placebo arm (3.7%), and the difference between the two groups is considered significant.

Participants were monitored for symptoms consistent with wild-type chikungunya infection. Chikungunya-like ARs were defined as fever (38 °C or higher) and one or more of any of the following: arthralgia or arthritis, myalgia, headache, back pain, rash, lymphadenopathy, or certain neurological, cardiac or ocular symptoms that occurred with an onset within 30 days after vaccination. Severe chikungunya-like ARs included symptoms that prevented daily activity and/or required medical intervention. Among participants, 361 (11.7%) in the Ixchiq group reported chikungunya-like ARs, including 48 participants (1.6%) who reported severe chikungunya-like ARs. Six (0.6%) participants in the placebo group reported chikungunya-like adverse reactions, none of which were severe.

Twenty-two Ixchiq recipients had prolonged chikungunya-like adverse reactions lasting longer than 14 days (median duration 33 days, range 15 days to at least 6 months). Prolonged arthralgia (lasting longer than 14 days) was reported by seven participants (five of these participants had arthralgia lasting longer than 28 days). Prolonged fatigue, myalgia, or headache (lasting longer than 14 days) were reported by 13 participants (nine of whom had symptoms lasting longer than 28 days).

The proportion of participants who reported at least one SAE within 6 months was 1.5% in the Ixchiq group and 0.8% in the placebo group. Overall, there were two SAEs (0.1%) requiring hospitalization that were considered related to Ixchiq: one event of myalgia, and one event of hypovolemic hyponatremia and atrial fibrillation. Full recovery was observed with both events. There were no SAEs reported in the placebo group.

A Risk Management Plan (RMP) for Ixchiq was submitted by Valneva Austria GmbH to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Ixchiq Product Monograph met the necessary regulatory labelling, plain language, and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Ixchiq was accepted. During the review of the proposed brand name, Ixchiq, it was determined that there is a heightened risk of confusion with Ixiaro (Japanese encephalitis vaccine), given the many orthographic and phonetic similarities and overlapping product profile characteristics. To monitor the risk of brand name confusion between Ixchiq and Ixiaro, the sponsor is requested to include a cumulative review of all cases suggestive of brand name confusion through ‘medication errors and other product use errors and issues’ involving Ixchiq in the Periodic Safety Update Reports. The review should also include cases without clinical consequences, such as complaints, reports of concern and near misses.

Based on the currently available immunogenicity and safety evidence, the benefit-risk profile of Ixchiq administered as a single dose to non-pregnant adults 18 years of age or older is considered favorable. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Ixchiq Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Ixchiq?

The review of the quality and clinical components of the New Drug Submission (NDS) for Ixchiq was based on a critical assessment of the data package submitted to Health Canada. The reviews and correspondence completed by the United States Food and Drug Administration were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Ixchiq NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Submission Milestones: Ixchiq

Submission Milestone

Date

Pre-submission meeting

2023-01-19

New Drug Submission filed

2023-05-29

Screening

Screening Deficiency Notice issued

2023-07-06

Response to Screening Deficiency Notice filed

2023-08-02

Screening Acceptance Letter issued

2023-08-25

Review

Quality evaluation completed

2024-06-17

Non-clinical evaluation completed

2024-06-18

Biostatistics evaluation completed

2024-06-18

Review of Risk Management Plan completed

2024-06-19

Labelling review completed

2024-06-19

Clinical/medical evaluation completed

2024-06-20

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2024-06-20
4 What follow-up measures will the company take?

As part of the marketing authorization for Ixchiq, Health Canada requested, and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Food and Drug Regulations, commitments include (but are not limited to):

  • Presenting a separate section on the potential vertical transmission of the vaccine virus within the safety review of safety in pregnancy in the Periodic Safety Update Reports (PSURs).

  • Monitoring the risk of brand name confusion between Ixchiq and Ixiaro (Japanese encephalitis vaccine) given a heightened risk of confusion due to the many orthographic and phonetic similarities and overlapping product profile characteristics. The sponsor is requested to include a cumulative review of all cases suggestive of brand name confusion through ‘medication errors and other product use errors and issues’ involving Ixchiq in the PSURs. The review should also include cases without clinical consequences, such as complaints, reports of concern and near misses.

  • Including relevant safety findings from the different studies identified as additional pharmacovigilance activities in the PSURs, once the studies are completed.

5 What post-authorization activity has taken place for Ixchiq?

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Ixchiq. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada’s decision?

Refer to the What steps led to the approval of Ixchiq? section for more information about the review process for this submission.

7.1 Clinical Basis for Decision

Clinical Pharmacology

The exact mechanism by which Ixchiq exerts protection has not been determined. However, IXCHIQ elicits specific immune responses against chikungunya virus (CHIKV).

Clinical pharmacology studies were not conducted and are typically not required for vaccines. The pharmacodynamics of Ixchiq was assessed through the analysis of immunogenicity described in the Clinical Efficacy section.

For further details, please refer to the Ixchiq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Ixchiq was evaluated in three prospective, double-blinded clinical studies. The first was the pivotal Phase III Study VLA1553-301. This multicentre, placebo-controlled study was conducted in 4,128 participants, 3,093 of whom received Ixchiq (1 x 104 50% tissue culture infectious dose [TCID50]), and 1,035 of whom received phosphate buffered saline as a placebo. The second study was the supportive Phase III Study VLA1553-302, a lot-to-lot consistency study conducted in 409 participants who received Ixchiq (1 x 104 TCID50). The third was the supportive Phase I dose-finding Study VLA1553-101 conducted in 120 participants. The CHIKV vaccine used in the Phase I study was a liquid formulation while that used in the two Phase III studies was a lyophilized formulation. All three studies were conducted in the United States and were designed to evaluate the immunogenicity and safety of Ixchiq after intramuscular administration in healthy adults without prior known or suspected CHIKV infections.

The pivotal Study VLA1553-301 enrolled healthy adult men (45.3% of participants) and women (54.7% of participants) without prior known or suspected CHIKV infections who were unlikely to become exposed to CHIKV during the study. Subjects with chronic illnesses or conditions that were stable and well controlled on therapy for the past 6 months were eligible to participate in the clinical studies. Immunocompromised subjects were not eligible. The ethnicity of the participants was reported as 80.4% White, 13.9% Black or African American, 1.7% Asian American, 0.8% American Indian/Alaska Native, 0.4% Native Hawaiian/Pacific Islander and 2.8% as other. The mean age of the participants was 45.0 years (range: 18 to 94 years of age) with a total of 463/4,115 (11.3%) identified as elderly participants (65 years of age or older). The Ixchiq and placebo groups were similar with regard to demographic characteristics.

Immunogenicity

Due to the difficulty of assessing vaccine efficacy for the prevention of sporadically occurring CHIKV disease, in the pivotal study (Study VLA1553-301), the clinical efficacy of Ixchiq was assessed using a surrogate immunogenicity endpoint after vaccination. Based on data from a non-clinical study (Study VAC1816-02, discussed in the Non-Clinical Studies section) conducted in non-human primates, the establishment of CHIKV-specific neutralizing antibody titer in 50% reduction in micro plaque reduction neutralization titer (μPRNT50) of 150 or higher was considered to predict a clinical benefit. Therefore, seroresponse, defined as achieving a virus neutralizing antibody in μPRNT50 titer of 150 or higher was used as the surrogate immunogenicity endpoint of efficacy. In the pivotal study, the primary immunogenicity endpoint was the seroresponse rate at 28 days post vaccination with 70% seroresponse rate in the Ixchiq group as the non-acceptance threshold. The results of the study showed that the seroresponse rate on Day 28 post-vaccination was 98.9% (95% confidence interval [CI]: 96.7, 99.8) in the Ixchiq group and 0% (95% CI: 0, 3.8) in the placebo group. The geometric mean titer (GMT) for CHIKV-specific neutralizing antibodies in μPRNT50 peaked at 3,361.6 (95% CI: 2,993.8, 3,774.5) on Day 29 post vaccination and then dropped by about 80% to 752.1 (95% CI: 665.9, 849.5) on Day 180.

In the supportive Phase I Study VLA1553-101, the level of GMT for CHIKV-specific neutralizing antibodies in μPRNT50 from Day 29 up to Day 365 following the initial vaccination on Day 1 was similar among the three dose groups, indicating that the immune response in CHIKV-specific neutralizing antibodies appears to reach a plateau when the lowest dose of Ixchiq (3.2 x 103 TCID50) was used.

Viremia

Viremia was studied in the supportive Study VLA1553-101 using plasma samples tested on Day 0, 3, 7, and 14 after initial vaccination (Day 0) in three Ixchiq dose groups (3.2 x 103 TCID50, 3.2 x 104 TCID50, and 3.2 x 105 TCID50) and then after re-vaccination in all study groups with the highest dose (3.2 x 105 TCID50) at Day 180 or Day 365. The amount of virus injected was too low to be detected on Day 0 after vaccination. The plasma viral titers following the initial vaccination in all study groups were the highest on Day 3. They then dropped sharply by about 85% on Day 7 and became undetectable on Day 14. The plasma viral titers increased with vaccine dose with mean viral ribonucleic acid (RNA) titer at 73,601.2 genome copy equivalents (GCE)/mL, 89,353.7 GCE/mL and 229,224.1 GCE/mL on Day 3 with increasing dose in the three dose groups, respectively. However, there was no detectable viremia in any of the study groups after revaccination with the highest dose (3.2 x 105 TCID50) of Ixchiq on Day 180 or Day 365 following the initial vaccination.

Indication

The New Drug Submission for Ixchiq was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Ixchiq (chikungunya vaccine, live, attenuated) powder for solution for intramuscular injection is a live, attenuated vaccine, intended for active immunization in individuals 18 years and older for the prevention of disease caused by the chikungunya virus (CHIKV), as a single-dose immunization.

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

Clinical Safety

The clinical safety of Ixchiq was evaluated using data from 4,115 participants (safety population) from the pivotal Phase III Study VLA1553-301. In total, 3,082 healthy adults received at least one dose of Ixchiq, and 1,033 healthy adults received a placebo. Overall, 3,644/4,115 (88.6%) participants were followed up for safety for at least 6 months post vaccination after a single dose.

In the study, solicited systemic and injection site adverse reactions (ARs) were reported within 10 days after vaccination. Overall, 1,547/3,082 (50.2%) Ixchiq recipients experienced at least one solicited systemic AR as compared to 278/1,033 (26.9%) placebo recipients. The most common systemic ARs were headache (31.6% in the Ixchiq arm versus [vs.] 14.7% in the placebo arm), fatigue (28.5% vs. 12.7%), myalgia (23.9% vs. 7.4%), and arthralgia (17.2% vs. 4.9%). Overall, 463/3,082 (15.0%) Ixchiq recipients vs. 115/1,033 (11.1%) placebo recipients experienced at least one injection site AR. The most common injection site AR was tenderness (10.6% vs 8.1%). Most injection site ARs resolved within 1 to 5 days. Most systemic ARs (more than 95%) were mild to moderate and resolved within 2 to 5 days (median duration of 2 days). Overall, 64/3,082 (2.1%) Ixchiq recipients experienced solicited ARs that were graded as severe with the majority (total number [n] = 44) due to fever. Only one of the 1,033 of placebo recipients (0.1%) experienced a solicited AR graded as severe.

Unsolicited adverse events (AEs) were monitored within 6 months post vaccination. Up to 28 days post vaccination, 21.8% of 3,082 participants receiving Ixchiq reported at least one unsolicited AE as compared with 13.3% of 1,033 participants receiving placebo. Most unsolicited AEs were graded as mild or moderate. Eighteen participants (0.6%) in the Ixchiq arm and six (0.6%) in the placebo arm experienced at least one unsolicited AE that was graded severe. Unsolicited AEs were more frequently considered to be related to the vaccination in the Ixchiq arm (9.2% of participants) than in the placebo arm (3.7% of participants), the difference between the two groups is considered significant.

Participants were monitored for symptoms consistent with wild-type chikungunya infection. Chikungunya-like ARs were defined as fever (38 °C or higher) and one or more the following: arthralgia or arthritis, myalgia, headache, back pain, rash, lymphadenopathy, or certain neurological, cardiac or ocular symptoms that occurred with an onset within 30 days after vaccination. Severe chikungunya-like ARs included symptoms that prevented daily activity and/or required medical intervention. Among participants, 361 of 3,082 (11.7%) in the Ixchiq group reported chikungunya-like ARs, including 48 (1.6%) participants who reported severe chikungunya-like ARs. Six (0.6%) participants of 1,033 in the placebo group reported chikungunya-like ARs, none of which were severe. The median onset of chikungunya-like ARs in Ixchiq recipients was 3 days (range: 0 to 10 days) after vaccination. The median duration of chikungunya-like ARs in Ixchiq recipients was 4 days (range: 1 day to at least 6 months).

Twenty-two Ixchiq recipients had prolonged chikungunya-like ARs lasting longer than 14 days (median duration 33 days, range: 15 days to at least 6 months) and 15 Ixchiq recipients had chikungunya-like ARs lasting longer than 28 days (median duration 94 days, range: 29 days to at least 6 months). Prolonged fatigue, myalgia, or headache (lasting longer than 14 days) were reported by 13 participants (nine of whom had symptoms lasting longer than 28 days). Prolonged arthralgia (lasting longer than 14 days) was reported by seven participants (five of whom had arthralgia lasting longer than 28 days).

The proportion of participants who reported at least one serious adverse event (SAE) within 6 months following administration was 1.5% (46/3,082) in the Ixchiq group and 0.8% (8/1,033) in the placebo group. Overall, there were two (0.1%) SAEs that required hospitalization and that were considered to be related to Ixchiq: one event of myalgia, and one event of hypovolemic hyponatremia and atrial fibrillation. Full recovery was observed with both events. There were no SAEs reported in the placebo group.

Three participants died during the pivotal study due to events independent of study procedures (coronary artery disease, coronavirus disease 2019 [COVID-19], and anoxic brain injury). None of the deaths were considered related to Ixchiq. Approximately 0.1% of participants who received Ixchiq vs. 0.2% in the placebo group discontinued their study participation due to AEs.

Laboratory data were collected at Day 7, 28, 84 and 180 post vaccination in the immunogenicity subset. Most hematology, chemistry and coagulation parameters were generally well balanced between the Ixchiq and placebo groups. One exception was abnormal white cell counts, specifically leukocytes (all types of white blood cells), neutrophils and lymphocytes, which were more frequently observed in the Ixchiq recipients compared with placebo recipients. Overall, changes in clinical laboratory test results were considered expected and consistent with a normal physiologic response to a live-attenuated viral vaccine.

Appropriate warnings and precautions are in place in the approved Ixchiq Product Monograph to address the identified safety concerns. For more information, refer to the Ixchiq Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Non-human primates susceptible to CHIKV infection are most commonly used as an animal model in studies of CHIKV disease and CHIKV vaccine candidates. A study in non-human primates (Study PHY1802-02) compared Ixchiq and its parent wild-type (WT) CHIKV strain following the same intramuscular dose (3.2 x 106 TCID50). The intramuscular administration of WT CHIKV at this dose level is expected to be capable of causing serious CHIKV disease and even fatal outcome in humans. The study showed that the WT CHIKV-inoculated animals (n = 4) had a very high viral plasma load [geometric mean peak titer at 1.3 x 109 GCE/mL] but experienced only mild to moderate fever from Day 1 to Day 6 post exposure and lymphopenia of short duration. Fever peaked on Day 1 or Day 2 post exposure. The severity of fever and lymphopenia in the Ixchiq-treated animals was disproportionally high considering the extremely low level of viremia in these animals.

A non-human primate pharmacology study (Study VAC1816-02) investigated the protective effects of pooled human sera from Ixchiq-vaccinated participants in the Phase I clinical Study VLA1553-101 against CHIKV infection induced by challenge of the animals with a subcutaneous dose of WT CHIKV (1.5 x 104 TCID50) strain LR2006-OPY1. The viral challenge in this study resulted in high levels of viremia accompanied by mild fever and lymphopenia in control animals. The CHIKV-specific neutralizing antibody titer in the blood of animals was determined by a micro plaque reduction neutralization test (μPRNT) method. The results of the study suggest that a human CHIKV-specific neutralizing antibody titer at a 50% reduction in micro plaque reduction neutralization titer (μPRNT50) of 150 in the plasma of non-human primates provided full protection in a mild chikungunya disease model in non-human primates induced by WT CHIKV.

Carcinogenicity, genotoxicity or mutagenic potential studies were not conducted and are typically not required for vaccines. Two toxicity studies were evaluated. These included a two-week repeat-dose toxicity study in rabbits (Study 505078) and a pre- and post-natal developmental study in female Sprague-Dawley rats (Study 490901). No significant safety issues were identified in these studies, with one exception. In Study 490901, the rate of post-implantation loss in the littering phase in female rats treated with an intramuscular dose of Ixchiq (1.9 x 104 TCID50) 15 days prior to mating and then on Gestation Day 6 was statistically higher than that in placebo-control animals. The rates of post-implantation loss in the Ixchiq-treated animals were within the historical range of the parameter obtained in the testing facility. However, unlike humans, rats and rabbits are not susceptible to CHIVK infection and therefore caution should be exercised in the interpretation of these results.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Ixchiq Product Monograph. In view of the intended use of Ixchiq, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Ixchiq Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

Characterization of the Drug Substance

The Ixchiq drug substance (chikungunya virus [CHIKV] live-attenuated) is produced by infecting Vero cells with live-attenuated CHIKV that has a deletion in the non-structural protein 3 (nsPS3) gene (Δ5nsP3), leading to reduced replication of the virus in vivo.

Detailed characterization studies were performed to provide assurance that the drug substance consistently exhibits the desired characteristic structure and biological activity. These studies were performed on the drug substance at various stages of development, from toxicology to confirmatory batches, to monitor particle content and integrity, formation of aggregates, and purity throughout the manufacturing process. The results of these studies demonstrated the ability of the manufacturing processes to generate drug substance of consistent quality.

Comparability of drug substance lots produced at different sites using different processes was performed and comparable physicochemical characteristics and immunoreactivity were demonstrated.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The Ixchiq drug substance is produced by infecting Vero cells with live-attenuated CHIKV that has a deletion in the nsPS3 gene (Δ5nsP3), leading to reduced replication of the virus in vivo. The drug substance manufacturing process is divided into several steps, including cell culture and viral amplification, viral harvest and purification, followed by drug substance formulation, filtration, filling, and freezing.

The Ixchiq drug product is a sterile, preservative-free, lyophilized powder containing not less than (NLT) 3.0 log10 TCID50 live-attenuated CHIKV per 0.5 mL human dose. Prior to intramuscular injection, the drug product is reconstituted directly in the vial using sterile water diluent supplied in a pre-filled syringe.

The drug product manufacturing process consists of the thawing of drug substance, aseptic formulation of the drug product by mixing drug substance with the formulation buffer and sterile filtration of the final bulk, aseptic filling of final bulk into vials followed by lyophilization, visual inspection, labelling and packaging. The drug product formulation target for virus concentration (5.1 log10 TCID50/mL) is slightly higher than the drug product release specification (3.6 - 4.6 log10 TCID50/0.5 mL dose or 3.9 - 4.9 log10 TCID50/mL), to account for the loss of virus activity during manufacturing. Furthermore, a lower potency specification (NLT 3.0 log10 TCID50/0.5 mL) is implemented for drug product stability monitoring, due to potency decline during storage at 2 to 8 °C. The potency specifications are considered appropriate and are supported by the quality attributes of the clinical lots and analytical and process variability.

The diluent for reconstituting the lyophilized drug product is sterile water for injection provided in pre-filled syringes. The manufacturing and control of the diluent complies with all regulatory requirements. The release specification for extractable volume, along with the in-process control of filling/expelled volumes, ensures consistent delivery of a single human dose.

The materials used in the manufacture of the drug substance, drug product, and diluent (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the live-attenuated chikungunya virus with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Ixchiq is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life at 2 °C to 8 °C for Ixchiq 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.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

On-site evaluations of the facilities involved in the manufacture and testing of Ixchiq have been successfully conducted by Health Canada.

All sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

Viral clearance studies were not conducted due to the nature of the vaccine. Adequate control is ensured by applying a comprehensive viral safety testing program and by assessing viral clearance during routine manufacture. Viral and microbial adventitious agents are adequately controlled through controls and specifications for starting materials, raw materials, and reagents, and appropriate in-process controls and specifications for the drug substance and drug product. Materials of biological origin are properly sourced and tested. Collectively, the measures in place to ensure the absence of extraneous organisms in the final vaccine are deemed satisfactory.

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