Regulatory Decision Summary for Ervebo

To support authorization of the ERVEBO vaccine, efficacy, immunogenicity, and safety data from thirteen clinical trials were provided which encompassed eight Phase 1 trials, one Phase 2 trial, one Phase 2/3 trial, and three Phase 3 trials that were designed and conducted independently by a number of different sponsors. Of the thirteen trials, V920-010 was considered the pivotal trial for demonstration of efficacy. 

Vaccine efficacy (VE) was evaluated in a field-based, Phase 3, open-label, cluster-randomized, controlled ring vaccination trial, designed to evaluate the efficacy, effectiveness and safety of 1 dose of V920 in the prevention of Ebola Virus Disease (EVD) when implemented as ring vaccination. Ring vaccination is a strategy to vaccinate individuals at highest risk of infection due to their social network connection to a patient confirmed with the virus. The trial was conducted in Guinea during the 2014-2016 EVD outbreak. Individuals who met the criteria for a defined ring around a subject with laboratory-confirmed EVD were randomised at the ring level into either the immediate or delayed (21 days) vaccination arms, then vaccinated with ERVEBO.

The primary objective was to assess vaccine efficacy against laboratory-confirmed EVD by performing a clinical trial comparing immediate versus delayed ring vaccination. The final primary efficacy analysis included all vaccinated subjects in the immediate arm (2,108 subjects in 51 rings) who were compared to all eligible subjects who consented on Day 0 in the delayed arm (1,429 subjects in 46 rings). Ten cases (in 4 rings) of confirmed EVD were observed in eligible subjects in the delayed vaccination arm who consented on Day 0 compared to 0 cases in the immediate vaccination arm. VE was estimated to be 100% (95% Confidence Interval (CI): 63.5 to 100%). Even though in real life use a VE oTo support authorization of the ERVEBO vaccine, efficacy, immunogenicity, and safety data from thirteen clinical trials were provided which encompassed eight Phase 1 trials, one Phase 2 trial, one Phase 2/3 trial, and three Phase 3 trials that were designed and conducted independently by a number of different sponsors. Of the thirteen trials, V920-010 was considered the pivotal trial for demonstration of efficacy. Vaccine efficacy (VE) was evaluated in a field-based, Phase 3, open-label, cluster-randomized, controlled ring vaccination trial, designed to evaluate the efficacy, effectiveness and safety of 1 dose of V920 in the prevention of Ebola Virus Disease (EVD) when implemented as ring vaccination. Ring vaccination is a strategy to vaccinate individuals at highest risk of infection due to their social network connection to a patient confirmed with the virus. The trial was conducted in Guinea during the 2014-2016 EVD outbreak. Individuals who met the criteria for a defined ring around a subject with laboratory-confirmed EVD were randomised at the ring level into either the immediate or delayed (21 days) vaccination arms, then vaccinated with ERVEBO. The primary objective was to assess vaccine efficacy against laboratory-confirmed EVD by performing a clinical trial comparing immediate versus delayed ring vaccination. The final primary efficacy analysis included all vaccinated subjects in the immediate arm (2,108 subjects in 51 rings) who were compared to all eligible subjects who consented on Day 0 in the delayed arm (1,429 subjects in 46 rings). Ten cases (in 4 rings) of confirmed EVD were observed in eligible subjects in the delayed vaccination arm who consented on Day 0 compared to 0 cases in the immediate vaccination arm. VE was estimated to be 100% (95% Confidence Interval (CI): 63.5 to 100%). Even though in real life use a VE of 100% may not be observed the vaccine is expected to be efficacious to a great degree and is expected to confer protection for a disease that is highly contagious with a high mortality. There are questions remaining regarding the long term durability of the vaccine efficacy, the need for a booster dose, and that the vaccine may not protect all individuals. Given the high mortality of the disease, following vaccination, individuals at risk should continue to protect themselves from exposure to Zaire ebolavirus. The safety of ERVEBO was based on a Phase III trial conducted mostly in the United States with some subjects from Canada and Spain, supported by two earlier Phase I studies conducted in Switzerland and United States, respectively. Like many vaccines that induce a robust immune response, the majority of vaccine recipients (71.8%) compared with placebo recipients (14.3%) experienced at least one local injection-site reaction such as pain, swelling or redness in the main safety study. Common adverse events occurring in ≥ 1% of vaccine recipients where rates were much lower in placebo recipients included signs and symptoms such as chills and fever, fatigue and weakness, nausea and diarrhea, runny nose and flu-like illness, as well as muscle and joint pains. First identified in earlier studies, vaccine-related arthritis was found in 3.5% of vaccine recipients compared with no placebo recipients in the main safety study. Also, vaccine-related rashes of different types were noted more commonly in vaccine recipients (3.5%) compared with placebo recipients (1.5%), as were skin blister (1.5% in vaccine vs no placebo recipients). Both, the vaccine-related arthritis and vaccine-related rashes occurred about 1-2 weeks after vaccination lasting about 1-2 more weeks with most of cases fully resolving by the end of the three clinical trials. The vaccine vector was detected in the fluid from joints in arthritis cases, and in skin biopsies of rashes suggesting a vaccine aetiology. Finally, detection of the vaccine virus in the blood or shedding in the saliva or urine was uncommon and short-lived suggesting that the risk of transmission to another person or to the environment is very low. Precautions recommended in the product monograph should be more than adequate to mitigate this theoretical concern. Based on the totality of the information, the benefit-risk profile for the ERVEBO Vaccine for active immunization of individuals 18 years of age or older to protect against EVD caused by ZEBOV is considered favourable. An updated Risk Management Plan (RMP) for ERVEBO was reviewed by Health Canada and considered acceptable. The chemistry and manufacturing information submitted for ERVEBO has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable. The overall, the benefit-harm-uncertainty profile is favourable for ERVEBO and the dosage strength of ≥ 72 million plaque forming units (pfu) /mL for the recommended indication. A Notice of Compliance (NOC) was issued. For further details about ERVEBO, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database. f 100% may not be observed the vaccine is expected to be efficacious to a great degree and is expected to confer protection for a disease that is highly contagious with a high mortality. There are questions remaining regarding the long term durability of the vaccine efficacy, the need for a booster dose, and that the vaccine may not protect all individuals. Given the high mortality of the disease, following vaccination, individuals at risk should continue to protect themselves from exposure to Zaire ebolavirus.

The safety of ERVEBO was based on a Phase III trial conducted mostly in the United States with some subjects from Canada and Spain, supported by two earlier Phase I studies conducted in Switzerland and United States, respectively. Like many vaccines that induce a robust immune response, the majority of vaccine recipients (71.8%) compared with placebo recipients (14.3%) experienced at least one local injection-site reaction such as pain, swelling or redness in the main safety study. Common adverse events occurring in ≥ 1% of vaccine recipients where rates were much lower in placebo recipients included signs and symptoms such as chills and fever, fatigue and weakness, nausea and diarrhea, runny nose and flu-like illness, as well as muscle and joint pains. First identified in earlier studies, vaccine-related arthritis was found in 3.5% of vaccine recipients compared with no placebo recipients in the main safety study. Also, vaccine-related rashes of different types were noted more commonly in vaccine recipients (3.5%) compared with placebo recipients (1.5%), as were skin blister (1.5% in vaccine vs no placebo recipients). Both, the vaccine-related arthritis and vaccine-related rashes occurred about 1-2 weeks after vaccination lasting about 1-2 more weeks with most of cases fully resolving by the end of the three clinical trials. The vaccine vector was detected in the fluid from joints in arthritis cases, and in skin biopsies of rashes suggesting a vaccine aetiology. Finally, detection of the vaccine virus in the blood or shedding in the saliva or urine was uncommon and short-lived suggesting that the risk of transmission to another person or to the environment is very low. Precautions recommended in the product monograph should be more than adequate to mitigate this theoretical concern.

Based on the totality of the information, the benefit-risk profile for the ERVEBO Vaccine for active immunization of individuals 18 years of age or older to protect against EVD caused by ZEBOV is considered favourable.

An updated Risk Management Plan (RMP) for ERVEBO was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for ERVEBO has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

The overall, the benefit-harm-uncertainty profile is favourable for ERVEBO and the dosage strength of ≥ 72 million plaque forming units (pfu) /mL for the recommended indication. A Notice of Compliance (NOC) was issued.

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

For more information on Health Canada's decision, please view the Summary Basis of Decision.