Regulatory Decision Summary for COVISHIELD (Verity Pharmaceuticals Inc.)

 

The AstraZeneca COVID-19 Vaccine (manufactured by AstraZeneca) and COVISHIELD (manufactured by Serum Institute of India) are ChAdOx1-S recombinant vaccines developed by Oxford University and AstraZeneca. Health Canada has reviewed the manufacturing information for these vaccines and found them to be comparable.

The purpose of this submission was to seek market authorization, via the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19, for COVISHIELD, which was developed for active immunization to prevent COVID-19. COVISHIELD is manufactured and commercialized by the Serum Institute of India (SIIPL) under a royalty bearing exclusive sub-license granted by AstraZeneca, and sponsored for use in Canada by Verity Pharmaceuticals. Authorization of COVISHIELD was based on comparability to the AstraZeneca COVID-19 Vaccine as determined by evaluation and direct comparison of manufacturing processes and controls and the quality characteristics of the two products. The results of this evaluation determined that the two products were sufficiently similar that the efficacy, immunogenicity and safety of COVISHIELD could be inferred from the non-clinical and clinical studies from the AstraZeneca vaccine.

The supporting clinical data from the comparable AstraZeneca product was based on efficacy, immunogenicity and safety data from an interim analysis of pooled data from four ongoing trials: COV001 (Phase I/II in healthy adults 18 to 55 years of age conducted in the UK), COV002 (Phase II/III in adults ≥18 years of age conducted in the UK), COV003 (Phase III in adults ≥18 years of age conducted in Brazil), and COV005 (Phase I/II study in adults 18 to 65 years of age conducted in South Africa). Two of these studies (COOV2 and COOV3) had sufficient COVID-19 cases to be included in the estimation of the efficacy of the vaccine. The two studies included a total of 11,636 participants evaluated for efficacy; 5,807 in the AstraZeneca COVID-19 Vaccine group and 5,829 in the control group).

Health Canada decision issued:

COVISHIELD was authorized for use in relation to the COVID-19 pandemic, in accordance with section 5 of the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19.

Date of decision:

2021-02-26

Indication (use):

COVISHIELD (ChAdOx1-S [recombinant]) is indicated for active immunization of individuals 18 years of age and older for the prevention of coronavirus disease 2019 (COVID-19).

The COVISHIELD vaccination course consists of two separate doses of 0.5 mL each. The second dose should be administered between 4 and 12 weeks after the first dose. Individuals should complete the vaccination course with either COVISHIELD or AstraZeneca COVID-19 Vaccine.

Health Canada analysis of known and potential benefits and known and potential risks:

The ongoing COVID-19 pandemic has a significant impact on public health. The availability of safe and effective vaccines will reduce the spread and severity of COVID-19 disease and reduce its social and economic consequences.

The AstraZeneca COVID-19 Vaccine (manufactured by AstraZeneca) and COVISHIELD (manufactured by Serum Institute of India) are ChAdOx1-S recombinant vaccines developed by Oxford University and AstraZeneca.

The quality information submitted by both SIIPL and AstraZeneca supported a conclusion by Health Canada that the COVISHIELD and AstraZeneca COVID-19 vaccines are sufficiently similar with respect to the manufacturing processes, in-process controls and critical quality attributes. Based on this conclusion it was determined that a formal pivotal clinical trial for COVISHIELD was not required and that its safety and efficacy could be inferred from the clinical and non-clinical studies performed by AstraZeneca.

Known and potential benefits:
The benefits of COVISHIELD are determined from non-clinical and clinical studies with the comparable AstraZeneca COVID-19 Vaccine. The data supporting the AstraZeneca COVID-19 Vaccine was based on pooled analyses from four ongoing clinical studies trials (Studies COV001, COV002, COV003, and COV005). Two of these studies (COOV2 and COOV3) had sufficient COVID-19 cases to be included in the estimation of the efficacy of the vaccine.

The two studies (total of 11,636 participants evaluated for efficacy; 5,807 in the AstraZeneca COVID-19 Vaccine group and 5,829 in the control group) were conducted in the UK and Brazil. The majority of participants received two doses of the vaccine intramuscularly four to twelve weeks apart. The analysis of the efficacy was based on the first case of COVID-19 (virologically confirmed) occurring ≥ 15 days after the second dose of the vaccine. Participants had been followed for symptomatic COVID-19 disease for a median of 63 days (range 16-94) after the second dose.

Participants in the vaccine arm received either two standard doses (SD/SD cohort) or, due to a difference in concentration determination between two analytical methods, one low dose (LD) followed by one SD (LD/SD cohort).

The results from the AstraZeneca COVID-19 Vaccine studies can be expressed in different ways, depending on the data set analyzed.

Based on the analysis derived from data collected until November 4, 2020, compared to the control, efficacy from 15 days after second dose in participants who received 2 standard doses (SD/SD cohort) of the vaccine was 62.1% (two-sided 95% CI: 41.0% to 75.7%); 27 cases were confirmed in the vaccine group and 71 in the control group.

Based on an updated analysis derived from data collected until December 7, 2020, which included participants who received two standard doses (SD/SD cohort) with the second dose administered 4 to 12 weeks after the first dose, the estimate of vaccine efficacy in this dataset was 59.5% (two-sided 95% confidence interval of 45.8% to 69.7%).

Of the available clinical trial data, the results were too limited to allow a reliable estimate of vaccine efficacy in individuals 65 years of age and older. Efficacy in individuals 65 years of age and older, however, is supported by immunogenicity data, emerging real world evidence and post-market experience in regions where the vaccine has been deployed, which suggest at this point in time a potential benefit and no safety concerns. Efficacy in this age group will be updated as additional data becomes available from currently ongoing trials.

Known and potential risks:
Safety was evaluated in 23,745 individuals from four studies (COV001, COV002, COV003 and COV005); 12,021 subjects received at least one dose of the AstraZeneca COVID-19 Vaccine and 11,724 received a control (meningococcal vaccine or saline placebo). The most frequently reported adverse reactions after any dose were tenderness (75.3%) and pain (54.2%) at the injection site, fatigue (62.3%), headache (57.5%) and myalgia (48.6%). The majority of these local and systemic adverse reactions were mild to moderate in severity and were self-limited. Local ARs were less common in participants ≥65 years, occurring in just over half of participants. Systemic adverse reactions were less common in participants ≥65 years, with fatigue occurring in 45% and headache in 35% of participants.

The incidence of adverse events (AEs) in the first 28 days was higher in the AstraZeneca COVID-19 Vaccine group than in the control group (37.8% and 27.9% respectively). Related AEs, including related neurological AEs, were also more common in the vaccine group than the control group (27.9% and 18.5%, respectively). Most of the non-serious adverse events were reported within the first 7 days of vaccination, were self-limited and were consistent with AEs commonly observed following vaccination. Decreased appetite, diarrhea and hyperhidrosis were also more common in the vaccine group than in the control group. Some reactions occurred at similar rates between the vaccine and control groups, such as lymphadenopathy, pruritis and rash.

The incidence of serious AEs (SAEs) were similar between the vaccine and control groups (0.7% and 0.8% respectively). Two immune-mediated neurological events were noted in the study for which a causal relationship to the AstraZeneca COVID-19 Vaccine could not be excluded: a case of transverse myelitis, and a case of grade 3 facial paralysis.

There were no life-threatening AEs or deaths related to the vaccine. Based on the available data, the vaccine at the indicated dose was considered safe and well-tolerated.

Although not necessary for approval, an immunogenicity and safety clinical study to compare the COVISHIELD and the AstraZeneca vaccines is currently being conducted in India. The interim data of this phase 2/3 study suggest no differences in the safety and in the immune response between the vaccines.

A Risk Management Plan (RMP) Canadian Specific Addendum was submitted for the COVISHIELD COVID-19 Vaccine with reference to the Core European (EU) RMP for AstraZeneca COVID-19 Vaccine. The RMP is designed to describe known and potential safety issues, to present the monitoring plan 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 acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures based on the safety profile of the product.

Important limitations of the data at this time include the lack of information on the long-term safety and efficacy of the vaccine, interactions with other vaccines, and the lack of or limited data in sub-populations (e.g. pregnant/breastfeeding women, pediatric population <18 years of age, immunocompromised patients and patients with chronic or debilitating conditions, use in subjects with severe and/or uncontrolled underlying disease). The identified limitations are managed through labelling. The RMP will be updated to reflect additional safety information following authorization. In addition to regulatory requirements for post-market monitoring and prioritized reporting of adverse events following immunization, monthly safety summary reports will be provided to Health Canada.

The four ongoing clinical trials included in the pooled analyses (Studies COV001, COV002, COV003, and COV005) will continue to collect information on the long-term safety, efficacy, and immunogenicity of the AstraZeneca COVID-19 Vaccine. An additional Phase 3 trial is underway in the US, Peru and Chile with interim analysis expected within the next few weeks. The sponsor is also planning four post-authorization studies: A Phase IV Enhanced Active Surveillance Study of People Vaccinated with the vaccine; a Pregnancy Registry; a Post-marketing Safety Study; and a Post-marketing Effectiveness Study. Terms and conditions are imposed on the authorization to require monitoring of the long-term safety and efficacy of AstraZeneca COVID-19 Vaccine. Similar terms and conditions are imposed on the authorization of COVISHIELD.

Manufacturing of COVISHIELD consists of the production of a replication-deficient chimpanzee adenovirus that encodes the unmodified SARS-CoV-2 spike protein. Evidence was provided to demonstrate that the vaccine is manufactured using Good Manufacturing Practices (GMP) at all manufacturing sites providing supply to Canada and that in-process controls, process parameters and quality control release tests have been established to monitor product quality throughout the process. The specifications used to evaluate key quality attributes and consistency of production were found acceptable and the results sufficiently similar to that of the AstraZeneca COVID-19 vaccine.

In conclusion, COVISHIELD is recommended for authorization for use under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19, for active immunization against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 18 years old and over. The efficacy of the vaccine was estimated to be 62.1%. Overall, there are no important safety concerns and the vaccine was well tolerated by participants.

Directions for use:

COVISHIELD is a clear to slightly opaque solution essentially free from visible particles. The vaccine should be inspected visually for particulate matter and discolouration prior to administration. Discard the vial if the solution is discoloured or visible particles are observed.

Each vaccine dose of 0.5 mL is withdrawn into a syringe for injection to be administered intramuscularly, preferably in the deltoid muscle. Use a separate sterile needle and syringe for each individual. It is normal for liquid to remain in the vial after withdrawing the final dose.

The vaccine does not contain any preservative. After first opening, use the vial within:

• 6 hours when stored at room temperature (up to 25ºC), or
• 48 hours when stored in a refrigerator (2 to 8ºC).

The vial can be re-refrigerated, but the cumulative storage time at room temperature must not exceed 6 hours, and the total cumulative storage time must not exceed 48 hours. After this time, the vial must be discarded.

For more information, refer to the Product Monograph for AstraZeneca COVID-19 Vaccine.

Terms and Conditions:

Terms and conditions were imposed upon the authorization with respect to quality, labelling, and Risk Management Plan requirements.

For more information, refer to the Authorization Terms and Conditions for COVISHIELD.