Guidance for market authorization requirements for COVID-19 vaccines: Rolling submissions, non-clinical and clinical requirements
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- Standard for accepting a rolling submission
- Non-clinical requirements for authorization
- Clinical testing requirements for authorization
Standard for accepting a rolling submission
Modified requirements for COVID-19 drugs allow for the filing of rolling submissions (section C.08.002(2.3) of Canada's Food and Drug Regulations). The ability to review data from early development while later-stage clinical trials are taking place helps to expedite the regulatory review process.
Before filing a submission for a rolling review, sponsors of clinical trials are expected to have gathered a certain level of evidence on the safety, quality and efficacy of their vaccine. We advise sponsors to consult with us before filing an application.
To file an application for a rolling review, sponsors should have, at a minimum:
- non-clinical and clinical phase 2 data that demonstrate promising evidence of safety and efficacy
- confirmation that phase 3 trials have started and there are enough people enrolled to provide evidence of safety and efficacy within a reasonable amount of time (expected to be within 6 months from initial filing)
- evidence that manufacturing is in compliance with good manufacturing practices (GMP) and that product quality and consistency are well controlled
Sponsors must also file a plan giving the anticipated timelines for submitting the various components of the application. A plan must be included in the initial filing.
For details on plan requirements, see our guidance document on amendments to the Food and Drug Regulations for drugs for use in relation to COVID-19.
Non-clinical requirements for authorization
Some non-clinical data requirements and the methods used for non-clinical testing may be specific to the type of vaccine being developed. However, certain non-clinical data will be required for all vaccines.
For the development of a COVID-19 vaccine, the non-clinical data package must include:
- studies that assess the toxicology of the vaccine
- proof of concept, including antibody and cell mediated immune responses and protection
- assessment of the theoretical risk of vaccine-associated enhanced respiratory disease (VAERD)
Assessment of toxicity
The development and authorization of COVID-19 vaccines must be supported by toxicology studies in relevant animal models. Key animal studies need to be conducted in compliance with the international standards of good laboratory practices. These studies look at the general toxicity, local tolerance and other relevant toxicity endpoints.
If the vaccine is to be used in pregnant women, developmental and reproductive toxicity studies must be conducted to better understand the risks.
Proof of concept assessment
We require non-clinical tests or studies that characterize the ability of the vaccine to elicit a neutralizing immune response against the SARS-CoV-2 virus. These studies should be performed before proceeding to first-in-human clinical trials. In vivo studies in relevant animal models should evaluate the vaccine's ability to elicit neutralizing immune responses using the same dosing regimen and formulation intended for humans (for instance, single-dose or repeat-dose, adjuvanted).
When demonstrating immune responsiveness, consideration should be given to the humoral and cellular immune responses. Non-clinical data should also demonstrate the capacity of the vaccine to protect from SARS-CoV-2 using an appropriate animal challenge model.
Vaccine-associated enhanced respiratory disease (VAERD)
Vaccines developed against some respiratory viruses, including other corona viruses, have been associated with VAERD. This occurs when people who are vaccinated and then exposed to the virus develop a worse form of the disease.
At the time of this guidance, the potential for vaccines against SARS-CoV-2 to induce VAERD is theoretical. However, it will be important for the non-clinical vaccine development program to address this theoretical risk. Viral challenge studies intended to demonstrate the capacity of the vaccine to protect against SARS-CoV-2 can provide a suitable model for assessing VAERD. This is the case if studies also include assessments that address enhanced disease such as T-helper cell type 1 and T-helper cell type 2 responsiveness, lung histopathology and immune cell infiltrates.
Clinical testing requirements for authorization
To assess the safety of a vaccine, Health Canada requires:
- an adequate number of vaccine recipients
- monitoring for a sufficiently long time
This requirement is needed to detect common and expected adverse reactions, as well as events that are less common but potentially more severe.
In line with the pre-authorization safety data requirements for preventive vaccines for infectious diseases, the safety database for a COVID-19 vaccine should have at least 3,000 study participants. They should be vaccinated with the dosing regimen intended for authorization.
The data should come from phase 3 randomized placebo-controlled trials that allow for the collection of adverse events in the vaccinated (>3,000 participants) vs. the placebo (>3,000 participants) group. This enables the detection of more common adverse events, which are in the range of at least 1 in 1,000 doses given.
Common adverse reactions include:
- redness and pain at the injection site
- sore arm
These should be monitored closely for at least 7 days to adequately characterize the frequency of those events.
Uncommon, rare or adverse events that may take longer to manifest should also be monitored closely. The median duration of safety follow-up to support authorization should be at least 2 to 3 months after all doses in the schedule have been given. Most adverse events are expected to occur within 2 months of vaccination.
Given the previous history with vaccines for other respiratory viruses, which have resulted in enhanced disease in people who were vaccinated and subsequently exposed to the virus (VAERD), this risk should be closely monitored for SARS-CoV-2 vaccines. The stability of the immune response following vaccination should be monitored. A period of 6 months may be required to assess for the potential for VAERD, if data from earlier phase clinical trials suggest that longer-term follow up is needed prior to authorization.
Following authorization, clinical trial participants should be monitored for as long as feasible. The ideal time is at least 1 to 2 years. This length of time is needed to assess the duration of protection and the potential for enhanced disease.
Health Canada may issue terms and conditions requiring the sponsor to provide longer-term clinical follow-up and post-market safety data on adverse events of special interest, such as VAERD, following authorization.
Internationally, regulators are in agreement on the safety assessment criteria. These criteria include defining:
- adverse events of special interest for close monitoring during clinical trials
- the size of the safety databases required
We will use these criteria when reviewing data submitted during the review.
Health Canada requires robust evidence of the vaccine's ability to prevent COVID-19 infection from well-conducted phase 3 clinical trials in humans. Ideally, we would like to see as high an efficacy as possible. However, as the virus that causes COVID-19 is new, we don't yet know how effective vaccines will be. We consider a target threshold of at least 50% efficacy to be reasonable for COVID-19 vaccines.
Clinical trials should demonstrate that the vaccine reduces the incidence of a symptomatic SARS-CoV-2 infection by at least 50% in people who are vaccinated, compared to a control group of people who don't receive the vaccine. Enough people should be enrolled so that the trial is sufficiently powered to exclude an efficacy result below 30%. The trial must have a sufficient number of participants with severe COVID-19 infection in the control group to show that the vaccine is effective.
This efficacy estimate is expected regardless of when the data are analyzed, including any pre-specified early looks at the data while the clinical trial is under way. Health Canada may issue terms and conditions requiring the sponsor to provide additional data confirming the duration of protection or other pertinent efficacy endpoints.
Although 50% efficacy is the target threshold, vaccines that don't reach this threshold may still be considered for authorization. We will review the safety and efficacy of each vaccine on a case-by-case basis. We will also consider the availability of other vaccines and treatments, public health needs, the status of the pandemic and the epidemiology of the disease in Canada.
When comparing a potential vaccine with a COVID-19 vaccine that has already met the efficacy criteria outlined above and been approved by a stringent regulatory authority, a non-inferiority trial design may be used with a non-inferiority margin of less than 10%. This means that the vaccine may show no more than 10% lower efficacy compared to the approved vaccine (lower bound of the confidence interval around the primary relative efficacy point estimate is >-10%).
Critical efficacy results will be summarized in the labelling for the vaccine along with the dosing regimen and the patient populations used to demonstrate efficacy. Efficacy should be shown using the dosing regimen intended for authorization. The National Advisory Committee on Immunization (NACI) and public health officials use this information to develop vaccination programs.
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