Guidance for market authorization requirements for COVID-19 drugs: Non-clinical and clinical testing requirements

On this page

• Non-clinical requirements
• Clinical testing requirements
• Addressing SARS-CoV-2 variants

Non-clinical requirements

Some non-clinical data requirements and methods used for non-clinical testing may be specific to the type of drug being developed. However, certain non-clinical data will be required for all drugs. This includes proof-of-concept and safety studies on such things as primary pharmacology, secondary pharmacology, drug interactions and toxicology. These studies should use adequate level of exposure, exposure duration and route of administration to support the clinical use of the drug to treat COVID-19.

Assessing proof-of-concept

We require non-clinical tests or studies that demonstrate a mechanism of action relevant to preventing and/or treating COVID-19. Examples are studies on activity against the SARS-CoV-2 virus, including relevant variants, and the effect on the hyperinflammatory immune response to SARS-CoV-2 infection. These studies should be done before the first-in-human clinical trials.

Assessing toxicity

For small molecule drugs, non-clinical toxicology and safety pharmacology studies in relevant animal or in vitro models are required to evaluate the following:

• genotoxicity
• local tolerance
• general toxicity
• reproductive and development toxicity
• other relevant toxicity endpoints (for example, carcinogenicity, immunotoxicity)

In addition, reproductive and developmental studies as well as carcinogenicity studies may be required. Factors such as target population, type of product, mechanism of action, weight of evidence and treatment duration will be considered.

These studies may also be required for biologic drugs. Please consult the European Medicines Agency's ICH S6 (R1) document, as key animal or in vitro studies should comply with international standards of good laboratory practice.

Assessing secondary pharmacology

Studies to address the potential for off-target pharmacological properties may be required. You should assess the risk of antibody-dependent enhancement for antibody products that interact directly with the virus.

Assessing drug interactions

In vitro and/or in vivo studies to characterize the potential for drug-drug interactions are required for small molecule drugs. Most often, these studies are not required for biologic drugs.

Clinical testing requirements

To support marketing authorization, sponsors should conduct randomized, placebo-controlled or active-controlled, double-blind phase 2 or 3 clinical trials using a superiority design. Background standard of care should be maintained in all treatment arms.

These trials should be long enough and have a sufficient sample size to evaluate safety and effectiveness reliably. Active-control should demonstrate clinically meaningful efficacy and acceptable safety with respect to preventing and/or treating COVID-19. Novel endpoints should be validated and be clinically meaningful.

Assessing clinical pharmacology

Clinical pharmacology data on drug absorption, distribution, metabolism and elimination, as well as the effect of intrinsic and extrinsic factors, are required.

Evidence supporting the dosing regimen investigated in the safety and efficacy studies is also required.

Assessing safety

To assess the safety of a drug, Health Canada requires:

• an adequate number of drug recipients
• monitoring for a sufficiently long time

These requirements are needed to detect common and expected adverse reactions, as well as events that are less common but potentially more severe.

Sponsors should include a broad range of people in their clinical trials to generate enough information on the drug's safety and efficacy. In addition, the trial group should include individuals at high risk of complications, such as:

• older people
• people with underlying cardiovascular or respiratory disease, diabetes, chronic kidney disease or other comorbidities
• people who have compromised immune systems (for example, those who are HIV-infected, organ transplant recipients or patients receiving cancer chemotherapy)

Pregnant and adolescent patients can be included if safety is reasonably assured.

The size and composition of the safety database needed to support an indication for COVID-19 depends on a number of factors. These include the following:

• treatment effect
• proposed population
• duration of treatment
• nature of the drug (small molecule versus biologic)
• extent of previous clinical experience with the drug
• pre-clinical and/or clinical evidence of the drug's toxicity

The schedules for safety assessments (for example, vital signs, laboratory studies, electrocardiograms) should consider the severity of illness and the identified potential risk of the study drug.

For small molecule drugs, assessment of safety should include data from studies:

• assessing the effect of food
• assessing drug-drug interactions
• evaluating QT/QTc interval prolongation
• involving people with kidney or liver impairment

If not, sponsors should have a plan on how they are going to generate this data. These studies are typically not required for biologic drugs.

Assessing efficacy

The development program involves comparing the effect of the investigational drug to the placebo or active comparator in order to generate clinically meaningful outcomes of COVID-19. The choice of clinical outcome measures should consider the population studied.

Examples of important clinical outcome measures in treatment trials include:

• all-cause mortality
• acute respiratory failure, including the need for:
  • mechanical ventilation
  • extracorporeal membrane oxygenation (ECMO)
  • non-invasive ventilation
  • high-flow oxygen
  • low-flow oxygen
• proportion of patients alive and free of respiratory failure at an appropriate time point
• need for and/or duration of COVID-19-related hospitalization or emergency department visits based on clear definitions and specific clinical criteria

Mortality and intensive care unit (ICU) admission results are preferred over results on the duration of hospitalization, recovery time or other event analyses. To demonstrate a potential benefit of the drug being tested, treatment should occur soon after confirming COVID-19.

In phase 2 treatment trials, a virologic measure could be used to support a promising clinical finding before efficacy is established in a phase 3 clinical study. However, virologic endpoints are not appropriate as primary endpoints in a phase 3 trial. There's no established predictive relationship between magnitude and timing of viral reductions and how a patient feels, functions or survives. The optimal sample size, timing, methods for collection procedures and assays for clinically relevant virologic measurements have also not been established.

In phase 3 treatment trials, virologic endpoints may be assessed as secondary endpoints.

In prevention trials, the efficacy endpoints should capture the occurrence of laboratory-confirmed SARS-CoV-2 infection with or without symptoms. They should also capture emergency room visits and hospitalizations.

These efficacy outcomes should be assessed at a pre-specified and clinically relevant time. When assessing the mitigation of symptoms, it's best to introduce the intervention as soon as possible following diagnosis. As well, there should be enough patients enrolled to account for the fact that most people will not become seriously ill with or without treatment.

Addressing SARS-CoV-2 variants

Variant strains of the SARS-CoV-2 virus are emerging as the virus continues to spread and evolve. Variants are identified by differences (mutations) in the viral genomic sequences. These differences may result in amino acid substitutions, insertions and/or deletions in viral proteins.

Genetic mutations affecting the spike protein that is targeted by therapeutics is particularly concerning, as they may reduce their effectiveness.

Non-clinical requirements

The following non-clinical tests or studies are required:

• non-clinical tests or studies that demonstrate a mechanism of action that's relevant to preventing and/or treating COVID-19
  • should investigate the expected or potential impact of relevant variants of the virus on this mechanism of action
• assays that evaluate a product's impact on SARS-CoV-2 infection
  • investigate and describe the performance characteristics and the impact of relevant variants on the assay(s)
• evaluation of the efficacy of the investigational drug that includes testing for activity against the relevant variants of the virus

Sponsors should continuously monitor for emerging SARS-CoV-2 spike protein variants and evaluate the product's performance against identified variants of concern (VOCs).

The efficacy established at the time of authorization could change or become uncertain due to the emergence of SARS CoV-2 variants and their prevalence in different geographical regions. We expect this will have a significant impact on monoclonal antibody products targeting SARS-CoV-2, in particular monoclonal antibody therapies that target the SARS-CoV-2 spike protein, where there have been key amino acid changes.

For these therapies, sponsors should:

• provide additional non-clinical data during the post-authorization period to address the binding and efficacy against emerging SARS-CoV-2 variants
• conduct these studies for authentic SARS CoV-2 variants, as pseudovirus results may not accurately capture the efficacy of the therapies against the emerging SARS-CoV-2 variants

Sponsors may be required to update the warnings and precautions section of the product monograph should there be evidence of a potential for reduced efficacy against the emerging SARS-CoV-2 variants.