Canada has a unique system which is divided into two levels, federal and provincial. The Constitution Act of 1867 attributes the competencies amongst these two levels. When it comes to health and health care, both the provinces and the federal government are involved in such matters. This often leads to confusion about provincial and federal jurisdiction and, consequently, towards which authority to turn when conducting certain kinds of activities in the country, including clinical trials. An important nuance between “health” and “health care” is to be drawn. Health, in its broadest sense, refers to the desirability of maintaining or achieving a positive state of overall well-being and will usually be framed by federal laws. Healthcare, which refers to medical services offered by physicians and hospitals, will fall under the jurisdiction of the provincial government.
Clinical trials and, more generally, medical products, are regulated by the federal department with responsibility for national public health, Health Canada. The applicable law in the matter is the Canadian Food and Drug Act (hereinafter “FDA”) and the FDA Regulations (hereinafter the “Regulations”). Canada has also adopted international and domestic guidelines that identify accepted principles and practices in the conduct of clinical trials, including the ICH Good Clinical Practice Consolidated Guideline.
What exactly is a clinical trial?
As defined under Canadian law, a clinical trial means “an investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug 1 .”
Health Canada classifies the different clinical trials according to a four-phase system:
Phase I
Initial safety studies on a new drug, including the first administration of the drug into humans, is usually conducted on healthy non patient volunteers. These trials may be conducted on patients when the administration of the drug to healthy volunteers is not ethical. Phase I trials are designed mainly to determine the pharmacological actions of the drug and the side effects associated with increasing doses. Pharmacokinetics as well as drug-drug interaction studies are usually considered as Phase I trials regardless of when they are conducted during drug development, as these are generally conducted on healthy volunteers. Phase I trials also include trials in which new drugs are used as research tools to explore biological phenomena or disease processes.
Phase II
Phase II applies to clinical trials aimed at evaluating the efficacy of the drug on patients with medical conditions to be treated, diagnosed or prevented and at determining the side effects and risks associated with the drug. If a new indication for a marketed drug is to be investigated, then those clinical trials may generally be considered Phase II trials.
Phase III
Phase III applies when controlled or uncontrolled trials conducted after preliminary evidence suggesting efficacy of the drug has been demonstrated. These are intended to gather additional information about efficacy and safety that is needed for further risk/benefit assessment of the drug. In this phase, clinical trials are also conducted in special patient populations (e.g., renal failure patients), or under special conditions dictated by the nature of the drug and disease.
Phase IV
Phase IV applies to all studies performed after the drug has been authorized by the regulator for the market. These studies are often important for optimizing the drug’s use. They may be of any type but must have valid scientific objectives. Commonly conducted studies include safety studies and studies designed to support use under the authorized indication such as mortality and morbidity studies, or epidemiological studies.
Authorization process for a clinical trial
The FDA prohibits conducting a clinical trial unless the person or organization conducting such trail holds an authorization to that effect 2 .
The sponsor of the trial must submit the clinical trial authorization (CTA) and is ultimately responsible for the conduct of the clinical trial. They must notify Health Canada of any changes to the CTA and of any adverse drug reactions, keep records in accordance with the Regulations, and follow good clinical practices for the proper use of drugs involved in the clinical trial.
The CTA outlines the objectives, methodology and goals of the proposed clinical trial. This information is to be supported by relevant documentation.
Applications must be submitted to Health Canada before conducting clinical trials in phases I, II and III. Submissions must be sent directly to the applicable review directorate, i.e., to the Therapeutic Products Directorate for pharmaceutical drugs and to the Biologics and Genetic Therapies Directorate for biological and radiopharmaceutical drugs. Authorization for a phase IV clinical trial (post-marketing surveillance trial) is not required if the trial involves marketed drugs and is conducted within the parameters of an approved notice of compliance. Thus, a CTA will be required to conduct clinical trials involving marketed products where the proposed use of the product is outside the parameters of the authorized Notice of Compliance (NOC) or Drug Identification Number (DIN) application (e.g., using a marketed product for a ‘new’ indication or using an unauthorized dose).
Health Canada reviews the applications and notifies the sponsor within 30 calendar days if the application is found to be deficient. If the application is deemed acceptable, a No Objection Letter (NOL) will be issued within the 30-day review period.
A CTA contains information and documentation to support the objectives of the proposed clinical trial. It also includes data to support the drug product quality. The clinical and quality components of the application are reviewed in parallel and both must be satisfactory before a No Objection Letter can be issued. The approval of local/institutional Research Ethics Boards at each concerned institution must also be obtained before a clinical trial is initiated.
Additional considerations
Obtaining Health Canada’s authorization to conduct a clinical trial is indeed a key step for the process. However, one must keep in mind that such a project presupposes numerous other considerations and the drafting of crucial documents, such as a comprehensive clinical trial agreement between the sponsor and the medical or research organization engaged to conduct the clinical trial. Consequently, it is essential to be accompanied by professionals who understand the legal subtleties of the Canadian legal and regulatory framework which applies to such activities.
The Law Office of S. Grynwajc advises pharmaceutical companies in their clinical trials and other operations on the Canadian market. If you wish to ensure that your organization complies with its obligations in connection with the conduct of clinical trials in Canada, do not hesitate to contact us, we will be delighted to assist you!
1 FDA Regulation, Part C (5).
2 FDA, art. 3.1.