Researchers planning to conduct a Phase I, II, or III clinical trial involving a drug or natural health product or a biologic or genetic therapy must contact the Office of Research Ethics prior to submitting a clinical trial application to Health Canada, to discuss the proposed research, Canada's regulatory requirements, and Waterloo's capacity to support the research. There are several types of clinical trials.
Similarly, researchers planning to conduct a Phase I clinical trial involving a class II or higher medical device must contact the Office of Research Ethics prior to submitting an application to Health Canada's Investigational Testing Authorization program.
Refer to the Q & A for considerations for developing a medical device.
A clinical trial is a research study conducted in humans to answer specific health questions. There are different phases and types of clinical trials.
For additional information on clinical trials visit ClinicalTrials.gov
Registering a clinical trial
Treatment Trials test experimental treatments, new drugs, combinations of drugs, medical devices, natural health products, or new approaches to surgery or therapy. An example of an experimental treatment is an investigational contact lens; contact lens are medical devices.
Prevention Trials test ways to prevent disease or prevent a disease from returning. The approaches may include drugs, vitamins, minerals, natural health products, educational programs, and lifestyle/behavioural change. Examples of specific approaches include, smoking prevention programs, smoking cessation, and use of echinacea (plant extract used to boost the immune system).
Quality of Life Trials test or explore ways to improve comfort and the quality of life for individuals with a chronic illness, disability, or condition. For example, trials may look at better ways to manage or prevent nausea and fatique caused by cancer treatments.
Diagnostic Trials are designed to find better tests or procedures for diagnosing a particular disease or condition. For example, a trial to determine if ultrasound is more effective than mammography in detecting breast cancer.
Screening Trials are conducted to test the best way to detect certain diseases or health conditions. For example, a trial to test a new medical imaging method or a new blood test that would detect markers that indicate cancer may be present in a person’s body.
Typically, clinical trials are conducted in four sequential phases with each phase involving a larger sample of participants.
Phase I trials are conducted to assess safety. Usually the testing involves a small number (e.g., 20-80) of healthy participants.
Phase II trials assess effectiveness and further evaluate safety. This phase of trial usually involves participants who have the disease or condition under investigation. Normally participants are randomly assigned to groups or conditions, with one condition being the treatment (program, drug, etc.) under consideration, and at least one comparison condition. Phase II studies involve a limited number (e.g., 100-300) of closely monitored participants.
Phase III trials involve a large number (e.g., 1,000-3,000) of participants, are intended to gather further evidence of effectiveness, monitor adverse reactions, and gather additional evidence of effectiveness for specific indications. Usually, these trials involve multiple sites.
Phase IV trials may explore specific effects, or be designed to determine effects on morbidity and mortality or on specific populations. For drugs, natural health products, and medical devices, Phase IV trials are conducted after the drug, medical device, or natural health product is on the market.
A sponsor of a clinical trial is usually a company, such as a pharmaceutical company, which has developed the drug, medical device, or natural health product; however the sponsor could be a researcher, for example, who is using a drug off-label in a study.
Guidance for clinical trial sponsors is available through Health Canada.
The sponsor submits a Clinical Trial Application (CTA) to Health Canada. If a researcher is submitting a CTA, the application must include a signature of a senior University of Waterloo administrator.
The Health Canada application includes:
- a protocol which details the objectives, benefits, risks, methods, and conditions for the trial to function
- Clinical Trial Site Information Form
- Clinical Trial Application (CTA)
- Qualified Investigator Undertaking
There must be a qualified investigator (QI) for Phase I, II, III clinical trials involving a drug or natural health product as defined under the regulation. The QI is responsible to the sponsor for the conduct of the clinical trial at the trial site and is entitled to provide health care under the laws of the province where the clinical trial site is located.
For a clinical trial involving a drug, the QI is:
- a physician and member in good standing of a professional medical association, or
- in the case of clinical trials respecting a drug to be used for dental purposes only, a physician or dentist and a member in good standing of a professional medical or dental association
At present, the same qualifications apply for the QI of a clinical trial involving a natural health product. The application for a clinical trial for a natural health product is presently the same as the application for a CT involving a drug.
A new drug or natural health product is tested in the laboratory to assess the drug's or product's components and study its effects on laboratory animals. Health Canada will consider a clinical trial only if the results of the initial studies demonstrate potential benefits and show no serious safety concerns.
The preparation and conduct of the trial is conducted in accordance with the Guideline for Good Clinical Practice.
Once the CTA is approved and has been reviewed and received ethics clearance through a Research Ethics Board (REB), the clinical trial can begin under the supervision of the REB and with the sponsor's funding. The sponsor, investigators, and REBs oversee the operation of the clinical trial. Health Canada's role is with respect to (i) the approval of the drug and related clinical trial or issuing a "No Objection Letter" for a medical device Class II or higher and (ii) monitoring of drug clinical trials.
Phase I, II, and III clinical trials for drugs and natural health products as defined under the Food and Drug Regulations (Division 5: Drugs for Clinical Trials Involving Human Subjects) and Natural Health Products Regulations of the Canadian Food and Drug Act are regulated by Health Canada.
If a study includes administering/using a drug or natural health product that is marketed in Canada but is being used off-label (e.g., with healthy individuals, new population), new dosage, or new formulation then the study is a clinical trial and is regulated by Health Canada.
Biologics differ from other drugs for human use in that they must - in addition to the information required for other drugs - include more detailed chemistry and manufacturing information. The Biologics and Genetic Therapies Directorate reviews and is responsible for approval of all types of drug submissions for Biological (Schedule D) and Radiopharmaceutical (Schedule C) drug products, including Clinical Trial Applications (CTAs).
Biologics and genetic therapies include:
- Blood and blood products,
- Cells, tissues and organs, including xenografts (living cells, tissues and organs from animal sources),
- Gene therapies,
- Viral and bacterial vaccines,
- Therapeutic products produced through biotechnology, and
- Radiopharmaceuticals which include drugs either of chemical or biological origin which are intentionally made radioactive for the purpose of diagnosing illness, as well as kits that are used for the preparation of radiopharmaceutical and radionuclide generators. Radiopharmaceuticals are used as diagnostic or therapeutic agents and are always prepared and administered by health care professionals; they are never self-administered.
Clinical trials involving medical devices are not regulated by Health Canada; however there are regulations governing investigational testing of medical devices.
Canadian regulations for medical devices
The manufacturer of a medical device:
- must ensure that the medical device meets the safety and effectiveness requirements laid out in the Medical Devices Regulations, and
- must keep objective evidence to establish that the medical device meets those requirements.
Medical device classes
Medical devices are classified into one of Classes I to IV. The classification is based on the level of invasiveness and whether the device is active (i.e., depends on a source of energy for operation, a source other than the energy generated by the human body or gravity).
Class I represents the lowest risk medical devices while Class IV represents the highest risk. If a medical device can be classified into more than one class, the class representing the highest risk applies.
Health Canada officially classifies all investigational medical devices. The medical device class designation letter from Health Canada must be submitted with the application for investigational testing of the device with humans.
Human experimentation and development of medical devices are not always established by phased development as with drugs (i.e., Phase I - IV clinical trials).
Proposed medical device research with humans is evaluated through the Device Evaluation Division of the Medical Devices Bureau of Health Canada.
An application is submitted and evaluated according to the Investigational Testing Authorization program governing the use of Class II, III, and IV medical devices. Class I medical devices do not require investigational testing authorization.
If the investigational testing of a device is in conjunction with a drug in a clinical trial then the sponsor must obtain authorization for the clinical trial and authorization for the use of the investigational medical device.
Following a favourable Health Canada review of the Application for Investigational Testing a "No Objection Letter" (NOL) is sent to the Manufacturer/Sponsor indicating Health Canada's agreement for the Manufacturer/Sponsor to conduct the research.
Health Canada requires notification of ethics clearance for the study through a Research Ethics Board prior to issuing a No Objection Letter. This is the Clinical Research Ethics Board (CREB) at the University of Waterloo.
The CREB can provide to the investigator certification of conditional ethics clearance for the study when the absence of ethics clearance is the only element preventing Health Canada from issuing a No Objection Letter. The study may not be initiated until the Office of Research Ethics receives the No Objection Letter from the Investigator via the sponsor.