Draft guidance on the registration of clinical trials and public disclosure of results: Appendices

On this page

• Appendix A: Regulatory authorities
• Appendix B: Glossary

Appendix A: Regulatory authorities

Pursuant to the FDA and its Regulations, Health Canada has regulatory authority over the sale and importation of drugs (pharmaceuticals, biologics and radiopharmaceuticals), medical devices and NHPs used in clinical trials.

For COVID-19 clinical trials, Health Canada also has authority over the:

• conduct of the trial
• sale and importation of the drugs or medical devices used in the trial

Health Canada has proposed that modernized clinical trial regulations would include prescribed foods for a special dietary purpose (FSDPs), for which there is currently no regulatory framework that allows clinical trials.

Drug and NHP trials are grouped according to 'phases':

1. Phase 1 trials test an experimental drug (or NHP) on a small group of people for the first time. The purpose is to:
• a. look at the drug's safety
• b. find out the safe dosage range
• c. see if there are any side effects
2. In Phase 2 trials, the drug is given to a larger group of people (usually 100 or more) to:
• a. gather data on how well the drug works to treat a disease or condition
• b. obtain information on the drug's safety on a wider range of people
• c. determine the best dose going forward
3. In Phase 3 trials the drug is given to even larger groups of people (usually 1,000 or more) to determine if it is effective in the treatment of the condition under study and further define its safety profile.
4. Finally, Phase 4 trials take place after the drug is approved and is on the market. These trials often include safety studies and studies designed to support optimum use of the drug under its approved indication.

Drugs

Part C, Division 5 of the FDR requires the filing of a Clinical Trial Application (CTA) for:

• drugs not yet marketed in Canada, including Phase 1, 2 and 3 of drug development
• marketed drugs used outside their Canadian market authorized conditions of use, such as different:
• indication
• population
• dosage regimen
• comparative bioavailability studies (used in generic drug development)

Phase 4 clinical trials involve drugs used in clinical trials according to their Canadian market authorized conditions of use and do not require the filing of a CTA.

Health Canada reviews the CTA to determine if:

• there is sufficient information to enable an assessment that the:
• objectives of the clinical trial are achievable
• use of the drug is not contrary to the best interests of the participant
• use of the drug in the clinical trial will not endanger the health of the clinical trial participant or other person
• the information and documents were provided in accordance with the FDR

A clinical trial site is the location where trial-related activities are actually conducted. Under Part C, Division 5 of the FDR, the sponsor must obtain approval of a properly constituted Research Ethics Board (REB) before the trial may begin at each clinical trial site.

All trials (including Phase 4) must be conducted in accordance with good clinical practice principles.

Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications

Medical devices

Part 3 (Sections 79 to 88) of the MDR governs the sale and importation of a medical device for investigational testing involving human participants. As per Section 6 of the MDR, medical devices are classified into one of four classes where Class 1 represents the lowest risk and Class 4 the highest.

Manufacturers and importers must meet the regulatory requirements therein, including requirements outlined in Subsection 80(2) and 83(1) of the MDR. They can then receive authorization from Health Canada to sell a device to a qualified investigator for the purpose of conducting investigational testing.

Under Section 80 of the MDR, the manufacturer or importer must possess the records specified in Section 81 prior to the sale of the medical device for investigational testing, including:

• device label
• patient consent form
• investigational testing protocol
• information on the investigators involved
• written approval from the institution indicating that investigational testing may be carried out there
• risk assessment comprising an analysis and evaluation of the risks associated with the use of the device being tested

The MDR requires the submission of an Investigational Testing Authorization (ITA) application in order to sell or import a Class 2, 3 or 4 medical device for conducting investigational testing. In addition, the MDR set out requirements to be followed post-authorization, including:

• recalls
• labelling
• advertising
• implant registration
• foreign risk notification
• incident reporting procedures
• complaint handling procedures
• maintaining distribution records

Applications for Medical Device Investigational Testing Authorizations Guidance Document

Natural health products

Clinical trials investigating NHPs are currently regulated under Part 4 of the NHPR. These trials may be conducted to provide further information about a product including its safety and efficacy. More precisely, Part 4 of the NHPR is to ensure:

• the safety, efficacy and quality of the study's:
• clinical trial protocol
• investigational product(s)
• placebo or comparator
• the safety of clinical trial participants and other people
• compliance with good clinical practices (Section 74 of the NHPR)
• that people with suitable expertise conduct properly designed clinical trials

In general, the requirements for clinical trials under the NHPR are similar to the clinical trial requirements for drugs; however, the NHPR recognize that NHPs may differ from single chemical entities in both manufacturing and evaluating processes.

Guidance for Clinical Trials for Natural Health Products

Food for a special dietary purpose: future planned scope

Foods that are not compliant with the FDR cannot be sold in Canada, including for the purpose of a clinical trial. The proposed modernized clinical trial regulations would prescribe certain foods for a special dietary purpose ("prescribed FSDPs"). They would enable Health Canada to authorize clinical trials on prescribed FSDPs that are not in compliance with certain compositional or premarket notification and authorization requirements set out in the FDR. Once the proposed regulations are in place, prescribed FSDPs would fall under the scope of this guidance.

As defined in the FDA, an FSDP is "a food that has been specially processed or formulated to meet the particular requirements of an individual in whom a physical or physiological condition exists as a result of a disease, disorder or abnormal physical state, or, to be the sole or primary source of nutrition for an individual."

For example, this category could include foods intended for vulnerable populations such as:

• infants (such as infant formula and human milk fortifiers, defined under Division 25 of Part B of the FDR)
• people with metabolic disorders or other health conditions (such as specially formulated liquid diets and other foods for special dietary uses defined under Division 24 of Part B of the FDR)

The proposed modernized clinical trial regulations would have a common approach for all of the above health products, as well as for prescribed FSDPs. There would be a few differences necessitated by the nature of the investigational products. Clinical trials investigating FDR-compliant foods, including compliant FSDPs, would be out of the scope of these regulations. Trials on these foods can currently be conducted in Canada without authorization from Health Canada.

Appendix B: Glossary

Clinical trial:

A study, involving human subjects, for the purpose of discovering or verifying the effects of a drug, a device or a food for a special dietary purpose. (Food and Drugs Act) Note: the definition of "drug" in the Act includes a natural health product.

Clinical trial application:

The information required by Health Canada from sponsors seeking authorization to sell or import a drug or NHP for the purpose of a clinical trial or a medical device for the purpose of investigational testing, involving human participants.

Device:

An instrument, apparatus, contrivance or other similar article, or an in vitro reagent, including a component, part or accessory of any of them, that is manufactured, sold or represented for use in

• a) diagnosing, treating, mitigating or preventing a disease, disorder or abnormal physical state, or any of their symptoms, in human beings or animals,
• b) restoring, modifying or correcting the body structure of human beings or animals or the functioning of any part of the bodies of human beings or animals,
• c) diagnosing pregnancy in human beings or animals,
• d) caring for human beings or animals during pregnancy or at or after the birth of the offspring, including caring for the offspring, or
• e) preventing conception in human beings or animals;

however, it does not include such an instrument, apparatus, contrivance or article, or a component, part or accessory of any of them, that does any of the actions referred to in paragraphs (a) to (e) solely by pharmacological, immunological or metabolic means or solely by chemical means in or on the body of a human being or animal. (Food and Drugs Act)

Note: "medical device": means a device within the meaning of the Act, but does not include any device that is intended for use in relation to animals (Medical Devices Regulations)

Drug:

Includes any substance or mixture of substances manufactured, sold or represented for use in

• a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals,
• b) restoring, correcting or modifying organic functions in human beings or animals, or
• c) disinfection in premises in which food is manufactured, prepared or kept. (Food and Drugs Act)

Food for a special dietary purpose:

Means a food that has been specially processed or formulated

• (a) to meet the particular requirements of an individual in whom a physical or physiological condition exists as a result of a disease, disorder or abnormal physical state, or
• (b) to be the sole or primary source of nutrition for an individual (Food and Drugs Act)

Good Clinical Practices:

Generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial participants and other persons, and the good clinical practices for drug trials referred to in Section C.05.010 of the Food and Drug Regulations and NHP trials referred to in Part 4, section 74 of the Natural Health Products Regulations. There is no applicable reference in the Medical Devices Regulations. Certain general practices are set out in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)-E6 Guideline.

Natural Health Product:

A substance set out in Schedule 1 or a combination of substances in which all the medicinal ingredients are substances set out in Schedule 1, a homeopathic medicine or a traditional medicine, that is manufactured, sold or represented for use in

• a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms in humans;
• b) restoring or correcting organic functions in humans; or
• c) modifying organic functions in humans

However, a natural health product does not include a substance set out in Schedule 2, any combination of substances that includes a substance set out in Schedule 2 or a homeopathic medicine or a traditional medicine that is or includes a substance set out in Schedule 2.

A substance or combination of substances or a traditional medicine is not considered to be a natural health product if its sale, under the Food and Drug Regulations, is required to be pursuant to a prescription when it is sold other than in accordance with section C.01.043 of those Regulations. (Natural Health Products Regulations)

Manufacturer:

Has the same meaning for drugs as in Section A.01.010 of the Food and Drug Regulations; for medical devices as in Section 1 of the Medical Devices Regulations; for NHPs as in Section 1(1) of the Natural Health Products Regulations.

Register and registration:

The act of placing information about a clinical trial into an electronic repository.

Registry:

An electronic repository of information about clinical trials, whether the information is about ongoing or completed trials. Includes results of clinical trials.

Research Ethics Board:

While there is no regulatory definition under the Medical Devices Regulations, both the Food and Drug Regulations and Natural Health Product Regulations share similar definitions. The Food and Drug Regulations definition is as follows:

A body that is not affiliated with the sponsor, and

• (a) the principal mandate of which is to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being; and
• (b) that has at least five members, that has a majority of members who are Canadian citizens or permanent residents under the Immigration Act, that is composed of both men and women and that includes at least
  • (i) two members whose primary experience and expertise are in a scientific discipline, who have broad experience in the methods and areas of research to be approved and one of whom is from a medical discipline or, if the clinical trial is in respect of a natural health product to be used for dental purposes only, is from a medical or dental discipline,
  • (ii) one member knowledgeable in ethics,
  • (iii) one member knowledgeable in Canadian laws relevant to the research to be approved,
  • (iv) one member whose primary experience and expertise are in a non-scientific discipline, and
  • (v) one member who is from the community or is a representative of an organization interested in the areas of research to be approved and who is not affiliated with the sponsor or the site where the clinical trial is to be conducted (Food and Drug Regulations)

Sell:

Includes

• (a) offer for sale, expose for sale or have in possession for sale — or distribute to one or more persons, whether or not the distribution is made for consideration, and
• (b) lease, offer for lease, expose for lease or have in possession for lease. (Food and Drugs Act)

Sponsor:

An individual, corporate body, institution or organization that conducts a clinical trial. (Food and Drug Regulations), (Natural Health Product Regulations)