Notice to Stakeholders: Statement on the Investigational Use of Marketed Drugs in Clinical Trials

1) Context

This statement provides guidance to clinical trial applicants about the investigational use of marketed drugs within clinical trials in Canada. It will serve as interim interpretive guidance until amendments can be made to the Food and Drug Regulations. The objective of the statement is to explain how the requirements of Part C, Division 5 of the Food and Drug Regulations apply in relation to the off-label use of a drug that is authorized for sale in Canada. The guidance describes when a marketed drug used off-label in a clinical trial is not considered to be investigational within the meaning of the definition of "drug" in section C.05.001 of the Food and Drug Regulations.

2) Background

Section C.05.001 of the Food and Drugs Regulations defines "drug" as "a drug for human use that is to be tested in a clinical trial"(Regulations Amending the Food and Drug Regulations (1024—Clinical Trials), SOR/2001-203). Clinical trial is defined for the purposes of these regulations as "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 and efficacy of the drug". The clinical trial regulations prohibit the sale of a marketed drug for a purpose that falls outside the recommended uses and conditions of use of the drug for which it has been authorized for sale (i.e. an "on-label" use).

Clinical trials often involve the off-label use of a marketed drug (i.e. a use not in accordance with the labelled uses or conditions of use for which the drug has received market authorization). Health Canada has taken the view that any drug sold for off-label use in a clinical trial is a study drug that must be identified as an investigational drug in a CTA. As the off-label uses of an authorized drug can often be supported by well-established clinical practice overseen by provincial bodies that govern medical practice, this interpretation may be creating an unnecessary barrier to clinical research.

Considering the above, the following considerations will inform whether the off-label use of a marketed drug in a clinical trial is investigational or not:

• Does the drug have an established safety profile when used off-label in the study population?
• Is the drug being used off-label:
  • in a clinical trial setting as part of a comparator arm,
  • as part of supportive/rescue therapy, or
  • as part of standard therapy that another investigational drug is being used to supplement in the investigational arm of the trial?
• What is the degree of uncertainty about the risks and benefits of the drug in the off-label use?
• Has the drug received Canadian market authorization and is presently being sold in Canada? Will the drug be obtained from the Canadian market?
• Is the off-label use of the drug in the clinical trial expected to significantly alter the risk to clinical trial subjects compared to normal clinical practice?
• Is it otherwise clear that the drug to be used off-label is not being tested in the clinical trial?

3) Interpretive Statement

Every marketed drug that will be used in accordance with, or outside its labelled uses or conditions of use in the context of a clinical trial must be described in a CTA. Applicants must either state that the drug is investigational or explain why, in the proposed clinical trial, it is not investigational in nature because it is not the subject of testing in the clinical trial. If it is determined by Health Canada that the drug is not investigational, then the regulatory requirements under Division 5 of the Food and Drug Regulations that are set out in Section 5 of this statement do not apply to the drug.

4) Application

For positron emitting radiopharmaceuticals such as Fludeoxyglucose 18F and Technetium-99, Health Canada recognizes that the use of these therapeutic products are well-established in clinical practice. Should a sponsor wish to consider the use of radiopharmaceuticals as non-investigational in the context of a clinical trial, Health Canada requires sponsors to provide the following attestation within the application:

As sponsor, we confirm that the positron emitting radiopharmaceutical (PER) used in this study will be in accordance with the Health Canada's criteria for clinical use as outlined below:

• The PER to be used at all clinical sites is licensed/marketed and sourced locally from the Canadian market;
• There is no intent to use the information in the CTA to support a new indication for PER, nor is there intent to use it to support any other significant change in the labeling of the PER;
• The CTA does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of PER;
• The scanning procedure will follow local/standard practice.

If the sponsor provides an attestation to these statements, they do not need to include the PER on the HC/SC 3011 Form, nor do they need to complete an Investigational Status Assessment (ISA) request, as these products are not considered investigational in practice, nor are they the product being investigated in the clinical trial.

For all other drugs, to determine whether the proposed off-label use of a market authorized drug in a clinical trial is investigational or not, Health Canada requires sponsors to provide the following information in the CTA:

• What is the Notice of Compliance (NOC) and/or Drug Identification Number (DIN) authorizing the sale of the drug in Canada and what is the purpose or condition of use for which the NOC/DIN was issued?
• What is the proposed off-label use of the drug in the clinical trial?
• How is this off-label use consistent with current or recognized medical practice?
• How is this drug and its off-label use not the subject of investigation in the clinical trial?
• What risk or uncertainty does this drug and its off-label use pose in the clinical trial?

Sponsors are required to explain if the off-label use involves a route of administration, dosage level, use in a patient population or any other factor that significantly increases the risks or decreases the acceptability of the risks associated with the use of the drug product. A sponsor seeking approval of a CTA with a protocol that includes a non-study drug being used off-label is further invited to show how the use of the drug in the population under study aligns with Canadian "best medical practices" and poses a "low risk" to the population under study. The supporting evidence could include:

• Canadian and/or American national medical organization guidelines, federal and/or provincial government Consensus Treatment Guidelines, Health Technology Assessment reports, Cochrane Reviews, or a systematic review of the existing literature based on an explicit and transparent process that minimizes distortions, biases, and conflicts of interest of the authors; and
• information confirming that the drug has been used in the population under study for a sufficient period of time, and has an established safety profile in the population under study.

Should a sponsor wish to apply this policy in the case of a protocol, the sponsor would need to make a determination of which products are considered investigational versus non-investigational in the context of their protocol. Only the investigational drugs should be captured on the HC/SC 3011 Form. For each product that is deemed non-investigational, the Health Canada Investigational Status Assessment (ISA) template should be completed by sponsor, and included in their CTA package. The completed ISA template and supporting evidence should be included in Module 1.4.1 and Module 5.4, respectively.

The ISA template is available upon request; sponsors are requested to contact the relevant directorate via the general enquiries email address should they require a copy.

Health Canada will, at the time of reviewing the CTA, review the ISA request and determine if the proposed off-label use of the marketed drug is investigational in the context of the particular application under consideration.

5) Regulatory Requirements

If Health Canada expresses no objection to the sponsor's application that includes an explanation as to why the use of a marketed drug is not investigational in the context of the particular clinical trial, the drug will not be listed on the No Objection Letter. Additionally, in an effort to reduce regulatory burden, the drug will be exempted from the following requirements of the Food and Drug Regulations:

Labelling

C.05.011 Despite any other provision of these Regulations respecting labelling, the sponsor shall ensure that the drug bears a label that sets out the following information in both official languages:

• a statement indicating that the drug is an investigational drug to be used only by a qualified investigator;
• the name, number or identifying mark of the drug;
• the expiration date of the drug;
• the recommended storage conditions for the drug;
• the lot number of the drug;
• the name and address of the sponsor;
• the protocol code or identification; and
• if the drug is a radiopharmaceutical as defined in section C.03.201, the information required by subparagraph C.03.202(1)(b)(vi).

Records

C0.5012 (3) The sponsor shall maintain complete and accurate records in respect of the use of a drug in a clinical trial, including

• a copy of all versions of the investigator's brochure for the drug;
• records respecting each change made to the investigator's brochure, including the rationale for each change and documentation that supports each change;
• records respecting the shipment, receipt, disposition, return and destruction of the drug;

The remainder of the requirements of clinical trial sponsors laid out in the Food and Drug Regulations continue to apply. For further information regarding these remaining requirements, please refer to the Guidance for Clinical Trial Sponsors: Clinical Trial Applications and the Guidance Document: Part C, Division 5 of the Food and Drug Regulations "Drugs for Clinical Trials Involving Human Subjects" (GUI-0100).

6) Effective Date

This policy statement is effective June 5, 2019. Revised on April 26, 2021.

7) Contact information:

Enquires and information regarding this notice should be submitted directly to the following:

For Pharmaceutical Drugs

Office of Clinical Trials
Therapeutic Products Directorate
5th Floor, Holland Cross, Tower B
Address Locator: 3105A
1600 Scott Street
Ottawa, Ontario
Canada
K1A 0K9
General Enquiries:
E-mail: hc.oct.enquiries-requetes.bec.sc@canada.ca

For Biologic and Radiopharmaceutical Drugs

Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
100 Eglantine Driveway,
Address Locator: 0601C
Ottawa, Ontario
Canada
K1A 0K9
General Enquiries:
Email: hc.brdd.ora.sc@canada.ca