Part C, Division 5 of the Food and Drug Regulations "Drugs for Clinical Trials Involving Human Subjects" (GUI-0100): Application and authorization

On this page

• Regulations and interpretations
  • Interpretation
  • Application
  • Prohibition
  • General
  • Application for authorization
  • Authorization
  • Notification
  • Amendment
  • Additional information and samples

Regulations and interpretations

For each section below, the exact text from Part C, Division 5 of the Food and Drug Regulations is provided first. This is followed by Health Canada's interpretation (what should be done in order to be compliant).

Interpretation

Application

Interpretation

The Regulations apply to the sale and importation of drugs to be used in clinical trials involving humans that are conducted in Canada. As per section C.05.002, no person can sell or import (refer to Glossary (terms) for definitions of sell and import) a drug for the purposes of a clinical trial involving humans unless authorized (refer to section 5.6 Authorization). For Phase IV clinical trials, limited provisions of Part C, Division 5 apply which are set out in subsection C.05.002(2) and described below.
Phase IV clinical trials include those trials that involve the use of:

• a new drug that has been issued a notice of compliance (NOC) under subsection C.08.004(1) of the Regulations, if the clinical trial is in respect of a purpose or condition of use for which the NOC was issued; or
• a drug, other than a new drug, that has been assigned a drug identification number (DIN) under subsection C.01.014.2(1) of the Regulations, if the clinical trial is in respect of a use or purpose for which the DIN was assigned.

Phase IV clinical trials are performed after the drug has been authorized by Health Canada for the market, and within the parameters of the authorized NOC or DIN application.

In accordance with subsection C.05.002(2), the sponsor of a Phase IV clinical trial does not have to file a clinical trial application (CTA) for importation and/or sale of the study drug. However, the following does apply:

• the person selling and/or importing the trial drug must be authorized under Part C, Division 5 [C.05.003(a)] (refer to next bullet below)
• a new drug has been issued a NOC [C.05.006(2)(a)] or a drug, other than a new drug, has been assigned a DIN [C.05.006(2)(b)], and the clinical trial is in respect of a purpose or condition of use for which the NOC was issued / DIN was assigned
• the sponsor cannot sell or import a trial drug during a period of suspension or cancellation of the trial [C.05.006(3)]
• the trial has to be conducted according to GCP [C.05.010 (a) to (i)]
• the drug must be labeled according to the Regulations (C.05.011)
• the sponsor must comply with records requirements referenced in this Division [C.05.012, with the exception of C.05.012(3)(e)]
• the criteria for submission of information and samples to Health Canada (C.05.013)
• the criteria for suspension and cancellation of a trial (C.05.016 and C.05.017)

Where a clinical trial is conducted on a marketed drug in order to test the safety and/or efficacy of the product under new conditions of use (that is, outside the conditions for which it has received a DIN or NOC), the sponsor must file a CTA for authorization to conduct the clinical trial in Canada.

For requirements regarding the reporting of adverse drug reactions (ADRs) for Phase IV clinical trials, please see the interpretation of C.05.014 in this document.

Please refer to the Guidance document for clinical trial sponsors: Clinical trial applications for detailed guidance on the application process and Phase IV studies classification. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

Inspection of Phase IV clinical trials

In general, Health Canada does not focus its inspection activities on Phase IV trials. However, because Phase IV studies are to be conducted in accordance with GCP, which includes good manufacturing practices (GMP) requirements, they may be subject to inspection.

Prohibition

Interpretation

Drugs that are sold and/or imported for the purpose of a clinical trial do not have to meet the regulatory requirements for a DIN (C.01.014) or a NOC (C.08.002 and C.08.003). However, the use of these drugs in a clinical trial (other than Phase IV) must be authorized through the submission of a CTA to Health Canada, including for each CTA-Amendment (CTA-A, see section C.05.008 Amendment).

In addition to Part C, Division 5 of the Regulations, the following provisions of Division 1 also apply to any drug sold for a clinical trial whether authorized under C.05.006(1) (CTA) or C.05.006(2) (DIN or NOC for Phase IV):

• disintegration times for drugs in tablet form (C.01.015)
• drugs containing phenacetin in combination with salicylic acid, drugs containing mercury and other ingredients, and drugs described in Schedule C or D to the Act (C.01.036)
• pediatric doses of salicylic acid, acetaminophen and their derivatives and other ingredients (C.01.037 to C.01.039)
• drugs containing chloroform or arsenic (C.01.040)
• use of coloring agents in drug products (C.01.040.2)
• drugs prepared for use in the eye (C.01.064, C.01.065)
• drugs prepared for use through injection or IV (C.01.066, C.01.067)
• instructions for the sale of hypodermic tablets (C.01.070)
• aminopyrine or dipyrone and appropriate warning labels (C.01.131, C.01.133)
• coated tablets containing potassium salts (C.01.134 to C.01.136), and
• distribution of promotional material about chloramphenicol and warning statements (C.01.435)

Marketed drugs used in Phase IV clinical trials are subject to the same requirements.

Importation of clinical trial drugs

The sponsor is the regulated party to whom the authorization to sell and/or import a clinical trial drug is issued. A sponsor who is not based in Canada must have a representative in Canada who is responsible for the import and sale of the drug in Canada and must be able to demonstrate compliance to the applicable regulatory requirements. As per section C.05.005, this person is the sponsor's senior medical or scientific officer residing in Canada who is responsible for providing an attestation with respect to the CTA/CTA-A at the time of filing.

Sponsors should be rigorous in their dealings with contracted third parties, including service providers, to ensure that the sponsor's obligations are met. When third parties have been delegated some of a sponsor's responsibilities, written agreements should be in place to clearly set out the division of responsibilities.

Drugs may be shipped directly from a foreign provider (manufacturer, distributor, etc.) to a clinical trial site in Canada provided that:

1. a No Objection Letter (NOL) has been issued by Health Canada authorizing the importation of the clinical trial material in Phase I-III trials. No such clinical trial drugs should be imported prior to the NOL issuance and the NOL should accompany the package at the time of the importation; If 30 days have passed and no NOL was obtained, specific requests to import clinical trial drugs should be directed to the Health Product Border Compliance Program at the following generic email account: hpbcp-pcpsf@hc-sc.gc.ca
2. each party, including individual Canadian clinical trial sites, importing drugs directly (i.e. receiving drug shipment directly from outside of Canada) is identified in Clinical Trial Application forms
3. Clinical Trial Site Information (CTSI) forms (PDF format) for each Canadian site conducting the clinical trial are submitted to Health Canada for Phase I-III trials, prior to the start of the study at the site (also refer to section C.05.010(e) "Clinical Trial Site Information Forms")
4. systems are in place, when appropriate, to monitor the transportation and storage conditions from the foreign source to the various clinical trial sites across Canada
5. there is documented accountability of the imported drugs used in clinical trials and distributed to various clinical trial sites located in Canada, including the disposition of drugs returned from the clinical trial sites
6. a written agreement is in place between the sponsor and the qualified investigator (QI) describing their specific responsibilities, and this agreement is available at the clinical trial site
7. there is evidence that the drugs used in clinical trials conducted in Canada meet GMP requirements. For example, adequate evidence of GMP compliance would include:
   • certificates of manufacture and certificates of analysis (CoA or batch certificates) for the lots of clinical trial material imported into Canada
   • evidence of approved lot release by a qualified individual

For additional information on GMP requirements, refer to the Guidance document – Annex 13 to the current edition of the GMP guidelines: Drugs used in clinical trials (GUI-0036).

Please refer to the Guidance document for clinical trial sponsors: Clinical trial applications and the information available on the Health Canada website in the section entitled Importation and Exportation for detailed guidance on importation of clinical trial drugs, including comparator, concomitant and rescue medications using Summary of Additional Drugs (SOAD) Form.

An example inspection observation (refer to Glossary (terms) for definition of observation) typically cited under this section of the Regulations:

The sponsor sold or imported for use, a drug for a clinical trial without being authorized under Part C, Division 5 of the Regulations

General

Interpretation

If a drug or substance is prohibited under the Regulations (refer to section C.05.003), a sponsor may submit a CTA to sell and/or import the drug for use in a clinical trial if the sponsor is able to justify that its use may result in a therapeutic benefit to human participants. Justification should include scientific evidence that the therapeutic benefits outweigh the risks for that particular drug or substance.

Application for authorization

Interpretation

Health Canada Pharmaceutical Drugs Directorate (PDD) and Biologic and Radiopharmaceutical Drugs Directorate (BRDD) are responsible for reviewing the CTAs for authorization to sell or import drugs for the purposes of conducting clinical trials in Canada.

Please refer to the Guidance document for clinical trial sponsors: Clinical trial applications for detailed guidance on the application process. Additional guidance can be found in the relevant sections of ICH E6, including Appendices A and B. The relevant Health Canada's Directorate (PDD or BRDD) should be consulted for further clarification.

Authorization

Interpretation

In order to sell or import a drug for the purposes of a Phase I-III clinical trial, the sale or importation must be authorized by Health Canada through the submission of a CTA prior to the initiation of the trial or the implementation of the amendment. Sale or importation of a drug for the purposes of a Phase I-III clinical trial is contingent on the following:

1. a CTA must be submitted in accordance with section C.05.005 of these Regulations (see also ICH E6, 3.8.1)
2. the sponsor should expect to receive a NOL within 30 days of the date of receipt of the complete CTA, indicating that the sponsor may sell or import the drug for the purposes of a clinical trial. However, due to the 30-day default period from the date of receipt of a complete CTA, the sponsor may proceed with the clinical trial after this period without receiving an NOL, provided the Research Ethics Board (REB) approval was obtained

3. the sponsor has received, for each clinical trial site, approval from a REB, in respect of the protocol and informed consent referred to in C.05.005(a) and (b)
4. before the sale or importation of the drug to a clinical trial site, the sponsor has submitted a CTSI form (PDF format) (refer to interpretation section of C.05.010) including the following information to Health Canada, if it has not already been submitted at the time of application:
   1. name, address, telephone number, fax number, and electronic mail address of the QI for each clinical trial site [C.05.005(c)(ix)]
   2. name, address, telephone number, fax number and electronic mail address of the REB that approved the protocol and informed consent at each clinical trial site [C.05.005(c)(x)]
   3. name, address, telephone number, fax number and electronic mail address of any REB (in or outside Canada) that has previously refused to approve the protocol, including its reason for doing so and the date on which the refusal was given [C.05.005(d)]
   4. the proposed date for the commencement of the clinical trial at each clinical trial site [C.05.005 (h)]

A sponsor does not have to submit a CTA for authorization to sell or import a drug used in a Phase IV clinical trial. Refer to C.05.002, Application and its interpretation, for a list of the provisions that govern a drug used in a Phase IV clinical trial.

A sponsor may also not sell or import a drug for the purpose of any clinical trial, including Phase IV clinical trials, if the trial has been suspended or cancelled under either C.05.016 or C.05.017.

Please refer to the Guidance document for Clinical Trial Sponsors: Clinical trial applications for detailed guidance on the authorization.

Examples of observations typically cited under this section of the Regulations include:

• The drug was sold or imported for use in a clinical trial without seeking authorization from Health Canada or before the end of the 30-day default period
• The drug was sold or imported for use in a clinical trial before the clinical trial site information was submitted to Health Canada

Notification

Interpretation

If a sponsor submits a CTA and has received a NOL, the sponsor may make one or more of the following changes, but the sponsor shall notify Health Canada in writing within 15 calendar days after the date of the change:

• a change to the chemistry and manufacturing information that does not affect the quality or safety of the drug
• a change to the protocol that does not alter the risk to the health of a clinical trial participant.

Examples of notifications may include:

• change of sponsor's address or contact name
• changes made to enable the consent to be read at the appropriate education level
• addition of an observational sub-study to the protocol or other administrative changes

Further to the above, section 3.15.2(e) of ICH E6 states that:

"If significant formulation changes are made in the investigational product(s)(including active control(s) and placebo, if applicable) during the course of clinical development, the results of any additional studies of the formulated product(s) (for example, stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials".

The impact assessment of this change may require submission of an amendment request to Health Canada instead of a notification. If the change meets the requirements of an amendment to the protocol as described in section C.05.008 (below), the sponsor must submit a CTA-A.

Note that Health Canada's Guidance document for Clinical Trial Sponsors: Clinical trial applications provides numerous examples of notifications. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

Examples of observations typically cited under this section of the Regulations include:

• The sponsor did not notify Health Canada within 15 days of making a change to the drug's chemistry and manufacturing information. The change does not affect the drug's quality or safety
• The sponsor did not notify Health Canada within 15 days of making a change to the protocol. The change does not affect the health risk of a clinical trial participant

Amendment

Interpretation

Clinical trial application-Amendments (CTA-As) are applications in which a sponsor submits information to support changes to a previously authorized clinical trial. They are required to be submitted when changes are made to the study drug or the protocol that could affect the quality or safety of the study drug, or the risk to clinical trial participants. Amendments must be authorized by Health Canada prior to implementing the changes.

Prior to implementation of a CTA-A at a site, a qualified investigator should obtain documented approval from the REB (ICH E6, 1.4.7). In addition, sponsors are required to complete and submit a CTSI form (PDF format) for each clinical trial site (C.05.008(1)(c)).

As per subsection C.05.008(4), if a sponsor needs to make an immediate amendment because the clinical trial or use of the drug endangers the trial participants or other persons, the sponsor may make the amendment without prior review by Health Canada. However, the sponsor must notify Health Canada of the change, and submit a CTA-A within 15 calendar days after the date of implementation of the amendment. Health Canada will issue a new NOL within the 30-day review period.

ICH E6 sections 2.5.4 and 2.5.5 also states that a QI may deviate from the protocol without prior approval if it is necessary to eliminate an immediate hazard(s) to a trial participant. Information on the deviation or change, the implemented change and the subsequent proposed protocol amendment should be submitted promptly to:

• the REB for review and approval
• the sponsor for agreement, and, if required
• the regulatory authority (i.e. Health Canada)

Note that Health Canada's Guidance document for Clinical Trial Sponsors: Clinical trial applications provides numerous examples of amendments. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

Examples of inspection observations typically cited under this section of the Regulations include:

• The sponsor did not submit a CTA-A after a change was made to the elements in the design of the study protocol or to the composition/formulation of the study drug that met the criteria for an amendment
• The sponsor did not notify Health Canada within 15 days of implementing an immediate amendment where the clinical trial or the use of the study drug endangered the health of a clinical trial participant or other person

Additional information and samples

Interpretation

Health Canada may require a sponsor to submit, within two (2) calendar days after receipt of the request, samples of the drug or additional information relevant to the drug or the clinical trial that are necessary to make a determination for issuance of the NOL.

A request for clarification or information may be required if the information and documents submitted in a CTA, or a CTA-A, were insufficient in either of the following ways:

• the information and documents in the application were either not provided in accordance with these Regulations or were insufficient to enable Health Canada to assess the safety and risks of the drug or the clinical trial, or
• based on an assessment of the application or any information or drug samples submitted as additional information Health Canada has reasonable grounds to believe that either:
  • the use of the drug for the purpose of the clinical trial endangers the health of a clinical trial participant or other person
  • the clinical trial is contrary to the best interests of a clinical trial participant; or
  • the objectives of the clinical trial will not be achieved