Natural Health Products Regulations

Part 4 - Clinical Trials Involving Human Subjects

Interpretation
Application
Prohibition
Application for Authorization
Authorization
Commencement Notice
Notification
Amendment
Additional Information and Samples
Sponsor's Obligations

Good Clinical Practices
Labelling
Records

Submission of Information and Samples
Reaction Reporting
Discontinuance of a Clinical Trial
Suspension and Cancellation

Interpretation

63. The following definitions apply in this Part.

"adverse event" means any adverse occurrence in the health of a clinical trial subject who is administered a natural health product, that may or may not be caused by the administration of the natural health product, and includes an adverse reaction, a serious adverse reaction and a serious unexpected adverse reaction. (incident thérapeutique)

"clinical trial" means an investigation in respect of a natural health product that involves human subjects and that is intended to discover or verify its clinical, pharmacological or pharmacodynamic effects, to identify any adverse events that are related to its use, to study its absorption, distribution, metabolism and excretion, or to ascertain its safety or efficacy. (essai clinique)

"good clinical practices" means generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons, and the good clinical practices referred to in section 74. (bonnes pratiques cliniques)

"import" means to import a natural health product into Canada for the purpose of sale in a clinical trial. (importer)

"investigator's brochure" means a document containing the preclinical and clinical information in respect of the natural health product that is described in paragraph 66(e). (brochure du chercheur)

"protocol" means a document that describes the objectives, design, methodology, statistical considerations and organization of a clinical trial. (protocole)

"qualified investigator" means the person responsible to the sponsor for the conduct of the clinical trial at a clinical trial site, who is entitled to provide health care under the laws of the province where the clinical trial site is located and who is

1. in the case of a clinical trial respecting a natural health product to be used for dental purposes only, a physician or dentist and a member in good standing of a professional medical or dental association; and
2. in any other case, a physician and a member in good standing of a professional medical association. (chercheur qualifié)

"research ethics board" means a body that is not affiliated with the sponsor, and

1. 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
2. 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
   1. 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,
   2. one member knowledgeable in complementary or alternative health care,
   3. one member knowledgeable in ethics,
   4. one member knowledgeable in Canadian laws relevant to the research to be approved,
   5. one member whose primary experience and expertise are in a non-scientific discipline, and
   6. 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. (comité d'éthique de la recherche)

"sponsor" means an individual, corporate body, institution or organization that conducts a clinical trial. (promoteur)

Application

64. (1) Subject to subsection (2), this Part applies to the sale or importation of natural health products to be used for the purposes of clinical trials involving human subjects.

(2) Except for paragraph 65(1)(a), subsection 65(2), section 68, paragraphs 74(a) to (i), subsections 75(1) and 76(1) and (2), paragraphs 76(3)(a) to (d) and (f) to (h), subsection 76(4) and sections 77 and 80 to 83, this Part does not apply to the sale or importation of a natural health product for the purposes of a clinical trial authorized under section 68.

Prohibition

65. (1) Despite section 4 and subject to subsection (2), no person shall sell or import a natural health product for the purposes of a clinical trial unless

1. the person is authorized under this Part;
2. the person complies with this Part and section C.01.064 of the Food and Drug Regulations; and
3. if the natural health product is to be imported, the person has a representative in Canada who is responsible for the sale of the natural health product.

(2) No person shall sell a natural health product for the purposes of a clinical trial

1. during the period of any suspension of the authorization under section 80 or 81; or
2. after cancellation of the authorization under paragraph 82(b).

Application for Authorization

66. An application by a sponsor for authorization to sell or import a natural health product for the purposes of a clinical trial shall be submitted to the Minister and shall contain the following information and documents:

1. a copy of the protocol for the clinical trial;
2. a copy of the statement, as it will be set out in each informed consent form, that states the risks and anticipated benefits arising to the health of clinical trial subjects as a result of their participation in the clinical trial;
3. a clinical trial attestation, signed and dated by the sponsor, containing
   1. the title of the protocol and the clinical trial number,
   2. the brand name or the code for the natural health product,
   3. for each medicinal ingredient of the natural health product
      1. the proper name and common name of the ingredient, and
      2. the quantity of the ingredient per dosage unit of the natural health product,
   4. a qualitative list of the non-medicinal ingredients of the natural health product,
   5. the dosage form of the natural health product,
   6. the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the sponsor,
   7. if the natural health product is to be imported, the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the sponsor's representative in Canada who is responsible for the sale of the natural health product,
   8. the address of each clinical trial site,
   9. for each clinical trial site, the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the qualified investigator,
   10. for each clinical trial site, the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the research ethics board that approved the protocol referred to in paragraph (a) and approved an informed consent form containing the statement referred to in paragraph (b),
   11. for each clinical trial site, the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of any research ethics board that has previously refused to approve the protocol referred to in paragraph (a), its reasons for doing so and the date on which the refusal was given, and
   12. a statement
       1. that the clinical trial will be conducted in accordance with good clinical practices and these Regulations, and
       2. that all information contained in, or referenced by, the application is complete and accurate and is not false or misleading;
4. an attestation, signed and dated by the research ethics board for each clinical trial site, that it has reviewed and approved the protocol referred to in paragraph (a) and an informed consent form containing the statement referred to in paragraph (b) and that the board carries out its functions in a manner consistent with good clinical practices;
5. an investigator's brochure that contains the following information, namely,
   1. the physical, chemical and, if any, the pharmaceutical properties of the natural health product,
   2. the chemistry and manufacturing information of each synthetically manufactured medicinal ingredient of the natural health product,
   3. the pharmacological properties of the natural health product, including its metabolites in all animal species tested, if any,
   4. the pharmacokinetics of the natural health product and the natural health product metabolism, including the biological transformation of the natural health product in all animal species tested, if any,
   5. the toxicological effects in any animal species tested under a single dose study, a repeated dose study or a special study in respect of the natural health product, if any,
   6. the results of carcinogenicity studies in any animal species tested in respect of the natural health product, if any,
   7. the results of clinical pharmacokinetic studies of the natural health product, if any,
   8. the information regarding natural health product safety, pharmacodynamics, efficacy and dose responses of the natural health product that were obtained from previous clinical trials in humans, if any,
   9. the known contra-indications for and the precautions to be taken in respect of the natural health product, and
   10. the recommended treatment in the event of an overdose of the natural health product, if any; and
6. the proposed date for the commencement of the clinical trial at each clinical trial site.

Authorization

67. (1) The Minister shall authorize a sponsor to sell or import a natural health product for the purposes of a clinical trial if

1. the sponsor submits an application to the Minister that is in accordance with section 66;
2. the sponsor provides the Minister with all additional information or samples requested under section 73; and
3. the Minister has reasonable grounds to believe, based on an assessment of the application, an assessment of any samples or information provided under section 73 or a review of any other information that
   1. the use of the natural health product for the purposes of the clinical trial will not endanger the health of a clinical trial subject or other person,
   2. the clinical trial is not contrary to the best interests of the clinical trial subjects, and
   3. the objectives of the clinical trial will be achieved.

(2) The Minister shall authorize the sponsor to sell or import a natural health product for the purposes of a clinical trial by sending the sponsor a notice of the authorization.

68. A sponsor is authorized to sell or import a natural health product for the purposes of a clinical trial if the clinical trial is in respect of a recommended use or purpose for which that natural health product is issued a product licence.

Commencement Notice

69. The sponsor shall notify the Minister of the date on which the sale or importation of a natural health product for the purposes of a clinical trial will commence at a clinical trial site at least 15 days before the day on which that sale or importation commences.

Notification

70. If the sale or importation of a natural health product for the purposes of a clinical trial is authorized under this Part, the sponsor may make one or more of the following changes if the sponsor provides the Minister with notification of the change within 15 days after the day on which the change is made:

1. a change to the information referred to in subparagraph 66(e)(ii) that does not affect the quality or safety of the natural health product; and
2. a change to the protocol that does not alter the risk to the health of a clinical trial subject, other than a change for which an amendment is required by section 71.

Amendment

71. (1) Subject to subsection (2), if the sale or importation of a natural health product for the purposes of a clinical trial is authorized under this Part, the sponsor may not make any of the following amendments unless the authorization is amended accordingly:

1. an amendment to the protocol that affects the selection, monitoring or dismissal of a clinical trial subject;
2. an amendment to the protocol that affects the evaluation of the clinical efficacy of the natural health product;
3. an amendment to the protocol that alters the risk to the health of a clinical trial subject;
4. an amendment to the protocol that affects the safety evaluation of the natural health product;
5. an amendment to the protocol that extends the duration of the clinical trial; and
6. an amendment to the information referred to in subparagraph 66(e)(ii) that may affect the safety or quality of that natural health product.

(2) If the sponsor is required to immediately make one or more of the amendments referred to in subsection (1) because the clinical trial or the use of the natural health product for the purposes of the clinical trial endangers the health of a clinical trial subject or other person, the sponsor may immediately make the amendment and shall provide the Minister with the information referred to in subsection (3) within 15 days after the day on which the amendment is made.

(3) An application by the sponsor to amend the authorization for the sale or importation of a natural health product under this Part shall be submitted to the Minister and, in addition to a reference to the application submitted under section 66, shall contain the following information and documents:

1. if as a result of the amendment it is necessary to amend the statement referred to in paragraph 66(b),
   1. a copy of the amended statement that indicates the new information, and
   2. for each clinical trial site, the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the research ethics board that approved the amended statement;
2. if the application is in respect of an amendment referred to in any of paragraphs (1)(a) to (e),
   1. a copy of the amended protocol that indicates the amendment,
   2. a copy of the protocol submitted under paragraph 66(a),
   3. the rationale for the amendment,
   4. for each clinical trial site, the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the research ethics board that approved the amended protocol, and
   5. the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of any research ethics board that has previously refused to approve any amendment to the protocol, its reasons for doing so and the date on which the refusal was given;
3. if the application is in respect of an amendment referred to in paragraph (1)(e), a copy of the amended investigator's brochure or an addendum to the investigator's brochure that indicates the new information, including supporting toxicological studies and clinical trial safety data, if any; and
4. if the application is in respect of an amendment referred to in paragraph (1)(f), a copy of the amended chemistry and manufacturing information that indicates the amendment, and the rationale for that amendment.

(4) The Minister shall amend the authorization to sell or import a natural health product for the purposes of a clinical trial if

1. the sponsor submits an application for amendment to the Minister that is in accordance with subsection (3);
2. the sponsor provides the Minister with all additional information or samples requested under section 73; and
3. the Minister has reasonable grounds to believe, based on an assessment of the application for amendment, an assessment of any samples or information submitted under section 73 or a review of any other information that
   1. the use of the natural health product for the purposes of the clinical trial will not endanger the health of a clinical trial subject or other person, and
   2. the clinical trial is not contrary to the best interests of the clinical trial subjects.

(5) The Minister shall amend the authorization to sell or import a natural health product for the purposes of a clinical trial by sending the sponsor a notice of the amendment.

72. If the authorization to sell or import a natural health product for the purposes of the clinical trial is amended in accordance with subsection 71(5), the sponsor shall

1. before commencing to sell or import the natural health product in accordance with the amended authorization
   1. cease to sell or import the natural health product in accordance with the existing authorization, and
   2. maintain records concerning the information referred to in subparagraph 66(c)(ix), if any of that information has changed since it was submitted, and the information referred to in paragraph 66(f); and
2. conduct the clinical trial in accordance with the amended authorization.

Additional Information and Samples

73. If the information and documents submitted in respect of an application under section 66 or an application for amendment under subsection 71(3) are insufficient to enable the Minister to determine whether the sale or importation of the natural health product should be authorized or whether the authorization should be amended, as the case may be, the Minister may request that the sponsor provide the Minister with samples of the natural health product or additional information relevant to the natural health product or the clinical trial that are necessary to make the determination.

Sponsor's Obligations

Good Clinical Practices

74. Every sponsor shall ensure that a clinical trial is conducted in accordance with good clinical practices and, without limiting the generality of the foregoing, shall ensure that

1. the clinical trial is scientifically sound and clearly described in a protocol;
2. the clinical trial is conducted, and the natural health product is used, in accordance with the protocol and this Part;
3. systems and procedures that assure the quality of every aspect of the clinical trial are implemented;
4. for each clinical trial site, the approval of a research ethics board is obtained before the clinical trial begins at the site;
5. at each clinical trial site, there is no more than one qualified investigator;
6. at each clinical trial site, medical care and medical decisions,in respect of the clinical trial, are under the supervision of the qualified investigator;
7. each individual involved in the conduct of the clinical trial is qualified by education, training and experience to perform his or her respective tasks;
8. written informed consent, given in accordance with the applicable laws governing consent, is obtained from every person before that person participates in the clinical trial but only after that person has been informed of
   1. the risks and anticipated benefits to his or her health arising from participation in the clinical trial, and
   2. all other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial;
9. the requirements respecting information and records set out in section 76 are met; and
10. the natural health product is manufactured and stored in accordance with the requirements set out in Part 3 except for section 61.

Labelling

75. (1) The sponsor shall ensure that the natural health product bears a label that sets out the following information in both official languages:

1. a statement indicating that the natural health product is an investigational natural health product to be used only by a qualified investigator;
2. the brand name or code of the natural health product;
3. the expiry date of the natural health product;
4. the recommended storage conditions for the natural health product, if any;
5. the lot number of the natural health product;
6. the name and address of the manufacturer;
7. the name and address of the sponsor; and
8. the protocol code or identification.

(2) Sections 86 to 94 do not apply to a natural health product used for the purposes of a clinical trial.

Records

76. (1) The sponsor shall record, handle and store all information in respect of a clinical trial in a way that allows its complete and accurate reporting as well as its interpretation and verification.

(2) The sponsor shall maintain complete and accurate records to establish that the clinical trial is conducted in accordance with good clinical practices and these Regulations.

(3) The sponsor shall maintain complete and accurate records in respect of the use of a natural health product in a clinical trial, including

1. a copy of all versions of the investigator's brochure for the natural health product;
2. records respecting each change made to the investigator's brochure, including the rationale for each change and documentation that supports each change;
3. records respecting all adverse events in respect of the natural health product that have occurred inside or outside Canada, including information that specifies the dosage form and the use and purpose of the natural health product at the time of the adverse event;
4. records respecting the enrolment of clinical trial subjects, including information sufficient to enable all clinical trial subjects to be identified and contacted in the event that the sale of the natural health product may endanger the health of the clinical trial subjects or other persons;
5. records respecting the shipment, receipt, disposition, return and destruction of the natural health product;
6. for each clinical trial site, an undertaking from the qualified investigator that is signed and dated by the qualified investigator prior to the commencement of his or her responsibilities in respect of the clinical trial, that states that
   1. the qualified investigator will conduct the clinical trial in accordance with good clinical practices, and
   2. the qualified investigator will immediately, on discontinuance of the clinical trial by the sponsor, in its entirety or at a clinical trial site, notify both the clinical trial subjects and the research ethics board of the discontinuance, provide them with the reasons for the discontinuance and advise them in writing of any potential risks to the health of clinical trial subjects or other persons;
7. for each clinical trial site, a copy of the protocol, informed consent form and any amendment to the protocol or informed consent form that have been approved by the research ethics board for that clinical trial site; and
8. for each clinical trial site, an attestation, signed and dated by the research ethics board for that clinical trial site, stating that it has reviewed and approved the protocol and informed consent form and that the board carries out its functions in a manner consistent with good clinical practices.

(4) The sponsor shall maintain all records referred to in this Part for a period of 25 years.

Submission of Information and Samples

77. (1) The Minister shall require a sponsor to provide, within two days after the day on which the request is received, information concerning the natural health product or the clinical trial, or samples of the natural health product, if the Minister has reasonable grounds to believe that

1. the use of the natural health product for the purposes of the clinical trial endangers the health of a clinical trial subject or other person;
2. the clinical trial is contrary to the best interests of a clinical trial subject;
3. a qualified investigator is not respecting the undertaking referred to in paragraph 76(3)(f); or
4. information submitted or provided in respect of the natural health product or the clinical trial is false or misleading.

(2) The Minister may require the sponsor to provide, within seven days after the day on which the request is received, any information or records referred to in section 76, or samples of the natural health product, in order to assess the safety of the natural health product or the health of clinical trial subjects or other persons.

Reaction Reporting

78. (1) During the course of a clinical trial, the sponsor shall notify the Minister of any serious adverse reaction and any serious unexpected adverse reaction to the natural health product that has occurred inside Canada as follows:

1. if it is neither fatal nor life threatening, within 15 days after the day on which the sponsor becomes aware of the information; and
2. if it is fatal or life threatening, within seven days after the day on which the sponsor becomes aware of the information.

(2) The sponsor shall, within eight days after the day on which the Minister is notified under paragraph (1)(b), provide the Minister with a complete report in respect of that information that includes an assessment of the importance and implication of any findings made.

Discontinuance of a Clinical Trial

79. (1) If the sponsor discontinues a clinical trial in its entirety or at a clinical trial site, the sponsor shall

1. notify the Minister of the discontinuance within 15 days after the day of the discontinuance;
2. provide the Minister with the reason for the discontinuance and its impact on the proposed or ongoing clinical trials in respect of the natural health product conducted in Canada by the sponsor;
3. as soon as possible, notify all qualified investigators of the discontinuance and of the reasons for the discontinuance, and advise them in writing of any potential risks to the health of clinical trial subjects or other persons; and
4. in respect of each discontinued clinical trial site, stop the sale or importation of the natural health product as of the day of the discontinuance and take all reasonable measures to ensure the recovery of all unused quantities of the natural health product that have been sold.

(2) If the sponsor discontinues a clinical trial in its entirety or at a clinical trial site, the sponsor may resume selling or importing the natural health product for the purposes of the clinical trial in its entirety or at the clinical trial site if, in respect of each clinical trial site where the sale or importation is to be resumed, the sponsor submits to the Minister the information referred to in subparagraphs 66(c)(ix) to (xi) and paragraphs 66(d) and (f).

Suspension and Cancellation

80. (1) Subject to subsection (2), the Minister may suspend the authorization to sell or import a natural health product for the purposes of a clinical trial, in its entirety or at a clinical trial site, if the Minister has reasonable grounds to believe that

1. the sponsor has contravened these Regulations or any provisions of the Act relating to the natural health product;
2. any information submitted or provided in respect of the natural health product or clinical trial is false or misleading;
3. the sponsor has failed to comply with good clinical practices; or
4. the sponsor has failed to
   1. provide information or samples of the natural health product as required under section 73 or 77, or
   2. notify the Minister or provide a report under section 78.

(2) Subject to section 81, the Minister shall not suspend the authorization unless

1. the Minister has sent the sponsor a notice that indicates whether the authorization is intended to be suspended in its entirety or at a clinical trial site and the reason for the intended suspension; and
2. the sponsor has not, within 30 days after the day on which the notice referred to in paragraph (a) is received, provided the Minister with information or documents demonstrating that the authorization should not be suspended on the grounds that
   1. the situation giving rise to the intended suspension did not exist, or
   2. the situation giving rise to the intended suspension has been corrected.

81. The Minister shall suspend the authorization to sell or import a natural health product for the purposes of a clinical trial, in its entirety or at a clinical trial site, before giving the sponsor an opportunity to be heard if, as a result of any circumstance, the Minister has reasonable grounds to believe that it is necessary to do so to prevent injury to the health of a clinical trial subject or other person.

82. If the Minister suspends the authorization under section 80 or 81, the Minister shall send the sponsor a notice that sets out the reason for the suspension, the day on which the suspension is effective and indicating whether the authorization is suspended in its entirety or at a clinical trial site, and the Minister shall

1. reinstate the authorization in its entirety or at a clinical trial site, as the case may be, if within 30 days after the day on which the suspension is effective the sponsor provides the Minister with information or documents demonstrating that the situation giving rise to the suspension did not exist or that it has been corrected; or
2. cancel the authorization in its entirety or at a clinical trial site, as the case may be, if within 30 days after the day on which the suspension is effective the sponsor has not provided the Minister with the information or documents referred to in paragraph (a).

83. If the Minister cancels the authorization under paragraph 82(b), the Minister shall send the sponsor a notice that sets out the reason for the cancellation, the day on which the cancellation is effective and indicating whether the authorization is cancelled in its entirety or at a clinical trial site.